WO 2004/87681 describes the preparation of an amorphous form of unsalted valsartan by vacuum treatment or spray drying of alcoholic solutions. WO 2004/83192 describes polymorphs of unsalted valsartan. Procedures are given for the preparation of amorphous valsartan from a variety of solvents. 11 apparently different partially crystalline forms of unsalted valsartan are also described. WO 2003/89417 also describes two polymorphs of unsalted valsartan.

US patent application 6,071,931 states that pharmaceutically acceptable salts of valsartan are typically acid addition salts and lists a number or mineral acids, carboxylic acids, and sulfonic acids. No examples of preparations and no descriptions are given. A general statement about salts with mineral bases and amines is also made, but again there are no examples of preparations and no descriptions. US patent application 6,294,197 also discusses acid addition salts of valsartan, but once more with no examples of the preparation of any such salt. WO 99/67231 discusses the nitrate salt of valsartan, but again there are no examples of the preparation of this salt. It is significant that the only nitrogen atoms in the molecular structure of valsartan are in an amide or tetrazole functional group.

WO 2002/06253 describes the preparation of sodium, potassium, magnesium, calcium diethylammonium, dipropylammonium, and dibutylammonium salts of valsartan. Crystalline hydrated disodium, dipotassium, magnesium and calcium salts, and bis-diethylammonium, bis- dipropylammonium, and bis-dibutylammonium salts are exemplified. WO 2003/66606 describes various hydrates of calcium and magnesium valsartan.

Valsartan is only available commercially as the crystalline unsalted product in numerous countries including the USA and EU. It would therefore appear to the skilled worker reviewing the art that this is the only preferred form of valsartan. Although certain other forms and salts have been described, there is technical prejudice against their use. Since unsalted valsartan is a relatively water insoluble salt, one skilled in the art would be led to conclude that alternatives with different solubility had been considered and rejected. In any event, the compounds of the present invention are not prima facie obvious over the disclosures in the art. Notwithstanding, the compounds of the present invention also exhibit unexpected technical properties and/or advantages.

The following patents describe various uses, compositions, formulations, and combinations containing valsartan. These patents are incorporated herein by reference. US Patent Nos. 6,800,668, 6,787,553, 6,784, 189, 6,784, 177, 6,780,997, 6,777,443, 6,777,435, 6,774,112, 6,770,663, 6,767,905, 6,761,903, 6,747,048, 6,730,689, 6,730,674, 6,727,271, 6,720,001, 6,713,487, 6,713,467, 6,706,720, 6,686,338, 6,677,363, 6,677,356, 6,673,931, 6,673,815, 6,673,778, 6,670,386, 6,670,380, 6,670,355, 6,669,955, 6,667,315, 6,664,230, 6,656,966, 6,653,314, 6,653,306, 6,649,622, 6,649,606, 6,645,965, 6,645,528, 6,642,252, 6,642,244, 6,638,528, 6,635,274, 6,635,273, 6,632, 180, 6,627,636, 6,624, 138, 6,620,821, 6,610,682, 6,605,612, 6,602,902, 6,596,751, 6,596,747, 6,596,745, 6,596,744, 6,595,926, 6,589,547, 6,586,004, 6,579,879, 6,576,644, 6,576,636, 6,576,256, 6,573,288, 6,570,013, 6,569,463, 6,562,849, 6,562,363, 6,555,568, 6,555,542, 6,548,529, 6,548,519, 6,545,009, 6,544,981, 6,544,968, 6,525,067, 6,521,747, 6,521,659, 6,515,117, 6,511,977, 6,511,973, 6,499,984, 6,495,581, 6,489,307, 6,486, 189, 6,485,745, 6,469,024, 6,465,502, 6,465,463, 6,458,797, 6,451,339, 6,440,991, 6,432,989, 6,420,426, 6,417,204, 6,414, 126, 6,414,002, 6,399,626, 6,399,625, 6,395,728, 6,395,300, 6,387,894, 6,383,471, 6,376,672, 6,372,917, 6,369,236, 6,369,069, 6,344,450, 6,340,772, 6,339,085, 6,335,451, 6,329,384, 6,326,379, 6,323,226, 6,316,438, 6,309,663, 6,300,356, 6,299,904, 6,297,233, 6,294, 197, 6,294, 192, 6,284,763, 6,284,277, 6,271,418, 6,271,375, 6,267,985, 6,251,926, 6,248,729, 6,248,363, 6,218,414, 6,211,217, 6,204,281, 6,201,002, 6, 197,959, 6, 187,340, 6,174,910, 6,150,356, 6, 127,370, 6,087,368, 6,071,931, 6,008,221, 5,985,915, 5,968,978, 5,889,020, 5,795,909, 5,696,116

and WO 2004/87681, WO 2004/83192, WO 2003/89417, WO 2003/66606, WO 2002/06253, WO 99/67231 are incorporated herein by reference, as also are all publications quoted in this specification. In particular, all information concerned with preparing the valsartan active moiety from readily available starting materials is incorporated in full. In addition, it should be appreciated that all information concerning the incorporation of valsartan into a formulation is herein incorporated by reference as is information on the use of such formulations in medical therapy.

Losartan i.e. 2-butyl-4-chloro-l-[(2'-tetrazol-5-yl)-biphenyl-4-yl]methyl]-5-(hydroxymethyl)- imidazole otherwise 2-butyl-4 -chloro- 1 - [p -(o - 1 H-tetrazol -5 -ylphenyl)benzyl] imidazole -5 -methanol otherwise 2-n-butyl-4-chloro-5-hydroxymethyl-l-[(2-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl] imidazole may be prepared by the methods described in U.S. patent 5, 138,069, WO 93/10106, U.S. patent 5, 130,439, U.S. patent 5,206,374, and U.S. Ser. No. 07/911,813. US patent 5,153, 197 examples 89 describes a procedure for the preparation of losartan whereby an impure light yellow crystalline solid with melting point 179-180°C is prepared, and in example 316 whereby a more pure product with melting point 184-5°C is prepared. Example 316 of that patent also describes a procedure for the preparation of a potassium salt whereby a crystalline product melting above 250°C is prepared. The chemical structure of losartan is as follows:

US patent 5,608,075 example 1 describes the preparation of light yellow crystals which melted broadly. The crystals were taken up in hot acetonitrile, and the solid that did not dissolve melted at 184-5°C after drying, while a second crop with melting point 179-180°C was obtained from the mother liquors. Example 4 of the same patent specification describes the preparation of a crystalline potassium salt and also mentions, but does not describe, isolation by spray-drying.

Example 10 refers to a second polymorph of the potassium salt formed during differential scanning calorimetry. US patent 6,350,880 example 1 describes the preparation of a crystalline losartan p- toluenesulfonate tetrahydrofuran solvate melting at 118-120°C, while examples 2 and 3 describe a crystalline hydrochloride melting at 188-196°C with decomposition and a crystalline hydrobromide melting at 186-210°C with decomposition respectively.

Other than the above -described examples, there are no descriptions let alone any enabling disclosures of any other pharmaceutically acceptable forms of losartan, whether it be combinations of losartan with other acids or bases, or other amorphous forms, or polymorphs, or solvates or dispersions in carriers of losartan itself or the p-toluenesulfonate, hydrochloride, or hydrobromide salts.

Losartan as the potassium salt is described in US patent 5,608,075 as an agent useful in the treatment of hypertension. US patent 5,210,079 states that losartan and pharmaceutically acceptable salts thereof are useful for treating chronic renal failure, mediated by angiotensin-II.

The above-mentioned patent specifications are incorporated herein by reference.

It would therefore appear to that the only preferred salt of losartan is the crystalline potassium salt with melting point above 250°C. Although certain p-toluenesulfonate, hydrochloride, or hydrobromide salts have been disclosed, there is technical prejudice in the prior art against their use. This is supported by the fact that losartan is only commercially available as the potassium salt in numerous countries including the USA and EU. Since the potassium salt is a relatively unusual salt, one skilled in the art would be led to conclude that less unusual choices had been considered and rejected. In any event, the compounds of the present invention are not prima facie obvious over the disclosures in the art. Notwithstanding, the losartan compounds, forms and formulations of the present invention described hereinbelow may also exhibit unexpected technical properties and/or advantages.

The following patents describe various uses, compositions, formulations, and combinations containing losartan. These patents are incorporated herein by reference. Other than the examples described above, the use of a mineral acid in combination with losartan is not known in the prior art. US Patents 6,800,668, 6,794,387, 6,787,553, 6,784,189, 6,784,185, 6,784,177, 6,780,997, 6,777,443, 6,777,435, 6,774, 112, 6,773,716, 6,770,663, 6,770,645, 6,770,624, 6,767,905, 6,762, 167, 6,761,903, 6,761,895, 6,759,431, 6,758,099, 6,756,373, 6,753,011, 6,747,048, 6,730,697, 6,730,689, 6,730,674, 6,730,505, 6,730,016, 6,727,271, 6,726,920, 6,723,340, 6,719,997, 6,713,487, 6,713,467, 6,713,295, 6,710, 183, 6,710,086, 6,706,732, 6,706,723, 6,706,720, 6,706,011, 6,686,338, 6,683,080, 6,680,203, 6,677,374, 6,677,363, 6,677,356, 6,677,335, 6,673,815, 6,673,802, 6,673,778, 6,670,386, 6,670,380, 6,670,355, 6,669,955, 6,667,315, 6,664,230, 6,660,756, 6,656,966, 6,653,314, 6,653,306, 6,649,636, 6,649,622, 6,649,606, 6,645,974, 6,645,965, 6,645,528, 6,642,252, 6,642,244, 6,641,811, 6,638,528, 6,635,648, 6,635,274, 6,635,273, 6,632, 180, 6,627,636, 6,627,234, 6,624,138, 6,620,821, 6,610,682, 6,605,629, 6,605,612, 6,603,008, 6,602,902, 6,596,751, 6,596,747, 6,596,745, 6,596,744, 6,595,926, 6,593,332, 6,592,865, 6,589,938, 6,589,556, 6,589,547, 6,586,439, 6,586,391, 6,586,023, 6,586,004, 6,586,000, 6,585,995, 6,582,724, 6,579,879, 6,576,652, 6,576,644, 6,576,636, 6,576,256, 6,573,288, 6,570,013, 6,569,461, 6,562,849, 6,562,363, 6,555,568, 6,555,542, 6,548,529, 6,548,519, 6,545,009, 6,544,981, 6,544,968, 6,541,479, 6,538,144, 6,537,992, 6,531,482, 6,531,297, 6,524,552, 6,521,747, 6,521,659, 6,515,117, 6,514,939, 6,514,536, 6,511,977, 6,511,973, 6,509,317, 6,506,785, 6,503,908, 6,499,984, 6,498, 179, 6,495,581, 6,495,338, 6,491,949, 6,491,903, 6,489,307, 6,486,299, 6,486, 189, 6,486, 188, 6,475,988, 6,469,024, 6,465,463, 6,458,797, 6,455,562, 6,455,501, 6,455,500, 6,451,339, 6,444,646, 6,440,991, 6,440,982, 6,436,684, 6,433,018, 6,429,222, 6,420,426, 6,420, 150, 6,417,213, 6,417,204, 6,414, 126, 6,414,002, 6,410,007, 6,407,135, 6,403,571, 6,399,626, 6,399,625, 6,395,300, 6,387,894, 6,383,789, 6,383,500, 6,383,471, 6,376,242, 6,375,956, 6,372,917, 6,369,236, 6,369,069, 6,365,579, 6,352,721, 6,350,880, 6,348,476, 6,344,450, 6,340,772, 6,340,708, 6,339,085, 6,335,451, 6,335, 195, 6,329,384, 6,326,498, 6,326,379, 6,323,236, 6,323,226, 6,322,532, 6,316,438, 6,310,052, 6,309,375, 6,306,826, 6,300,356, 6,299,904, 6,297,233, 6,294,561, 6,294,542, 6,294, 192, 6,288,078, 6,284,763, 6,284,277, 6,274,627, 6,271,418, 6,271,375, 6,267,985, 6,264,914, 6,258,032, 6,251,926, 6,251,852, 6,251,436, 6,248,766, 6,248,729, 6,248,587, 6,239,109, 6,235,766, 6,235,731, 6,235,706, 6,228,867, 6,218,414, 6,211,224, 6,201,002, 6,200,957, 6,197,975, 6,191,156, 6,187,340, 6,183,444, 6,180,642, 6,179,809, 6,177,452, 6,172,080, 6, 165,978, 6, 162,813, 6, 159,989, 6, 159,975, 6, 156,772, 6,156,767, 6,150,522, 6, 150,356, 6, 150,352, 6, 147,088, 6,140,319, 6,139,860, 6,139,847, 6,127,370, 6,110,931, 6,110,895, 6, 103,266, 6,096,772, 6,093,748, 6,087,386, 6,087,368, 6,077,858, 6,077,847, 6,046,224, 6,025,366, 6,017,944, 6,013,630, 6,008,221, 6,004,984, 5,998,432, 5,990,092, 5,985,915, 5,985,901, 5,985,892, 5,985,856, 5,981,550, 5,981,470, 5,977,377, 5,972,990, 5,968,978, 5,962,500, 5,958,884, 5,952,305, 5,925,012, 5,916,910, 5,900,428, 5,891,465, 5,889,020, 5,883, 122, 5,869,476, 5,859,258, 5,858,990, 5,849,764, 5,849,753, 5,834,432, 5,824,696, 5,795,909, 5,795,904, 5,780,437, 5,767,310, 5,756,507, 5,736,561, 5,696,116, 5,693,812, 5,691,348, 5,688,499, 5,668, 176, 5,665,738, 5,663, 187, 5,663, 186, 5,658,936, 5,645,839, 5,643,939, 5,629,331, 5,608,075, 5,565,485, 5,559, 135, 5,550, 127, 5,538,991, 5,525,614, 5,489,686, 5,466,692, 5,464,854, 5,453,436, 5,436,259, 5,382,587, 5,350,757, 5,308,862, 5,266,583, 5,264,447, 5,246,943 are incorporated herein by reference. In particular, all information concerned with preparing the losartan active moiety from readily available starting materials is incorporated in full. In addition, it should be appreciated that all information concerning the incorporation of losartan into a formulation is herein incorporated by reference as is information on the use of such formulations in medical therapy.

Further known angiotensin II receptor antagonists include candesartan, eprosartan, irbesartan, olmesartan, telmisartan, azilsartan, fimasartan, saprisartan, tasosartan and elisartan, whose chemical structures are shown below.

telmisartan (Micardis)

elisartan Valsartan and losartan are both powerful anti-hypertensive drugs, which act at the angiotensin II receptor antagonistic site. Valsartan and Losartan were major medical advancements over previous classes of compounds such as beta blockers and ace inhibitors. During their exclusivity periods they became mega blockbusters and with other drugs of the same class - i.e. other angiotensin II receptor antagonists of the kind discussed above - they became the standard of care amongst hypertensive agents.

Hypertension as a disease causes a number of symptoms such as tiredness, and a general feeling of un-wellness such as dizziness, nausea and other symptoms which affect the quality of a patient's life, although these symptoms are of themselves not life threatening. Hypertension, however leads to more serious complications which are life threating such as stroke and heart attack. Valsartan and losartan have been shown drastically to reduce the rate of these events from occurring at all, let alone death, from these conditions.

Whilst valsartan and losartan are medically powerful drugs with major benefits over other drugs, both valsartan and losartan, and indeed other angiotensin II receptor antagonists, suffer from a short half-life, which manifests itself as causing the body to become devoid of drug in the pk plasma during the early hours after the drug has metabolized below the minimum inhibitory concentration, causing a marked increase in early morning stroke, heart attack and associated death. This phenomenon is known as the early morning deficit or nocturnal deficit problem and is associated with a marked increase in morbidity. Angiotensin II receptor antagonists, and particularly valsartan and losartan, are well tolerated and if their pk profiles could be addressed, they would make an excellent drugs having an ideal therapeutic profile giving 24 hour relief from hypertensive effects and the associated morbidity and serious clinical consequences associated with such compounds. Such an improved side effect profile would be of huge benefit in any of the known uses of angiotensin II receptor antagonists, and particularly in their use in the treatment and prevention of hypertension and associated disorders. The present invention seeks to address these and other problems with the current use of angiotensin II receptor antagonists.

SUMMARY OF THE INVENTION

The present inventors have surprisingly found a way to give rapidity, longevity and dose to dose maintenance within the therapeutic window, in order to address the early morning deficit or nocturnal deficit problem and reduce the side effect profile of angiotensin II receptor antagonists. These and other advantages are provided by the forms and formulations of angiotensin II receptor antagonists described herein, which are typically multicomponent solid dosage forms. It has in particular been found that a multicomponent tablet gives the benefit of one or more of the technical effects selected from, rapidity, longevity and dose to dose maintenance within the therapeutic window. Accordingly, the invention provides a pharmaceutical composition which comprises: a first fraction comprising an angiotensin II receptor antagonist; and a controlled-release fraction comprising the angiotensin II receptor antagonist.

The invention also provides a pharmaceutical composition of the invention, for use in a method for treatment of the human or animal body by therapy.

In another aspect, the invention provides a pharmaceutical composition of the invention, for use in a method for treatment or prophylaxis of a condition selected from hypertension, heart failure, chronic renal failure, diabetic neuropathy and a cardiovascular disease.

The invention also provides the use of a pharmaceutical composition of the invention in the manufacture of a medicament for use in the treatment or prophylaxis of a condition selected from hypertension, heart failure, chronic renal failure, diabetic neuropathy and a cardiovascular disease.

The invention also provides the use of an angiotensin II receptor antagonist in the manufacture of a pharmaceutical composition of the invention for use in the treatment or prophylaxis of a condition selected from hypertension, heart failure, chronic renal failure, diabetic neuropathy and a cardiovascular disease.

The invention also provides a method for the treatment or prophylaxis of a condition selected from hypertension, heart failure, chronic renal failure, diabetic neuropathy and a cardiovascular disease, which method comprises administering a pharmaceutical composition of the invention to a subject in need thereof.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 is a table of pharmacokinetic parameters of angiotensin II receptor blockers, where metab indicates metabolite and bioavail indicates bioavailability (Sankyo Pharma Inc (US)

Benicar(®) (Olmesartan Medoxomil) [product monograph] New York: Advantage Communications; 2002; Olin BR. Drug Facts and Comparisons. St. Louis: JB Lippincott Co; 2002. pp. 514-518; Proc (Bayl Univ Med Cent). 2003 Jan; 16(1): 123-126).

Fig. 2 shows the dissolution profile in pH 6.8 buffer of the sustained-release core development formulation no. 17CF08/001 comprising valsartan, as described in Example 54.

Fig. 3 shows the dissolution profile in pH 6.8 buffer of the sustained-release core development formulation no. 17CF08/002 comprising valsartan, as described in Example 54.

Fig. 4 shows the dissolution profile in pH 6.8 buffer of the sustained-release core development formulation no. 17CF08/003 comprising valsartan, as described in Example 54.

Fig. 5 shows the dissolution profile in pH 6.8 buffer of the immediate-release development formulation no. 17CF08/004 comprising valsartan, as described in Example 54.

Figs. 6(a) and 6(b) show PK profile and impact on systolic blood pressure (SBP) and diastolic blood pressure (DBP) after administration of 160 mg IR single dose of valsartan, as described in Example 55. Fig. 6(a) shows the plasma (black) and biophase (grey) concentration of a 160mg dose together with the IC50 value (grey horizontal line). Fig. 6(b) shows the effect of a 160mg dose on SBP (dark-grey) and DBP (light-grey) together with baseline value (dashed lines).

Fig. 7 is a heat-map showing the % reduction in either SBP or DBP immediately prior to the next dose after 14 days of dosing for varying amounts of the MR product with varying durations of zero-order release (total dose = 160 mg), as described in Example 55.

Fig. 8 is a heat-map showing the minimum to maximum ratio for reduction in either SBP or DBP immediately within the dosing interval after 14 days of dosing for varying amounts of the MR product with varying durations of zero-order release (total dose = 160 mg), as described in Example 55.

Fig. 9 is a heat-map showing the proportion of time valsartan plasma concentration are above the IC50 within the dosing interval after 14 days of dosing for varying amounts of the MR product with varying durations of zero-order release (total dose = 160 mg), as described in Example 55.

Fig. 10 presents three plots on the left hand side which show the plasma (black) and biophase (grey) concentration time profiles on day 14 of once daily dosing for three different release rates of the MR product for varying combinations of IR+MR doses, as described in Example 55. In each left- hand plot: 160mg IR+Omg MR (solid line), 120mg IR+40mg MR (dashed-dotted line), 80mg IR+80mg MR (dotted line), 40mg IR + 120mg MR (dashed line), and the in vivo IC50 (solid grey horizontal line) are plotted. The three plots on the right hand side show the corresponding effects on the percentage change in SBP/DBP.

Fig. 11 presents three plots on the left hand side which show the plasma (black) and biophase (grey) concentration time profiles for a single dose with three different release rates of the MR product and for varying combinations of IR+MR doses, as described in Example 55. In each left-hand plot: 160mg IR+Omg MR (solid), 120mg IR+40mg MR (dashed-dotted line), 80mg IR+80mg MR (dotted line), 40mg IR + 120mg MR (dashed line) and the in vivo IC50 (solid grey horizontal line) are plotted. The three plots on the right hand side show the relationship between different biophase profiles and percentage change in SBP/DBP.

Fig. 12 presents two plots on the left hand side showing the plasma (black) and biophase (grey) concentration time profiles on day 1 and day 14 of once daily dosing for a fixed dose combination of 30mg IR + 130mg MR with varying release rates of the MR product. In each left hand plot: 12 hours (dotted line), 10 hours (dashed line), 8 hours (dashed-dotted line), the 160mg IR product for comparison (solid line), and the in vivo IC50 (solid grey horizontal line) are plotted. The two plots on the right hand side show the relationship between different biophase profiles and percentage change in SBP/DBP.

Fig. 13 top panel shows the plasma (black) and biophase (grey) concentration time profiles over 14 days for 160mg IR product (solid lines) and 30mg IR + 130mg MR: 12 hour release (dotted lines) together with in vivo IC50 (solid grey horizontal line). The bottom panel shows the corresponding effect on the percentage change in SBP/DBP. 15 Fig. 14 presents two plots on the left panel showing the plasma (black) and biophase (grey) concentration time profiles on day 1 and day 14 of a once daily schedule for 160mg IR product (solid lines) and 30mg IR + 130mg MR: 12 hour release (dotted lines) together with in vivo IC50 (solid horizontal grey line). The two right hand panels show the corresponding effects on the percentage changes in SBP/DBP.

Fig. 15 presents two plots on the left panel showing the plasma (black) and biophase (grey) concentration time profiles on day 1 and day 14 of a once daily schedule for 160mg IR product (solid lines) and 30mg IR + 130mg MR: 24 hour release / extreme release (dotted lines) together with in vivo IC50 (solid green line). The two right hand panels show the corresponding effects on the percentage changes in SBP/DBP.

Fig. 16 is a heat-map showing the % reduction in either SBP or DBP immediately prior to the next dose after 14 days of dosing for varying amounts of the MR product with varying durations of zero-order release (total dose = 320 mg).

Fig. 17 is a heat-map showing the minimum to maximum ratio for reduction in either SBP or DBP immediately within the dosing interval after 14 days of dosing for varying amounts of the MR product with varying durations of zero-order release (total dose = 320 mg).

Fig. 18 is a heat-map showing the proportion of time valsartan plasma concentration is above the IC50 within the dosing interval after 14 days of dosing for varying amounts of the MR product with varying durations of zero-order release (total dose = 320 mg).

Fig. 19 presents three plots on the left hand side showing the plasma (black) and biophase (grey) concentration time profiles on day 14 of once daily dosing for three different release rates of the MR product for varying combinations of IR+MR doses, as described in Example 55. In each left- hand plot: 320mg IR+Omg MR (solid), 240mg IR+80mg MR (dashed-dotted line), 160mg IR+160mg MR (dotted line), 80mg IR + 240mg MR (dashed line) and in vivo IC50 (solid horizontal grey line) are plotted. The three plots on the right hand side show the relationship between different biophase profiles and percentage change in SBP/DBP.

Fig. 20 presents three plots on the left hand side showing the plasma (black) and biophase (grey) concentration time profiles for a single dose with three different release rates of the MR product and for varying combinations of IR+MR doses, as described in Example 55. In each left-hand plot: 320mg IR+Omg MR (solid), 260mg IR+60mg MR (long dashed line - - ), 200mg IR+120mg MR (dashed-dotted line), 140mg IR + 180mg MR (short dashed line --), 80mg IR + 240mg MR (dotted line) and the in vivo IC50 (solid grey horizontal line) are plotted. The three plots on the right hand side show the relationship between different biophase profiles and percentage change in SBP/DBP.

Fig. 21 presents two plots on the left hand side showing the plasma (black) and biophase (grey) concentration time profiles on day 1 day 14 of once daily dosing for a fixed dose combination of 30mg IR + 290mg MR with varying release rates of the MR product, as described in Example 55. In each left-hand plot: 12 hours (dashed line), 10 hours (dotted line), 8 hours (dashed-dotted line), the 320mg IR product (solid line) for comparison, and the in vivo IC50 (solid grey horizontal line) are plotted. The two plots on the right hand side show the relationship between different biophase profiles and percentage change in SBP/DBP.

Fig. 22 top panel shows the plasma (black) and biophase (grey) concentration time profiles over 14 days for 320mg IR product (solid lines) and 30mg IR + 290 mg MR: 12 hour release (dotted lines) together with in vivo IC50 (solid grey horizontal line). The bottom panel shows the

corresponding effect on the percentage change in SBP/DBP.

Fig. 23 presents two plots on the left panel showing the plasma (black) and biophase (grey) concentration time profiles on day 1 and day 14 of a once daily schedule for 320mg IR product (solid lines) and 30mg IR + 290mg MR: 12 hour release (dotted lines) together with in vivo IC50 (solid grey horizontal line). The two plots on the right hand side show the corresponding effect on the percentage change in SBP/DBP.

Fig. 24 presents two plots on the left hand side showing the plasma (black) and biophase (grey) concentration time profiles on day 1 and day 14 of a once daily schedule for 320mg IR product (solid lines) and 30mg IR + 290mg MR: 24 hour release / 'extreme release' (dotted lines) together with in vivo IC50 (solid grey horizontal line). The two plots on the right hand side show the corresponding effects on the percentage changes in SBP/DBP.

Fig. 25 presents two plots on the left hand side which show the plasma (black) and biophase (grey) concentration time profiles on day 1 and day 14 of once daily dosing for a fixed dose combination of 30mg IR + 450mg MR with varying release rates of the MR product. In each left-hand plot: 12 hours (dashed line), 10 hours (dotted line), 8 hours (dashed-dotted line), the 480mg IR product for comparison (solid line) and the in vivo IC50 (solid grey horizontal line) are plotted. The two plots on the right hand side show the relationship between different biophase profiles and percentage change in SBP/DBP.

Fig. 26 top panel shows the plasma (black) and biophase (grey) concentration time profiles over 14 days for 480mg IR product (solid lines) and 30mg IR + 450mg MR: 12 hour release (dotted lines) together with in vivo IC50 (solid grey horizontal line). The bottom panel shows the

corresponding effect on the percentage change in SBP/DBP.

Fig. 27 presents two plots on the left hand side showing the plasma (black) and biophase (grey) concentration time profiles on day 1 and day 14 of a once daily schedule for 480mg IR product (solid lines) and 30mg IR + 450mg MR: 12 hour release (dotted lines) together with in vivo IC50 (solid grey horizontal line). The two plots on the right hand side show the corresponding effect on the percentage change in SBP/DBP.

Fig. 28 presents two plots on the left hand side showing the plasma (black) and biophase (grey) concentration time profiles on day 1 and day 14 of once daily dosing for a fixed dose combination of 30mg IR + 610mg MR with varying release rates of the MR product. In each left-hand plot: 12 hours (dashed line), 10 hours (dotted line), 8 hours (dashed-dotted line), the 640mg IR product for comparison (solid line) and the in vivo IC50 (solid grey horizontal line) are plotted. The two plots on the right hand side show the relationship between different biophase profiles and percentage change in SBP/DBP.

Fig. 29 top panel shows the plasma (black) and biophase (grey) concentration time profiles over 14 days for 640mg IR product (solid lines) and 30mg IR + 610mg MR: 12 hour release (dotted lines) together with the in vivo IC50 (solid grey horizontal line). The bottom panel shows the corresponding effect on the percentage change in SBP/DBP.

Fig. 30 presents two plots on the left hand side showing the plasma (black) and biophase (grey) concentration time profiles on day 1 and day 14 of a once daily schedule for 640mg IR product (solid lines) and 30mg IR + 610mg MR: 12 hour release (dotted lines) together with in vivo IC50 (solid grey horizontal line). The two plots on the right hand side show the corresponding effect on the percentage change in SBP/DBP.

DETAILED DESCRIPTION OF THE INVENTION

Information on how to make and use the invention is provided herein. The references mentioned herein are also incorporated herewith. The pharmacological test methods are also incorporated.

The invention provides multicomponent pharmaceutical compositions that provide rapidity, longevity and dose to dose maintenance within the therapeutic window, in order to address the early morning deficit or nocturnal deficit problem and reduce the side effect profile of angiotensin II receptor antagonists. The compositions, which are typically multicomponent solid dosage forms (e.g. multicomponent tablets or capsules) give the benefit of one or more, typically two or three, of the technical effects selected from longevity, rapidity and dose to dose maintenance within the therapeutic window.

In terms of dose to dose maintenance within the therapeutic window, when administering a conventional swallow tablet from which the active moiety is absorbed into the bloodstream, there is usually a minimum blood plasma concentration which is required to achieve a therapeutic effect. As the blood plasma level increases, so does the therapeutic effect in a dose-related manner until a maximal therapeutic effect has been achieved. However, when drug blood plasma levels exceed a certain concentration, undesired side -effects become apparent. When drug blood plasma levels drop below a certain concentration there is little or no therapeutic benefit. Drug blood plasma

concentrations between these two levels are often referred to as the "therapeutic window". The term "therapeutic window" as used herein is defined accordingly, i.e. as the range of drug plasma concentrations that provide efficacy without unacceptable side effects. Hence, blood plasma levels outside the therapeutic window are associated with either a lack of efficacy or unacceptable side- effects. For example, as discussed above, valsartan and losartan, and indeed other angiotensin II receptor antagonists, suffer from a short half-life, which manifests itself as causing the body to become devoid of drug in the pk plasma during the early hours after the drug has metabolized below the minimum inhibitory concentration, causing a marked increase in early morning stroke, heart attack and associated death. Thus the drug falls well outside of the therapeutic window early on in the dosing interval - the early morning deficit or nocturnal deficit problem - and this is associated with a marked increase in morbidity. Therefore, addressing the pk profiles of angiotensin II receptor antagonists, in accordance with the present invention, so that they are maintained in the therapeutic window from dose to dose, makes the angiotensin II receptor antagonists excellent drugs having an ideal therapeutic profile giving 24 hour relief from hypertensive effects and the associated morbidity and serious clinical consequences.

Accordingly, in a preferred embodiment of the present invention the pharmaceutical composition - which is typically a unit dosage form - is adapted to ensure maintenance of the angiotensin II receptor antagonist within the therapeutic window from dose to dose. The term "from dose to dose" herein, refers to the dosing interval. In once daily (OD) dosing the dosing interval is 24 hours and therefore maintaining the angiotensin II receptor antagonist within the therapeutic window from dose to dose in that case means maintaining the angiotensin II receptor antagonist in the therapeutic window until the next dose which is 24 hours after administration of the pharmaceutical composition to the subject.

The pharmaceutical composition of the invention comprises a first fraction comprising an angiotensin II receptor antagonist; and a controlled-release fraction comprising the angiotensin II receptor antagonist. The angiotensin II receptor antagonists in the two fractions are generally the same one, e.g. both valsartan or both losartan, as opposed to losartan in one fraction and valsartan in the other. However, the angiotensin II receptor antagonist may be in different forms in the first fraction and the controlled-release fraction. For instance, the angiotensin II receptor antagonist in the first fraction may be in an amorphous form and the angiotensin II receptor antagonist in the controlled- release fraction may be in a crystalline form, or vice versa, and/or the angiotensin II receptor antagonist in the first fraction may be in the form or a pharmaceutically acceptable salt, or in the form of a co-crystal, whereas the angiotensin II receptor antagonist in the controlled-release fraction may be in the free form. Various particular different forms of valsartan and losartan, which can be employed in the first fraction or the controlled-release fraction or both, are discussed in detail hereinbelow.

The term "pharmaceutically acceptable salt thereof refers to salts which are physically, chemically and physiologically acceptable for either human or veterinary use. Generally, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.

Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines and heterocyclic amines.

It should also be understood that "angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof includes solutions, amorphous forms, and crystalline forms of the angiotensin II receptor antagonist including solvates, hydrates, co-crystals and polymorphs.

The pharmaceutical composition of the invention may further comprise other fractions or components in addition to the first fraction and the controlled-release fraction. For example, in cases where the first fraction is a rapid release fraction, the pharmaceutical composition of the invention may further comprise a third fraction which is neither a rapid release fraction nor a controlled-release fraction but a conventional release component.

The controlled-release fraction is generally suitable for causing delayed or prolonged release of the angiotensin II receptor antagonist from the controlled-release fraction after administration of the composition to a subject.

The term "delayed release", in the context of controlled release or modified release in the context of this specification, is understood to indicate a formulation that is designed to retard the initial release of drug from the dosage form by a pre-determined interval of time. Delayed release may for instance be understood to mean retardation of release, when compared to a currently approved product. The term "prolonged release", in the context of controlled release or modified release in the context of this specification, may be understood to indicate a formulation that is designed to maintain the release of drug over a period of time that is substantially greater than is achieved in the currently marketed formulation.

Typically, the controlled-release fraction in the pharmaceutical composition of the invention is adapted to provide longevity of action of the angiotensin II receptor antagonist from dose to dose by causing delayed or prolonged release of the angiotensin II receptor antagonist from the controlled- release fraction after administration of the composition to a subject.

Often, prolonged release is employed, and therefore the controlled-release fraction is suitable for causing prolonged release of the angiotensin II receptor antagonist from the controlled-release fraction after administration of the composition to a subject. The controlled-release fraction may be adapted to provide longevity of action of the angiotensin II receptor antagonist from dose to dose by causing prolonged release of the angiotensin II receptor antagonist from the controlled-release fraction after administration of the composition to a subject.

The controlled-release fraction is typically adapted to release the angiotensin II receptor antagonist from the controlled-release fraction in vivo over a period of x hours from the time of administration of the composition to a subject. Generally, in this embodiment, all of the angiotensin II receptor antagonist is released from the controlled-release fraction over the defined period. Typically, x is at least 8, so that it takes at least 8 hours for all of the angiotensin II receptor antagonist to be released from the controlled-release fraction. However, x may be at least 9, or, for instance, at least 10, so that it takes at least 8 hours for all of the angiotensin II receptor antagonist to be released from the controlled-release fraction, x may for instance be from 8 to 24, so that it takes from 8 to 24 hours for all of the angiotensin II receptor antagonist to be released from the controlled-release fraction, x may for instance be from 9 to 24, or from 10 to 24. Often, x is at least 12, so that it takes at least 12 hours for all of the angiotensin II receptor antagonist to be released from the controlled-release fraction, x may for instance be at least 15, for example at least 17, at least 18, or at least 20. x may for instance be from 12 to 24, or from 15 to 24, or for instance from 17 to 24, or from 20 to 24.

The controlled-release fraction is usually adapted to ensure maintenance of the angiotensin II receptor antagonist within the therapeutic window from dose to dose, or at least for a certain, preferably high, proportion of the time during the dosing interval.

Thus, in the pharmaceutical composition of the invention, the controlled-release fraction is often adapted to ensure maintenance of the angiotensin II receptor antagonist within the therapeutic window for a certain percentage - y % - of the time during the dosing interval. The dosing interval may be defined as, say, z hours beginning with administration of the composition to a subject. When the pharmaceutical composition is a unit dosage form suitable for once daily (OD) dosing, z is generally 24, i.e. the dosing interval is 24 hours. Accordingly, z is typically from 20 to 28, for instance about 24. Often, z is 24. However, other dosing frequencies may of course be employed, depending on the drug, patient and condition being treated, and z may therefore have other values. Thus, z may for instance be 6, 8 or 12, or even 48. Thus, z may be from 6 to 48, but is typically from 12 to 36, for instance from 20 to 28. Often, z is 24.

Typically, y is at least 50, such that the angiotensin II receptor antagonist is maintained within the therapeutic window for at least 50% of the time during the dosing interval. It is of course preferred, however, that y is greater than 50. Preferably, for instance, y is at least 60, and more preferably at least 70, for instance at least 75. Typically, y is at least 80, for instance at least 85. Often, y is at least 90, and is preferably at least 95. y may for instance be 100, such that the angiotensin II receptor antagonist is maintained within the therapeutic window throughout the dosing interval, i.e. from dose to dose.

Typically, z is 24 and y is at least 50. More preferably, z is 24 and y is at least 60, and more preferably at least 70, for instance at least 75. Typically, z is 24 and y is at least 80, for instance at least 85. Often, z is 24 and y is at least 90, and is preferably at least 95. In some cases, z is 24 and y is 100.

In the compositions of the present invention, the controlled-release fraction is usually adapted to maintain the angiotensin II receptor antagonist at or above a drug plasma level, 1, in a subject for a certain percentage (q %) of the time during the dosing interval. The dosing interval may in this case be defined as t hours beginning with administration of the composition to the subject. The term "drug plasma level of the angiotensin II receptor antagonist" refers to the plasma concentration of the active form of the angiotensin II receptor antagonist. This is often the angiotensin II receptor antagonist compound as administered to the subject, but it may be an active metabolite thereof.

The drug plasma level, 1, of the angiotensin II receptor antagonist, at or above which the controlled-release fraction is adapted to maintain the angiotensin II receptor antagonist for q % of the time during the dosing interval, may be any drug plasma level within the therapeutic window.

Alternatively, it may be the plasma concentration required for obtaining 50% of a maximum therapeutic effect in vivo. This is known as the IC50, and as the skilled person will appreciate, an IC50 value is specific to a particular drug and to the therapeutic effect that is desired and therefore the condition being treated by the drug. For instance, as explained in Example 55 herein, the IC50 for valsartan in connection with the treatment of hypertension is 1.2 mg/L, this being the plasma concentration of valsartan required for obtaining 50% of a maximum reduction in blood pressure in vivo obtainable by valsartan.

Typically, therefore, the drug plasma level, 1, of the angiotensin II receptor antagonist, at or above which the controlled-release fraction is adapted to maintain the angiotensin II receptor antagonist for q % of the time during the dosing interval, is the plasma concentration (IC50) required for obtaining 50% of a maximum therapeutic effect in vivo.

The drug plasma level, 1, may for instance be the plasma concentration (IC50) required for obtaining 50% of a maximum reduction in blood pressure in vivo. This is generally the plasma concentration required for obtaining 50% of a maximum reduction in blood pressure in vivo that is obtainable by the angiotensin II receptor antagonist in question.

The drug plasma level, 1, may for instance be 1.2 mg/L. As mentioned above, this is the IC50 for valsartan: the plasma concentration of valsartan required for obtaining 50% of a maximum reduction in blood pressure in vivo. Typically, therefore, in this embodiment, the angiotensin II receptor antagonist is valsartan.

Alternatively, the drug plasma level, 1, may be 0.5 mg/L. It may for instance be 0.8 mg/L, for instance 1.0 mg/L, or for example 1.4 mg/L. The drug plasma level, 1, may for instance be 1.8 mg/L, or, for instance 2.0 mg/L.

The pharmaceutical composition is often a unit dosage form suitable for once daily (OD) dosing. Thus, t is generally 24, i.e. the dosing interval is 24 hours. Accordingly, t is typically from 20 to 28, for instance about 24. Often, t is 24. However, other dosing frequencies may of course be employed, depending on the drug, patient and condition being treated, and t may therefore have other values. Thus, t may for instance be 6, 8 or 12, or even 48. Thus, t may be from 6 to 48, but is typically from 12 to 36, for instance from 20 to 28. Often, t is 24.

Typically, q is at least 40, such that the angiotensin II receptor antagonist is maintained at or above the drug plasma level, 1, for at least 40% of the time during the dosing interval. It is of course preferred, however, that q is greater than 40. Preferably, for instance, q is at least 45, and more preferably at least 50, for instance at least 60. Typically, q is at least 65, for instance at least 70. Often, q is at least 75. Typically, q is at least 80, for instance at least 85. Often, q is at least 90, and is preferably at least 95. q may for instance be 100, such that the angiotensin II receptor antagonist is maintained at or above the drug plasma level, 1, throughout the dosing interval, i.e. from dose to dose.

Typically, t is 24 and q is at least 45. More preferably, t is 24 and q is at least 50, and more preferably at least 60, for instance at least 65, at least 70, or for instance at least 75. Typically, t is 24 and q is at least 80, for instance at least 85. Often, t is 24 and q is at least 90, and is preferably at least 95. In some cases, t is 24 and q is 100.

Typically, in the pharmaceutical composition of the invention, the first fraction is a rapid release fraction. Thus, the first fraction is usually adapted to provide rapid release of the angiotensin II receptor antagonist into the bloodstream to provide fast onset of action. As discussed below, rapid release may be achieved by a formulation of the angiotensin II receptor antagonist comprising a rapidly dispersing wafer containing the angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof which is placed on the tongue and dissolves in the mouth, for example within the buccal fluids. Suitably the wafer is dispersed and/or dissolved over a period of about 1 to 60 seconds, preferably about 1 to 30 seconds, most preferably about 1 to 10 seconds.

Alternatively, however, the first fraction may be a conventional formulation of an angiotensin II receptor antagonist, i.e. neither adapted for rapid release nor delayed or prolonged release. Usually, however, it is adapted for rapid release of the angiotensin II receptor antagonist.

Usually, the pharmaceutical composition of the invention is a dosage form, for instance a unit dosage form. The dosage form is typically a solid dosage form. It is typically an oral dosage form, for instance a tablet or capsule. It is often a tablet.

The oral dosage form, which is typically a tablet, often comprises an outer layer which comprises the first fraction, which outer layer is disposed on all or part of the surface of the controlled-release fraction.

The oral dosage form, typically a tablet, often comprises an outer layer which comprises the first fraction, and an inner region. The inner region is generally completely within the outer layer, and comprises the controlled-release fraction.

Thus, the oral dosage form may have a core-shell structure wherein the controlled-release fraction defines a core and the first fraction is disposed on the surface of the core to form a shell which surrounds the core.

The oral dosage form may advantageously further comprise a coating for delaying exposure of the angiotensin II receptor antagonist in the controlled-release fraction to the buccal, gastric, or intestinal fluids. Such a coating, which may be an enteric coating, is discussed in further detail hereinbelow. The coating for delaying exposure of the angiotensin II receptor antagonist is typically disposed on the surface of the controlled-release fraction. It may then delay release of the angiotensin II receptor antagonist from the controlled-release fraction but not adversely affect rapid release of the angiotensin II receptor antagonist from the first fraction. The coating may advantageously therefore be disposed between the first fraction and the controlled-release fraction, in a core shell structure wherein the controlled-release fraction defines a core and the first fraction is a shell disposed around that core. In such a core-shell structure, the coating may advantageously be disposed between the core and the shell.

In the pharmaceutical composition of the invention, the ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is typically from 98:2 to 60:40. Thus, typically, the first fraction comprises from 2% to 40% by mass of the total amount of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction, and the controlled-release fraction comprises from 98% to 60% by mass of the total amount of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction.

The mass here refers to the mass of the angiotensin II receptor antagonist in the free form, irrespective of whether the angiotensin II receptor antagonist is present in the composition in salt form, co-crystal form, or indeed the free form. This is to allow for the possibility that the antagonist may be present in different forms in the first fraction and the controlled-release fraction, for instance it may be present in the free form in one fraction and in a salt form in the other fraction. Thus, masses are quoted on a "free form" basis.

Indeed, except where specified otherwise, all doses and masses of angiotensin II receptor antagonists are cited on a "free form" basis. Thus, for example, if the angiotensin II receptor antagonist is in the free form (as opposed to a salt form or in the form of a co-crystal), reference to "80mg" of the angiotensin II receptor antagonist, as used herein, means 80mg of the angiotensin II receptor antagonist in the said free form. If on the other hand the angiotensin II receptor antagonist is in the form of a salt or cocrystal, reference to "80mg" of the angiotensin II receptor antagonist, as used herein, does not mean 80mg of that salt or cocrystal; rather, it refers to the particular amount of that salt that would provide 80mg of the angiotensin II receptor antagonist in the free form. In other words, it refers to the mass of the salt or co-crystal of the angiotensin II receptor antagonist which is the molar equivalent of 80mg of the angiotensin II receptor antagonist in the free form.

Thus, in the pharmaceutical composition of the invention, the ratio of the number of moles of the angiotensin II receptor antagonist in the controlled-release fraction to the number of moles of the angiotensin II receptor antagonist in the first fraction is typically from 98:2 to 60:40. Thus, typically, the first fraction comprises from 2 mol. % to 40 mol. % of the total amount of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction, and the controlled-release fraction comprises from 98 mol. % to 60 mol. % by mass of the total amount of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction.

The total amount of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction typically corresponds to the total amount of the angiotensin II receptor antagonist in the pharmaceutical composition itself. In other words, the first fraction and the controlled-release fraction are typically the only fractions in the composition that comprise the angiotensin II receptor antagonist. Generally, therefore, the terms "total amount of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction" and "total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction", as used herein, are interchangeable with the terms "total amount of the angiotensin II receptor antagonist in the pharmaceutical composition" and "total mass of the angiotensin II receptor antagonist in the pharmaceutical composition" respectively.

Typically, the ratio of the mass of the angiotensin II receptor antagonist in the controlled- release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is from 96:4 to 70:30. Usually, therefore, the ratio of the number of moles of the angiotensin II receptor antagonist in the controlled-release fraction to the number of moles of the angiotensin II receptor antagonist in the first fraction is from 96:4 to 70:30.

The ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction may for instance be from 96:4 to 80:20. Likewise, the ratio of the number of moles of the angiotensin II receptor antagonist in the controlled-release fraction to the number of moles of the angiotensin II receptor antagonist in the first fraction may be from 96:4 to 80:20.

In the pharmaceutical composition of the invention, the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction is typically from 50 mg to 700 mg.

Examples of the total masses of the angiotensin II receptor antagonist that are commonly employed in the composition of the invention (in the first fraction and the controlled-release fraction thereof) include 80 mg, 160 mg, 240 mg, 320 mg, 400 mg, 480 mg, 560 mg and 640 mg. Usually, these total masses of angiotensin II receptor antagonist are distributed between the first fraction and the controlled-release fraction in accordance with the ratios defined above. Thus, in a composition comprising 80 mg, 160 mg, 240 mg, 320 mg, 400 mg, 480 mg, 560 mg or 640 mg of the angiotensin II receptor antagonist in total, the ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is typically from 98:2 to 60:40. It is often from 96:4 to 70:30, and may for instance be from 96:4 to 80:20.

Accordingly, in the pharmaceutical composition of the invention, the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction is typically from 80 mg to 640 mg, for instance from 160 mg to 640 mg. This typically also corresponds to the total mass of the angiotensin II receptor antagonist in the pharmaceutical composition itself. Often, in these embodiments, the ratio of the mass of the angiotensin II receptor antagonist in the controlled- release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is typically from 98:2 to 60:40. It is often from 96:4 to 70:30, and may for instance be from 96:4 to 80:20. Often, from 5 mg to 50 mg, for instance from 10 mg to 40 mg, or from 20 mg to 50 mg, of the angiotensin II receptor antagonist is employed in the first fraction and the remainder of the total mass of the angiotensin II receptor antagonist is employed in the controlled-release fraction. For instance, from 20 mg to 40 mg, from 25 mg to 30 mg, or for instance from 28 mg to 32 mg, of the angiotensin II receptor antagonist may be employed in the first fraction and the remainder of the total mass of the angiotensin II receptor antagonist is employed in the controlled-release fraction.

Often, in the pharmaceutical composition of the invention, the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction is 80 mg, 160 mg, 240 mg, 320 mg, 400 mg, 480 mg, 560 mg or 640 mg. This typically also corresponds to the total mass of the angiotensin II receptor antagonist in the pharmaceutical composition itself. Often, in these embodiments, the ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is from 98:2 to 60:40. It is typically for instance from 96:4 to 70:30, and may for instance be from 96:4 to 80:20. Often, from 5 mg to 50 mg, for instance from 10 mg to 40 mg, or from 20 mg to 50 mg, of the angiotensin II receptor antagonist is employed in the first fraction and the remainder of the total mass of the angiotensin II receptor antagonist is employed in the controlled-release fraction. For instance, from 20 mg to 40 mg, from 25 mg to 30 mg, or for instance from 28 mg to 32 mg, of the angiotensin II receptor antagonist may be employed in the first fraction and the remainder of the total mass of the angiotensin II receptor antagonist is employed in the controlled-release fraction.

For instance, in the pharmaceutical composition of the invention, the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction may be about 160 mg, the first fraction may comprise from 10 mg to 50 mg of the angiotensin II receptor antagonist, and the controlled-release fraction may comprise the remainder of the angiotensin II receptor antagonist. The first fraction may for instance comprise from 10 mg to 40 mg of the angiotensin II receptor antagonist, and the controlled-release fraction may comprise the remainder of the angiotensin II receptor antagonist.

Often, in the pharmaceutical compositions of the invention, the mass of the angiotensin II receptor antagonist in the first fraction is from 10 mg to 50 mg, for instance from 20 mg to 40 mg, or for example from 25 mg to 30 mg. It may for instance be from 28 mg to 32 mg, i.e. about 30 mg. The remainder is typically in the controlled-release fraction and the total amount of the angiotensin II receptor antagonist in the composition may be anywhere as defined above, for instance from 80 mg to 640 mg, e.g. any of 80 mg, 160 mg, 240 mg, 320 mg, 400 mg, 480 mg, 560 mg and 640 mg. Often, in the pharmaceutical compositions of the invention, the ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is from 98:2 to 60:40, preferably from 96:4 to 70:30, for instance from 96:4 to 80:20, and the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction (which is typically the same as the total mass of the angiotensin II receptor antagonist in the whole composition) is anywhere as defined above, for instance from 80 mg to 640 mg, e.g. any of 80 mg, 160 mg, 240 mg, 320 mg, 400 mg, 480 mg, 560 mg and 640 mg.

For instance, the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction may be from 160 mg to 640 mg, e.g. any of 160 mg, 240 mg, 320 mg, 400 mg, 480 mg, 560 mg and 640 mg, wherein the mass of the angiotensin II receptor antagonist in the first fraction is from 28 mg to 32 mg, i.e. about 30 mg.

The total mass of the angiotensin II receptor antagonist employed in the composition of the invention may for instance be from 50 mg to 120 mg. Typically, in this embodiment, the total mass of the antagonist in the composition is from 70 mg to 90 mg, for instance about 80 mg. The angiotensin II receptor antagonist in the composition is generally distributed solely between the first fraction and controlled-release fraction of the composition. The ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is typically from 98:2 to 60:40. It is often from 96:4 to 70:30, and may for instance be from 90: 10 to 70:30, or for instance from 90: 10 to 80:20. Thus, in this embodiment, the first fraction typically comprises from 2 mg to 32 mg of the angiotensin II receptor antagonist wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The first fraction may for instance comprise from 4 mg to 24 mg of the antagonist, or for example from 8 mg to 16 mg of the antagonist, wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The angiotensin II receptor antagonist may be as further defined anywhere herein, but often, in this embodiment, it is valsartan or losartan, and more typically it is valsartan.

The total mass of the angiotensin II receptor antagonist employed in the composition of the invention may for instance be from 120 mg to 200 mg. Typically, in this embodiment, the total mass of the antagonist in the composition is from 150 mg to 170 mg, for instance about 160 mg. The angiotensin II receptor antagonist in the composition is generally distributed solely between the first fraction and controlled-release fraction of the composition. The ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is typically from 98:2 to 60:40. It is often from 96:4 to 70:30, and may for instance be from 90: 10 to 70:30, or for instance from 90: 10 to 80:20. Thus, in this embodiment, the first fraction typically comprises from 3 mg to 64 mg of the angiotensin II receptor antagonist wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The first fraction may for instance comprise from 6 mg to 48 mg, for instance from 10 mg to 40 mg, of the antagonist, or for example from 16 mg to 32 mg of the antagonist, wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The angiotensin II receptor antagonist may be as further defined anywhere herein, but often, in this embodiment, it is valsartan or losartan, and more typically it is valsartan.

The total mass of the angiotensin II receptor antagonist employed in the composition of the invention may for instance be from 200 mg to 280 mg. Typically, in this embodiment, the total mass of the antagonist in the composition is from 230 mg to 250 mg, for instance about 240 mg. The angiotensin II receptor antagonist in the composition is generally distributed solely between the first fraction and controlled-release fraction of the composition. The ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is typically from 98:2 to 60:40. It is often from 96:4 to 70:30, and may for instance be from 90: 10 to 70:30, or for instance from 90: 10 to 80:20. Thus, in this embodiment, the first fraction typically comprises from 5 mg to 96 mg of the angiotensin II receptor antagonist wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The first fraction may for instance comprise from 10 mg to 72 mg of the antagonist, or for example from 24 mg to 48 mg of the antagonist, wherein the controlled- release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The angiotensin II receptor antagonist may be as further defined anywhere herein, but often, in this embodiment, it is valsartan or losartan, and more typically it is valsartan.

The total mass of the angiotensin II receptor antagonist employed in the composition of the invention may for instance be from 280 mg to 360 mg. Typically, in this embodiment, the total mass of the antagonist in the composition is from 310 mg to 330 mg, for instance about 320 mg. The angiotensin II receptor antagonist in the composition is generally distributed solely between the first fraction and controlled-release fraction of the composition. The ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is typically from 98:2 to 60:40. It is often from 96:4 to 70:30, and may for instance be from 90: 10 to 70:30, or for instance from 90: 10 to 80:20. Thus, in this embodiment, the first fraction typically comprises from 6 mg to 128 mg of the angiotensin II receptor antagonist wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The first fraction may for instance comprise from 13 mg to 96 mg of the antagonist, or for example from 32 mg to 64 mg of the antagonist, wherein the controlled- release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The angiotensin II receptor antagonist may be as further defined anywhere herein, but often, in this embodiment, it is valsartan or losartan, and more typically it is valsartan. The total mass of the angiotensin II receptor antagonist employed in the composition of the invention may for instance be from 360 mg to 440 mg. Typically, in this embodiment, the total mass of the antagonist in the composition is from 390 mg to 410 mg, for instance about 400 mg. The angiotensin II receptor antagonist in the composition is generally distributed solely between the first fraction and controlled-release fraction of the composition. The ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is typically from 98:2 to 60:40. It is often from 96:4 to 70:30, and may for instance be from 90: 10 to 70:30, or for instance from 90: 10 to 80:20. Thus, in this embodiment, the first fraction typically comprises from 8 mg to 160 mg of the angiotensin II receptor antagonist wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The first fraction may for instance comprise from 16 mg to 120 mg of the antagonist, or for example from 40 mg to 80 mg of the antagonist, wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The angiotensin II receptor antagonist may be as further defined anywhere herein, but often, in this embodiment, it is valsartan or losartan, and more typically it is valsartan.

The total mass of the angiotensin II receptor antagonist employed in the composition of the invention may for instance be from 440 mg to 520 mg. Typically, in this embodiment, the total mass of the antagonist in the composition is from 470 mg to 490 mg, for instance about 480 mg. The angiotensin II receptor antagonist in the composition is generally distributed solely between the first fraction and controlled-release fraction of the composition. The ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is typically from 98:2 to 60:40. It is often from 96:4 to 70:30, and may for instance be from 90: 10 to 70:30, or for instance from 90: 10 to 80:20. Thus, in this embodiment, the first fraction typically comprises from 10 mg to 192 mg of the angiotensin II receptor antagonist wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The first fraction may for instance comprise from 20 mg to 144 mg of the antagonist, for instance from 20 mg to 100 mg of the antagonist or for example from 48 mg to 96 mg of the antagonist, wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The angiotensin II receptor antagonist may be as further defined anywhere herein, but often, in this embodiment, it is valsartan or losartan, and more typically it is valsartan.

The total mass of the angiotensin II receptor antagonist employed in the composition of the invention may for instance be from 520 mg to 600 mg. Typically, in this embodiment, the total mass of the antagonist in the composition is from 550 mg to 570 mg, for instance about 560 mg. The angiotensin II receptor antagonist in the composition is generally distributed solely between the first fraction and controlled-release fraction of the composition. The ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is typically from 98:2 to 60:40. It is often from 96:4 to 70:30, and may for instance be from 90: 10 to 70:30, or for instance from 90: 10 to 80:20. Thus, in this embodiment, the first fraction typically comprises from 11 mg to 224 mg of the angiotensin II receptor antagonist wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The first fraction may for instance comprise from 22 mg to 168 mg of the antagonist, for instance from 30 mg to 120 mg of the antagonist or for example from 56 mg to 112 mg of the antagonist, wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The angiotensin II receptor antagonist may be as further defined anywhere herein, but often, in this embodiment, it is valsartan or losartan, and more typically it is valsartan.

The total mass of the angiotensin II receptor antagonist employed in the composition of the invention may for instance be from 600 mg to 700 mg. Typically, in this embodiment, the total mass of the antagonist in the composition is from 620 mg to 670 mg. It may for instance be from 630 mg to 650 mg, for example about 640 mg. The angiotensin II receptor antagonist in the composition is generally distributed solely between the first fraction and controlled-release fraction of the composition. The ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is typically from 98:2 to 60:40. It is often from 96:4 to 70:30, and may for instance be from 90: 10 to 70:30, or for instance from 90: 10 to 80:20. Thus, in this embodiment, the first fraction typically comprises from 10 mg to 280 mg of the angiotensin II receptor antagonist wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The first fraction may for instance comprise from 13 mg to 256 mg of the antagonist, for instance from 26 mg to 192 mg of the antagonist or for example from 64 mg to 128 mg of the antagonist, wherein the controlled-release fraction comprises the remainder of the total mass of the angiotensin II receptor antagonist in the composition. The angiotensin II receptor antagonist may be as further defined anywhere herein, but often, in this embodiment, it is valsartan or losartan, and more typically it is valsartan.

Controlled release fraction embodiments

The controlled-release fraction typically comprises said angiotensin II receptor antagonist (typically in a particular defined dose amount as discussed above) and a matrix suitable for promoting prolonged release of the angiotensin II receptor antagonist. The controlled-release fraction often further comprises a filler. It may also comprise a glidant, a lubricant, or both.

The matrix may be a hydrophilic matrix or an erodible matrix. Suitable hydrophilic and erodible matrix materials which may be employed are discussed further herein.

The matrix may for instance be a hydrophilic matrix, which may for instance comprise a hydrophilic polymer, for instance a water-soluble polymer. Suitable polymers include cellulose ether and xanthan gum. Accordingly, the hydrophilic matrix may for example comprise a polymer which is a cellulose ether or xanthan gum.

The controlled-release fraction typically comprises a hydrophilic polymer which is a cellulose ether. Cellulose ethers are available from Dow under the trade name Methocel and are suitable for use for controlled release of drugs in hydrophilic matrix systems. The cellulose ether may be selected from carboxymethylcellulose (CMC), methylcellulose (MC) and derivatives thereof,

hydroxyethylcellulose (HEC) and derivatives thereof, hydroxylpropyl cellulose (HPC),

hydroxypropylmethylcellulose, and ethylcellulose (EC). Often, however, the cellulose ether is hydroxypropylmethylcellulose or ethylcellulose. Hydroxypropylmethylcellulose, in particular, is usually employed.

The controlled-release fraction may comprise the angiotensin II receptor antagonist in an amount of from 10 wt. % to 40 wt. % based on the total weight of the controlled-release fraction, or for instance in an amount of from 20 wt. % to 30 wt. %, for example from 23 wt. % to 27 wt. %.

The controlled-release fraction may additionally comprise the matrix suitable for promoting prolonged release of the angiotensin II receptor antagonist (which is typically a hydrophilic matrix, for instance a hydrophilic polymer as defined above, and may suitably be a cellulose ether, such as, for example, hydroxypropylmethylcellulose or ethylcellulose) in an amount of from 15 wt. % to 45 wt. % based on the total weight of the controlled-release fraction. The controlled-release fraction may for instance comprise the matrix in an amount of from 15 wt. % to 35 wt. %. The controlled-release fraction may for example comprise the matrix in an amount of from 25 wt. % to 35 wt. %, for instance from 28 wt. % to 32 wt. %, based on the total weight of the controlled-release fraction. Alternatively, the controlled-release fraction may comprise the matrix in an amount of from 15 wt. % to 25 wt. %, for instance from 18 wt. % to 22 wt. %, based on the total weight of the controlled-release fraction.

Typically the hydrophilic polymer is said cellulose ether, and the controlled-release fraction comprises the angiotensin II receptor antagonist in an amount of from 20 wt. % to 30 wt. % and comprises the cellulose ether in an amount of from 15 wt. % to 35 wt. %, and preferably in an amount of from 25 wt. % to 35 wt. %, based on the total weight of the controlled-release fraction.

The controlled-release fraction may additionally comprise a glidant. The controlled-release fraction typically comprises up to 2 wt. %, for instance up to 1 wt. %, of a glidant, for instance from 0.1 wt. % to 0.9 wt. % of a glidant, or for example from 0.3 wt. % to 0.7 wt. % of the glidant, based on the total weight of the controlled-release fraction. Examples of suitable glidants include but are not limited to: colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc. Often, however, silicon dioxide (silica) is employed as a glidant in the controlled-release fraction. This is typically hydrophilic silica. It is often for instance hydrophilic fumed silica, which is commercially available under the trade name Aerosil 200.

The controlled-release fraction may additionally comprise a lubricant. The controlled-release fraction typically comprises up to 2 wt. %, for instance up to 1 wt. %, of a lubricant, for instance from 0.1 wt. % to 0.9 wt. % of a lubricant, or for example from 0.3 wt. % to 0.7 wt. % of the lubricant, based on the total weight of the controlled-release fraction. Examples of suitable lubricants include but are not limited to: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate. Often, however, a stearate, usually a metal stearate, and typically magnesium stearate, is employed as a lubricant in the controlled-release fraction.

The balance of the controlled-release fraction typically comprises, and often consists of, one or more fillers. Examples of suitable fillers include but are not limited to: calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol. Often, however, the fillers employed in the controlled-release fraction are selected from lactose and cellulose, and typically from anhydrous lactose and microcrystalline cellulose.

The balance of the controlled-release fraction typically comprises, and often consists of, a filler which comprises lactose. The filler is often for instance anhydrous lactose, which is

commercially available from DFE Pharma under the trade name SuperTab® 24AN. Alternatively, the balance of the controlled-release fraction may comprise, for instance consist of, a filler which comprises cellulose. The filler is often for instance microcrystalline cellulose, which is commercially available as Microcrystalline Cellulose PHI 02 under the trade name Avicel® from FMC Corporation.

The controlled-release fraction may for instance comprise, or consist of, the following:

the angiotensin II receptor antagonist, in an amount of from 20 wt. % to 30 wt. % based on the total weight of the controlled-release fraction;

a hydrophilic polymer, in an amount of from 15 wt. % to 35 wt. % based on the total weight of the controlled-release fraction;

optionally, a lubricant, in an amount of up to 2 wt. % based on the total weight of the controlled-release fraction;

optionally, a glidant, in an amount of up to 2 wt. % based on the total weight of the controlled-release fraction; and

a filler. The filler typically makes up the balance of the controlled-release fraction.

In this embodiment of the controlled-release fraction, the hydrophilic polymer is typically a cellulose ether, for instance hydroxypropylmethylcellulose or ethylcellulose; the lubricant, when present, is typically a stearate, for instance magnesium stearate; the glidant, when present, is typically hydrophilic silica; and the filler is usually microcrystalline cellulose or anhydrous lactose. Additionally, in this embodiment of the controlled-release fraction, the angiotensin II receptor antagonist may be as further defined anywhere herein. Often, however, it is valsartan. It is typically valsartan in the free form.

from 20 wt. % to 30 wt. % of the angiotensin II receptor antagonist;

from 25 wt. % to 35 wt. %, for instance from 28 wt. % to 32 wt. %, of a hydrophilic polymer; optionally up to 2 wt. % of a lubricant;

optionally up to 2 wt. % of a glidant; and

a filler. The filler typically makes up the balance of the controlled-release fraction. As would be understood by the skilled person, the percentages by weight here are the percentages by weight of the components in the controlled-release fraction, based on the total weight of the controlled-release fraction.

Again, in this embodiment of the controlled-release fraction, the hydrophilic polymer is typically a cellulose ether, for instance hydroxypropylmethylcellulose or ethylcellulose; the lubricant, when present, is typically a stearate, for instance magnesium stearate; the glidant, when present, is typically hydrophilic silica; and the filler is usually microcrystalline cellulose or anhydrous lactose. The filler may comprise, of for instance consist of, microcrystalline cellulose. Additionally, in this embodiment of the controlled-release fraction, the angiotensin II receptor antagonist may be as further defined anywhere herein. Often, however, it is valsartan. It is typically valsartan in the free form.

from 20 wt. % to 30 wt. % of the angiotensin II receptor antagonist;

from 15 wt. % to 25 wt. %, for instance from 18 wt. % to 22 wt. %, of a hydrophilic polymer; optionally up to 2 wt. % of a lubricant;

optionally up to 2 wt. % of a glidant; and

Again, in this embodiment of the controlled-release fraction, the hydrophilic polymer is typically a cellulose ether, for instance hydroxypropylmethylcellulose or ethylcellulose; the lubricant, when present, is typically a stearate, for instance magnesium stearate; the glidant, when present, is typically hydrophilic silica; and the filler is usually microcrystalline cellulose or anhydrous lactose. Additionally, in this embodiment of the controlled-release fraction, the angiotensin II receptor antagonist may be as further defined anywhere herein. Often, however, it is valsartan. It is typically valsartan in the free form.

First fraction embodiments The first fraction may be a rapid release fraction. Thus, the first fraction may be adapted to provide rapid release of the angiotensin II receptor antagonist into the bloodstream to provide fast onset of action.

The first, rapid release fraction typically comprises said angiotensin II receptor antagonist (typically in a particular defined dose amount as discussed above) and a disintegrating agent, also known as a disintegrant. The disintegrant produces a rapidly disintegrable fraction which disperses rapidly on contact with aqueous fluids. The first fraction often further comprises one or more fillers. It may also comprise a glidant, a lubricant, or both.

Any suitable disintegrant may be employed. A wide range of disintegrants are known to the skilled person. Examples of these include, but are not limited to, polyvinylpyrrolidone (PVPP, crospovidone), alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone (PVP), polacrilin potassium, prege latinised starch, sodium alginate, sodium lauryl sulphate, sodium starch glycolate.

Often, polyvinylpyrrolidone (PVPP), which is also known as crospovidone, is employed as the disintegrant.

The first fraction may comprise the angiotensin II receptor antagonist in an amount of from 5 wt. % to 15 wt. % based on the total weight of the first fraction, or for instance in an amount of from 7 wt. % to 13 wt. %, for example from 9 wt. % to 11 wt. %, based on the total weight of the first fraction.

The first fraction may additionally comprise the disintegrant (which is typically one of the types listed above and may for instance be crospovidone) in an amount of up to 15 wt.%, for instance from 0.5 wt. % to 10 wt. %, or more typically for example from 1 wt. % to 5 wt. %, based on the total weight of the first fraction. The first fraction may for instance comprise the disintegrant in an amount of from 2 wt. % to 4 wt. %, for instance from 2.5 wt. % to 3.5 wt. %, based on the total weight of the first fraction.

The first fraction may additionally comprise a glidant. The first fraction typically comprises up to 2 wt. %, for instance up to 1 wt. %, of a glidant, for instance from 0.1 wt. % to 0.9 wt. % of a glidant, or for example from 0.3 wt. % to 0.7 wt. % of the glidant, based on the total weight of the first fraction. Examples of suitable glidants include but are not limited to: colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc. Often, however, silicon dioxide (silica) is employed as a glidant in the first fraction. This is typically hydrophilic silica. It is often for instance hydrophilic fumed silica, which is commercially available under the trade name Aerosil 200.

The first fraction may additionally comprise a lubricant. The first fraction typically comprises up to 2 wt. %, for instance up to 1 wt. %, of a lubricant, for instance from 0.1 wt. % to 0.9 wt. % of a lubricant, or for example from 0.3 wt. % to 0.7 wt. % of the lubricant, based on the total weight of the first fraction. Examples of suitable lubricants include but are not limited to: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate. Often, however, a stearate, usually a metal stearate, and typically magnesium stearate, is employed as a lubricant in the first fraction.

The balance of the first fraction typically comprises, and often consists of, one or more fillers. Examples of suitable fillers include but are not limited to: calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol, and mixtures of two or more than two of these fillers. Often, however, the fillers employed in the first fraction are selected from lactose, cellulose, and a mixture of lactose and cellulose. The fillers employed in the first fraction may for instance be selected from anhydrous lactose and

microcrystalline cellulose. Often, both lactose and cellulose fillers are employed in the first fraction, for instance both anhydrous lactose and microcrystalline cellulose. For instance, the fillers in the first fraction may comprise, or consist of, a cellulose filler and a lactose filler in a weight ratio of from 2: 1 to 3 : 1. The fillers in the first fraction may for instance comprise, or consist of, microcrystalline cellulose and anhydrous lactose in a weight ratio of from 2: 1 to 3: 1.

The first fraction may for instance comprise, or consist of, the following:

the angiotensin II receptor antagonist, in an amount of from 5 wt. % to 15 wt. % based on the total weight of the first fraction;

a disintegrant, in an amount of from 0.5 wt. % to 10 wt. %, based on the total weight of the first fraction;

optionally, a lubricant, in an amount of up to 2 wt. % based on the total weight of the first fraction;

optionally, a glidant, in an amount of up to 2 wt. % based on the total weight of the first fraction; and

one or more fillers. The one or more fillers typically make up the balance of the first fraction.

In this embodiment of the first fraction, the disintegrant is typically crospovidone; the lubricant, when present, is typically a stearate, for instance magnesium stearate; the glidant, when present, is typically hydrophilic silica; and the one or more fillers are usually microcrystalline cellulose, anhydrous lactose, or a mixture of microcrystalline cellulose and anhydrous lactose for instance in a weight ratio of from 2: 1 to 3 : 1. Additionally, in this embodiment of the first fraction, the angiotensin II receptor antagonist may be as further defined anywhere herein. Often, however, it is valsartan. It is typically valsartan in the free form. The first fraction may for instance comprise, or consist of, the following:

the angiotensin II receptor antagonist, in an amount of from 7 wt. % to 13 wt. %, for example from 9 wt. % to 11 wt. %, based on the total weight of the first fraction;

a disintegrant, in an amount of from 1 wt. % to 5 wt. %, for instance from 2 wt. % to 4 wt. %, based on the total weight of the first fraction;

Again, in this embodiment of the first fraction, the disintegrant is typically crospovidone; the lubricant, when present, is typically a stearate, for instance magnesium stearate; the glidant, when present, is typically hydrophilic silica; and the one or more fillers are usually microcrystalline cellulose, anhydrous lactose, or a mixture of microcrystalline cellulose and anhydrous lactose for instance in a weight ratio of from 2: 1 to 3 : 1. Additionally, in this embodiment of the first fraction, the angiotensin II receptor antagonist may be as further defined anywhere herein. Often, however, it is valsartan. It is typically valsartan in the free form.

Combined controlled-release fraction and first fraction embodiments

Preferably, the controlled-release fraction is as defined above under the heading "controlled release fraction embodiments" and the first fraction is as defined above under the heading "first fraction embodiments".

Thus, typically:

- the controlled-release fraction comprises:

the angiotensin II receptor antagonist, in an amount of from 20 wt. % to 30 wt. % based on the total weight of the controlled-release fraction; a hydrophilic polymer as defined in claim 43 or claim 44, in an amount of from 15 wt. % to 35 wt. % based on the total weight of the controlled-release fraction; optionally, a lubricant as defined in claim 50, in an amount of up to 2 wt. % based on the total weight of the controlled-release fraction; optionally, a glidant as defined in claim 49, in an amount of up to 2 wt. % based on the total weight of the controlled- release fraction; and a filler as defined in claim 48, optionally wherein the filler makes up the balance of the controlled-release fraction; and

- the first fraction comprises:

the angiotensin II receptor antagonist, in an amount of from 5 wt. % to 15 wt. % based on the total weight of the first fraction; a disintegrant as defined in any one of claims 54 to 56, in an amount of from 0.5 wt. % to 10 wt. % based on the total weight of the first fraction;

optionally, a lubricant as defined in claim 59, in an amount of up to 2 wt. % based on the total weight of the first fraction; optionally, a glidant as defined in claim 58, in an amount of up to 2 wt. % based on the total weight of the first fraction; and one or more fillers as defined in claim 57, optionally wherein the filler makes up the balance of the first fraction.

Typically, in this embodiment, the hydrophilic polymer in the controlled-release fraction is a cellulose ether and is present in an amount of from 25 wt. % to 35 wt. % based on the total weight of the controlled-release fraction, and preferably in an amount of from 28 wt. % to 32 wt. %. The hydrophilic polymer is often for instance hydroxypropylmethylcellulose or ethylcellulose. The filler in the controlled-release fraction usually comprises microcrystalline cellulose or anhydrous lactose. The filler may preferably comprise microcrystalline cellulose. The lubricant, when present in the controlled-release fraction, is typically a stearate, for instance magnesium stearate, and the glidant, when present in the controlled-release fraction, is typically hydrophilic silica.

Additionally, in this embodiment, the angiotensin II receptor antagonist in the first and controlled-release fractions may be as further defined anywhere herein. Often, however, it is valsartan. It is typically valsartan in the free form. Often the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction is from 80 mg to 640 mg, and: (i) the ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is from 96:4 to 70:30, preferably from 96:4 to 80:20; or (ii) the mass of the angiotensin II receptor antagonist in the first fraction is from 28 mg to 32 mg.

Also, typically, in this embodiment, the disintegrant is crospovidone; the lubricant, when present, is typically a stearate, for instance magnesium stearate; and the glidant, when present, is typically hydrophilic silica. The one or more fillers in the first fraction are usually microcrystalline cellulose, anhydrous lactose, or a mixture of microcrystalline cellulose and anhydrous lactose, for instance in a weight ratio of from 2: 1 to 3 : 1.

Further first fraction embodiments

Further rapid release formulations for use in the first fraction of the composition of the invention may be achieved by several different methodologies, as described below, which may be used alone or in combination.

For example, rapid release may be achieved by a dosage form of angiotensin II receptor antagonist comprising a rapidly dispersing wafer containing the angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof which is placed on the tongue and dissolves in the mouth, for example within the buccal fluids. Suitably the wafer is dispersed and/or dissolved over a period of about 1 to 60 seconds, preferably about 1 to 30 seconds, most preferably about 1 to 10 seconds. Suitably the wafer is made from a freeze -dried compact containing the angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof, in a matrix of a buccal fluid-dispersible polymer such as gelatine and a polysaccharide such as mannitol. The angiotensin II receptor antagonist is dissolved or dispersed into a suspension of mannitol and gelatine prior to filling into blister cavities. These liquid filled blisters are then conveyed through a liquid nitrogen freezing tunnel for freezing and then into a freeze dryer where the solvent is removed leaving behind a highly porous wafer loaded with the angiotensin II receptor antagonist. Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000), M J Rathbone, J Hadgraft & M S Roberts in Modified Release Drug Delivery Systems, Marcel Dekker, New York, 2003, US Patent No. 4,642,903 and US Patent No 5,738,875 which are incorporated herein by reference.

Alternatively, rapid release of the angiotensin II receptor antagonist may be provided by the blending and compression of the angiotensin II receptor antagonist with water soluble excipients, such as a sugar such as but not limited to mannitol, and an effervescence agent, at low compression forces. The low compression forces lead to the formation of a highly porous tablet which disintegrates rapidly. Rapid disintegration is further aided by the inclusion of the effervescence agent, which in the context of this specification is defined as one or more agents which produce carbon dioxide upon contact with buccal, gastric, or intestinal fluids.

Typically, effervescence is derived by the reaction which takes place between alkali metal carbonates or bicarbonates and organic acids such as citric acid or tartaric acid to release carbon dioxide. Examples of effervescent agents are effervescent couples such as an organic acid and a metal carbonate or bicarbonate. Suitable organic acids include but are not limited: citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid, and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L- lysine carbonate and arginine carbonate. Alternatively, only the base component of the effervescent couple may be present. Effervescence may also result from the inclusion of a carbonate or bicarbonate alone to react with acidic gastrointestinal fluids. Suitably the porous tablet disperses over a period of about 1 to 60 seconds, preferably about 1 to 45 seconds, most preferably about 1 to 30 seconds.

Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000), M J Rathbone, J Hadgraft & M S Roberts in Modified Release Drug Delivery Systems, Marcel Dekker, New York, 2003, US Patent No. 5,178,878 and US Patent No 5,607,697 which are incorporated herein by reference.

Alternatively, rapid release of the angiotensin II receptor antagonist may be achieved by blending and compressing the angiotensin II receptor antagonist with a suitable sugar such as but not limited to sucrose which has been melt-spun to form a mass of thin filaments with a high surface area. The resulting tablets are highly porous. Upon contact with buccal fluids, they disintegrate rapidly as the mass of thin filaments dissolves. Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000) and US Patent No 4,855,326 which are incorporated herein by reference. Alternatively, rapid release of the angiotensin II receptor antagonist may be achieved by blending and compressing the angiotensin II receptor antagonist with a low mould ability saccharide (e.g. such as but not limited to lactose and mannitol) which has been granulated using a high mould ability saccharide (e.g. such as but not limited to maltose and maltitol) as a binder. The resulting tablets possess characteristics which enable them to dissolve rapidly on contact with aqueous fluids, typically within about 1 to 60 seconds, preferably about 1 to 30 seconds, most preferably about 1 to 15 seconds. Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000) and US Patent No 5,576,014 which are incorporated herein by reference.

Alternatively, rapid release of the angiotensin II receptor antagonist may be achieved by blending and compressing the angiotensin II receptor antagonist with a disintegrating agent (e.g. such as but not limited to carboxymethylcellulose) and a swelling agent (e.g. such as but not limited to modified starch, e.g. Sodium Starch Glycolate) to produce a rapidly disintegrable tablet which preferably on contact with aqueous fluids disperses over a period of about 1 to 90 seconds, preferably about 1 to 60 seconds, most preferably about 1 to 30 seconds. Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000) and US Patent No 5,464,632 which are incorporated herein by reference.

It should be appreciated that such tablets will afford advantages over the existing marketed swallow tablets even if swallowed before complete dissolution in the mouth, since dissolution in the gastric fluids will still allow a faster dissolution of the angiotensin II receptor antagonist than is achievable from conventional swallow tablets.

One way of augmenting the rapid release achievable by a suitable choice of formulation, is to utilise a salt of the angiotensin II receptor antagonist which is very soluble in saliva or in gastric fluid.

Yet another way of augmenting the rapid release achieved by a suitable choice of formulation is to utilise an amorphous form of a salt of the angiotensin II receptor antagonist or the angiotensin II receptor antagonist in the free form. In addition the amorphous or crystalline form of a salt of the angiotensin II receptor antagonist or the angiotensin II receptor antagonist in the free form may be dispersed or adsorbed in a thin layer over a high surface area inert substrate. Suitable substrates include but are not limited to: Amberlite ® XAD-4, Amberlite ® XAD-7, Amberlite ® XAD-16, AMBERSORB ® 348F, AMBERSORB ® 563, AMBERSORB ® 572, Activated carbon, Activated carbon Darco ®, Activated carbon Darco ® G-60, Activated carbon Darco ® KB, Activated carbon Darco ® KB-B, Activated carbon Norit ®, silica gel high purity grades with high pore volume, for example about 0.75 cc/g and average pore diameter 6θΑ.

It will be appreciated that other materials with comparable properties may also be used as substrates. Any of the "further first fraction embodiments" described above may be combined with any of the "controlled release fraction embodiments" described further above or any of the "further controlled release fraction embodiments" described in the following text.

Further controlled release fraction embodiments

Further modified (prolonged or delayed) release formulations, which are suitable for use in the controlled release fraction of the composition of the invention, may be achieved by several different methodologies, as described below, which may be used alone or in combination.

Controlled release may be provided in the form of prolonged release. A prolonged release dosage form may consist of a matrix dosage unit, such as a hydrophilic and/or an erodible matrix, usually in tablet form. Release from such a unit can be controlled by a number of mechanisms, such as dissolution, erosion, diffusion, osmotic pressure or any combination thereof. Embodiment of prolonged release dosage forms may utilise excipients which control release of the angiotensin II receptor antagonist by more than one formal mechanism.

An erosion controlled prolonged release dosage unit can be achieved by compressing the angiotensin II receptor antagonist with a slowly dissolvable and/or erodable polymeric material into a tablet form. Release of the angiotensin II receptor antagonist occurs as the polymer dissolves and/or erodes away. Suitable polymers include but are not restricted to glyceryl monostearate, acrylic resins, ethylcellulose, stearyl alcohol, hydroxypropylcellulose, carboxymethylcellulose, hypromellose, methylcellulose, hydroxyethylmethylcellulose, sodium carboxymethylcellulose. Further information can be found in Controlled Drug Delivery, second edition, J R Robinson & V H Lee (editors), Marcel Dekker, New York, 1987, in Drug Delivery Systems, second edition, V Ranade & M A Hollinger, CRC Press, Boca Raton, 2004, and in Modified Release Drug Delivery Systems, M J Rathbone, J Hadgraft & M S Roberts, Marcel Dekker, New York, 2003 which publications are incorporated herein by reference.

A diffusion controlled prolonged release dosage form may be produced by compressing a water-swellable hydrophilic polymer in combination with the angiotensin II receptor antagonist drug substance. Such systems are often referred to as "hydrophilic matrices" or "swellable-soluble" systems. Water continues to penetrate the matrix causing the swelling of the hydrophilic polymer. The gelatinous layer that is formed, retards the rate of ingress of water into the matrix and the flux of drug out of the matrix. The angiotensin II receptor antagonist is released from such matrices either by diffusion through the gel layer or by erosion and/or dissolution of the gel layer. Suitable materials would include any pharmaceutically acceptable excipient which can swell and form a gelatinous mass upon hydration, for example, hydroxypropylmethylcellulose, and xanthan gum. Further information and descriptions of such dosage forms can be found in Controlled Drug Delivery, second edition, J R Robinson & V H Lee (editors), Marcel Dekker, New York, 1987 which publication is incorporated herein by reference. An osmosis controlled prolonged release dosage form may be produced by compressing the angiotensin II receptor antagonist in combination with an osmagent into a tablet matrix core formulation. This matrix core is then in part coated with a semi-permeable membrane in known manner, utilising such polymers such as methacrylates, ethyl cellulose, and cellulose acetate. Aqueous fluids are drawn by osmosis from the exterior environment across the membrane at a controlled rate into the core, causing dissolution of both the angiotensin II receptor antagonist and the osmogent and increased pressure within the matrix core. The pressure forces the solubilised angiotensin II receptor antagonist out through a specially created aperture or passageway. Examples of osmagents include but are not restricted to sodium chloride, potassium chloride, lithium chloride, magnesium chloride, magnesium sulphate, lithium sulphate, sodium sulphate, potassium sulphate, citric acid, mannitol, ribose, arabinose, galactose, leucine, glycine, fructose, sucrose, sodium and other bicarbonates.

Further information can be found in the scientific and patent literature, for example: Controlled Drug Delivery, second edition, J R Robinson & V H Lee (editors), Marcel Dekker, New York, 1987, Modified Release Drug Delivery Systems, M J Rathbone, J Hadgraft & M S Roberts, Marcel Dekker, New York, 2003, and US Patents 3,760,984, 3,845,770, 3,987,790, 3,916,899, 4008,719, 4,036,227, 4,576,604, 4,578,075, 4,673,405, 4,681,583, 4,693,895, 4,705,515, 4,773, 907, 5,229,133 which documents are incorporated herein by reference.

Prolonged release can also be achieved by applying a porous or semipermeable membrane coat onto a tablet surface by the application of such polymers such as methacrylates, ethylcellulose, and cellulose acetate. Release from such systems can occur by more than one of the mechanisms described above, for example a combination of dissolution, diffusion, erosion, and osmosis.

Alternatively, prolonged release can be achieved by coating multiparticulates with semipermeable membranes. The multiparticulates include drug-coated substrates, such as lactose beads, and drug- containing substrates, such as drug-containing lactose spheres.

Delayed release of the angiotensin II receptor antagonist can be achieved by means of a physical barrier or coating which delays exposure of the active material to the buccal, gastric, or intestinal fluids. One technique which provides delayed release involves the application of a coating of a fluid resistant barrier to a single dosage unit, or to a multiparticulate dosage unit, for example one composed of beadlets, pellets, spheroids, minitablets and/or granules. These coatings can be designed to dissolve at a specific pH range, for example an enteric coating which dissolves at a pH greater than 5.0. Typical pH-dependent polymers suitable for coating dosage forms (single or multiparticulate) include the following:

cellulose acetate phthalate, which dissolves at pH 6.0-6.4

hydroxypropylmethylcellulose phthalate 50, which dissolves at about pH 4.8

hydroxypropylmethylcellulose phthalate 55, which dissolves at about pH 5.2

polyvinylacetate phthalate, which dissolves at about pH 5.0

methacrylic acid-methyl methacrylate copolymer (1 : 1), which dissolves at about pH 6.0 methacrylic acid-methyl methacrylate copolymer (2: 1), which dissolves at pH 6.5-7.5 methacrylic acid-ethyl acrylate copolymer (2: 1), which dissolves at about pH 5.5

hydroxypropylmethylcellulose acetate succinate, which dissolves at about pH 7.0

poly(methylvinylether/maleic acid) monoethylester, which dissolves at pH 4.5 -5.0

poly(methylvinylether/maleic acid)n-butyl ester, which dissolves at about pH 5.4

shellac, which dissolves at about pH 7.0

Alternatively a non-pH-dependant coating may be used, which initially impedes the ingress of aqueous fluid, but subsequently erodes and/or dissolves to expose the active agent to dissolution. Typical non-pH-dependent polymers suitable for coating dosage forms (single or multiparticulate) to provide a fluid resistant barrier which subsequently erodes or dissolves include, but are not restricted to acacia, alginate, amylase, beeswax, carboxymethylcellulose, carnuba wax, cellulose acetate, cholesterol, ethylcellulose, fatty acids, gelatine, glyceryl behenate, glyceryl monostearate, glyceryl monodistearate, glyceryl tripalmitate, hypromellose, hydroxypropylcellulose, hydrogenated vegetable oil, lecithin, methylcellulose, paraffin wax, pectin, polyethylene glycol, polycaprolactone, polyglycolic acid, polylactic acid, polyglyclide-co-lactide co-polymers, polyvinylprroylidone, starch, stearic acid, stearyl alcohol, partially hydrogenated cottonseed oil/soyabean oil (melting at 51-55°C), partially hydrogenated palm oil (melting at 58-63°C), partially hydrogenated cottonseed oil (melting at 61-65°C), partially hydrogenated soyabean oil (melting at 67-71°C), partially hydrogenated castor oil (melting at 85-88°C), polyethylene glycol 3350 (melting at 54-58°C).

Delayed release of the angiotensin II receptor antagonist may also be achieved by a fluid resistant barrier which combines one or more pH-dependant polymers optionally with one or more non-pH-dependant polymers.

Examples of delayed release dosage forms include enteric coated tablets or enteric coated multiparticulate formulations, in which drug-loaded multi-particulate spheres are coated with methacrylic acid-methyl methacrylate co-polymers such as Eudragit L100-55, Eudragit L30D-55, or Eudragit FS 30D or Eudragit S100/S12.5. Such formulations will not release the angiotensin II receptor antagonist in the acidic environment of the stomach but only on exposure to the higher pH typically found in the small and large intestine (pH range 5 to 8). An enteric coated tablet illustrating one aspect of this invention may be a single-layer tablet or a multi-layer tablet, such as a bi- or tri- layer tablet, wherein the active agent is present in one or more discrete layers within the compressed tablet form. The discrete tablet layers can be arranged to provide modified or non-modified release of active agent. General descriptions and methods for the preparation of suitable tablets may be found in Aqueous polymeric coatings for pharmaceutical dosage forms, J W McGinty (ed), Marcel Dekker, 1989, New York, and in in Microencapsulation and related drug processes, P Deasy, Marcel Dekker, 1984, New York, which publications are incorporated herein by reference.

Similarly, a capsule can be prepared in which the active dose is provided in the form of beads of the angiotensin II receptor antagonist and is divided into two or more parts, each part having a non- pH-dependant protective coat of different thickness, which takes a different time to erode. Suitable non-pH-dependent coating materials have already been described above. Further information can be found in J R Robinson & V H Lee (eds) in Controlled Drug Delivery, second edition, Marcel Dekker, New York, 1987 , V Ranade & M A Hollinger in Drug Delivery Systems, second edition, CRC Press, Boca Raton, 2004 and M J Rathbone, J Hadgraft & M S Roberts in Modified Release Drug Delivery Systems, Marcel Dekker, New York, 2003 which are incorporated herein by reference.

Any of the "further controlled release fraction embodiments" described above may be combined with any of the "first fraction embodiments" or "further first fraction embodiments" described above.

Preferably, the compositions of the invention are in unit dosage form. Unit dosage forms for oral administration may be in tablet or capsule form and may as necessary contain conventional excipients such as binding agents, fillers, lubricants, glidants, disintegrants, effervescent agents, and wetting agents. Examples of binding agents include but are not limited to: acacia, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinised starch, sodium alginate, sorbitol, starch, syrup, tragacanth.

Examples of fillers include but are not limited to: calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol. Examples of lubricants include but are not limited to: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate. Examples of glidants include but are not limited to: colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc. Examples of disintegrants include but are not limited to: alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, polacrilin potassium, pregelatinised starch, sodium alginate, sodium lauryl sulphate, sodium starch glycolate. Examples of effervescent agents are effervescent couples as described hereinbefore.

The solid oral compositions may be prepared by conventional methods of blending, filling or tableting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may be coated according to methods known in normal pharmaceutical practice. For example see Pharmaceutical dosage forms: tablets, Volume 1 second edition, H A Lieberman, L Lachman and J B Schwartz (eds) Marcel Dekkker, 1989, New York and G C Cole & J Hogan in Pharmaceutical coating technology, Taylor & Francis, London, 1995 which are herein included by reference.

The quantity of the angiotensin II receptor antagonist required in each component of each formulation can be determined by the skilled worker from the information provided in this invention. Firstly the target pharmacokinetic profile for the formulation is selected in line with the objects of the present invention. Then, from knowledge of the therapeutic window as defined herein, the mean rate of elimination of the angiotensin II receptor antagonist in the body, and the release profile of the angiotensin II receptor antagonist from each component, it is a matter of routine experimentation to establish the necessary quantity of angiotensin II receptor antagonist in each component in light of the information provided here. Information on particular preferred dosages overall and in the first and controlled-release fractions is nonetheless also provided herein.

Angiotensin II receptor antagonist

In the pharmaceutical composition of the invention, any angiotensin II receptor antagonist may in principle be employed. A wide range of angiotensin II receptor antagonist compounds are known to the skilled person, and the skilled person is also readily able to test candidate compounds for angiotensin II receptor antagonist activity.

Often, however, the angiotensin II receptor antagonist employed in the composition of the invention is valsartan, losartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan, azilsartan, fimasartan, saprisartan, tasosartan, elisartan, or a pharmaceutically acceptable salt thereof.

It should also be understood that "or a pharmaceutically acceptable salt thereof in this context includes amorphous forms and crystalline forms of the angiotensin II receptor antagonist including solvates, hydrates, co-crystals and polymorphs of the angiotensin II receptor antagonist.

Typically, the angiotensin II receptor antagonist is valsartan, losartan, candesartan, eprosartan, irbesartan, olmesartan, azilsartan, fimasartan, saprisartan, tasosartan, elisartan, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment of the pharmaceutical composition of the invention the angiotensin II receptor antagonist is valsartan, or a pharmaceutically acceptable salt thereof.

Usually, in this preferred embodiment, the angiotensin II receptor antagonist is valsartan in the free form. In other words, typically, the valsartan is unsalted.

As will be described in more detail below in relation to the various forms of valsartan that may be employed in the present invention, the valsartan may be present in the composition as an amorphous solid, a crystalline solid, or it may be adsorbed on a solid carrier or matrix. Indeed, novel amorphous and crystalline forms of unsalted valsartan and valsartan dispersed or adsorbed in a solid, liquid or polymeric carrier or matrix or exeipient are discussed hereinbelow, which may optionally be employed as the valsartan in the pharmaceutical composition of the invention. The valsartan which is employed in the composition may be in the form of an amorphous solid. Typically the amorphous valsartan is unsalted, i.e. in the free form.

Alternatively, the valsartan may be in crystalline form. Typically the crystalline valsartan is unsalted, i.e. in the free form.

As also described elsewhere herein, when valsartan is employed as the angiotensin II receptor antagonist in the pharmaceutical composition of the invention, the valsartan may be adsorbed on a solid carrier or matrix. The valsartan may for instance be adsorbed on any of the following solid carriers or matrices: Amberlite ® XAD-4; Amberlite ® XAD-7; Amberlite ® XAD-16;

AMBERSORB ® 348F; AMBERSORB ® 563; AMBERSORB ® 572; Activated carbon; Activated carbon Darco ®; Activated carbon Darco ® G-60; Activated carbon Darco ® KB; Activated carbon Darco ® KB-B; Activated carbon Norit ®; silica gel; silica gel with high pore volume (e.g. 0.75 cc/g and average pore diameter 60A); calcium hydrogen phosphate; maltose; lactose; cellulose; starch; talc and mixtures thereof. The valsartan may alternatively for instance be dissolved or dispersed in a liquid or polymeric carrier or matrix, as is described in more detail elsewhere herein. For instance, the valsartan may be dispersed in polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) or chocolate, for instance in PVP or PEG. Typically the valsartan adsorbed on the solid carrier or matrix is unsalted, e.g. in the free form.

In another embodiment of the pharmaceutical composition of the invention, the angiotensin II receptor antagonist is losartan or a pharmaceutically acceptable salt thereof. The losartan is typically in the form of a pharmaceutically acceptable salt of losartan. The pharmaceutically acceptable salt of losartan may be the approved salt, losartan potassium, or a salt of losartan with a mineral acid. The salt of losartan with a mineral acid may for instance be selected from losartan hydriodide, losartan sulfate, losartan nitrate, losartan phosphate, losartan phosphite, losartan sulphite, losartan sulfamate, losartan thiocyanate, losartan tetraborate and losartan tetrafluoroborate.

The losartan employed in the pharmaceutical composition of the invention is often in crystalline form. Typically the crystalline losartan is in the salt form. For instance losartan potassium or a salt of losartan with a mineral acid, as discussed above.

The losartan may be dispersed in a liquid or polymeric carrier or matrix, as is described in more detail elsewhere herein. For instance, the losartan, which may be in salt form as discussed above, may dispersed in PVP, PEG or chocolate, for instance in PVP or PEG.

In another embodiment of the pharmaceutical composition of the invention, the angiotensin II receptor antagonist is candesartan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of this embodiment of the invention may be as further defined anywhere herein for the pharmaceutical composition of the invention.

In another embodiment of the pharmaceutical composition of the invention, the angiotensin II receptor antagonist is eprosartan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of this embodiment of the invention may be as further defined anywhere herein for the pharmaceutical composition of the invention.

In another embodiment of the pharmaceutical composition of the invention, the angiotensin II receptor antagonist is irbesartan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of this embodiment of the invention may be as further defined anywhere herein for the pharmaceutical composition of the invention.

In another embodiment of the pharmaceutical composition of the invention, the angiotensin II receptor antagonist is olmesartan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of this embodiment of the invention may be as further defined anywhere herein for the pharmaceutical composition of the invention.

In another embodiment of the pharmaceutical composition of the invention, the angiotensin II receptor antagonist is azilsartan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of this embodiment of the invention may be as further defined anywhere herein for the pharmaceutical composition of the invention.

In another embodiment of the pharmaceutical composition of the invention, the angiotensin II receptor antagonist is telmisartan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of this embodiment of the invention may be as further defined anywhere herein for the pharmaceutical composition of the invention.

In another embodiment of the pharmaceutical composition of the invention, the angiotensin II receptor antagonist is fimasartan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of this embodiment of the invention may be as further defined anywhere herein for the pharmaceutical composition of the invention.

In another embodiment of the pharmaceutical composition of the invention, the angiotensin II receptor antagonist is saprisartan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of this embodiment of the invention may be as further defined anywhere herein for the pharmaceutical composition of the invention.

In another embodiment of the pharmaceutical composition of the invention, the angiotensin II receptor antagonist is tasosartan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of this embodiment of the invention may be as further defined anywhere herein for the pharmaceutical composition of the invention.

In another embodiment of the pharmaceutical composition of the invention, the angiotensin II receptor antagonist is elisartan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of this embodiment of the invention may be as further defined anywhere herein for the pharmaceutical composition of the invention.

The angiotensin II receptor antagonist employed in the compositions of the present invention is typically selected from valsartan and losartan. The valsartan or losartan may be in the free form, or in the form of a pharmaceutically acceptable salt of valsartan or losartan, or indeed in the form of a cocrystal of valsartan or losartan. Various particular forms of valsartan and losartan, and their preparation are described herein, any of which may be employed in the pharmaceutical composition of the invention.

The angiotensin II receptor antagonist employed in the compositions of the invention is usually valsartan. The valsartan may be in the free form, or in the form of a pharmaceutically acceptable salt of valsartan, or indeed in the form of a cocrystal of valsartan. Various particular forms of valsartan and their preparation are described herein, any of which may be employed in the pharmaceutical composition of the invention.

The angiotensin II receptor antagonist employed in the compositions and formulations of the invention may for instance be losartan. The losartan may be in the free form, or in the form of a pharmaceutically acceptable salt of losartan, or indeed in the form of a cocrystal of losartan. Various particular forms of losartan and their preparation are described herein, any of which may be employed in the pharmaceutical composition of the invention.

Valsartan and losartan are medically powerful drugs with major benefits over other drugs, but they each suffer from a short half-life which manifests itself as causing the body to become devoid of drug in the pk plasma during the early hours after the drug has metabolized below the minimum inhibitory concentration, causing a marked increase in early morning stroke, heart attack and associated death. This phenomenon is known as the early morning deficit or nocturnal deficit problem and is associated with a marked increase in morbidity. The present inventors have surprisingly found a way to give rapidity, longevity and dose to dose action within the therapeutic window from dose to dose, which also leads to a marked reduction in side effect profile. It has been found that a multicomponent tablet gives the benefit of one or more of the technical effects selected from, rapidity, longevity and dose to dose maintenance within the therapeutic window.

The following formulation information is included to show how such a formulation can be made and used. The sections on rapidity, dose to dose maintenance within the therapeutic window and dose to dose longevity are incorporated by reference and form the basis where one or more of the end points are addressed and dealt with. Longevity is the key issue and the present application provides clear direction on how this can be achieved and how such formulations can be made.

Valsartan is the active ingredient in Diovan®, which is approved for use in the treatment of hypertension, either alone or in combination with other antihypertensive agents, and for heart failure in patients who are intolerant of angiotensin converting enzyme inhibitors. The choice of a form of a pharmaceutical agent having acidic functional groups is not a matter of routine. The fact that Novartis (the originator company) markets one specific crystalline form of the unsalted compound could lead one skilled in the art to believe that other forms were less preferred since this form of the unsalted compound has a low aqueous solubility and is therefore restricted in its utility for general therapeutic formulations. The choice of forms of valsartan other than the prior art forms is not therefore prima facie obvious in view of this technical prejudice and other concerns about the formation and properties of such forms. There are problems and technical hurdles to be overcome when selecting a form other than the prior art compounds such as whether a different form can exist at all, whether the properties of such a form would be satisfactory, comparable or better than the prior art forms.

Whether a suitable method exists for the preparation of a form other than the prior art forms is not a matter of routine experimentation.

There is a need to find alternative forms of valsartan other than the prior art forms which are pharmaceutically acceptable, and which have improved stability, solubility, purity and ease of use compared to the prior art forms. Such forms apart from finding use in medical therapy are also useful in providing new active ingredients containing the active moiety valsartan which could form the basis for providing new value-added line extenders in the form of advantageous formulations or new uses.

The inventors have surprisingly found that various novel amorphous, crystalline, and liquid forms of unsalted valsartan and valsartan dispersed or adsorbed in a solid, liquid or polymeric carrier or matrix or excipient, can be prepared and have properties which permit these forms to be used in pharmaceutical preparations and in the preparation of novel and improved pharmaceutical products.

Losartan potassium is the active ingredient in Cozaar® and one of the active ingredients of Hyzaar® which have been approved for use in the treatment of hypertension, chronic renal failure and diabetic neuropathy. The choice of a form of a pharmaceutical agent having a basic functional group is not a matter of routine. The fact that Merck (the originator company) only markets the potassium salt could lead one skilled in the art to believe that other forms were less preferred since the potassium salt is an unusual choice of salt to market. The choice of salts and forms of losartan other than those described in the prior art is not therefore prima facie obvious in view of this technical prejudice and other concerns about the formation and properties of such salts and forms. There are problems and technical hurdles to be overcome when selecting a salt or form other than those described in the prior art such as whether a different salt or form can exist at all, whether the properties of such a salt or form would be satisfactory, comparable or better than those described in the prior art. Whether a suitable method exists for the preparation of a salt or form other than those described in the prior art is not a matter of routine experimentation.

There is a need to find alternative forms of losartan other than those described in the prior art which are pharmaceutically acceptable. Such forms apart from finding use in medical therapy and as useful intermediates are also useful in providing new active ingredients containing the active moiety of losartan which could form the basis for providing new value-added line extenders in the form of advantageous formulations or new uses.

The inventors have surprisingly found that novel salts and forms of losartan combined with certain mineral acids can be prepared and have properties which permit the salts and forms to be used in pharmaceutical preparations and as intermediates for purification and in the preparation of other pharmaceutical products. Whilst the compounds of the present invention - in particular the novel forms and formulations of the sartans, particularly of valsartan or losartan - are prima facie inventive, they also show unexpected advantages and /or overcome technical prejudice. When hereinafter mentioned, the issue of whether a particular novel form would have advantageous properties in this area over prior art forms would not be predictable. Therefore an advantage of the present novel forms over the prior art forms would be an unexpected advantage. Examples of unexpected advantages are selected from one or more of the following:

Advantages during manufacture in terms of the timing and cost of production, availability of starting materials, reproducibility, and safety.

Advantages during manufacture in terms of improved yield and purity. The yield is established by comparison of the weights of cost-critical starting material and product making allowance for molecular weights and purities. Purities are established by hplc, gc or other conventional analytical method by means of a validated procedure and comparison with a reference standard. See for example Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA, ISBN 0-683-306472, page 597.

Advantages during manufacture in terms of improved filterability, for example the avoidance of clogging or blinding of filter cloths, and the need for large or expensive or sophisticated filtration apparatus. Filterability testing procedures are based on the concept of Vma_X. Vma_X modelling is based on the theory that there is some maximum volume of a fluid which will pass a filter at a given pressure. At that point, the flow across the filter will be zero and therefore the resistance of the pad to flow infinite. On the basis of this model the rate of flow of filtrate is proportional to the driving force and the cross-sectional area of the filter bed. Measurements of flow rates and timing of standardised operations may be used to demonstrate advantage.

Advantages during manufacture in terms of improved wash ability result from the physical properties of the material and the size, shape and surface properties of any particles may be present, which are not per se predictable. Quantification is possible by measurement of, for example, the volume and cost of solvent, duration of agitation, and number of washes required to achieve a standardised reduction in adherent impurity levels. Another relevant factor which would constitute an advantage is a reduction in the loss of product resulting from washing procedures.

Advantages during manufacture in terms of improved ease of drying also result from the physical properties of the material and the size, shape and surface properties of the material, which are not per se predictable. Quantification is achievable by measurement of the length of time and temperature in a specific drying apparatus to achieve a standardised reduction in the solvent level in a standardised quantity of product. Other relevant factors which may give rise to an advantage include the need for agitation, and the need for or suitability for use in efficient apparatus such as filter driers. Improvements in the colour of a product are linked in perception and often in reality with purity and quality, so may constitute a valuable advantage. Standard colour tests are described in the major pharmacopoeias, for example the European Pharmacopoeia 4^th edition 2001, and United States Pharmacopeia 24^rd edition 1999-2003 and for example USP 2000 page 1926. Colour may be defined as the perception or subjective response of an observer to the objective stimulus of radiant energy in the visible spectrum extending over a range 400nm to 700nm in wavelength. Three attributes are commonly used to identify a colour: 1) hue, or the quality by which one colour family is distinguished from another, such as red, yellow, blue, green and intermediate terms; 2) value, or the quality that distinguishes a light colour from a dark one; and 3) Chroma, or the quality that distinguishes a strong colour from a weak one, or the extent to which a colour differs from a grey of the same value. The perception of colour and colour matches is dependent on conditions of viewing and illumination. Determinations should be made using diffuse, uniform illumination under conditions that reduce shadows and non-spectral reflectance to a minimum. The surfaces of powders should be smoothed under gentle pressure so that a planar surface free from irregularities is presented. Liquids should be compared in matched colour-comparison tubes, against a white background. If results are found to vary with illumination, those obtained in natural or artificial daylight are to be considered correct. Colours of standards should be as close as possible to those of the test specimens for quantifying colour differences. Instrumental methods for measurement of colour provide more objective data than the subjective viewing of colours by a small number of individuals.

The extent to which a product is associated with chemical impurities arising from earlier stages of synthesis is essentially unpredictable and depends both on the synthetic process, the nature of reagents used in the process, and on the physical, chemical, and surface properties of the product. For example a novel polymorph or pseudo polymorph will have a different and unpredictable profile of trace impurities than a comparator product. Quantification may be achieved by measurement and characterisation of impurity profiles, for example by GC-MS or LC-MS analysis and comparison with a reference material. Identification of all impurities is not essential providing sufficient

characterisation is obtained from the analytical methodology, though it is of course desirable.

From the point of view of manufacturing and formulation efficiency high bulk density in a product is generally regarded as an advantage, since it allows for smaller apparatus and more acceptable unit doses. Furthermore, the need for costly grinding and compaction procedures can be avoided or at least reduced. The European Pharmacopoeia describes definitions and methods by which bulk density of a powder may be measured. Apart from the inherent density of a material which depends on factors such as crystal structure which is unpredictable, there is also the contribution of inter particulate void volume which is equally unpredictable. The bulk density is determined by measuring the volume of a known mass of powder, which has been passed through a screen, into a graduated cylinder. The tapped density is achieved by mechanically tapping a measuring cylinder containing a powder sample. After observing the initial volume, the cylinder is mechanically tapped, and volume readings are taken until little further volume change is observed.

The ability of a powder to flow efficiently through manufacturing apparatus is a significant factor affecting the economics of manufacture and will vary according to the form of material. For example different polymorphs and pseudo polymorphs will have different inherent flow properties, though isolation procedures will also have an effect. Suitable definitions and methods of

measurement are described in standard reference texts, for example European Pharmacopoeia 4^th edition 2001, and United States Pharmacopeia 24^rd edition 1999-2003 and Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA. Measurement may be for example in terms of the angle of repose, which may be determined experimentally by a number of methods with slightly differing results. A typical method is to pour the powder in a conical heap on a level, flat surface and measure the included angle with the horizontal.

One of the factors affecting the safety of a manufacturing process and hence the cost of the manufacturing facility is the flammability of a material. Typical measurement procedure include the "Burning Rate Test" or "Fire Train Test" as defined in United States Department of Transportation and United Nations regulations (49 CFR 173 Appendix E and UN Recommendations on the

Transport of Dangerous Goods, also EEC Directive 79/831 Annex Part A: Methods for the

Determination of Physio-Chemical Properties 3.10 Flammability of Solids. A typical test involves applying a source of ignition to a powder "train" measuring 250 mm x 20 mm x 10 mm and measuring the rate at which the powder burns.

Another unpredictable property of particulate pharmaceutical products which affects safety and hence cost of manufacture is the tendency to produce dusts or fines during processing, which dusts or fines vary in their hazardous nature. This property is associated with the static electrical properties of the material. Standard test methods and protocols exist to quantify these problems. For example BS 5958 part 1 - Code of practice for control of undesirable static electricity, British Standards Institute, 1991; VDI Fortschritt-Berichte 2263; ISO 6184/1; IEC 1241-2-1, Electrical apparatus for use in the presence of combustible dust Part 2: Test methods, Section 1 : Methods for determining the minimum ignition temperatures of dust. International Electrotechnical Commission, first edition, 1994-12

Other advantages which differentiate unpredictably between alternative forms of a drug substance may be quantified in terms of improved chemical stability. Standard test methods are described in the major pharmacopoeias and are also referenced on the US Food and Drug

Administration Web site. Typically accelerated storage tests are performed by storage for a period of 1 year or more at elevated temperature (e.g.40°C) and at standard humidity conditions (e.g. 75% RH), with samples being taken at regular intervals of approximately 1 month and assayed for overall purity, specific impurities, and a general impurity screen. In addition, chemical interactions between drug substance and typical excipients used for formulation will differ for different forms of a drug substance, making one form advantageous in one formulation, though not necessarily advantageous in a different formulation. Examples include the interaction between amine drugs and lactose.

Stability to irradiation, especially visible and ultra-violet light is of increasing importance in pharmaceutical science and represents another area in which alternative forms of a drug substance may have significantly and unpredictably different properties. Testing details, such as light source, flux density, and duration are described in Federal Register Notices Volume 62, Number 95, pages 27115-27122, together with recommendations for analytical methodology and assessment of results.

Pharmaceutical materials with relatively high melting points are generally easier to formulate and are subject to less attrition and clumping during processing. Melting points and glass transition temperatures will differ greatly for different polymorphs, pseudo polymorphs, or other forms of a drug and are in essence unpredictable. Methods for measuring melting points are well-described in the European Pharmacopoeia 4^th edition 2001, and United States Pharmacopeia 24^rd edition 1999- 2003. Various methods are acceptable but differ in detail, for example the melting point determined by the capillary method is the temperature at which the last solid particle of a compact column of a substance in a tube passes into the liquid phase. Suitable apparatus is described in the above mentioned publications and may be calibrated using melting point reference substances such as those of the World Health Organisation or other appropriate substances.

Some materials have a tendency to change their physical form during storage, which can be a disadvantage in pharmaceutical manufacture. For example materials can settle and compact and lose their ability to low freely. One polymorphic form may wholly or partially convert to another over an uncertain time-frame, or solvates and hydrates may lose their solvent or water, and the resultant change in the physical properties of the drug substance can lead to a formulation with uncertain, unreliable, and unpredictable characteristics. Clearly a polymorphic conversion can only occur from a less stable to a more stable form, so there are advantages associated with thermodynamic stability, and the relative stability of a novel form is a priori unpredictable.

All substances absorb moisture when exposed to different relative humidity environments, but the extent and humidity response and temperature response varies very considerably. The term hygroscopicity describes both the rate and the extent of water uptake. It is well established that hygroscopic products are difficult to handle and hence more expensive to formulate. Hygroscopicity is not a priori predictable, and an alternative form may well be advantageous in this respect.

Apparatus for measurement of moisture contents of samples under controlled humidity conditions is available commercially, e.g from I Holland Ltd., Nottingham, U.K. Simple measurements may be made by monitoring the appearance and weight of samples exposed to atmospheres of known constant humidity and temperature, as described in, for example, The Merck Index 12^th edition, Merck and Co Inc. An important property of a drug substance is its solubility in water and other solvents. There is a link between solubility and bioavailability in as much as very water-insoluble drugs can only be made bioavailable by very careful formulation. The need for high solubility in water or other parenteral media is self-evident, and in general both high, moderate, or low solubility's can be important for different formulations. Formulations designed for sustained release may benefit from very low aqueous solubility. Apparatus and procedures for the measurement of solubility are described in detail in both the European Pharmacopoeia 4^th edition 2001, and United States

Pharmacopeia 24^rd edition 1999-2003.

Another property that influences the ability of a drug substance to go into solution and which varies among different solid forms of a drug substance is the degree of wetting, which affects the rate of dissolution. Wetting is the ability of liquids to form boundary surfaces with solid materials, and is determined by measuring the contact angle which a liquid forms in contact with a solid. The smaller the contact angle the larger the wetting tendency. Wetting phenomena are described in Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA on pages 278-9. In order for immersion of a solid to occur, the liquid must displace air and spread over the surface of the solid. When liquids cannot spread over a solid surface spontaneously, and therefore the spreading coefficient S is negative, it is said that the solid is not wetted. An important parameter reflecting the degree of wetting is the angle made by the liquid with the solid surface at the point of contact. By convention, when wetting is complete, the contact angle is 0°. In non-wetting situations it theoretically can increase to a value of 180°, where a spherical droplet makes contact with solid at only one point.

The ability of different forms of a drug to admix with specific common excipients across the formulation / delivery range of technologies is very important and will differ in a non-predictable manner depending on the specific properties of the drug form. Pharmaceutical excipients are substances, other than the active pharmaceutical ingredient, that are used in the finished dosage form. There are very many widely differing excipients each with particular characteristics which form the basis of many widely differing formulations. Excipients and their properties are described in detail in the pharmaceutical literature, for example in Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA. They serve many functions, for example they stabilise the drug substance by providing antioxidant, heavy -metal chelating, or light-protection properties. They also may be used to enhance bioavailability and to control the release from dosage forms. For solid dosage forms, they provide suitable properties for dispensing the drug substance in accurate dosage units that have reproducible release properties. Diluents provide a flow able bulk, binders hold powders together after wet granulation, lubricants provide punch-releasing properties, and disintegrates help to disperse dosage forms in the GI tract. There is a risk, which may be avoided by careful selection of the form of the drug, of incompatibilities between drug substance and excipients. Screens to detect drug-excipient incompatibilities have been developed using elevated temperature and added water to accelerate potential interactions in ternary and more complex powder blends (Serajuddin ATM et al Pharm Res 1991 8(suppl): S103) and such methods have been shown to be capable of rapidly detecting chemical incompatibilities and giving good correlations with results using powder blends of drug and excipients at elevated temperatures and humidity.

The invention provides novel forms of amorphous, crystalline and liquid valsartan. Such novel forms of valsartan may be employed as the angiotensin II receptor antagonist in any of the formulations of the present invention.

In one aspect of this invention, the novel form of valsartan may be a form of amorphous solid. Such amorphous valsartan may be used as an ingredient for inclusion in a range of formulations such as conventional tablets and capsules, in particular, a chewable tablet, or formulated into a chewing gum or suspension or liquid for oral administration, or may be prepared in a form in which valsartan is absorbed in a carrier, for example an excipient or a mixture of excipients for tabletting or other formulation, or as a solution in a wax or similar pharmaceutically acceptable polymer, such as PEG or PVA. In one preferred aspect of the invention, the amorphous form of valsartan is formulated as a component of a sweet or chocolate based confection. The novel amorphous forms of valsartan are understood to exclude the amorphous forms of valsartan described in the prior art.

Alternatively, the novel form of valsartan may be in crystalline form. More than one novel crystalline form may be possible and polymorphs and pseudo polymorphs including hydrates and solvates also form an aspect of this invention. The novel valsartan is understood to exclude the crystalline valsartan's described in the prior art.

In a third aspect of this invention, liquids containing valsartan may be formed for oral or parenteral administration to a patient in need thereof. Such liquids may be prepared by conventional methods such as dissolving or suspending a crystalline or amorphous material in a suitable solvent.

The present invention specifically covers:

Novel amorphous forms of unsalted valsartan.

Novel crystalline forms of unsalted valsartan.

Liquid solutions and suspensions containing unsalted valsartan.

Unsalted valsartan adsorbed on the following solid carriers or matrices: Amberlite ® XAD-4;

Amberlite ® XAD-7; Amberlite ® XAD-16; AMBERSORB ® 348F; AMBERSORB ® 563; AMBERSORB ® 572; Activated carbon; Activated carbon Darco ®;

Activated carbon Darco ® G-60; Activated carbon Darco ® KB; Activated carbon Darco ® KB-B; Activated carbon Norit ®; silica gel; silica gel with high pore volume (e.g. 0.75 cc/g and average pore diameter 60A); and materials from other

manufacturers having similar properties. Unsalted valsartan adsorbed on the following solid carriers or matrices: common excipients including but not limited to calcium hydrogen phosphate, maltose, lactose, cellulose, starch, talc and mixtures thereof.

The preparation of un-salted valsartan is described in US patent 5,399,578, WO 2004 87681, WO 2004 83192, and WO 2003 89417. All these patent specifications are incorporated herein by reference. Solutions of valsartan may be prepared in a variety solvent, inter alia those quoted in the preceding references. For example unsalted valsartan may be dissolved in methanol at a

concentration of 1 gram in 5 ml, in ethanol at a concentration of 1 gram in 6 ml, in propan-2-ol at a concentration of 1 gram in 7 ml, in acetone at a concentration of 1 gram in 14 ml,or in a mixture of water and ethanol ( 1 : 1 by volume) at a concentration of 1 gram in 30 ml, with ultra sonication and warming. Alternatively valsartan may be dissolved in ethyl acetate or diethyl ether.

Amorphous valsartan may be prepared by rapid vacuum evaporation of a solution or by spray drying a solution. The product may be dried under high vacuum and elevated temperature until the solvents are reduced to an acceptable level (below 0.2%). Alternatively purification can be taken further by the use of short path distillation at ultra high vacuum or molecular distillation, for example at pressures at or below 10-5 mm Hg. The technology and apparatus and also suitable procedures for molecular distillation are described in the following publications which are incorporated herein by reference: Vogel's Textbook of Practical Organic Chemistry 5th edition, published by Longman Scientific & Technical; The Applications of Molecular Distillation by Janos Hollo, Academiai Kiado, Budapest, 1971. Suitable apparatus includes, but is not limited to the following commercial instruments: Leybold Hochvakuum Anlagen commercial still models MO 3, 5, M13, M14,and M15, Falling film/wiped film stills e.g Speedivac TM™ Edwards High Vacuum Ltd; Asco 50 Rota-film Still from Arthur Smith Co.; Centrifugal stills models CMS-36 and CMS-60 from Consolidated Vacuum Corporation.

Alternatively, a solution of pharmaceutically pure unsalted valsartan may be prepared by chromatographic techniques, such as by means of a continuous counter-current adsorption process, for example simulated moving bed chromatography (US Patent No. 2,985,589). A typical industrial implementation of this technology utilises a four zone cascade apparatus, and suitable conditions may be determined by the procedures discussed in Journal of Chromatography A, vol. 702, pages 97-112 (1995). Other methods of purification include recrystallization, for example from di-isopropyl ether or a mixture of ethyl acetate and n-hexane (1 : 1).

If a vacuum evaporation technique is used to isolate amorphous valsartan, it should be carried out as rapidly as possible and under conditions which avoid the presence of seeds of any crystalline form, to avoid crystallisation of the prior art or other crystalline unsalted valsartan form. Solid or liquid excipients, matrices, carriers, or other formulation components may be added to the valsartan solution prior to evaporation to prepare novel forms of valsartan suitable for further formulation. If a spray drying technique is used, a concentration of between 2% and 40% weight/volume valsartan in solution, optionally at elevated temperature, may be used though a concentration of between 10 and 25% is preferred. Aqueous mixtures containing organic solvents may be spray dried in a closed loop spray dryer. If a closed loop spray drier is used the organic solvent content may be raised further up to 100%. The apparatus parameters are adjusted to give an acceptable product by routine means, but control of outlet gas temperature and solvent content of the outlet gas is particularly important. Hence it is preferred that the outlet temperature is kept above 40°C but below 70°C, more preferably below 50°C, and the solvent content of the outlet gases is kept below 2 grammes per 100 grammes, more preferably below 1.2 grammes per 100 grammes. The technology of spray drying is described in the following publications which are incorporated herein by reference: Spray-drying handbook 5th edition by K Masters, Longman Scientific & Technical, 1991 ISBN 0582062667; Spray-drying of pharmaceuticals for controlled release pulmonary drug delivery by Noha Patel, University of Bath, 2000; Spray-drying of particles intended for inhalation by Kristina Mos'em, Department of Pharmaceutics, Copenhagen, Danish University of Pharmaceutical Sciences 2003, ISBN 8778345243.

In a preferred embodiment of the spray drying procedure, the solution of valsartan may be mixed with a suspension of one or more finely powdered carriers, matrix materials, excipients or excipients in solution before spray drying, thus preparing in one step a platform formulation for tabletting or other preparation of a drug product. Known techniques may be employed to coat the particles with enteric or other known coatings for control of drug release after administration.

Drying to the full extent that is desirable for a stable pharmaceutical product is not always practicable during efficient use of the isolation apparatus, particularly in the case of spray drying, so in all the above procedures, a final air or vacuum drying step may be necessary to reduce residual water and solvent to an acceptable level.

One advantage of the amorphous valsartan of this invention is the suitability of this material for the formation of novel polymorphs and solvates of crystalline valsartan. Novel forms of crystalline valsartan are prepared by trituration of amorphous valsartan with one of the solvents (or a mixture of solvents) preferably from the following list of preferred solvents, i.e., diethyl ether, di- isopropyl ether, tert-butylmethylether, di-n-butyl ether, butylvinylether, tert-butylvinylether, tetrahydrofuran, 1,4-dioxane, n-heptane, n-hexane, cyclohexane, cyclopentane, toluene, o-xylene, m- xylene, p-xylene, dichloromethane, chloroform, carbon tetrachloride, chlorodibromofluoromethane.

Alternatively, a solvent (or a mixture of solvents) from the following list may be used to triturate and crystallise novel forms of valsartan: methyl acetate, ethyl acetate, propyl acetate, ethyl formate, isobutyl acetate, isobutyl formate, acetonitrile, isobutyronitrile, acetone, butanone, isopropylmethylketone, isobutylmethylketone, tert-butylmethylketone, sec-butylmethylketone, n- butylmethylketone, cyclopentanone, cyclohexanone. Other more polar solvents which also have utility for trituration are the following: water, methanol, ethanol, n-propanol, propan-2-ol, 1-butanol, isobutyl alcohol, cyclopentanol, 2- ethoxyethanol, 2-methyl-2-butanol, ethyleneglycol, tert-butanol, acetic acid, propionic acid.

And, though less preferred, the solvents below may also be used for trituration: N,N- dimethylformamide, Ν,Ν'-dimethylacetamide, N-methylpyrrolidone, formamide, anisole, sulfolane, nitromethane, Ν,Ν'-dimethylpropyleneurea, dimethylsulfoxide, benzene , chlorobenzene, 1,2- dichlorobenzene, 4-methylmoφholine, Ν,Ν,Ν',Ν'-tetramethylethylenediamine, pyridine , diisopropylamine, triethylamine, aqueous ammonia.

Suitable trituration techniques include addition of a small amount of solvent to the amorphous material, insufficient to cause complete solution, and scratching with a glass rod and/or

ultrasonication. Scratching is carried out in a glass tube for periods of approximately 5-10 minutes at a time, then leaving the tube to stand for 1 to 2 hours. Preferably the suspension/paste is brought onto the sides of the vessel during scratching to allow partial evaporation of the solvent. The procedure is then repeated several times. Alternatively the process may be automated by agitating the

suspension/paste very vigorously with a small magnetic stirrer in the presence of some quartz anti- bumping granules or other abrasive material such as carborundum. Alternatively the mixture may be subjected to thermal shock by repeated cyclic ultra-freezing with liquid nitrogen followed by heating. Combinations of these techniques may be used.

Another technique which may be employed is to raise the temperature of the amorphous material above the glass point and to raise and lower the temperature in a cyclic manner. This technique may be used in combination with thermal shock treatment and scratching.

After trituration, the crystalline product is dried under moderate vacuum to remove excess solvent but not such vigorous conditions as to desolate any solvate that may have been formed.

The existence of a novel crystalline product may be demonstrated by a combination of techniques. Solution NMR and or elemental analysis may be used to demonstrate that valsartan is present and any solvate or hydrate. The product is characterised by one or more of the following techniques: infra-red spectroscopy, Raman spectroscopy, X-ray powder or single crystal diffraction, solid-state NMR, melting point, DSC, DTA, optical and electron microscopy. The product may be present as a hydrate or a solvate.

Once a novel crystalline unsalted form of valsartan has been prepared on the small scale by one of the techniques described above so that seeds are available and a suitable solvent has been identified, other methods may be employed which are more suitable for large scale synthesis. For example, direct crystallisation from a solvent or solvent mixture. The solution is made supersaturated by cooling, partial evaporation, or addition of an anti-solvent. Alternatively, crystallisation from a supercritical fluid may be employed.

Repeated application of the above techniques for inducing crystallisation of amorphous valsartan may give rise to more than one novel crystal form, including polymorphs and pseudo polymorphs such as hydrates and solvates. Even when products are the same crystal form as determined by spectroscopic methods, it is often the case that the product that crystallises from one set of solvent conditions will have superior properties from a product obtained from another set of conditions. This may be the result of an improved crystal shape (habit) or density. Additional ways of preparing polymorphs and pseudo polymorphs include repeated small-scale precipitation from a range of solvents (for example the lists of solvents recommended for trituration procedures above) by heating to dissolution, then cooling or partly evaporating. In addition an anti -solvent may be added (selected from those solvents which experimentally are found not to dissolve valsartan, even with heating). Preferably non-crystalline valsartan is used for these preparations since this minimises the presence of pre-existing crystal forms which may inhibit the production of alternative crystalline products. Alternatively, hydrates and solvates may be treated with solvents or subjected to a range of different humidity's to give other solvates or hydrates. Alternatively, the solvates or hydrates may be subjected to vacuum or oven drying/desolations, or plunged into a non-dissolving hot solvent (for example xylene).

Alternatively existing crystalline or non-crystalline forms of valsartan may be subjected to a combination of very high pressure and optionally high temperature, for example melts, or amorphous material maintained above the glass temperature can be induced to crystallise to give a new product.

More stable polymorphs may be generated by means of a "polymorph amplifier" . This procedure comprises the preparation of a stirred suspension of a crystalline valsartan in a selected solvent (approximately 5-10% in solution at the lower temperature) and raising the temperature until approximately 90-95% of the solid is dissolved, then allowing the suspension to cool slowly, with stirring, until most of the valsartan has crystallised. This procedure is repeated cyclically many times, and the product at each stage tested for any change in form.

Crystallisation of novel crystal forms of valsartan may be brought about by crystallising (for example by evaporation) on quartz or other active surfaces.

Once a novel crystalline form has been produced by application of the above described techniques, improved direct crystallisation techniques can be determined by routine experimentation, since seeds of the new form will now be available.

As will be discussed further below, the valsartan products of this invention may also be prepared as solid or liquid solutions or dispersions in a liquid or polymeric carrier or matrix. Such valsartan products may be employed in any of the formulations of the present invention. Suitable ratios of valsartan to liquid or polymeric carrier or matrix material may vary from 1 : 100 to 10: 1, preferably from 1 :20 to 3: 1. As will be appreciated by he skilled person, the term "ratios" in this context refers to weight ratios.

The invention also provides amorphous, crystalline or liquid losartan salts with certain mineral acids other than hydrochloric and hydrobromic acid. Such losartan salts may be employed as the angiotensin II receptor antagonist in any of the formulations of the present invention. In one aspect of this, the novel salts of losartan with mineral acids may be in the form of amorphous solids. Such amorphous losartan salts with mineral acids may be used as an ingredient for inclusion in a range of formulations such as conventional tablets and capsules, in particular, a chewable tablet or formulated into a chewing gum or suspension or liquid for oral administration, or may be prepared in a form in which the salt is absorbed in a carrier, for example an excipient or a mixture of excipients for tabletting or other formulation, or as a solution in a wax or similar pharmaceutically acceptable polymer, such as PEG or PVA. In one preferred aspect of the invention, the salt is formulated as a component of a sweet or chocolate based confection.

Alternatively, losartan salts with mineral acids may be in crystalline form. More than one crystalline form or stoichiometry may be possible and such stoichiometries, polymorphs and pseudo polymorphs including hydrates and solvates also form an aspect of this invention.

Alternatively, losartan salts with mineral acids may be in liquid form. Such liquids may be prepared by conventional methods such as dissolving a crystalline or amorphous material in a suitable solvent.

Losartan is the active moiety in losartan potassium which is the active ingredient in Cozaar® and Hyzaar®.

The term mineral acid is understood by one skilled in the art. It should be appreciated that mineral acids are inorganic molecules and do not incorporate carboxylic acid functional groups in their chemical structure.

Examples of salted versions of losartan with mineral acids include: Losartan hydriodide, Losartan sulfate, Losartan nitrate, Losartan phosphate, Losartan phosphite, Losartan sulphite, Losartan sulfamate, Losartan thiocyanate, Losartan tetraborate and Losartan tetrafluoroborate.

The preparation of un-salted losartan is described in U.S. patent 5, 138,069, WO 93/10106, U.S. patent 5, 130,439, U.S. patent 5,206,374, U.S. Ser. No. 07/911,813, and US patent 5,153, 197, all of which patent specifications are incorporated herein by reference.

Alternatively, a solution of losartan potassium may be prepared from the commercially available salt by dissolving it in ethanol, water, or other suitable solvent, with optional heating. Un- salted losartan may be obtained by acidifying an aqueous solution of losartan potassium to pH 3-3.5, for example 10 g losartan potassium in 40 ml water with optional warming, in the presence of tetrahydrofuran (40 ml) and chlorobenzene (40 ml). The organic phase may then be separated and dried, and the un-salted losartan obtained by evaporation of the resulting organic phase.

The mineral acids of this invention are available commercially from chemical suppliers such as Aldrich Chemical Company in the UK. In the case of losartan tetra borate, a suitable acid reagent is boric acid which is available commercially.

A solution of a salt of losartan with a mineral acid may be prepared by contacting losartan, optionally in solution, for example 1 g losartan dissolved in 5 ml tetrahydrofuran and 10 g chlorobenzene, with an aqueous solution of the mineral acid with optional heating at a concentration of 1% to 20% by weight. At least a stoichiometric quantity of the acid is advantageously used, but an excess, for example between 1.1 and 1.5 equivalents, is preferred and may be used to neutralise lower molecular weight impurities and ensure complete dissolution. Alternatively a water-miscible co- solvent may be used at a proportion of between 1 : 10 and 10: 1. Suitable acids include hydriodic acid, phosphoric acid (including partially neutralised phosphoric acid), sulfuric acid, nitric acid, phosphorous acid, sulfurous acid, sulfamic acid, thiocyanic acid, boric acid, and tetrafluoroboric acid. Suitable co-solvents include methanol, ethanol, n-propanol, propan-2-ol, acetone, 2-butanone, and acetonitrile or a mixture thereof. An amorphous losartan acid salt is then isolated by either rapid vacuum evaporation or spray drying, or freeze drying.

If a vacuum evaporation technique is used, it should be carried out as rapidly as possible and under conditions which avoid the presence of seeds of the crystalline salt, to avoid crystallisation of the salt.

If a spray drying technique is used, a concentration of between 2% and 40% weight/volume salt in solution, optionally at elevated temperature, may be used, though a concentration of between 10 and 25% is preferred. Aqueous mixtures containing organic solvents may be spray dried in a closed loop spray dryer. If a closed loop spray drier is used the organic solvent content may be raised further up to 100%. The apparatus parameters are adjusted to give an acceptable product by routine means, but control of outlet gas temperature and solvent content of the outlet gas is particularly important. Hence it is preferred that the outlet temperature is kept above 40°C but below 70°C, more preferably below 50°C, and the solvent content of the outlet gases is kept below 2 grams per 100 grams, more preferably below 1.2 grams per 100 grams. The technology of spray drying is described in the following publications which are incorporated herein by reference: Spray -drying handbook 5th edition by K Masters, Longman Scientific & Technical, 1991 ISBN 0582062667; Spray-drying of pharmaceuticals for controlled release pulmonary drug delivery by Noha Patel, University of Bath, 2000; Spray-drying of particles intended for inhalation by Kristina Mos'em, Department of

Pharmaceutics, Copenhagen, Danish University of Pharmaceutical Sciences 2003, ISBN

8778345243.

If a freeze-drying technique is used, the non-aqueous solvent content should be minimised to allow for a solid ice matrix for freeze-drying. Suitably the solution of the salt is frozen very rapidly from a temperature at which the solution is stable toward crystallisation, which may be an elevated temperature. Sufficiently rapid cooling avoids the formation of salt crystals during the freezing procedure. Freeze drying is accomplished by applying a high vacuum to the frozen salt/ice matrix so that water or water/solvent is removed by sublimation and the latent heat of evaporation keeps the matrix solid. On a small scale a simple glass flask may be used, alternatively a commercial freeze- drying apparatus may be used.

The technology of freeze-drying is described in the following publications which are incorporated herein by reference: Freeze-drying by Georg-Wilhelm Oetjen, Wiley-VCH, 2004, ISBN 352730620X; Freeze-drying/lyophilisation of pharmaceutical and biological products by Louis Rey & Joan C. May, Marcel Dekker, New York 1999, ISBN 0824719832. Additionally, freeze drying procedures and apparatus therefor are also provided to the skilled artisan by commercial manufacture of equipment such as APV Anhydrous (see brochures therefrom). Also see web site thereto which are incorporated herein by reference.

In a variation on freeze-drying, the solution may be added dropwise to a cold water-miscible solvent (-78°C, acetone/solid carbon dioxide bath) in which the product amorphous salt is insoluble. The salt droplets freeze on contact and the water is leached out of the ice droplets by the cold solvent.

In a variation of the spray drying procedure, the solution of losartan mineral acid salt may be mixed with a suspension of one or more finely powdered excipients or excipients in solution before spray drying, thus preparing in one step a platform formulation for tabletting or other preparation of a drug product. Known techniques may be employed to coat the particles with enteric or other known coatings for control of drug release after administration.

Since some of the mineral acids are polybasic, such as sulfuric and phosphoric acids, it is possible to prepare salts with more than one molecular equivalent of losartan with respect to the mineral acid. Such salts need not necessarily be stoichiometric.

A solution of a salt of losartan may also be prepared by adding an acid of this invention to a solution of another acid salt of losartan. This procedure is particularly preferred if the original salt is with a weak acid and a strong acid is added. The original acid component may be removed by evaporation if it is volatile (e.g. acetic acid) or by filtration if the product can be induced to precipitate from solution, for example as a crystalline salt.

Crystalline salts of losartan with mineral acids may be prepared during attempted preparation of the amorphous salts if, for example, the rate of evaporation is too slow, alternatively crystalline salts of losartan with mineral acids may be prepared by trituration of the amorphous salts with one of the solvents (or a mixture of solvents) preferably from the following list of preferred solvents, i.e., diethyl ether, di-isopropyl ether, tert-butylmethylether, di-n-butyl ether, butylvinylether, tert- butylvinylether, tetrahydrofuran, 1,4-dioxane, n-heptane, n-hexane, cyclohexane, cyclopentane, toluene, o-xylene, m-xylene, p-xylene, dichloromethane, chloroform, carbon tetrachloride, chlorodibromofluoromethane .

Alternatively, a solvent (or a mixture of solvents) from the following list may be used to triturate and crystallise losartan salts with mineral acids: methyl acetate, ethyl acetate, propyl acetate, ethyl formate, isobutyl acetate, isobutyl formate, acetonitrile, isobutyronitrile, acetone, butanone, isopropylmethylketone, isobutylmethylketone, tert-butylmethylketone, sec-butylmethylketone, n- butylmethylketone, cyclopentanone, cyclohexanone.

Other more polar solvents which also have utility for trituration are the following: water, methanol, ethanol, n-propanol, propan-2-ol, 1-butanol, isobutyl alcohol, cyclopentanol, 2- ethoxyethanol, 2-methyl-2-butanol, ethyleneglycol, tert-butanol, acetic acid, propionic acid.

And, though less preferred, the solvents below may also be used for trituration: N,N- dimethylformamide, Ν,Ν'-dimethylacetamide, N-methylpyrrolidone, formamide, anisole, sulfolane, nitromethane, Ν,Ν'-dimethylpropyleneurea, dimethylsulfoxide, benzene , chlorobenzene, 1,2- dichlorobenzene, 4-methylmorpholine, Ν,Ν,Ν',Ν'-tetramethylethylenediamine, pyridine , diisopropylamine, triethylamine, aqueous ammonia.

Suitable trituration techniques include addition of a small amount of solvent to the amorphous salt, insufficient to cause complete solution, and scratching with a glass rod and/or ultra-sonication. Scratching is carried out in a glass tube for periods of approximately 5-10 minutes at a time, then leaving the tube to stand for 1 to 2 hours. Preferably the suspension/paste is brought onto the sides of the vessel during scratching to allow partial evaporation of the solvent. The procedure is then repeated several times. Alternatively the process may be automated by agitating the suspension/paste very vigorously with a small magnetic stirrer in the presence of some quartz anti-bumping granules or other abrasive material such as carborundum. Alternatively the mixture may be subjected to thermal shock by repeated cyclic ultra-freezing with liquid nitrogen followed by heating. Combinations of these techniques may be used.

Another technique which may be employed is to raise the temperature of the amorphous salt above the glass point and to raise and lower the temperature in a cyclic manner. This technique may be used in combination with thermal shock treatment and scratching.

The existence of a crystalline salt may be demonstrated by a combination of techniques. Solution nmr and or elemental analysis is used to demonstrate that both acid and base components are present. The salt is characterised by one or more of the following techniques: infra-red spectroscopy, Raman spectroscopy, X-ray powder or single crystal diffraction, solid-state nmr, melting point, DSC, DTA, optical and electron microscopy. The salt may be present as a hydrate or a solvate.

In the case of salts with polybasic acids such as sulfuric acid, and phosphoric acid, the ratio of losartan to acid may be greater than 1 : 1 , for example 2 : 1. As the skilled person will appreciate, the "ratio" here refers to the molar ratio.

Once a crystalline salt has been prepared on the small scale by one of the techniques described above so that seeds are available and a suitable solvent has been identified, other methods may be employed which are more suitable for large scale synthesis. For example, direct

crystallisation from a solvent or solvent mixture which has been prepared by mixing the acid and base components optionally at elevated temperature. The solution is made supersaturated by cooling, partial evaporation, or addition of an ant solvent. Alternatively, crystallisation from a supercritical fluid may be employed. Alternatively a salt may be prepared by adding a soluble conjugate salt to a soluble salt of losartan in a solvent in which the target salt is insoluble, i.e. the salt of losartan with X is prepared by mixing losartan/Y with Z/X (a soluble salt of X). For example a salt of losartan with a mineral acid may be prepared by adding an ammonium salt of the mineral acid to a solution of a salt of losartan with a weak acid such as acetic acid or similar, preferably in the presence of seeds of the crystalline target salt. In a variation to this procedure, the mineral acid may be added directly or diluted with solvent to a solution of a salt of losartan with a weak acid such as acetic acid or similar. Once again it is preferable to add seeds of the losartan mineral acid salt to the supersaturated solution.

Repeated application of the above techniques for inducing crystallisation of amorphous losartan salts may give rise to more than one crystal form of each salt, including polymorphs and pseudo polymorphs such as hydrates and solvates. Even when products are the same crystal form as determined by spectroscopic methods, it is often the case that the product that crystallises from one set of solvent conditions will have superior properties from a product obtained from another set of conditions. This may be the result of an improved crystal shape (habit) or density. Additional ways of preparing polymorphs and pseudo polymorphs include repeated small-scale precipitation of salts from a range of solvents (for example the lists of solvents recommended for trituration procedures above) by heating to dissolution, then cooling or partly evaporating. In addition an anti-solvent may be added (selected from those solvents which experimentally are found not to dissolve the salt, even with heating). Preferably non-crystalline losartan salts are used for these preparations since this minimises the presence of pre-existing crystal forms which may inhibit the production of alternative crystalline products. Alternatively, hydrates and solvates may be treated with solvents or subjected to a range of different humidity's to give other solvates or hydrates. Alternatively, the solvates or hydrates may be subjected to vacuum or oven drying/desolation, or plunged into an immiscible hot solvent (for example xylene).

Alternatively existing crystalline forms may be subjected to a combination of very high pressure and optionally high temperature, for example melts, or amorphous material maintained above the glass temperature can be induced to crystallise to give a new product.

More stable polymorphs may be generated by means of a "polymorph amplifier". This procedure comprises the preparation of a stirred suspension of a crystalline salt in a selected solvent (approximately 5-10% in solution at the lower temperature) and raising the temperature until approximately 90-95% of the solid is dissolved, then allowing the suspension to cool slowly, with stirring, until most of the salt has crystallised. This procedure is repeated cyclically many times, and the product at each stage tested for any change in form.

Crystallisation of novel crystal forms may be brought about by crystallising (for example by evaporation) on quartz or other active surfaces. Once a novel crystalline form has been produced by application of the above described techniques, improved direct crystallisation techniques can be determined by routine experimentation, since seeds of the new form will now be available.

The existence of polymorphs and pseudo polymorphs may be demonstrated by a combination of techniques. Solution NMR and or elemental analysis are used to demonstrate that both acid and base components are present. The salt is characterised by one or more of the following techniques: infra-red spectroscopy, Raman spectroscopy, X-ray powder or single crystal diffraction, solid-state NMR, melting point, DSC, DTA, optical and electron microscopy, measurements of density, wetting angle, solubility, stability, and flow properties.

The losartan salts of this invention may also be prepared as solid or liquid solutions or dispersions in a liquid or polymeric carrier or matrix. Suitable ratios of the losartan salt to liquid or polymeric carrier or matrix material may vary from 1: 100 to 10: 1, preferably from 1 :20 to 3: 1. As the skilled person will appreciate, "ratio" in this context refers to weight ratio. Such losartan salts, and such solutions or dispersions of the salts in a liquid or polymeric carrier or matrix, may be employed in any of the formulations of the present invention.

Also, as was mentioned earlier in the present application, the valsartan products of this invention may be prepared as solid or liquid solutions or dispersions in a liquid or polymeric carrier or matrix. Such valsartan products, and such solutions or dispersions of the valsartan in a liquid or polymeric carrier or matrix, may be employed in any of the formulations of the present invention. Suitable ratios of valsartan to liquid or polymeric carrier or matrix material may vary from 1 : 100 to 10: 1, preferably from 1 :20 to 3: 1. As the skilled person will appreciate, "ratio" in this context refers to weight ratio.

Such matrix dispersions may be prepared in a variety of ways; the losartan salt, or indeed the unsalted valsartan, may be added to the matrix material either as a solid or in solution and the matrix material itself may also be either in the form of a solid (or liquid, as appropriate) or in solution. If both materials are solids then heating and stirring of a melt may be utilised to form a homogenous mixture before the product is cooled, and either ground to a powder, or left as a liquid or semi-liquid suitable for further formulation. Various techniques are known for the formation of suitable granules and platform products from melts, for example spray congealing techniques to produce pellets have been described by Kanig J.Pharm Sci 53, 188, 1964 and by Kreuschner et al. Acta Pharm. Tech. 23, 159, 1980. A liquid matrix may be used to dissolve the solid salt, or a solution of the matrix product may be formed by mixing a solution of the salt with a solution of the matrix material, and the solvent subsequently removed by evaporation or spray-drying. Suitable solvents for preparing solid or liquid solutions or dispersions include water, common alcohols, ketones, esters, and ethers. Particularly preferred solvents are water, methanol, ethanol, n-propanol, propan-2-ol, 1-butanol, isobutyl alcohol, cyclopentanol, 2-ethoxyethanol, 2-methyl-2-butanol, ethyleneglycol, tert-butanol, acetone, butanone, isopropylmethylketone, isobutylmethylketone, tert-butylmethylketone, sec-butylmethylketone, n- butylmethylketone, cyclopentanone, cyclohexanone, methyl acetate, ethyl acetate, propyl acetate, ethyl formate, isobutyl acetate, isobutyl formate, diethyl ether, di-isopropyl ether, tert- butylmethylether, di-n -butyl ether, butylvinylether, tert-butylvinylether, tetrahydrofuran, 1,4-dioxane, dichloromethane, acetonitrile, and isobutyronitrile.

In a variation on the procedures described above for the preparation of amorphous losartan salts, the liquid or polymeric carrier or matrix material or solution thereof may form the solvent for the salt formation reaction. Hence the acid and base components may be added separately to the matrix material or solution thereof, optionally with heating to produce a melt or otherwise ensure a homogenous mixture. The product may then be cooled or evaporated and further treated to produce a form suitable for further formulation.

If a volatile solvent is used to form the matrix dispersion, it may be difficult to remove it all by evaporation. In the case of solvents such as water or ethanol this is not a problem and substantial residues may be tolerated, indeed may improve the stability and properties of the product. However residues which decrease the viscosity to the extent that crystallisation may occur on storage are undesirable. Less desirable solvents must be removed sufficiently by extended, optionally elevated temperature evaporation to ensure a pharmaceutically acceptable product.

Suitable liquid or polymeric carrier or matrix materials include the following: animal, vegetable or mineral oils, fats, waxes, chocolate, chewing gum base, maize oil, lecithin, groundnut oil, sunflower oil, cottonseed oil, lauroylmonoglyceride, lanolin, gelatin, isinglass, agar, carnauba wax, beeswax, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyethylene glycol esters, ovalbumin, soybean proteins, gum arabic, starch, modified starch, crospovidone, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, chicle, polypropylene, dextrans, including dexran 40, dextran 70 and dextran 75, dextrins, alpha-, beta-, gamma-cyclodextrins, hydroxypropyl-beta-cyclodextrins, alkylpolyglucosides, chitosan, polyvinylacetate, ethylene vinyl acetate, lectins, carbopols, silicon elastomers, polyacrylic polymers, maltodextrins, lactose, fructose, inositol, trehalose, maltose, raffinose, lauryl alcohol, polysorbate 80, almond oil; babassu oil; borage oil; blackcurrant seed oil; canola oil; castor oil;

coconut oil; corn oil; cottonseed oil; evening primrose oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed and castor oil; partially hydrogenated soybean oil; soy oil; glyceryl tricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl

tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic/capric glycerides; modified triglycerides; fractionated triglycerides; and mixtures thereof.

Preferred materials are PVP and PEG, which are available in various grades differing chiefly in their mean molecular weight. In the case of PVP this may be between 2,000 and 3,000,000, however material in the range 8,000 to 500,000 is more preferred e.g. PVP K-15, K-30, K-40, K-90. In the case of PEG products the mean molecular weight may be in the range 200 to 20,000, but 1,000 to 10,000 is more preferred e.g. PEG 2000, PEG 8000.

It should be appreciated that the valsartan products of the present invention may be prepared on any suitable scale according to the procedures herein outlined and those procedures which are conventional to one skilled in the art of pharmaceutical chemistry. Techniques for scale-up are described in the literature for example Pharmaceutical Process Scale-Up by Michael Levin, Marcel Dekker, New York 2003, ISBN 0824706250, which publication is incorporated herein by reference.

It should also be appreciated that the losartan salts of the present invention may be prepared on any suitable scale according to the procedures herein outlined and those procedures which are conventional to one skilled in the art of pharmaceutical chemistry, in particular in the preparation of salt forms. Techniques for scale-up are described in the literature for example Pharmaceutical Process Scale-Up by Michael Levin, Marcel Dekker, New York 2003, ISBN 0824706250.

Once prepared as described above, amorphous and crystalline forms of valsartan, solid dispersions of valsartan, valsartan absorbed onto carriers, liquid and solid solutions of valsartan, and amorphous, crystalline and liquid solutions of losartan salts with mineral acids, may be formulated into pharmaceutical compositions, according to procedures well known in the art. Suitable procedures include those provided in Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA, ISBN 0-683-306472; The art, science, and technology of pharmaceutical compounding by Lloyd V Allen, American Pharmaceutical Association, 2001, ISBN 1582120358 - incorporated herein by reference. Suitably, these

compositions are adapted for oral use such as tablets, capsules, zydis, gums, candies, chocolates, sachet and oral liquids, or are adapted for topical use such as gels, lotions, patches, or ointments, or are adapted for parenteral use such as intravenous, intramuscular, or subcutaneous injection, or are adapted for use as suppositories, or finally are adapted for inhalation therapy such as bronchial or nasal inhalation therapy.

The pharmaceutical composition of the invention comprises an angiotensin II receptor antagonist and may therefore be used for the treatment or prophylaxis of any condition or disorder which is treatable using an angiotensin II receptor antagonist. The pharmaceutical composition of the invention provides for maintenance of the angiotensin II receptor antagonist in the therapeutic window from dose to dose, i.e. throughout the dosing interval, for such conditions and disorders such that an improved treatment for such conditions and disorders, with increased efficacy, reduced side effects, or both, is obtained compared to prior art formulations. Conditions and disorders which are treatable using angiotensin II receptor antagonists, and for which improved treatments can therefore be provided by the present invention, include:

Disorders associated with hypertension. The pharmaceutical composition of the invention may be employed either alone or in combination with other antihypertensive agents in order to treat such disorders. Such disorders of course include hypertension itself. Valsartan and Losartan are already approved for the treatment of these conditions, alone or in combination with other antihypertensive agents. Hypertension as a disease causes a number of symptoms such as tiredness, dizziness, and nausea. Hypertension, however leads to more serious complications which are life threating such as stroke and heart attack. Thus, the following specific conditions are treatable and/or preventable with the compositions of the invention:

tiredness resulting from hypertension (hypertension-induced tiredness), dizziness resulting from hypertension (hypertension-induced dizziness), and nausea resulting from hypertension

(hypertension-induced nausea);

stroke resulting from hypertension (hypertension-induced stroke);

heart attack resulting from hypertension (hypertension-induced heart attack);

early-morning stroke or heart attack;

early-morning stroke;

early-morning heart attack;

death associated with early -morning stroke or heart attack;

death associated with early-morning stroke;

death associated with early -morning heart attack;

death associated with stroke or heart attack resulting from hypertension;

death associated with early -morning stroke or heart attack resulting from hypertension;

death associated with stroke resulting from hypertension;

death associated with early -morning stroke resulting from hypertension;

death associated with heart attack resulting from hypertension;

death associated with early-morning heart attack resulting from hypertension.

Heart failure, particularly heart failure in patients who are intolerant of angiotensin converting enzyme (ACE) inhibitors. Valsartan is already approved for this indication.

Chronic renal failure. Losartan is already approved for this indication.

Diabetic neuropathy. Again, losartan is already approved for this indication.

Cardiovascular diseases involving the blood vessels (known as vascular diseases), including: coronary artery disease (also known as coronary heart disease and ischemic heart disease); peripheral arterial disease - disease of blood vessels that supply blood to the arms and legs; and cerebrovascular disease - disease of blood vessels that supply blood to the brain (includes stroke).

Renal artery stenosis.

Aortic aneurysm. Cardiovascular diseases that involve the heart, including:

cardiomyopathy - diseases of cardiac muscle; hypertensive heart disease - diseases of the heart secondary to high blood pressure or hypertension; heart failure - a clinical syndrome caused by the inability of the heart to supply sufficient blood to the tissues to meet their metabolic requirements; pulmonary heart disease - a failure at the right side of the heart with respiratory system involvement; cardiac dysrhythmias - abnormalities of heart rhythm; inflammatory heart disease may be treated with agents such as valsartan and losartan; endocarditis - inflammation of the inner layer of the heart, the endocardium (the structures most commonly involved are the heart valves); inflammatory

cardiomegaly; myocarditis - inflammation of the myocardium; valvular heart disease; congenital heart disease - heart structure malformations existing at birth; and rheumatic heart disease - heart muscles and valves damage due to rheumatic fever caused by Streptococcus pyogenes a group A streptococcal infection.

Accordingly, the invention provides a pharmaceutical composition of the invention for use in a method for treatment of the human or animal body by therapy.

The invention further provides a pharmaceutical composition of the invention for use in the treatment or prophylaxis of a condition or disorder which is treatable using an angiotensin II receptor antagonist.

Typically, the pharmaceutical composition of the invention is for use in a method for the treatment or prophylaxis of a condition selected from hypertension, heart failure, chronic renal failure, diabetic neuropathy, and a cardiovascular disease.

In a preferred embodiment, the pharmaceutical composition of the invention is for use in a method for treatment or prophylaxis of hypertension. In particular, the pharmaceutical composition of the invention may be for use in the treatment or prophylaxis of stroke or heart attack resulting from hypertension.

In a preferred embodiment, the invention provides the pharmaceutical composition of the invention for use in the treatment or prophylaxis of early-morning stroke or early-morning heart attack resulting from hypertension.

The pharmaceutical composition may for instance be used in a method for treatment or prophylaxis of heart failure in patients who are intolerant of angiotensin converting enzyme (ACE) inhibitors.

The pharmaceutical composition of the invention may for instance be used in a method for treatment or prophylaxis of a cardiovascular disease selected from coronary artery disease, peripheral arterial disease, cerebrovascular disease, renal artery stenosis, aortic aneurysm, cardiomyopathy, hypertensive heart disease, heart failure, pulmonary heart disease, cardiac dysrhythmia, inflammatory heart disease, endocarditis, inflammatory cardiomegaly, myocarditis, valvular heart disease, congenital heart disease and rheumatic heart disease. As discussed hereinbefore, the controlled-release fraction in the pharmaceutical composition of the invention is usually adapted to ensure maintenance of the angiotensin II receptor antagonist within the therapeutic window from dose to dose, or at least for a certain, preferably high, proportion of the time during the dosing interval.

Accordingly, in all of the above-defined medical uses for the composition of the invention, the method for the treatment or prophylaxis of the condition in question typically comprises administering the composition to a subject in need thereof once every dosing interval, and thereby ensuring maintenance of the angiotensin II receptor antagonist within the therapeutic window throughout each dosing interval. This ensures maintenance of the angiotensin II receptor antagonist within the therapeutic window from dose to dose. The dosing interval (i.e. the interval of time between administration of consecutive doses of a drug) may be as defined above for z. However, the dosing interval is often 24 hours. Typically, therefore, the method for the treatment or prophylaxis of the condition comprises administering the composition to a subject in need thereof once every 24 hours, and thereby ensuring maintenance of the angiotensin II receptor antagonist within the therapeutic window throughout each 24 hours.

Often, the method for the treatment or prophylaxis of the condition comprises administering the pharmaceutical composition of the invention to a subject in need thereof, and thereby releasing the angiotensin II receptor antagonist from the controlled-release fraction in vivo over a period of x hours from the time of administration of the composition to the subject. Generally, in this embodiment, all of the angiotensin II receptor antagonist is released from the controlled-release fraction over the defined period. Typically, x is at least 8, so that it takes at least 8 hours for all of the angiotensin II receptor antagonist to be released from the controlled-release fraction. However, x may be at least 9, or, for instance, at least 10, so that it takes at least 8 hours for all of the angiotensin II receptor antagonist to be released from the controlled-release fraction, x may for instance be from 8 to 24, so that it takes from 8 to 24 hours for all of the angiotensin II receptor antagonist to be released from the controlled-release fraction, x may for instance be from 9 to 24, or from 10 to 24. Often, x is at least 12, so that it takes at least 12 hours for all of the angiotensin II receptor antagonist to be released from the controlled-release fraction, x may for instance be at least 15, for example at least 17, at least 18, or at least 20. x may for instance be from 12 to 24, or from 15 to 24, or for instance from 17 to 24, or from 20 to 24.

The method for the treatment or prophylaxis of the condition may comprise administering the pharmaceutical composition of the invention to a subject in need thereof once every dosing interval, and thereby maintaining the angiotensin II receptor antagonist within the therapeutic window for y % of the time during each dosing interval. The dosing interval may be defined as, say, z hours beginning with administration of the composition to a subject. When the pharmaceutical composition is a unit dosage form suitable for once daily (OD) dosing, z is generally 24, i.e. the dosing interval is 24 hours. Accordingly, z is typically from 20 to 28, for instance about 24. Often, z is 24. However, other dosing frequencies may of course be employed, depending on the drug, patient and condition being treated, and z may therefore have other values. Thus, z may for instance be 6, 8 or 12, or even 48. Thus, z may be from 6 to 48, but is typically from 12 to 36, for instance from 20 to 28. Often, z is 24.

Typically, y is at least 50, such that the angiotensin II receptor antagonist is maintained within the therapeutic window for at least 50% of the time during the dosing interval. It is of course preferred, however, that y is greater than 50. Preferably, for instance, y is at least 60, and more preferably at least 70, for instance at least 75. Typically, y is at least 80, for instance at least 85. Often, y is at least 90, and is preferably at least 95. y may for instance be 100, such that the angiotensin II receptor antagonist is maintained within the therapeutic window throughout the dosing interval, i.e. from dose to dose. Typically, z is 24 and y is at least 50. More preferably, z is 24 and y is at least 60, and more preferably at least 70, for instance at least 75. Typically, z is 24 and y is at least 80, for instance at least 85. Often, z is 24 and y is at least 90, and is preferably at least 95. In some cases, z is 24 and y is 100.

The method for the treatment or prophylaxis of the condition may comprise administering the pharmaceutical composition of the invention to a subject in need thereof once every dosing interval, and thereby maintaining the angiotensin II receptor antagonist at or above a drug plasma level, 1, in the subject for q % of the time during each dosing interval.

The dosing interval may in this case be defined as t hours beginning with administration of the composition to the subject. The pharmaceutical composition is often a unit dosage form suitable for once daily (OD) dosing. Thus, t is generally 24, i.e. the dosing interval is 24 hours. Accordingly, t is typically from 20 to 28, for instance about 24. Often, t is 24. However, other dosing frequencies may of course be employed, depending on the drug, patient and condition being treated, and t may therefore have other values. Thus, t may for instance be 6, 8 or 12, or even 48. Thus, t may be from 6 to 48, but is typically from 12 to 36, for instance from 20 to 28. Often, t is 24. Typically, q is at least 40, such that the angiotensin II receptor antagonist is maintained at or above the drug plasma level, 1, for at least 40% of the time during the dosing interval. It is of course preferred, however, that q is greater than 40. Preferably, for instance, q is at least 45, and more preferably at least 50, for instance at least 60. Typically, q is at least 65, for instance at least 70. Often, q is at least 75. Typically, q is at least 80, for instance at least 85. Often, q is at least 90, and is preferably at least 95. q may for instance be 100, such that the angiotensin II receptor antagonist is maintained at or above the drug plasma level, 1, throughout the dosing interval, i.e. from dose to dose. Typically, t is 24 and q is at least 45. More preferably, t is 24 and q is at least 50, and more preferably at least 60, for instance at least 65, at least 70, or for instance at least 75. Typically, t is 24 and q is at least 80, for instance at least 85. Often, t is 24 and q is at least 90, and is preferably at least 95. In some cases, t is 24 and q is 100.

The drug plasma level, 1, may be any drug plasma level within the therapeutic window.

Alternatively, it may be an IC50, i.e. a plasma concentration required for obtaining 50% of a maximum therapeutic effect in vivo. Usually, 1 is the plasma concentration (IC50) required for obtaining 50% of a maximum therapeutic effect in vivo. 1 may for instance be the plasma concentration (IC50) required for obtaining 50% of a maximum reduction in blood pressure in vivo. It may for instance be 1.2 mg/L, which is the IC50 for valsartan: the plasma concentration of valsartan required for obtaining 50% of a maximum reduction in blood pressure in vivo. Typically, therefore, in this embodiment, the angiotensin II receptor antagonist is valsartan. The disorder in this embodiment is typically hypertension, and may for instance be early-morning stroke or early-morning heart attack resulting from hypertension.

The invention also provides the use of a pharmaceutical composition of the invention in the manufacture of a medicament for use in the treatment or prophylaxis of a condition selected from hypertension, heart failure, chronic renal failure, diabetic neuropathy and a cardiovascular disease. The condition may be as further defined anywhere herein, as may the pharmaceutical composition of the invention.

The method, which may be as further defined anywhere herein, generally comprises administering a therapeutically effective amount of the pharmaceutical composition of the invention to the subject. The subject is generally a human or animal. Usually the subject is a human or mammal. The subject is typically human, i.e. a human patient.

As discussed throughout, the pharmaceutical compositions of the invention, are typically oral dosage forms and are typically therefore administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes. A therapeutically effective amount of a compound of the invention is

administered to a patient. A typical dose is as discussed further hereinbefore, and may for example range from 10 mg to 1000 mg, and typically from 50 mg to 700 mg, per day, and may vary according to the activity of the specific angiotensin II receptor antagonist, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of

administration.

The following Examples illustrate the invention. They do not however, limit the invention in any way.

EXAMPLES

Example 1

Amorphous valsartan

A solution of valsartan (4.4 g) in ethanol (1 : 1 by volume; 60 ml) is prepared in a rotary evaporator flask by heating solid pharmaceutically pure valsartan with ethanol to reflux until all internal surfaces have been subjected to condensing vapour. High vacuum is applied and the flask is maintained at an external temperature of about 40°C and rotated rapidly to remove the majority of the solvent as quickly as possible. The flask and amorphous product is then placed in a desiccator containing a dish of phosphoric oxide drying agent, and dried under high vacuum to a residual solvent level of below 0.5%. X-ray powder diffraction of the solid product shows a very broad diffraction peak typical of non-crystalline material.

Example 2

Amorphous valsartan

Amorphous valsartan, prepared by the method of example 1, is distilled in a wiped film still

(Speedivac TM™, Edwards High Vacuum Ltd).

Example 3

Crystalline valsartan

Amorphous valsartan from examples 1 or 2 (approx. 0.02 g) is triturated (as described above in the main specification) until the form of the solid is observed to change. The product is isolated and dried carefully. Analysis by x-ray powder diffraction shows characteristic sharp reflections in the range 5 to 30 degrees 2 theta.

Example 4

Spray-dried amorphous valsartan on a solid support

Amorphous valsartan (4 g) is dissolved in water/ethanol (200 ml, 1 : 1 by volume) with warming and ultra-sonication. The cooled solution is slurried with finely ground maltose (40 g) and spray dried in a commercial closed-loop spray -drying apparatus, Fielder Mobile Minor ® manufactured by Niro. Inlet temperature setting 90°C

Outlet temperature: 42-49°C

Nozzle diameter 2 mm

Pump speed (peristaltic): 26-28 rpm

Feed rate 2 kg/hour

Nitrogen flow 87 kg/hour

After completion of spray-drying, the collection flask is placed in a desiccator containing a dish of phosphoric oxide drying agent, and dried under high vacuum to a residual solvent level of below 0.5%.

Example 5

Spray-dried amorphous valsartan on a solid support

Amorphous valsartan (4.0 g) is dissolved in water/ethanol (200 ml, 1 : 1 by volume) with warming and ultra sonication. The solution is cooled and slurried with finely ground calcium hydrogen phosphate dihydrate (40 g) and spray dried in a commercial closed-loop spray-drying apparatus, Fielder Mobile Minor ® manufactured by Niro.

Inlet temperature setting 90°C

Outlet temperature: 42-49°C

Nozzle diameter 2 mm

Pump speed (peristaltic): 26-28 rpm

Feed rate 2 kg/hour

Nitrogen flow 87 kg/hour

Example 6

Amorphous valsartan solid dispersion in PVP

PVP K-30 (10 g) is heated to a mobile melt and stirred while amorphous valsartan (0.5 g) is added. After stirring for 10 minutes the mixture is allowed to cool and solidify. The product is ground to a powder. Analysis by X-ray powder diffraction shows no evidence for valsartan in a crystalline state.

Example 7

Amorphous valsartan solid dispersion in chocolate Plain chocolate (Lindt Excellence dark 70% cocoa, Lindt & Sprungli S.A. (France), 20 g) is warmed gently until molten and stirred while amorphous pharmaceutically pure valsartan (0.5 g) is added. After stirring for 10 minutes the mixture is allowed to cool and solidify. Analysis by X-ray powder diffraction shows no evidence for valsartan in a crystalline state.

Example 8

Amorphous valsartan solid dispersion in PEG 8000

PEG 8000 (10 g) is dissolved with warming in ethanol (200 ml) and stirred while amorphous valsartan (1.0 g) is added. After stirring for 5 minutes the mixture is evaporated under vacuum on a rotary evaporator. The rotary evaporator flask is placed in a desiccator containing a dish of phosphoric oxide drying agent, and dried under high vacuum. The product is then transferred to a vacuum oven and further dried over fresh phosphoric oxide at a temperature which is gradually increased to 45°C. Drying is continued until analysis shows the residual solvent level to be below 0.5%. Analysis by X-ray powder diffraction shows no evidence for valsartan in a crystalline state.

Example 9

Amorphous losartan hydroiodide

A solution of losartan (0.42 g) in a mixture of tetrahydrofuran (3 ml) and chlorobenzene (6 ml) is stirred thoroughly with an aqueous solution of hydriodic acid (0.1 molar, 10.5 ml) with gentle warming. The aqueous phase is separated and transferred to a rotary evaporator flask. High vacuum is applied and the flask is maintained at an external temperature of about 40°C and rotated rapidly to remove the majority of the solvent as quickly as possible. The flask and amorphous product is then placed in a desiccator containing a dish of phosphoric oxide drying agent, and dried under high vacuum to a residual solvent level of below 0.2%. Yield 0.55 g. X-ray powder diffraction shows a single very broad diffraction peak typical of non-crystalline material.

Example 10

Amorphous losartan hydroiodide

A solution of losartan (0.42 g) in a mixture of tetrahydrofuran (3 ml) and chlorobenzene (6 ml) is stirred thoroughly with an aqueous solution of hydriodic acid (0.1 molar, 10.5 ml) with gentle warming. The warm aqueous phase is separated and transferred to a flask which is suitable for use with a commercial freeze-drying apparatus (Quickfit ®) lyophiliser, Bibby Science Products). The solution is frozen rapidly by plunging and swirling vigorously in a cooling bath containing industrial methylated spirit and solid carbon dioxide. The flask is attached to the freeze-drying apparatus and the frozen matrix is immediately subjected to very high vacuum. After completion of freeze-drying, the flask is placed in a desiccator containing a dish of phosphoric oxide drying agent, and dried under high vacuum to a residual water level of below 0.2%. The freeze dried solid then obtained is subjected to X-ray powder diffraction which shows a single very broad diffraction peak typical of noncrystalline material. Yield 0.55 g.

Example 11

Amorphous losartan hydroiodide

A solution of losartan (8.4 g) in a mixture of tetrahydrofuran (60 ml) and chlorobenzene (120 ml) is stirred thoroughly with an aqueous solution of hydriodic acid (0.1 molar, 205 ml) with gentle warming. The aqueous phase is separated, kept hot by means of a jacketed feeder system, and spray dried in a commercial spray-drying apparatus, Fielder Mobile Minor ® manufactured by Niro.

Inlet temperature setting 90°C

Outlet temperature: 42-49°C

Nozzle diameter 2 mm

Pump speed (peristaltic): 26-28 rpm

Feed rate 2 kg/hour

Nitrogen flow 87 kg/hour

After completion of spray-drying, the collection flask is placed in a desiccator containing a dish of phosphoric oxide drying agent, and dried under high vacuum to a residual water level of below 0.2%. X-ray powder diffraction shows a single very broad diffraction peak typical of non-crystalline material.

Example 12

Crystalline losartan hydroiodide

Amorphous losartan hydroiodide (approx. 0.02 g) is triturated (as described above in the main specification) until the form of the solid is observed to change. The product is isolated and dried carefully. Analysis by x-ray powder diffraction shows characteristic sharp reflections in the range 5 to 30 degrees 2 theta.

Examples 13-21

Amorphous losartan salts with mineral acids

The following amorphous losartan salts with mineral acids are prepared by procedures analogous to the procedures described in Example 9:

Losartan sulfate

Losartan nitrate

Losartan phosphate Losartan phosphite

Losartan sulfite

Losartan sulfamate

Losartan thiocyanate

Losartan tetraborate

Losartan tetrafluoroborate

Examples 22-30

Amorphous losartan salts with mineral acids

The following amorphous losartan salts with mineral acids are prepared by procedures analogous to the procedures described in Example 10:

Losartan sulfate

Losartan nitrate

Losartan phosphate

Losartan phosphite

Losartan sulfite

Losartan sulfamate

Losartan thiocyanate

Losartan tetraborate

Losartan tetrafluoroborate

Examples 31-39

Amorphous losartan salts with mineral acids

The following amorphous losartan salts with mineral acids are prepared by procedures analogous to the procedures described in Example 11 :

Losartan sulfate

Losartan nitrate

Losartan phosphate

Losartan phosphite

Losartan sulfite

Losartan sulfamate

Losartan thiocyanate

Losartan tetraborate

Losartan tetrafluoroborate Example 40-48

Crystalline losartan salts with mineral acids

The following crystalline losartan salts with mineral acids are prepared by procedures analogous to the procedures described in Example 12:

Losartan sulfate

Losartan nitrate

Losartan phosphate

Losartan phosphite

Losartan sulfite

Losartan sulfamate

Losartan thiocyanate

Losartan tetraborate

Losartan tetrafluoroborate

Example 49

Spray-dried amorphous losartan hydroiodide on a solid support

Amorphous losartan hydroiodide (2.0 g) is dissolved in water (200 ml) with warming and ultrasonication. The cooled solution is slurried with finely ground maltose (40 g) and spray dried in a commercial closed-loop spray -drying apparatus, Fielder Mobile Minor ® manufactured by Niro.

Inlet temperature setting 90°C

Outlet temperature: 42-49°C

Nozzle diameter 2 mm

Pump speed (peristaltic): 26-28 rpm

Feed rate 2 kg/hour

Nitrogen flow 87 kg/hour

After completion of spray-drying, the collection flask is placed in a desiccator containing a dish of phosphoric oxide drying agent, and dried under high vacuum to a residual water level of below 0.5%. Spray-dried amorphous losartan mineral acid salts on a solid support may be prepared by analogous means for the following mineral acid salts: losartan sulfate, losartan nitrate, losartan phosphate, losartan phosphite, losartan sulfite, losartan sulfamate, losartan thiocyanate,losartan tetraborate, and losartan tetrafluoroborate.

Example 50

Spray-dried amorphous losartan hydroiodide on a solid support Amorphous losartan hydroiodide (2.0 g) is dissolved in water (200 ml) with warming and ultrasonication. The solution is cooled and slurried with finely ground calcium hydrogenphosphate dihydrate (40 g) and spray dried in a commercial closed-loop spray-drying apparatus, Fielder Mobile Minor ® manufactured by Niro.

Inlet temperature setting 90°C

Outlet temperature: 42-49°C

Nozzle diameter 2 mm

Pump speed (peristaltic): 26-28 rpm

Feed rate 2 kg/hour

Nitrogen flow 87 kg/hour

Example 51

Amorphous losartan hydroiodide solid dispersion in PVP

PVP K-30 (10 g) is heated to a mobile melt and stirred while amorphous losartan hydroiodide (0.5 g) is added. After stirring for 2 minutes the mixture is allowed to cool and solidify. The product is ground to a powder. Analysis by X-ray powder diffraction shows no evidence for losartan hydroiodide in a crystalline state.

Amorphous losartan mineral acid salt solid dispersions in PVP may be prepared by analogous means for the following mineral acid salts: losartan sulfate, losartan nitrate, losartan phosphate, losartan phosphite, losartan sulfite, losartan sulfamate, losartan thiocyanate,losartan tetraborate, and losartan tetrafluoroborate .

Example 52

Amorphous losartan hydroiodide solid dispersion in chocolate

Plain chocolate (Lindt Excellence dark 70% cocoa, Lindt & Sprungli S.A. (France), 20 g) is warmed gently until molten and stirred while amorphous pharmaceutically pure losartan hydroiodide (0.5 g) is added. After stirring for 2 minutes the mixture is allowed to cool and solidify. Analysis by X-ray powder diffraction shows no evidence for losartan hydroiodide in a crystalline state.

Amorphous losartan mineral acid salt dispersions in chocolate may be prepared by analogous means for the following mineral acid salts: losartan sulfate, losartan nitrate, losartan phosphate, losartan phosphite, losartan sulfite, losartan sulfamate, losartan thiocyanate,losartan tetraborate, and losartan tetrafluoroborate .

Example 53

Amorphous losartan hydroiodide solid dispersion in PEG 8000

PEG 8000 (10 g) is dissolved with warming in ethanol (200 ml) and stirred while amorphous losartan hydroiodide (0.5 g) is added. After stirring for 2 minutes the mixture is evaporated under vacuum on a rotary evaporator. The rotary evaporator flask is placed in a desiccator containing a dish of phosphoric oxide drying agent, and dried under high vacuum. The product is then transferred to a vacuum oven and further dried over fresh phosphoric oxide at a temperature which is gradually increased to 45°C. Drying is continued until analysis shows the residual solvent level to be below 0.5%. Analysis by X-ray powder diffraction shows no evidence for losartan hydroiodide in a crystalline state.

Amorphous losartan mineral acid salt solid dispersions in PEG 8000 may be prepared by analogous means for the following mineral acid salts: losartan sulfate, losartan nitrate, losartan phosphate, losartan phosphite, losartan sulfite, losartan sulfamate, losartan thiocyanate,losartan tetraborate, and losartan tetrafluoroborate.

The invention is further defined by reference to the following examples describing in detail the testing and preparation of the compositions of the present invention. It will be apparent to those skilled in the art, that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention.

PHARMACOLOGICAL TEST DATA

Angiotensin II (All) produces numerous biological responses including vasoconstriction through stimulation of receptors on cell membranes. A ligand-receptor binding assay may be utilized for an initial screen to identify compounds with All antagonist activity. One such assay is described by Glossmann, et al. ( J. Biol. Chem., 249, 825 (1974)), and may be modified as follows. The reaction mixture may be adrenal cortical microsomes in Tris buffer and 2 nM of H-AII with or without potential All antagonist. This mixture may be incubated for 1 hour at room temperature and the reaction subsequently terminated by rapid filtration and rinsing through glass micro-fibre filter. Any receptor-bound H-AII trapped in the filter may be quantitated by scintillation counting.

The potential antihypertensive effects of the compounds of this invention may be demonstrated by administering the compounds to awake rats made hypertensive by ligation of the left renal artery [Cangiano, et al, J. Pharmacol. Exp. Ther., 208, 310 (1979)] . This procedure increases blood pressure by increasing renin production with consequent elevation of All levels. Compounds are administered orally at 100 mg/kg and/or intravenously via a cannula in the jugular vein at 10 mg/kg. Arterial blood pressure is continuously measured directly through a carotid artery cannula and recorded using a pressure transducer and a polygraph. Blood pressure levels after treatment are compared to pretreatment levels to determine the antihypertensive effects of the compounds.

Other ligand-receptor binding assays may be utilised, one using a rabbit aortae membrane preparation, another using a bovine adrenal cortex preparation, and another using a rat brain membrane preparation.

Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) are suspended in 5 mM Tris-0.25M Sucrose, pH 7.4 buffer (50 ml) homogenized, and then centrifuged. The mixture is filtered through a cheesecloth and the supernatant is centrifuged for 30 minutes at 20,000 rpm at 4^°C. The pellet thus obtained is resuspended in 30 ml of 50 mM Tris-5 mM MgCb buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/ml Bacitration and the suspension is used for 100 assay tubes. Samples for screening are tested in duplicate. To the membrane preparation (0.25 ml) there is added¹²⁵ 1-Sar¹ lie⁸ - angiotensin II [obtained from New England Nuclear] (10 ul; 20,000 cpm) with or without the test sample and the mixture is incubated at 37°C. for 90 minutes. The mixture is then diluted with ice-cold 50 mM Tris-0.9% NaCl, pH 7.4 (4 ml) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter is soaked in scintillation cocktail (10 ml) and counted for radioactivity using a Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC50) of a potential All antagonist which gives 50% displacement of the total specifically bound¹²⁵ 1-Sar¹ lie⁸ - angiotensin II is presented as a measure of the efficacy of such compounds as All antagonists.

Bovine adrenal cortex is selected as the source of All receptor. Weighed tissue (0.1 g is needed for 100 assay tubes) is suspended in Tris.HCl (50 mM), pH 7.7 buffer and homogenized. The homogenate is centrifuged at 20,000 rpm for 15 minutes. Supernatant is discarded and pellets resuspended in buffer [Na₂HP0₄ (10 mM)-NaCl (120 mM)-disodium EDTA (5 mM) containing phenylmethane sulfonyl fluoride (PMSF)(0.1 mM)] . Duplicate tubes are used for screening compounds. To the membrane preparation (0.5 ml) there is added 3H-angiotensin II (50 πιΜ)(10μ1) with or without the test sample and the mixture is incubated at 37^°C. for 1 hour. The mixture is then diluted with Tris buffer (4 ml) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter is soaked in scintillation cocktail (10 ml) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC.sub.50) of a potential All antagonist which gives 50% displacement of the total specifically bound 3H-angiotensin II is presented as a measure of the efficacy of such compounds as All antagonists.

Membranes from rat brain (thalamus, hypothalamus and midbrain) are prepared by homogenization in 50 mM Tris HQ (pH 7.4), and centrifuged at 50,000 x g. The resulting pellets are washed twice in 100 mM NaCl, 5 mM Na₂EDTA, 10 mM Na₂HP0₄ (pH 7.4) and 0.1 mM PMSF by resuspension and centrifugation. For binding assays, the pellets are resuspended in 160 volumes of binding assay buffer (100 mM NaCl, 10 mM Na₂HP0₄, 5 mM Na₂EDTA, pH 7.4, 0.1 mM PMSF, 0.2 mg/ml soybean trypsin inhibitor, 0.018 mg/ml o-phenanthroline, 77 mg/ml dithiothreitol and 0.14 mg/ml bacitracin. For¹²⁵ 1-Sar¹ lie⁸ - angiotensin II binding assays, ΙΟμΙ of solvent (for total binding), Sar¹ lie⁸ - angiotensin H (ΙμΜ) (for nonspecific binding) or test compounds (for displacement) and ΙΟμΙ of [¹²⁵ I] -Sar¹ lie⁸ - angiotensin II (23-46 pM) are added to duplicate tubes. The receptor membrane preparation (500μ1) is added to each tube to initiate the binding reaction. The reaction mixtures are incubated at 37°C for 90 minutes. The reaction is then terminated by filtration under reduced pressure through glass-fiber GF/B filters and washed immediately 4 times with 4 ml of 5 mM ice-cold Tris HC1 (pH 7.6) containing 0.15M NaCl. The radioactivity trapped on the filters is counted using a gamma counter.

Using the methodology described above, representative compounds of this invention may be evaluated and an IC50 <50μΜ determined, thereby demonstrating and confirming the utility of the compounds of the invention as effective All antagonists.

The antihypertensive effects of the compounds described in the present invention may be evaluated using the methodology described below: Male Charles River Sprague-Dawley rats (300-375 gm) are anesthetized with methohexital (Brevital; 50 mg/kg i.p.) and the trachea is cannulated with PE 205 tubing. A stainless steel pithing rod (1.5 mm thick, 150 mm long) is inserted into the orbit of the fight eye and down the spinal column. The rats are immediately placed on a Harvard Rodent Ventilator (rate 60 strokes per minute, volume 1.1 cc per 100 grams body weight). The fight carotid artery is ligated, both left and right vagal nerves are cut, and the left carotid artery is cannulated with PE 50 tubing for drug administration, and body temperature is maintained at 37°C by a thermostatically controlled heating pad which receives input from a rectal temperature probe. Atropine (1 mg/kg i.v.) is then administered, and 15 minutes later propranolol (1 mg/kg i.v.). Thirty minutes later antagonists of formula I are administered intravenously or orally. Angiotensin II is then typically given at 5, 10, 15, 30, 45 and 60 minute intervals and every half-hour thereafter for as long as the test compound showed activity. The change in the mean arterial blood pressure is recorded for each angiotensin II challenge and the percent inhibition of the angiotensin II response is calculated.

Example 54

Part 1 : Valsartan sustained release core tablet formulation and dissolution data

Aim: To produce dissolution profiles in pH 6.8 buffer for sustained release development formulations of valsartan. The sustained release formulations 17CF08/001-3 in this Example may be employed as the controlled-release fraction in the compositions of the invention.

Formulation details

Batch: 17CF08/001 Sustained Release (30% Methocel in lactose filler):

Method of manufacture: the components in the table above were blended and then compressed to a hardness of approximately 1 lkp

Batch: 17CF08/002 Sustained Release (20% Methocel in lactose filler):

Method of manufacture: the components in the table above were blended and then compressed to a hardness of approximately 1 lkp Batch: 17CF08/003 Sustained Release (30% Methocel in microcrystalline cellulose filler):

Analytical Testing

Tablets were tested using dissolution with UV endpoint to obtain drug release profiles.

Sustained Release Formulation Dissolution conditions (pH 6.8 buffer)

Dissolution Results

Batch 17CF08/001 (30% Methocel in lactose filler): see also the plot of these results in Fig. 2:

17CF08/001

Time-point (hours) /o valsartan dissolved

Vessel 1 Vessel 2 Mean

0 0 0 0

2 22 28 25

3 31 41 36 4 40 53 46

5 49 64 56

6 57 74 65

7 66 82 74

8 73 90 81

10 86 103 94

12 100 109 104

14 108 110 109

Batch 17CF08/002 (20% Methocel in lactose filler): see also the plot of these results in Fig. 3 :

Batch 17CF08/003 (30% Methocel in microcrystalline cellulose filler): see also the plot of these results in Fig. 4:

17CF08/003

Time-point (hours) /o valsartan dissolved

Vessel 5 Vessel 6 Mean

0 0 0 0

2 15 14 14

3 23 21 22

4 32 28 30 5 40 35 37

6 47 42 45

7 54 49 52

8 60 57 58

10 70 68 69

12 79 78 79

14 86 87 87

Part 2: Valsartan immediate release formulation and dissolution data

Aim: To produce dissolution profiles in pH 6.8 buffer for immediate release development formulations of valsartan. The immediate release formulation 17CF08/004 in this Example may be employed as the first, rapid release fraction in the compositions of the invention.

Formulation details:

Batch: 17CF08/004 Immediate Release

Method of manufacture: the components in the table above were blended and then compressed to an approximate hardness of 9kp and a disintegration time of approximately 5 minutes.

Analytical Testing

Immediate Release Formulation Dissolution conditions (pH 6.8 buffer)

Apparatus USP II (paddle)

Dissolution media pH 6.8 phosphate buffer Volume dissolution 1000ml

media

Temperature 37.0°C ± 0.5

Speed 50rpm

Sampling points 5, 10, 20, 30, 45, 60 minutes

Detection UV at 250nm, 10mm cell path-length

Dissolution Results

Batch: 17CF08/004: see also the plot of these results in Fig. 5:

Part 3 : Final proposed manufacture combing the two formulations

• The valsartan sustained release core will be made as described above in part 1 of this Example

• Depending on the final size required the tooling will be changed to 10 - 20mm Flat tooling

• The tablet die will be filled with approximately 50% of the immediate release blend described in part 2 of this Example

• The sustained release core will be placed centrally into the pre-filled die.

• The remaining immediate release blend will be added

• Tablet will be compressed to a suitable hardness

Example 55

Valsartan pharmacokinetic/pharmacodynamic (PKPD) modelling

Summary PKPD modelling was carried out in order to explore the relationship between Valsartan PK and blood pressure response for different PK input (product release) profiles. The methods employed in the modelling were to:

Perform a literature search for PKPD models/data for Valsartan for the currently marketed immediate release (IR) tablet.

Implement a PKPD model that is deemed most relevant.

Subsequently alter the input PK profile to analyse a combination product that consists of IR and modified release (MR) components.

Explore how the new product effects blood pressure time-series profiles at the end of a 2 week once daily (OD) dosing and how it compares to the current IR product.

The results showed that in order to see an improved PD response profile at the end of 2 weeks of OD dosing the new product would be required to have a longer duration of release than the current IR tablets (the current IR tablet provides input lasting ~ 5 hours). Furthermore, the MR element of the new product would need to be the major constituent of the combination product. However for other metrics such as time over IC50 and min/max ratio in blood pressure reduction there is an optimal balance between the IR and MR components.

References

The following references are referred to in this Example:

Criscione et al. Valsartan: Preclinical and Clinical Profile of an Antihypertensive Angiotensin-II Antagonist. Cardiovasc Drug Rev. 1995 1 : 230-250.

Chen et al. A Single-Center, Open-Label, 3-Way Crossover Trial to Determine the Pharmacokinetic and Pharmacodynamic Interaction Between Nebivolol and Valsartan in Healthy Volunteers at Steady State. Am J Ther. 2015 22: el30-140.

Cho et al. Pharmacokinetic and Pharmacodynamic Study Determines Factors Affecting Blood Pressure Response to Valsartan. J Korean Soc Hypertens. 2012 18: 88-96.

Czendlik et al. Pharmacokinetic and pharmacodynamic interaction of single doses of valsartan and atenolol. Eur J Clin Pharmacol. 1997 52: 451-459.

FDA Diovan Label https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021283s501bl.pdf FDA Glucophage® XR Clinical Pharmacology and Biopharmaceutics Review

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-202_Glucophage_biopharmre.pdf FDA Glumetza® Clinical Pharmacology and Biopharmaceutics Review

https://www.accessdata.fda.gov/dnigsatfda_docs/nda/2005/021748s000_Glumetza_ClinPharmR.pdf Flesch et al. Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol. 1997 52: 115-120. Heo et al. Quantitative model for the blood pressure-lowering interaction of valsartan and amlodipine. Br J Clin Pharmacol. 2016 82: 1557-1567.

Kim et al. Pharmacokinetic comparison of 2 fixed-dose combination tablets of amlodipine and valsartan in healthy male Korean volunteers: a randomized, open-label, 2-period, single-dose, crossover study. Clin Ther. 2013 35: 934-490.

Leidig et al. Pharmacokinetics of Valsartan in Hypertensive Patients on Long-Term Haemodialysis. Clin Drug Investig. 2001 21 : 59-66.

Lim et al. Angiotensin II type 1 receptor 1166A/C polymorphism in association with blood pressure response to exogenous angiotensin II. Eur J Clin Pharmacol. 2007 63: 17-26.

Miiller et al. Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects. Eur. J. Clin. Pharmacol. 1997 52: 441-449. Naveen et al. Use of the liquisolid compact technique for improvement of the dissolution rate of valsartan. Acta Pharmaceutica Sinica B 2012 2: 502-508.

Rausova et al. Quantifying pharmacodynamic interaction between atenolol and valsartan. Cent Eur J Med. 2014 9: 1-9.

Siddiqui et al. Pharmacological and Pharmaceutical Profile of Valsartan: A Review. J. Applied Pharm. Sci. 2011 1 : 12-19

Tannergren et al. Toward an Increased Understanding of the Barriers to Colonic Drug Absorption in Humans: Implications for Early Controlled Release Candidate Assessment. Mol. Pharm. 2009 6:60-73

Introduction

A literature review based on the papers that cited the first preclinical/clinical pharmacology report of Valsartan by CIBA (Criscione et al., 1995) was conducted. A total of 132 articles citing this original report were found. Of these articles 9 related to PK or PKPD relationships/modelling (Chen et al, 2015; Cho et al, 2012 ; Czendlik et al, 1997; Flesch et al., 1997; Heo et al., 2016; Kim et al, 2013; Leidig et al., 2001; Lim et al., 2007; Rausova et al., 2014). These were the subject of further investigation.

The most recent PKPD paper was by Heo et al which used all previous PKPD data reported in the literature together with new data on a combination study to develop a PKPD model for Valsartan as a monotherapy agent. The doses of Valsartan used in the PK studies were 80mg and 160mg. Therefore, due to the amount of data used within Heo et al. study their model was chosen for this analysis.

The PK model used by Heo et al. was a 2-compartmental model with zero-order absorption and first order elimination. The effects on the PD, SBP and DBP, did not track with plasma PK and showed signs of a hysteresis. Thus, to model the PD an extra compartment which represents the biophase was included to account for this delayed effect on blood pressure. The effect of the biophase concentration on changes in blood pressure was modelled using an Ema_X model. The Ema_X model assumes that there is a maximal effect Valsartan can have on the pre-dose blood pressure value. This maximal effect for a single dose was estimated to be 16.4%. Note that the effect of Valsartan on SBP and DBP were found to be equivalent i.e. they have the same Ema_X and IC50 values.

The Valsartan PKPD model by Heo et al. was coded up before modifying the input profile to look at the combination of a modified (MR) and immediate release (IR) product. The effects on blood pressure between this new combined product and the original immediate release tablet were then compared.

Methods

All simulations were done using R v3.4.0. Original Model - Immediate Release (IR)

The model by Heo et al. was coded up in R v3.4.0 and simulated using the deSolve package. The original parameters of the model are given below in Table.

Table 1 : Key parameters in the Valsartan PKPD model by Heo et al.

Do: duration of zero-order release; Vc: volume central compartment; Vp volume peripheral compartment; CL: clearance; Q: transfer rate between Vc and Vp; Keq: equilibrium rate constant for biophase concentration; IC50: concentration at which 50% reduction in SBP or DBP is observed; Imax: maximal fraction by which blood pressure can be reduced by.

New Model - Immediate and Modified Release (IR/MR)

The MR mechanism was incorporated by introducing a second zero-order input rate (to mimic likely zero order release from a MR product). Thus, two new parameters were introduced into the model: a zero order rate constant, Di, and also the initial dose of MR. Providing two parameters that optimisation can be performed on.

Sensitivity Analysis - Optimal IR/MR

The following blood pressure related end-points were chosen to assess the effect of varying Di and initial MR dose.

At the end of 2 week once daily dosing:

1. Percentage reduction in DBP and SBP (pre-dose) compared to pre-treatment values

2. Ratio of min/max of blood pressure over the final 24 hour dosing interval.

3. Proportion of time above in-vivo IC50 over the final 24 hour dosing interval. We chose to vary Di from 5 to 12 hours (see Error! Reference source not found.) and the initial dose of the MR component of a combined IR/MR product from 0 to X-10mg of a total Xmg dose (e.g. 0 to 150mg for a total 160mg dose). For example, if the dose of the MR component was 30mg then the dose of the IR component was 130mg.

Biopharmaceutics and assumptions

Valsartan exhibits moderate permeability (Siddiqui et al, 2011) and as such would not be expected to be absorbed or have much reduced absorption from the colon (Tannergren et al., 2009). Additionally, Valsartan is reported as having an absorption window in the upper gastrointestinal tract (Naveen et al, 2012). Flesch and co-workers (1997) showed that absorption from a capsule was largely complete by 4.55 hours (90% amount absorbed) although some subjects took >8 hours even though the bioavailability of the capsule was approximately 60% of an oral solution indicating drug would still have been available for absorption.

Consequently, the simulations have focussed on a zero-release order for the modified release component from 5 to 12 hours with the expectation that drug released after 12 hours would not be absorbed, as by that time drug would be in the colon.

The modified release component was assumed to have the same relative bioavailability as the immediate release component. This assumption was based on data for metformin which also displays moderate permeability and similar bioavailability between immediate release formulations and modified release formulations that release drug in vitro over 10/12 hours (FDA Clinical

Pharmacology and Biopharmaceutics Reviews for Glumetza® and Glucophage® XR). For any future clinical evaluations, however, it should be noted that taking the modified release product in the fed state increased bioavailability. This is potentially as a consequence of gastric retention maintaining the drug release above the absorption window / small intestine for longer than in the fasted state.

A dose of 160 mg OD was initially modelled as this was the dose modelled in by Heo and co-workers, it is a recommended starting dose and falls within the range of recommended doses of 80 to 320 mg for the treatment of adult hypertension (FDA, Diovan Label). Other doses were modelled assuming dose proportional pharmacokinetics.

Most simulations were run for 14 days as for Valsartan "the reduction in blood pressure with any dose is substantially present within 2 weeks" (FDA, Diovan Label) and additionally this may reflect clinical practice where medicine effectiveness is assessed after 2 weeks (Hitesh Mistry personal communication, St Mary's Hospital, Manchester) although other guidelines recommend assessment of a medicine effectiveness after a month (http://www.aafp.org/patient-care/clinical- recommendations/all/highbloodpressure .html) .

Multiple dose Valsartan PK and PK-PD models are not described in the literature and so both PK and PD were assumed to be time independent and linearly related to single dose kinetics and dynamics. This is based on the data of Miiller et al. (1997) in which blood pressure response to Valsartan appears similar on Day 1 and Day 8.

Results

Original Model - Immediate Release (IR)

A single 160mg dose simulation of the original Heo et al. model can be seen in Figure 6. The first panel - Fig. 6(a) - shows the concentration time profile of the amount of drug in plasma and the biophase (active site). Figure 6(a) also shows the IC50 value for both SBP and DBP. In the second panel - Fig. 6(b) - we can see what effect this single dose has on the time-series of DBP and SBP.

The initial values of SBP and DBP were based on the original article by Heo et al. and is based on healthy volunteers. Figure 6(a) and (b) clearly show that a single dose of Valsartan causes a reduction in SBP and DBP and that they are close to returning to baseline at Cmin (24 hours when the next dose would be administered). Thus, with repeat dosing we would expect to see a modest increase in the reduction of blood pressure at subsequent Cmin's, reflecting what is observed in the clinic.

New Model - Immediate and Modified Release (IR MR)

The result of the sensitivity analyses where the duration of zero-order release of the MR product and the proportion of the MR dose as a proportion of a total dose of 160 mg are varied can be seen in Figures 7 to Figure 9.

Figure 7 describes the % reduction in either SBP or DBP compared to pre-treatment values at the Cmin time-point on the last day of a 14 day once daily dosing schedule (i.e. just before the next dose will be taken). The original IR product is also shown on the plot and corresponds to 0 mg of MR Product, which is the bottom row of the heatmap. Figure 7 clearly shows that as duration of zero-order release is prolonged and the amount of MR dose increases the drop in blood pressure increases.

Figure 8 shows what effect of varying amount of MR and duration of zero-order release has on the min/max ratio of blood pressure values on the final day of a 14 day once daily dosing schedule. We can see that the ratio approaches 1 with increasing amount of MR and duration of zero-order release but that the magnitude of increase is minimal compared to the original product. Ratio of 1 indicates a constant level of blood pressure reduction throughout the dosing interval. However there is an optimal balance of IR and MR components with a IR component of 10-40 mg (out of 160 mg) allied to longer release duration of the MR component (10-12 hours).

Finally, Figure 9 shows the proportion of the last 24 hours dosing interval which is spent above the IC50 value. Again the results are similar to the other figures in that an improvement is seen with increasing amounts of the MR product with increasing duration of zero-order release. However there is an optimal balance of IR and MR components with a IR component of 20-50 mg (out of 160 mg) allied to longer release duration of the MR component (10-12 hours).

Figures 10 to 12 look at the areas of the heat map in more detail and show the expected PK profile and resulting blood pressure response for different combination of IR component (40-120 mg) and MR release duration (8-12 hours) for a total dose of 160 mg and also show the IR tablet PK and resulting blood pressure profile. Figure 13 and Figure 14 show PK and resulting blood pressure profiles for the IR tablets and 30mg IR + 130mg MR 12 hour release product on days 1 to 14 and day 1 and 14 respectively. Figure 15 shows show PK and resulting blood pressure profiles for the IR tablets and 30mg IR + 130mg MR 24 hour release product on days 1 and 14. It should be noted that for this release profile a gastro-retentive formulation (e.g. enteric coating) would be advantageous to maximise absorption from the colon.

Figures 16 to 24 are analogous figures to Figures 7 to 15 but for a total dose of 320 mg (rather than 160 mg). Figures 25 to 27 show selected PK and blood pressure simulations / plots for a total dose of 480 mg. Figures 28 to 30 show selected PK and blood pressure simulations / plots for a total dose of 640 mg.

The modelling and simulation described in this Example highlights that a combined IR/MR product can improve the amount of reduction in both SBP and DBP for the same total daily dose of the original IR product and there is an optimal balance of IR and MR components.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications can be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Claims

1. A pharmaceutical composition which comprises:

a first fraction comprising an angiotensin II receptor antagonist; and

a controlled-release fraction comprising the angiotensin II receptor antagonist.

2. A pharmaceutical composition according to claim 1 wherein the controlled-release fraction is suitable for causing delayed or prolonged release of the angiotensin II receptor antagonist from the controlled-release fraction after administration of the composition to a subject.

3. A pharmaceutical composition according to claim 1 or claim 2 wherein the controlled-release fraction is suitable for causing prolonged release of the angiotensin II receptor antagonist from the controlled-release fraction after administration of the composition to a subject.

4. A pharmaceutical composition according to any one of claims 1 to 3 wherein the controlled- release fraction is adapted to ensure maintenance of the angiotensin II receptor antagonist within the therapeutic window from dose to dose.

5. A pharmaceutical composition according to any one of the preceding claims wherein the controlled-release fraction is adapted to release the angiotensin II receptor antagonist from the controlled-release fraction in vivo over a period of x hours from the time of administration of the composition to a subject, wherein x is at least 8.

6. A pharmaceutical composition according to claim 5 wherein x is at least 10.

7. A pharmaceutical composition according to claim 5 or claim 6 wherein x is at least 12.

8. A pharmaceutical composition according to any one of claims 5 to 7 wherein x is at least 15, optionally wherein x is: at least 17, or at least 20.

9. A pharmaceutical composition according to any one of the preceding claims wherein the controlled-release fraction is adapted to ensure maintenance of the angiotensin II receptor antagonist within the therapeutic window for y % of the time during a dosing interval of z hours beginning with administration of the composition to a subject.

10. A pharmaceutical composition according to claim 9 wherein z is 24 and y is at least 50.

11. A pharmaceutical composition according to claim 10 wherein y is at least 90, preferably at least 95, and most preferably 100.

12. A pharmaceutical composition according to any one of the preceding claims wherein the controlled-release fraction is adapted to maintain the angiotensin II receptor antagonist at or above a drug plasma level, 1, in a subject for q % of the time during a dosing interval of t hours beginning with administration of the composition to the subject.

13. A pharmaceutical composition according to claim 12 wherein said drug plasma level, 1, is the plasma concentration (IC50) required for obtaining 50% of a maximum therapeutic effect in vivo.

14. A pharmaceutical composition according to claim 12 or claim 13 wherein the drug plasma level, 1, is the plasma concentration (IC50) required for obtaining 50% of a maximum reduction in blood pressure in vivo.

15. A pharmaceutical composition according to any one of claims 12 to 14 wherein the drug plasma level, 1, is 1.2 mg/L.

16. A pharmaceutical composition according to any one of claims 12 to 15 wherein t is 24 and q is at least 45, and preferably at least 50.

17. A pharmaceutical composition according to claim 16 wherein q is at least 65, and preferably at least 70.

18. A pharmaceutical composition according to claim 16 wherein q is at least 75, preferably at least 80, more preferably at least 85.

19. A pharmaceutical composition according to claim 16 wherein q is at least 90, preferably at least 95, more preferably 100.

20. A pharmaceutical composition according to any one of the preceding claims wherein the first fraction is a rapid release fraction.

21. A pharmaceutical composition according to claim 20 wherein the first fraction is adapted to provide rapid release of the angiotensin II receptor antagonist into the bloodstream to provide fast onset of action.

22. A pharmaceutical composition according to any one of the preceding claims wherein the pharmaceutical composition is a dosage form.

23. A pharmaceutical composition according to any one of the preceding claims wherein the pharmaceutical composition is an oral dosage form.

24. A pharmaceutical composition according to claim 23 wherein the oral dosage form is a tablet.

25. A pharmaceutical composition according to claim 23 or claim 24 wherein the oral dosage form comprises an outer layer which comprises the first fraction, and an inner region, which inner region is within the outer layer and comprises the controlled-release fraction.

26. A pharmaceutical composition according to any one of claims 23 to 25 wherein the oral dosage form has a core-shell structure wherein the controlled-release fraction defines a core and the first fraction is disposed on the surface of the core to form a shell which surrounds the core.

27. A pharmaceutical composition according to any one of claims 23 to 26 wherein the oral dosage form further comprises a coating for delaying exposure of the angiotensin II receptor antagonist in the controlled-release fraction to the buccal, gastric, or intestinal fluids.

28. A pharmaceutical composition according to claim 27 wherein the coating is an enteric coating.

29. A pharmaceutical composition according to claim 27 or claim 28 wherein the coating is disposed on the surface of the controlled-release fraction.

30. A pharmaceutical composition according to claim 29 wherein the coating is disposed between the first fraction and the controlled-release fraction.

31. A pharmaceutical composition according to any one of the preceding claims wherein the ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is from 98:2 to 60:40.

32. A pharmaceutical composition according to any one of the preceding claims wherein the ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is from 96:4 to 70:30.

33. A pharmaceutical composition according to any one of the preceding claims wherein the ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is from 96:4 to 80:20.

34. A pharmaceutical composition according to any one of the preceding claims wherein the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction is from 50 mg to 700 mg.

35. A pharmaceutical composition according to any one of the preceding claims wherein the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction is from 80 mg to 640 mg.

36. A pharmaceutical composition according to any one of the preceding claims wherein the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction is from 160 mg to 640 mg.

37. A pharmaceutical composition according to any one of the preceding claims wherein the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction is 80 mg, 160 mg, 240 mg, 320 mg, 400 mg, 480 mg, 560 mg or 640 mg.

38. A pharmaceutical composition according to any one of claims 34 to 37 wherein the mass of the angiotensin II receptor antagonist in the first fraction is from 20 mg to 40 mg, preferably from 25 mg to 30 mg, more preferably from 28 mg to 32 mg.

39. A pharmaceutical composition according to any one of claims 34 to 37 wherein the ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is from 96:4 to 70:30, preferably from 96:4 to 80:20.

40. A pharmaceutical composition according to any one of claims 34 to 37 wherein the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction is from 160 mg to 640 mg and the mass of the angiotensin II receptor antagonist in the first fraction is from 28 mg to 32 mg.

41. A pharmaceutical composition according to any one of claims 34 to 40 wherein the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction is the same as the total mass of the angiotensin II receptor antagonist in the composition.

42. A pharmaceutical composition according to any one of the preceding claims wherein the controlled-release fraction comprises: said angiotensin II receptor antagonist and a hydrophilic matrix suitable for promoting prolonged release of the angiotensin II receptor antagonist.

43. A pharmaceutical composition according to claim 42 wherein the hydrophilic matrix comprises a hydrophilic polymer which is a cellulose ether or xanthan gum.

44. A pharmaceutical composition according to claim 43 wherein the cellulose ether is selected from carboxymethylcellulose (CMC), methylcellulose (MC) and derivatives thereof,

hydroxypropylmethylcellulose, and ethylcellulose (EC).

45. A pharmaceutical composition according to claim 43 or 44 wherein the hydrophilic polymer is said cellulose ether, and the controlled-release fraction comprises the angiotensin II receptor antagonist in an amount of from 20 wt. % to 30 wt. % and comprises the cellulose ether in an amount of from 15 wt. % to 35 wt. %, based on the total weight of the controlled-release fraction.

46. A pharmaceutical composition according to any one of claims 43 to 45 wherein the hydrophilic polymer is said cellulose ether, and the controlled-release fraction comprises the angiotensin II receptor antagonist in an amount of from 20 wt. % to 30 wt. % and comprises the cellulose ether in an amount of from 25 wt. % to 35 wt. %, based on the total weight of the controlled- release fraction.

47. A pharmaceutical composition according to any one of claims 42 to 46 wherein the controlled-release fraction further comprises a filler, optionally wherein the filler comprises lactose or cellulose.

48. A pharmaceutical composition according to claim 45 or claim 46 wherein the controlled- release fraction further comprises a filler which comprises anhydrous lactose or microcrystalline cellulose.

49. A pharmaceutical composition according to any one of claims 42 to 48 wherein the controlled-release fraction further comprises a glidant, optionally wherein the glidant comprises hydrophilic silica.

50. A pharmaceutical composition according to any one of claims 42 to 49 wherein the controlled-release fraction further comprises a lubricant, optionally wherein the lubricant comprises magnesium stearate.

51. A pharmaceutical composition according to any one of claims 42 to 50 wherein the controlled-release fraction comprises:

a hydrophilic polymer as defined in claim 43 or claim 44, in an amount of from 15 wt. % to 35 wt. % based on the total weight of the controlled-release fraction;

optionally, a lubricant as defined in claim 50, in an amount of up to 2 wt. % based on the total weight of the controlled-release fraction;

optionally, a glidant as defined in claim 49, in an amount of up to 2 wt. % based on the total weight of the controlled-release fraction; and

a filler as defined in claim 48, optionally wherein the filler makes up the balance of the controlled-release fraction.

52. A pharmaceutical composition according to any one of claims 42 to 51 wherein the controlled-release fraction comprises:

a hydrophilic polymer as defined in claim 43 or claim 44, in an amount of from 25 wt. % to 35 wt. % based on the total weight of the controlled-release fraction;

a filler as defined in claim 48, wherein the filler makes up the balance of the controlled- release fraction.

53. A pharmaceutical composition according to claim 52 wherein the filler comprises microcrystalline cellulose.

54. A pharmaceutical composition according to any one of the preceding claims wherein the first fraction comprises said angiotensin II receptor antagonist and a disintegrant.

55. A pharmaceutical composition according to claim 54 wherein the disintegrant is selected from polyvinylpyrrolidone (PVPP, crospovidone), alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone (PVP), polacrilin potassium, pregelatinised starch, sodium alginate, sodium lauryl sulphate, and sodium starch glycolate.

56. A pharmaceutical composition according to claim 54 or claim 55 wherein the disintegrant is crospovidone.

57. A pharmaceutical composition according to any one of claims 54 to 56 wherein the first fraction further comprises one or more fillers, optionally wherein the one or more fillers comprise lactose, cellulose, or lactose and cellulose.

58. A pharmaceutical composition according to any one of claims 54 to 57 wherein the first fraction further comprises a glidant, optionally wherein the glidant is hydrophilic silica.

59. A pharmaceutical composition according to any one of claims 54 to 58 wherein the first fraction further comprises a lubricant, optionally wherein the lubricant is magnesium stearate.

60. A pharmaceutical composition according to any one of claims 54 to 59 wherein the first fraction comprises:

a disintegrant as defined in any one of claims 54 to 56, in an amount of from 0.5 wt. % to 10 wt. % based on the total weight of the first fraction;

optionally, a lubricant as defined in claim 59, in an amount of up to 2 wt. % based on the total weight of the first fraction;

optionally, a glidant as defined in claim 58, in an amount of up to 2 wt. % based on the total weight of the first fraction; and

one or more fillers as defined in claim 57, optionally wherein the filler makes up the balance of the first fraction.

61. A pharmaceutical composition according to any one of the preceding claims wherein the controlled-re lease fraction is as defined in any one of claims 42 to 53 and the first fraction is as defined in any one of claims 54 to 60.

62. A pharmaceutical composition according to claim 61 wherein:

- the controlled-release fraction comprises:

the angiotensin II receptor antagonist, in an amount of from 20 wt. % to 30 wt. % based on the total weight of the controlled-release fraction; a hydrophilic polymer as defined in claim 43 or claim 44, in an amount of from 15 wt. % to 35 wt. % based on the total weight of the controlled-release fraction; optionally, a lubricant as defined in claim 50, in an amount of up to 2 wt. % based on the total weight of the controlled-release fraction; optionally, a glidant as defined in claim 49, in an amount of up to 2 wt. % based on the total weight of the controlled- release fraction; and a filler as defined in claim 48, optionally wherein said filler makes up the balance of the controlled-release fraction; and

- the first fraction comprises:

optionally, a lubricant as defined in claim 59, in an amount of up to 2 wt. % based on the total weight of the first fraction; optionally, a glidant as defined in claim 58, in an amount of up to 2 wt. % based on the total weight of the first fraction; and one or more fillers as defined in claim 57, optionally wherein the one or more fillers make up the balance of the first fraction.

63. A pharmaceutical composition according to claim 62 wherein the hydrophilic polymer is a cellulose ether and is present in an amount of from 25 wt. % to 35 wt. % based on the total weight of the controlled-release fraction, preferably in an amount of from 28 wt. % to 32 wt. %.

64. A pharmaceutical composition according to claim 63 wherein the filler in the controlled- release fraction comprises microcrystalline cellulose.

65. A pharmaceutical composition according to any one of claims 62 to 65 wherein the total mass of the angiotensin II receptor antagonist in the first fraction and the controlled-release fraction is from 80 mg to 640 mg, and:

the ratio of the mass of the angiotensin II receptor antagonist in the controlled-release fraction to the mass of the angiotensin II receptor antagonist in the first fraction is from 96:4 to 70:30, preferably from 96:4 to 80:20; or

the mass of the angiotensin II receptor antagonist in the first fraction is from 28 mg to 32 mg.

66. A pharmaceutical composition according to any one of claims 1 to 53 wherein the first fraction is a rapidly disintegrating component comprising: said angiotensin II receptor antagonist, a disintegrating agent and optionally a swelling agent.

67. A pharmaceutical composition according to claim 66 wherein the first fraction comprises: said angiotensin II receptor antagonist; a disintegrant which is a dissacharide alcohol,

carboxymethylcellulose or sodium croscarmellose; and optionally a modified starch.

68. A pharmaceutical composition according to claim 66 or claim 67 wherein the first fraction comprises said angiotensin II receptor antagonist, isomalt and sodium starch glycolate.

69. A pharmaceutical composition according to any one of claims 1 to 53 wherein the first fraction is a rapidly disintegrating component comprising: said angiotensin II receptor antagonist in a matrix of a buccal fluid-dispersible polymer, and a polysaccharide, optionally wherein:

the buccal fluid-dispersible polymer comprises gelatine, or the polysaccharide comprises mannitol, or the buccal fluid-dispersible polymer comprises gelatine and the polysaccharide comprises mannitol.

70. A pharmaceutical composition according to any one of claims 1 to 53 wherein the first fraction is a rapidly disintegrating component comprising: (i) said angiotensin II receptor antagonist, (ii) an effervescence agent, and (iii) a disintegrating agent or a water soluble excipient, optionally wherein:

the effervescence agent comprises: an alkali metal carbonate or bicarbonate and optionally an organic acid; and

the water soluble excipient is: a sugar, optionally wherein the sugar is mannitol.

71. A pharmaceutical composition according to any one of claims 1 to 53 wherein the first fraction is a rapidly disintegrating component comprising: said angiotensin II receptor antagonist and a melt-spun sugar which comprises filaments of the sugar, optionally wherein the sugar is sucrose.

72. A pharmaceutical composition according to any one of claims 1 to 53 wherein the first fraction is a rapidly disintegrating component comprising: said angiotensin II receptor antagonist, a low mould ability saccharide and a high mould ability saccharide, wherein the low mould ability saccharide is granulated using the high mould ability saccharide as a binder, optionally wherein: the low mould ability saccharide is lactose or mannitol; and/or

the high mould ability saccharide is maltose or maltitol.

73. A pharmaceutical composition according to any one of claims 1 to 53 wherein the first fraction is a rapidly disintegrating component comprising: said angiotensin II receptor antagonist which is dispersed or adsorbed over a high surface area inert substrate, optionally wherein: the substrate is an ion exchange resin, a polymeric absorbent, activated carbon, or silica gel; or

the substrate is selected from: Amberlite ® XAD-4, Amberlite ® XAD-7, Amberlite ® XAD- 16, AMBERSORB ® 348F, AMBERSORB ® 563, AMBERSORB ® 572, Activated carbon, Activated carbon Darco ®, Activated carbon Darco ® G-60, Activated carbon Darco ® KB, Activated carbon Darco ® KB-B, Activated carbon Norit ®, and silica gel.

74. A pharmaceutical composition according to any one of claims 1 to 53 wherein the controlled- release fraction comprises said angiotensin II receptor antagonist and one or more excipients which promote modified release, optionally wherein the excipients which promote modified release comprise one or more polymers.

75. A pharmaceutical composition according to any one of claims 1 to 53 wherein the controlled- release fraction comprises said angiotensin II receptor antagonist and a dissolvable or erodible polymer suitable for promoting prolonged release of the angiotensin II receptor antagonist, optionally wherein:

the polymer is selected from glyceryl monostearate, acrylic resins, ethylcellulose, stearyl alcohol, hydroxypropylcellulose, carboxymethyl-cellulose, hypromellose, methylcellulose, hydroxyethyl-methylcellulose, sodium carboxymethylcellulose.

76. A pharmaceutical composition according to any one of claims 1 to 53 wherein the controlled- release fraction comprises: a composition comprising said angiotensin II receptor antagonist, which composition is coated with a porous or semipermeable membrane suitable for promoting prolonged release of the angiotensin II receptor antagonist, optionally wherein:

the semi-permeable membrane comprises a polymer, optionally wherein the polymer is a methacrylate polymer, ethylcellulose, cellulose acetate, poly(ethylene glycol), or a mixture of two or more thereof; or

the semi-permeable membrane comprises cellulose acetate and poly(ethylene glycol).

77. A pharmaceutical composition according to claim 76 wherein the composition comprising said angiotensin II receptor antagonist, which is coated with the membrane, further comprises an osmagent, optionally wherein the osmagent is selected from sodium chloride, potassium chloride, lithium chloride, magnesium chloride, magnesium sulphate, lithium sulphate, sodium sulphate, potassium sulphate, citric acid, mannitol, ribose, arabinose, galactose, leucine, glycine, fructose, sucrose, and sodium and other bicarbonates, or a mixture of two or more thereof.

78. A pharmaceutical composition according to any one of claims 1 to 53 wherein the controlled- re lease fraction comprises: said angiotensin II receptor antagonist and a coating for delaying exposure of the angiotensin II receptor antagonist to buccal, gastric, or intestinal fluids; optionally wherein the controlled-release fraction further comprises beadlets, pellets, spheroids, minitablets and/or granules comprising the angiotensin II receptor antagonist which are coated with said coating.

79. A pharmaceutical composition according to claim 78 wherein the coating comprises an enteric coating which dissolves at a pH greater than 5.0.

80. A pharmaceutical composition according to claim 28 or claim 79 wherein the enteric coating comprises a methacrylic acid-methyl methacrylate co-polymer.

81. A pharmaceutical composition according to claim 78 wherein the coating comprises a pH- dependent polymer, optionally wherein the pH-dependent polymer is selected from cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate 50, hydroxypropylmethylcellulose phthalate 55, polyvinylacetate phthalate, methacrylic acid-methyl methacrylate copolymer (1 : 1), methacrylic acid- methyl methacrylate copolymer (2: 1), methacrylic acid-ethyl acrylate copolymer (2: 1),

hydroxypropylmethylcellulose acetate succinate, poly(methylvinylether/maleic acid) monoethylester, poly(methylvinylether/maleic acid)n-butyl ester, and shellac.

82. A pharmaceutical composition according to claim 78 wherein the coating comprises a non- pH-dependent polymer, optionally wherein the polymer is selected from: acacia, alginate, amylase, beeswax, carboxymethylcellulose, carnuba wax, cellulose acetate, cholesterol, ethylcellulose, fatty acids, gelatine, glyceryl behenate, glyceryl monostearate, glyceryl monodistearate, glyceryl tripalmitate, hypromellose, hydroxypropylcellulose, hydrogenated vegetable oil, lecithin,

methylcellulose, paraffin wax, pectin, polyethylene glycol, polycaprolactone, polyglycolic acid, polylactic acid, polyglyclide-co-lactide co-polymers, polyvinylprroylidone, starch, stearic acid, stearyl alcohol, partially hydrogenated cottonseed oil/soyabean oil, partially hydrogenated palm oil, partially hydrogenated cottonseed oil, partially hydrogenated soyabean oil, partially hydrogenated castor oil, and polyethylene glycol 3350.

83. A pharmaceutical composition according to any one of claims 74 to 82 wherein the first fraction is as defined in any one of claims 54 to 60 and 66 to 73.

84. A pharmaceutical composition according to any one of the preceding claims wherein the angiotensin II receptor antagonist is valsartan, losartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan, azilsartan, fimasartan, saprisartan, tasosartan, elisartan, a pharmaceutically acceptable salt thereof, or a co-crystal thereof.

85. A pharmaceutical composition according to any one of the preceding claims wherein the angiotensin II receptor antagonist is valsartan, or a pharmaceutically acceptable salt thereof.

86. A pharmaceutical composition according to claim 85 wherein the angiotensin II receptor antagonist is valsartan in the free form.

87. A pharmaceutical composition according to any one of claims 1 to 84 wherein the angiotensin II receptor antagonist is losartan or a pharmaceutically acceptable salt thereof.

88. A pharmaceutical composition according to claim 87 wherein the pharmaceutically acceptable salt of losartan is losartan potassium or a salt of losartan with a mineral acid.

89. A pharmaceutical composition according to claim 88 wherein the salt of losartan with a mineral acid is selected from losartan hydriodide, losartan sulfate, losartan nitrate, losartan phosphate, losartan phosphite, losartan sulphite, losartan sulfamate, losartan thiocyanate, losartan tetraborate and losartan tetrafluoroborate.

90. A pharmaceutical composition according to any one of claims 1 to 84 wherein the angiotensin II receptor antagonist is candesartan or a pharmaceutically acceptable salt thereof.

91. A pharmaceutical composition according to any one of claims 1 to 84 wherein the angiotensin II receptor antagonist is eprosartan or a pharmaceutically acceptable salt thereof.

92. A pharmaceutical composition according to any one of claims 1 to 84 wherein the angiotensin II receptor antagonist is irbesartan, olmesartan, azilsartan or a pharmaceutically acceptable salt thereof.

93. A pharmaceutical composition according to any one of claims 1 to 84 wherein the angiotensin II receptor antagonist is telmisartan or a pharmaceutically acceptable salt thereof.

94. A pharmaceutical composition according to any one of claims 1 to 84 wherein the angiotensin II receptor antagonist is fimasartan, saprisartan, tasosartan, elisartan, or a pharmaceutically acceptable salt thereof.

95. A pharmaceutical composition as defined in any one of claims 1 to 94, for use in a method for treatment of the human or animal body by therapy.

96. A pharmaceutical composition as defined in any one of claims 1 to 94, for use in a method for treatment or prophylaxis of a condition selected from hypertension, heart failure, chronic renal failure, diabetic neuropathy, and a cardiovascular disease.

97. A pharmaceutical composition according to claim 96, for use in a method for treatment or prophylaxis of hypertension.

98. A pharmaceutical composition according to claim 97, for use in a method for treatment or prophylaxis of stroke or heart attack resulting from hypertension.

99. A pharmaceutical composition according to claim 98, for use in a method for treatment or prophylaxis of early-morning stroke or early-morning heart attack resulting from hypertension.

100. A pharmaceutical composition according to claim 96, for use in a method for treatment or prophylaxis of heart failure in patients who are intolerant of angiotensin converting enzyme (ACE) inhibitors.

101. A pharmaceutical composition according to claim 96, for use in a method for treatment or prophylaxis of a cardiovascular disease selected from coronary artery disease, peripheral arterial disease, cerebrovascular disease, renal artery stenosis, aortic aneurysm, cardiomyopathy, hypertensive heart disease, heart failure, pulmonary heart disease, cardiac dysrhythmia, inflammatory heart disease, endocarditis, inflammatory cardiomegaly, myocarditis, valvular heart disease, congenital heart disease and rheumatic heart disease.

102. A pharmaceutical composition according to any one of claims 95 to 101, for use as defined in said claim, wherein the method comprises administering the composition to a subject in need thereof once every dosing interval, and thereby ensuring maintenance of the angiotensin II receptor antagonist within the therapeutic window throughout the dosing interval.

103. A pharmaceutical composition according to claim 102 wherein the dosing interval is 24 hours.

104. A pharmaceutical composition according to any one of claims 95 to 103, for use as defined in said claim, wherein the method comprises administering the composition to a subject in need thereof, and thereby releasing the angiotensin II receptor antagonist from the controlled-release fraction in vivo over a period of x hours from the time of administration of the composition to the subject, wherein x is at least 8.

105. A pharmaceutical composition according to claim 104, for use as defined in said claim, wherein x is at least 10.

106. A pharmaceutical composition according to claim 104 or claim 105, for use as defined in said claim, wherein x is at least 12.

107. A pharmaceutical composition according to any one of claims 104 to 106, for use as defined in said claim, wherein x is at least 15, optionally wherein x is: at least 17, or at least 20.

108. A pharmaceutical composition according to any one of claims 104 to 107 wherein x is up to 24.

109. A pharmaceutical composition according to any one of claims 95 to 108, for use as defined in said claim, wherein the method comprises administering the composition to a subject in need thereof once every dosing interval, and thereby maintaining the angiotensin II receptor antagonist within the therapeutic window for y % of the time during the dosing interval, wherein y is at least 50.

1 10. A pharmaceutical composition according to claim 109, for use as defined in said claim, wherein y is at least 90, preferably at least 95, and most preferably 100.

1 1 1. A pharmaceutical composition according to claim 109 or claim 1 10, for use as defined in said claim, wherein the dosing interval is 24 hours.

1 12. A pharmaceutical composition according to any one of claims 95 to 1 1 1, for use as defined in said claim, wherein the method comprises administering the composition to a subject in need thereof once every dosing interval, and thereby maintaining the angiotensin II receptor antagonist at or above a drug plasma level, 1, in the subject for q % of the time during the dosing interval, wherein q is at least 45.

1 13. A pharmaceutical composition according to claim 1 12, for use as defined in said claim, wherein the dosing interval is 24 hours.

114. A pharmaceutical composition according to claim 112 or claim 113, for use as defined in said claim, wherein q is at least 50, preferably least 65, and more preferably at least 70.

115. A pharmaceutical composition according to any one of claims 112 to 114, for use as defined in said claim, wherein q is at least 75, preferably at least 80, more preferably at least 85.

116. A pharmaceutical composition according to any one of claims 112 to 115, for use as defined in said claim, wherein q is at least 90, preferably at least 95, more preferably 100.

117. A pharmaceutical composition according to any one of claims 112 to 116, for use as defined in said claim, wherein said drug plasma level, 1, is the plasma concentration (IC50) required for obtaining 50% of a maximum therapeutic effect in vivo.

118. A pharmaceutical composition according to any one of claims 112 to 117, for use as defined in said claim, wherein the drug plasma level, 1, is the plasma concentration (IC50) required for obtaining 50% of a maximum reduction in blood pressure in vivo.

119. A pharmaceutical composition according to any one of claims 112 to 118, for use as defined in said claim, wherein the drug plasma level, 1, is 1.2 mg/L.

120. A pharmaceutical composition according to claim 118 or claim 119, for use as defined in said claim, wherein the method is for treatment or prophylaxis of hypertension and the angiotensin II receptor antagonist is valsartan.

121. Use of a pharmaceutical composition as defined in any one of claims 1 to 94 in the manufacture of a medicament for use in the treatment or prophylaxis of a condition selected from hypertension, heart failure, chronic renal failure, diabetic neuropathy and a cardiovascular disease, optionally wherein the treatment or prophylaxis of said condition is as further defined in any one of claims 97 to 120.

122. A method for the treatment or prophylaxis of a condition selected from hypertension, heart failure, chronic renal failure, diabetic neuropathy and a cardiovascular disease, which method comprises administering a pharmaceutical composition as defined in any one of claims 1 to 94 to a subject in need thereof.

123. A method according to claim 122, wherein the method is as further defined in any one of claims 97 to 120.