The compounds of Formula I and their pharmaceutically acceptable salts are HIV integrase inhibitors. These compounds, their preparation, and uses are further described in US 2007/0179196, WO 2005/087767 and WO 2005/087768, the disclosures of which are incorporated by reference herein in their entireties.

An aspect of Embodiment E6 is the formulation as defined in Embodiment E6, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, Xl is fiuoro; χ2 is -H or chloro; R.4 is:

(1) -C(=O)N(Ci-₃ alkyl)2,

(2)

wherein the asterisk * denotes the point of attachment to the rest of the compound,

(3) -C(O)N(Ci -3 alkyl)-(CH2)0-l-cyclopropyl, or

(4) -C(O)N(Ci_3 alkyl)-(CH2)0-l-cyclobutyl; and R5 is -Ci-4 alkyl

In a feature of this aspect, the compound of Formula I is Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A is:

Compound A.

A seventh embodiment of the present invention (Embodiment E7) is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in any of the preceding embodiments, wherein the API is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: R7 is hydrogen, Ci-6 alkyl, (CH2)l-3CF3, O-Ci-6 alkyl, halogen, OH, NO2, CN, 0<CH2)2-3CF3_> CO2RA, CONRARB, O(CH2)2-3NR^AR^B, O(CH2)l-2CORA, S(O)2R^A, or SO2NRARB;

RA and RB are each independently H or Cl -6 alkyl; R3 and R^ are each independently selected from the group consisting of hydrogen, halogen, Ci -6 alkyl and Ci_g fluoroalkyl; and

R4, R5 and Rό are each independently selected from the group consisting of hydrogen, halogen, CN, Ci .5 alkyl and Cμg fluoroalkyl.

The compounds of Formula II and their pharmaceutically acceptable salts are HIV non-nucleoside reverse transcriptase inhibitors. These compounds, their preparation and uses are further described in US 2007/0021442, WO 2007/015809 and WO 2007/015812, the disclosures of which are incorporated by reference herein in their entireties.

In an aspect of Embodiment E7, the compound of Formula π is Compound B, or a pharmaceutically acceptable salt thereof, wherein Compound B is:

Compound B.

As used herein, the term "alkyl" refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, "Cμg alkyl" (or "Ci-Cg alkyl") refers to any of the hexyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso- propyl, ethyl and methyl. As another example, "Ci -4 alkyl" refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.

The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

The term "fluoroalkyl¹' refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a fluorine. Thus, for example, "Ci _g fluoroalkyl" (or "Ci-Cg fluoroalkyl") refers to a Cl to Cg linear or branched alkyl group as defined above with one or more fluorine substituents. Suitable fluoroalkyls include the series (CH2)θ-3CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.). A fluoroalkyl of particular interest is CF3.

The term "cycloalkyl" refers to any monovalent monocyclic ring of an alkane having a number of carbon atoms in the specified range. Thus, for example, "C3-6 cycloalkyl" (or "C3-C6 cycloalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. An asterisk ("*") as the end of an open bond in a chemical group denotes the point of attachment of the group to the rest of the compound.

Combinations of substituents and/or variables are permissible for compounds of Formula I and Formula II only if such combinations result in a stable compound. The present invention includes a process {alternatively referred to herein as

"Process P") for preparing a solid pharmaceutical formulation comprising a hydrophobic active pharmaceutical ingredient, vitamin E TPGS, a filler/spheronization agent, a binder and a superdisintegrant, said solid formulation being in the form of beads, wherein the process comprises: (A) granulating a dry mixture that has been wetted with a solution of the vitamin E TPGS in a granulation fluid to provide a granulated mass, wherein the dry mixture comprises the active pharmaceutical ingredient, the filler/spheronization agent, the binder and the superdisintegrant;

(B) extruding the granulated mass to form an extrudate; (C) spheronizing the extrudate from Step B to provide the beads; and

(D) drying the beads from Step C at a temperature of less than about 35°C; wherein: the active pharmaceutical ingredient is employed in an effective amount; the vitamin E TPGS is employed in an amount of at least about 1 wt.%; the filler/spheronization agent is employed in an amount of at least about 5 wt.%; the binder is employed in an amount of at least about 0.5 wt.%; and the superdisintegrant is employed in an amount of at least about 0.5 wt.%; wherein all of the foregoing weight percents are based on the total weight of all individual components excluding the granulation fluid from the vitamin E TPGS granulation fluid solution.

A first embodiment of Process P (Embodiment El-P) is Process P as originally described above, wherein: the concentration of vitamin E TPGS in the granulation fluid solution is in a range of from about 2 wt.% to about 20 wt.%, and the weight of the granulating solution added to the dry mixture is in a range of from about 20 to about 65 wt.% w/w based on the weight of the dry mixture; the granulation in Step A is conducted using a high shear granulator at an impeller speed in a range of from about 200 rpm to about 600 rpm and a chopper speed of from about 500 rprn to about 2000 rpm for a time in a range of from about 1 to about 10 minutes (e.g., from about 2 to about 8 minutes) to provide the granulated mass; the extrusion in Step B is conducted using a screw or basket extruder fitted with an axial radial or dome screw head at a screw speed in a range of from about 10 rpm to about 60 rpm; the spheronizing in Step C is conducted using a rotating disc spheronizer at a speed in a range of from about 800 rpm to about 2000 rpm, for a time in a range of from about 1 minute to about 15 minutes to provide beads; and the drying in Step D is conducted in an oven at a temperature in a range of from about 30⁰C to about 35°C (e.g., from about 30⁰C to about 32⁰C) to obtain dried beads; wherein:

(i) the beads are approximately spherical in shape and have an average diameter in a range of from about 0.6 mm to about 1.5 mm;

(ii) at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1.2 mm; and

(iii) the beads have a roundness R in the range of from about 1.0 to about 1.5.

A second embodiment of Process P (Embodiment E2-P) is Process P as originally described or as described in Embodiment El-P, wherein: the granulation fluid employed in the vitamin E TPGS solution is water, a Cl -4 alkyl alcohol (e.g., methanol or ethanoϊ), or a mixture of water and a C 1-4 alkyl alcohol (e.g., water + methanol or water + ethanol); the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 20 wt.% (e.g., from about 1 wt.% to about 10 wt.%); the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.% to about 10 wt.%; and the super disintegrant is employed in an amount in a range of from about 1 wt.% to about 10 wt.%.

When the amount of vitamin E TPGS employed is relatively high (e.g., from about 13 wt.% to about 20 wt.%), the granulation fluid is typically water in combination with an alcohol co-solvent. For lower amounts of TPGS, either water alone or a water-alcohol mixture is suitable as the granulation fluid.

A third embodiment of Process P (Embodiment E3-P) is Process P as originally described or as described in either of Embodiments El-P or E2-P, wherein: the filler/spheronization agent is microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinyl pyrollidone; and the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate, A fourth embodiment of Process P (Embodiment E4-P) is Process P as originally described or as described in any of the foregoing embodiments of Process P, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 15 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 5 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 2 wt.% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.% to about 6 wt.%.

A fifth embodiment of Process P (Embodiment E5-P) is Process P as originally described or as described in any of the foregoing embodiments of Process P, wherein the active pharmaceutical ingredient is a compound of Formula I as defined above (see Embodiment E6), a compound of Formula II as defined above (see Embodiment E7), or a pharmaceutically acceptable salt thereof.

A sixth embodiment of Process P (Embodiment E6-P) is Process P as originally described or as described in any of the foregoing embodiments of Process P₅ wherein the active pharmaceutical ingredient is Compound A as defined above, Compound B as defined above, or a pharmaceutically acceptable salt thereof.

A seventh embodiment of Process P (Embodiment E7-P) is Process P as originally described or as described in any of the foregoing embodiments of Process P, wherein Process P further comprises:

(E) encapsulating the dried beads. The present invention also includes the solid pharmaceutical formulations prepared in accordance with Process P as originally described and as described in the foregoing embodiments of Process P.

The present invention includes another process (alternatively referred to herein as "Process Q") for preparing a solid pharmaceutical formulation comprising a hydrophobic active pharmaceutical ingredient, vitamin E TPGS, a filler/spheronization agent, a binder and a superdisintegrant, said solid formulation being in the form of beads, wherein the process comprises: (A) blending a dry mixture comprising the active pharmaceutical ingredient, the vitamin E TPGS in the form of spray-dried granules, the fiϊler/spheronization agent, the binder and the superdisintegrant;

(B) wet granulating the blended mixture of Step A using a granulation fluid comprising water;

(C) extruding the granulated blend to form an extrudate;

(D) spheronizing the extrudate from Step C to provide the beads; and

(E) drying the beads from Step C at a temperature of less than about 35°C; wherein: the active pharmaceutical ingredient is employed in an effective amount; the vitamin E TPGS is employed in an amount of at least about 1 wt.%; the fϊller/spheronization agent is employed in an amount of at least about 5 wt.%; the binder is employed in an amount of at least about 0.5 wt.%; and the superdisintegrant is employed in an amount of at least about 0.5 wt.%; wherein all of the foregoing weight per cents are based on the total weight of all individual components excluding the granulation fluid.

A first embodiment of Process Q (Embodiment El-Q) is Process P as originally described above, wherein: the weight of the granulation fluid added to the blended mixture in Step B is in a range of from about 20 to about 65 wt.% w/w based on the weight of the dry mixture; the wet granulation in Step B is conducted using a high shear granulator at an impeller speed in a range of from about 200 rpm to about 600 rpm and a chopper speed of from about 500 rpm to about 2000 rpm for a time in a range of from about 1 to about 10 minutes to provide the granulated blend; the extrusion in Step C is conducted using a screw or basket extruder fitted with an axial radial or dome screw head at a screw speed in a range of from about 10 rpm to about 60 rpm; the spheronizing in Step D is conducted using a rotating disc spheronizer at a speed in a range of from about 800 rpm to about 2000 rpm, for a time in a range of from about 1 minute to about 15 minutes to provide beads; and the drying in Step E is conducted in an oven at a temperature in a range of from about 30⁰C to about 35°C to obtain dried beads; wherein:

(i) the beads are approximately spherical in shape and have an average diameter in a range of from about 0.6 mm to about 1.5 mm; (ii) at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1 ,2 mm; and

(iii) the beads have a roundness R in the range of 1.0 to 1.5. A second embodiment of Process Q (Embodiment E2-Q) is Process Q as originally described or as described in Embodiment El-Q, wherein: the granulation fluid employed in Step B is water, a Ci_4 alkyl alcohol, or a mixture of water and a Ci_4 alkyl alcohol; the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.% (e.g., from about 5 wt.% to about 75 wt.%); the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 45 wt.% (e.g., from about 5 wt.% to about 45 wt.%); the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.% to about 10 wt.%; and the superdisintegrant is employed in an amount in a range of from about 1 wt.% to about 10 wt.%. A third embodiment of Process Q (Embodiment E3-Q) is Process Q as originally described or as described in either of Embodiments El-Q or E2-Q, wherein: the filler/spheronization agent is microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinyl pyrollidone; and the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate.

A fourth embodiment of Process Q (Embodiment E4-Q) is Process Q as originally described or as described in any of the foregoing embodiments of Process Q, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.% (e.g., from about 20 wt.% to about 50 wt.%); the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 40 wt.% (e.g., from about 10 wt.% to about 35 wt.%); the filler/spheronization agent is employed in an amount in a range of from about

5 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 2 wt.% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.% to about 6 wt.%.

A fifth embodiment of Process Q (Embodiment E5-Q) is Process Q as originally described or as described in any of the foregoing embodiments of Process Q, wherein the active pharmaceutical ingredient is a compound of Formula I as defined above (see Embodiment E6), a compound of Formula II as defined above (see Embodiment E7), or a pharmaceutically acceptable salt thereof.

A sixth embodiment of Process Q (Embodiment E6-Q) is Process Q as originally described or as described in any of the foregoing embodiments of Process Q, wherein the active pharmaceutical ingredient is Compound A as defined above, Compound B as defined above, or a pharmaceutically acceptable salt thereof.

A seventh embodiment of Process Q (Embodiment E7-Q) is Process Q as originally described or as described in any of the foregoing embodiments of Process Q, wherein Process Q further comprises:

(F) encapsulating the dried beads.

The present invention also includes the solid pharmaceutical formulations prepared in accordance with Process Q as originally described and as described in the foregoing embodiments of Process Q, All processing steps in Processes P and Q are conducted at temperatures less than the melting point of vitamin E TPGS, and typically all processing steps other than the drying step are conducted at ambient temperatures (i.e., 2O⁰C to 25°C). Bead drying is typically conducted at temperatures of about 35°C or less (e.g., from about 30⁰C to about 35°C). The extruding step in Processes P and Q is typically conducted under ambient pressure conditions. While either Process P or Process Q can be employed to prepare bead formulations of the present invention, Process Q is typically more suitable for the preparation of bead formulations containing relatively large amounts (i.e., about 15 wt.% or more) of vitamin E TPGS. Process P utilizes a solution of TPGS and requires the use of a relatively large amount of granulation fluid in order to incorporate a large amount (i.e., more than about 15 wt.%) of TPGS in the bead formulation. On the other hand, Process Q employs TPGS in a solid form and thus increasingly larger quantities of granulation fluid are not required to prepare bead formulations with progressively higher TPGS concentrations.

Process P and Process Q can avoid the problems associated with the preparation of formulations containing high TPGS levels using conventional process trains wherein the melting of the TPGS can occur under the thermal conditions typically encountered in the milling and compacting steps. Furthermore, the processes of the invention can accommodate relatively large amounts of granulation fluid and potential over-granulation in Step A, because, unlike in a conventional granulation process, downstream processing involves extruding to strands followed by spheronization to larger beads. The need for granule growth control is greater for a conventional process than the process of the invention and thus the described process is more forgiving with respect to granule size and uniformity. Because Process P can employ relatively large amounts of fluid, it permits the incorporation of higher levels of TPGS than is practical with conventional processing.

Abbreviations employed herein include the following: API = active pharmaceutical ingredient; g = gram(s); GFL = Granulation fluid; HPC = hydroxypropyl cellulose; TPGS = tocopherol polyethylene glycol succinate.

The following examples serve only to illustrate the invention and its practice. The examples are not to be construed as limitations on the scope or spirit of the invention.

In Examples 1 to 5, all processing steps prior to the oven drying step the temperature was at or close to ambient (i.e., 20 to 25°C).

EXAMPLE 1 Preparation of a formulation of Compound A via extrusion spheronization

Compound A, microcrystalline cellulose (Avicel PH 101), hydroxypropyl cellulose and croscarmellose sodium in the proportions set forth in Table 1 below (excluding the amount of the PH 101 that was sprinkled on extrudate as noted below) were transferred to the bowl of a high shear granulator (Bohle mini granulator Model No. A-Nr 60628) and dry mixed for 5 minutes at an impeller speed of 200 rpm and a chopper speed of 500 rpm. A 20 wt.% aqueous solution of vitamin E TPGS was then gradually added to the dry mixture. The impeller speed was increased to 250 rpm during the addition of the aqueous solution and the chopper speed was maintained at 500 rpm. Approximately 12,5 g of the vitamin E TPGS solution was added to provide 2.5 g of vitamin E TPGS per se, thus providing for a theoretical total batch size of 25 g in which vitamin E TPGS represented 10 wt.% of the total weight of the dry components (i.e., excluding water). The resulting granulated wet mass was then extruded on a lab scale basket extruder (CaI eva Model No. 10) fitted with a screen having an aperture size of 1 mm and operated at 30 rpm, followed by spheronization of the extrudate in a spheronizer (Caleva Model No. 120 ) operated at a speed of 1000 rpm for 5 minutes to provide beads. Approximately 1 g of the Avicel PH 101 was sprinkled on the extrudate during the spheronization to avoid aggregation of the beads. The beads were dried in an oven at 32⁰C for 24 hours to obtain 75 wt.% Compound A-loaded beads. Table 1

Figure 1 is an optical micrograph of a sample of the dried beads prepared in the manner described above. The diameter of the beads obtained by this process is primarily dependent upon the aperture size of the screen used during the extrusion process. In the current case, an aperture size of 1 mm yielded beads in the size range of 0.8 to 1.2 mm.

Figure 2 is a plot of R for beads prepared in the same manner as those described above. The R values were determined using an Olympus SZXl 6 microscope in conjunction with 'Image Pro Plus' version 4.5.0.29 for Windows 2000. A description of the software application can be found in the Image-Pro® Plus manual MAN 7841N42 20010530 (Media Cybernetics Inc, Silver Spring, MD), the disclosure of which is incorporated by reference herein in its entirety. The median R value is 1.11 , and the range of R values is from about 1.09 to about 1 ,19,

The optical microscope and Image Pro-Plus software described in the preceding paragraph were also used to measure the diameters of the beads. The bead diameters were determined to be in a range of from about 0.85 mm to 1.19 mm, and the median diameter of the beads was 0.96 mm.

EXAMPLE 2 Preparation of a formulation of Compound A via extrusion spheronization A formulation containing Compound A was prepared as follows using a batch size of 200 g in which the components were employed in the relative amounts set forth in Table 1 of Example 1 above; Weighed amounts of Compound A, microcrystalline cellulose (Avicel PH 101) (excluding the amount sprinkled on the extrudate as describe below), HPC₃ and croscarmellose sodium were transferred to the bowl of a high shear granulator (Diosna Model No. P-l/6) and dry mixed for 90 seconds at an impeller speed of 300 rpm and a chopper speed of 2000 rpm. A 20 wt.% aqueous solution of vitamin E TPGS was then gradually added using a spray gun at a rate of 40 g/minute, wherein the impeller speed and the chopper speed were maintained at 300 rpm and 2000 rpm respectively during the addition. A total of approximately 100 g of the vitamin E TPGS solution was added resulting in the addition of 10 wt.% dry vitamin E TPGS. The wet mass obtained upon granulation was then extruded using a screw extruder (Fuji Paudal Model No. MG- 55) fitted with a dome extrusion head at a screw speed of 30 rpm, wherein the extrusion head had an opening size and a die thickness of 1 mm. The extrudate was spheronized using a rotating disc spheronizer (Fuji Paudal Model No. QJ230T) at around 1200 rpm. MicrocrystalHne cellulose (2-3 g of Avicel PH 101) was sprinkled on the extrudate during the spheronization to avoid aggregation of the beads. The beads were dried in an oven at 32°C for 24 hours to obtain 75 wt.% Compound A-loaded beads.

The resulting beads were characterized in the manner described in Example 1. Figure 3 is a plot of R for the beads prepared as just described. The median R value is 1.11, and the range of R values is from about 1.07 to about 1.19. The beads had diameters in a range of from about 0.77 mm to about 1.19 mm, and a median diameter of 0.95 mm.

EXAMPLE 3 Preparation of a formulation of Compound A via extrusion spheronization

Table 2

A formulation containing Compound A was prepared as follows using a batch size of 200 g in which the components were employed in the relative amounts set forth in Table 2. Weighed amounts of Compound A, spray dried granular TPGS, microcrystalline cellulose (Avicel PH 101) (excluding the amount sprinkled on the extrudate as described below), HPC, and croscarmellose sodium were transferred to the bowl of a high shear granulator (Diosna Model No. P- 1/6) and dry mixed for 3 minutes at an impeller speed of 300 rpm and a chopper speed of 1000 rpm. After the dry mixing deionized water was gradually added using a spray gun at a rate of 26 g/minute, during which time the impeller speed and the chopper speed were maintained at 300 rpm and 1000 rpm respectively, A total of approximately 56 g of water as GFL was added. The wet mass obtained upon granulation was then extruded using a screw extruder (Fuji Paudal Model No. MG- 55) fitted with a dome extrusion head at a screw speed of 30 rpm, wherein the extrusion head had an opening size and a die thickness of 1 mm. The extrudate was spheronized using a rotating disc spheronizer (Fuji Paudal Model No. QJ230T) at around 1200 rpm. Microcrystalline cellulose (-20 g of Avicel PH 101) was sprinkled on the extrudate during the spheronization to avoid aggregation of the beads. The beads were dried in an oven at 32⁰C for 24 hours to obtain 37.4 % w/w Compound A-loaded beads.

EXAMPLE 4

Preparation of a formulation of Compound A via conventional high shear wet granulation Compound A, microcrystalline cellulose (Avicel PH 101), hydroxypropyl cellulose and croscarmellose sodium in the proportions shown in Table 3 were transferred to a high shear granulator (Bohle mini granulator) bowl and dry mixed for 5 minutes at an impeller speed of 200 rprn and a chopper speed of 500 rpm, after which a 20% w/w solution of vitamin E TPGS in water was gradually added while the impeller speed was increase to 250 rpm and the chopper speed was maintained 500 rpm. A total of approximately 12.5 g of the TPGS solution was added to a theoretical total batch size of 25 g resulting in the addition of 10% w/w dry vitamin E TPGS. The granulation was dried in an oven at 32°C for 24 hours to obtain 61.54% w/w/ of drug-loaded granules. An attempt to encapsulate the granules was unsuccessful - the encapsulator became stuck and would not run.

Table 3

EXAMPLE 5 Preparation of a formulation of Compound A via conventional high shear wet granulation

A formulation containing the components and amounts shown in Table 4 was prepared using the procedure set forth in Example 4.

Table 4

EXAMPLE 6 Bioperformance Study

Pharmacokinetic (PK) values for Compound A were determined in Beagle dogs orally dosed with encapsulated beads (pellets) prepared in the manner described in Example 1 and with encapsulated granules prepared in the manner described in Example 5. Fasted male beagle dogs (Marshall Farms) were used in the studies. The dogs were housed in an AAALAC- accredited facility in accordance with USDA guidelines. Studies were conducted under a protocol approved by the WP-IACUC. 3 dogs were employed in each study. The dose was approximately 10 mg per kg of body weight (i.e., 10 mpk).

Dosing: Following an overnight fast, the dogs were orally administered encapsulated formulations followed by 3.5 mL/kg of water. Food was returned 4 hours after dosing. Blood was drawn from 21 gauge catheters placed in the cephalic vein at pre-dose, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours after dosing. The plasma was separated by centrifugation (15 minutes at 2500 g) and stored overnight at -7O⁰C for LC/MS/MS the following day.

Sample preparation and analysis: The plasma samples were extracted using protein precipitation. Plasma extracts were injected onto a Waters Atlantis dC18, 2.1 x 50 mm, 5 μm HPLC column and analyzed using a 4.11 minute gradient consisting of mobile phase A = 0.1% formic acid in water and mobile phase B = 0.1% formic acid in acetonitrile. The following gradient was used: 20%B to 95% B in 1.0 minute, hold at 95%B for 2.0 minutes, then re- equilibrate to 20%B for 1.1 minutes. Column oven temperature was 40⁰C. The flow rate was 0.3 mL/min. The sample extracts were ionized using a Turbolonspray interface and were monitored by selected reaction monitoring (SRM) in the negative ionization mode. The dynamic range of the LC/MS/MS assay was 5-3000 ng/mL based on a 50 μL aliquot of dog plasma

PK Calculations: Area under the curve (AUCθ-24hr)_> observed maximum plasma concentration (C_maχ), and time of C_max (Tmax)^were calculated using a linear trapezoidal, non- compartmental model of WinNonLin v5.01. Means and SE were calculated using WinNonlin v5.01 or Microsoft^® Excel 2002 SP3. Plasma profiles were generated using Sigmaplot 9.0 or WinNonlin v5.01 The results are shown in Table 5.

Table 5

1. The value in parentheses in each table entry is the standard deviation.

2. AUC ratio is the ratio of the AUCs in the table with respect to the AUC of Example 5.

The results in Table 5 show that the bead formulation of Example 1 with a surfactant to drug w/w ratio of 1 : 7.5 provided in vivo exposures comparable to those achieved with the granulated formulation of Example 5 having a surfactant to drag w/w ratio of 1 : 2.5. In other words, the bead formulation obtained via extrusion spheronization provided a PK profile comparable to that of an analogous granulated formulation containing 3 -fold more surfactant obtained by high-shear extrusion but without spheronization.

EXAMPLE 7 Bioperformance Study

A bead formulation of Compound A (Formulation 7-1) was prepared via extrusion spheronization in a manner similar to that described in Example 1. A granule formulation of Compound A (Formulation 7-2) was prepared via conventional high shear granulation in a manner similar to that described in Example 4. The compositions of Formulations 7-1 and 7-2 are shown in Tables 6 and 7 respectively. Table 6- Formulation 7-1

Formulations 7-1 and 7-2 were tested in dogs using a protocol similar to that described above in Example 6. The results are shown in Table 7

Table 7

The bead formulation of Example 7-1 and the granule formulation of Example 7-2 have about the same surfactant to drug w/w ratios; i.e., 1 :7.2 and 1 :7.5 respectively. The results in Table 7 show that the bead formulation provided in vivo exposures the same or better than those achieved the granule formulation. However, the bead formulation of 7-1 had a C24 hr about 5x higher than that achieved by granulated formulation 7-2, indicating that the overall PK profile of the bead formulation is superior.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, the practice of the invention encompasses all of the usual variations, adaptations and/or modifications that come within the scope of the following claims. All publications, patents, and patent applications cited herein are incorporated by reference herein in their entireties into the disclosure.

Claims

WHAT IS CLAIMED IS:

1. A solid pharmaceutical formulation for oral administration which comprises: (a) an effective amount of a hydrophobic active pharmaceutical ingredient,

(b) at least about 1 wt.% of vitamin E TPGS,

(c) at least about 5 wt.% of a filler/spheronization agent,

(d) at least about 0.5 wt.% of a binder, and

2. The formulation according to claim 1, wherein substantially all of the beads are approximately spherical in shape; the beads have an average diameter in a range of from about 0.6 mm to about 1.5 mm; at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1.2 mm; and the beads have a roundness value in a range of from about 1.0 to about 1.5.

3. The formulation according to claim 1 or claim 2, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 40 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.% to about 10 wt.%; and the superdisintegrant is employed in an amount in a range of from about 1 wt.% to about 10 wt.%.

4. The formulation according to claim 3, wherein: the filler/spheronization agent is microcrystallme cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose ; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or povidone; and the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate.

5. The formulation according to claim 4, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 40 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 5 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 2 wt.% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.% to about 6 wt.%.

6. The formulation according to any one of claims 1 to 5, wherein the active pharmaceutical ingredient is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

XMs:

0) -H₃ (2) bromo,

(3) chloro,

(4) fluoro, or

(5) methoxy;

X2 is: (1) -H,

(2) bromo,

(3) chloro,

(4) fluoro,

(5) methoxy, (6) -Ci_4 alkyl,

(V) -CF₃,

(8) -OCF₃, (9) -CN, or

(10) -SO2(Ci-₄ alkyl);

Rl is:

(1) -CO₂H,

(2) -C(O)-O-CM alkyl,

(3) -C(O)NH₂,

(4) -C(=O)NH-C i_4 alkyl,

(5) -CCO)N(Ci-4 alkyl)₂,

(6) -C(O)-NH-(CH₂)₂-3-0-Ci-4 alkyl,

(7) -C(O)-NCCM alkyrKCH2)2-3-O-Ci-4 alkyl,

(8) -NHC(O)-C 1-4 alkyl,

(9) -N(C 1.4 alkyl)C(O)-Ci-4 alkyl,

(10) -NHSO₂-C 1-4 alkyl,

(11) -N(CM alkyl)Sθ2-Cμ4 alkyl,

(12)

rest of the compound,

(13) -C(O)NH-(CH₂)O-I ~(C3-ό cycloalkyl), (14) -C(O)N(CM alkyl)-(CH₂)0-l-(C3-6 cycloalkyl),

(15) -C(O)NH-CH₂-ρhenyl, or

(16) -C(O)N(Ci-4 alkyl)-CH₂-ρhenyl; and R2 is:

(1) -H, (2) -Ci -4 alkyl,

(3) cyclopropyl,

(4) cyclobutyl,

(5) -CH₂- cyclopropyl,

(6) -CH₂-cycIobutyl, or (7) -CH₂-phenyl.

7. The formulation according to claim 6, wherein the active pharmaceutical ingredient is Compound A:

Compound A,

or a pharmaceutically acceptable salt thereof.

8. The formulation according to any one of claims 1 to 5, wherein the active pharmaceutical ingredient is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R7 is hydrogen, C\.(, alkyl, (CH2)l-3CF3, OCi -6 alkyl, halogen, OH, NO2, CN, O(CH2)2-3CF3, CC>2R^A_> CONRARB, O(CH2)2 -3NRARB₅ 0(CH2)1-2CORA_J S(O)2R^A, or SO2NRARB;

RA and RB are each independently H or Ci_6 alkyl;

R3 and R8 are each independently selected from the group consisting of hydrogen, halogen, C\_~β alkyl and Ci_6 fluoroalkyl; and

R4_? R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, CN, Cl -6 alkyl and Cl -6 fluoroalkyl.

9. The formulation according to claim 8, wherein the active pharmaceutical ingredient is Compound B:

Compound B, or a pharmaceutically acceptable salt thereof.

10. The formulation according to any one of claims 1 to 9, wherein the beads are encapsulated.

I L A process for preparing a solid pharmaceutical formulation comprising a hydrophobic active pharmaceutical ingredient, vitamin E TPGS, a filler/spheronization agent, a binder and a superdisintegrant, said solid formulation being in the form of beads, wherein the process comprises:

(A) granulating a dry mixture that has been wetted with a solution of vitamin E TPGS in a granulation fluid to provide a granulated mass, wherein the dry mixture comprises the active pharmaceutical ingredient, the filler/spheronization agent, the binder and the superdisintegrant;

(B) extruding the granulated mass to form an extradate;

(C) spheronizing the extrudate from Step B to provide the beads; and (D) drying the beads from Step C at a temperature of less than about 35°C; wherein: the active pharmaceutical ingredient is employed in an effective amount; the vitamin E TPGS is employed in an amount of at least about 1 wt.%; the filler/spheronization agent is employed in an amount of at least about 5 wt.%; the binder is employed in an amount of at least about 0.5 wt.%; and the superdisintegrant is employed in an amount of at least about 0.5 wt.%; wherein all of the foregoing weight percents are based on the total weight of all individual components excluding the granulation fluid from the vitamin E TPGS granulation fluid solution.

12. The process according to claim 11 , wherein: the concentration of vitamin E TPGS in the granulation fluid solution is in a range of from about 2 wt.% to about 20 wt.%, and the weight of the granulating solution added to the dry mixture is in a range of from about 20 to about 65 wt.% w/w based on the weight of the dry mixture; the granulation in Step A is conducted using a high shear granulator at an impeller speed in a range of from about 200 rpm to about 600 rpm and a chopper speed of from about 500 rpm to about 2000 rpm for a time in a range of from about 1 to about 10 minutes to provide the granulated mass; the extrusion in Step B is conducted using a screw or basket extruder fitted with an axial radial or dome screw head at a screw speed in a range of from about 10 rpm to about 60 rpm; the spheronizing in Step C is conducted using a rotating disc spheronizer at a speed in a range of from about 800 rpra to about 2000 rpm, for a time in a range of from about 1 minute to about 15 minutes to provide beads; and the drying in Step D is conducted in an oven at a temperature in a range of from about 30⁰C to about 35⁰C to obtain dried beads; wherein:

(i) the beads are approximately spherical in shape and have an average diameter in a range of from about 0.6 mm to about 1.5 mm',

(ii) at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1.2 mm; and (iii) the beads have a roundness R in the range of 1 ,0 to 1.5.

13. The process according to claim 11 or claim 12, which further comprises: (E) encapsulating the dried beads from Step D.

14. The process according to any one of claims 11 to 13, wherein: the granulation fluid employed in the vitamin E TPGS solution is water, a C\ -.4 alkyl alcohol, or a mixture of water and a C] .4 alkyl alcohol; the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 20 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.% to about 10 wt.%; and the superdisintegrant is employed in an amount in a range of from about 1 wt.% to about 10 wt.%.

15. The process according to claim 14, wherein: the filler/spheronization agent is microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinyl pyrollidone; and the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate.

16. The process according to claim 14 or claim 15, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 15 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 5 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 2 wt.% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.% to about 6 wt.%.

17. The process according to any one of claims 11 to 16, wherein the active pharmaceutical ingredient is a compound of Formula I as defined in claim 6, a compound of Formula II as defined in claim 8, or a pharmaceutically acceptable salt thereof.

18. The process according to any one of claims 11 to 16, wherein the active pharmaceutical ingredient is Compound A as defined in claim 7, Compound B as defined in claim 9, or a pharmaceutically acceptable salt thereof.

19. A solid pharmaceutical formulation prepared according to the process recited in any one of claims 11 to 18.

20. A process for preparing a solid pharmaceutical formulation comprising a hydrophobic active pharmaceutical ingredient, vitamin E TPGS, a filler/spheronization agent, a binder and a superdisintegrant, said solid formulation being in the form of beads, wherein the process comprises:

(A) blending a dry mixture comprising the active pharmaceutical ingredient, the vitamin E TPGS in the form of spray-dried granules, the filler/spheronization agent, the binder and the superdisintegrant;

(C) extruding the granulated blend to form an extrudate;

(D) spheronizing the extrudate from Step C to provide the beads; and (E) drying the beads from Step C at a temperature of less than about 35⁰C; wherein: the active pharmaceutical ingredient is employed in an effective amount; the vitamin E TPGS is employed in an amount of al least about 1 wt.%; the filler/spheronization agent is employed in an amount of at least about 5 wt.%; the binder is employed in an amount of at least about 0.5 wt.%; and the superdisintegrant is employed in an amount of at least about 0.5 wt.%; wherein all of the foregoing weight percents are based on the total weight of all individual components excluding the granulation fluid.

21. The process according to claim 20, wherein: the weight of the granulation fluid added to the blended mixture in Step B is in a range of from about 20 to about 65 wt.% w/w based on the weight of the dry mixture; the wet granulation in Step B is conducted using a high shear granulator at an impeller speed in a range of from about 200 rpm to about 600 rpm and a chopper speed of from about 500 rpm to about 2000 rpm for a time in a range of from about 1 to about 10 minutes to provide the granulated blend; the extrusion in Step C is conducted using a screw or basket extruder fitted with an axial radial or dome screw head at a screw speed in a range of from about 10 rpm to about 60 rpm; the spheronizing in Step D is conducted using a rotating disc spheronizer at a speed in a range of from about 800 rpm to about 2000 rpm, for a time in a range of from about 1 minute to about 15 minutes to provide beads; and the drying in Step E is conducted in an oven at a temperature in a range of from about 3O⁰C to about 35°C to obtain dried beads; wherein:

(i) the beads are approximately spherical in shape and have an average diameter in a range of from about 0.6 mm to about 1.5 mm; (ii) at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1.2 mm; and

(iii) the beads have a roundness R in the range of 1.0 to 1.5.

22. The process according to claim 20 or claim 21 , which further comprises: (F) encapsulating the dried beads from Step E.

23. The process according to any one of claims 20 to 22, wherein: the granulation fluid employed in Step B is water, a C 1-4 alkyl alcohol, or a mixture of water and a Cl -4 alkyl alcohol; the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 45 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.% to about 10 wt.%; and the superdisintegrant is employed in an amount in a range of from about 1 wt.% to about 10 wt.%.

24. The process according to claim 23, wherein: the filler/spheronization agent is microcrystalline cellulose, carboxymethyl cellulose, starch or a mixture of microcrystalline cellulose and carboxymethyl cellul ose; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinyl pyrollidone; and the superdisintegrant is croscarrnellose Na, crospovidone or sodium starch glycolate.

25. The process according to claim 23 or claim 24, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 40 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 5 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 2 wt,% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.% to about 6 wt.%.

26. The process according to any one of claims 20 to 25, wherein the active pharmaceutical ingredient is a compound of Formula I as defined in claim 6, a compound of Formula H as defined in claim 8, or a pharmaceutically acceptable salt thereof.

27. The process according to any one of claims 20 to 25 , wherein the active pharmaceutical ingredient is Compound A as defined in claim 7, Compound B as defined in claim 9, or a pharmaceutically acceptable salt thereof.

28. A solid pharmaceutical formulation prepared according to the process recited in any one of claims 20 to 27.