Invention content
It is an object of the present invention to provide new solid-state form of the Valsartan sand library than bent trisodium salt composite, these figured silk fabricsSha Tanshaku solid-state form preparation methods newer than bent trisodium salt composite are simple, crystal form is easily controllable, stability and dissolubility are goodIt is good.
Another object of the present invention is to provide preparation of the Valsartan sand library than the new solid-state form of bent trisodium salt compositeMethod.
It is newer than bent trisodium salt composite another object of the present invention is to provide the Valsartan sand library for including therapeutically effective amountThe pharmaceutical composition of solid-state form.
Another object of the present invention is to provide Valsartan sand library solid-state form newer than bent trisodium salt composite to prepare useIn prevention or the purposes of the drug of chronic heart failure or hypertension.
In order to achieve the above-mentioned object of the invention, present invention firstly provides a kind of Valsartan sand library than bent trisodium salt composite crystalline substanceType A.
Further, the present invention provides a kind of Valsartan sand library is more amorphous α than bent trisodium salt composite.
Further, the present invention provides a kind of amorphous β of Valsartan-Sha Kubi songs trisodium salt composite.
Further, the present invention provides a kind of amorphous γ of Valsartan-Sha Kubi songs trisodium salt composite.
Further, the present invention provides above-mentioned Valsartan sand library is more husky than bent trisodium salt composite crystal form A and ValsartanThe library preparation method more amorphous α, β, γ than bent trisodium salt composite.
Further, the present invention provides containing above-mentioned Valsartan sand library than bent trisodium salt composite crystal form A, ValsartanMixture more amorphous α, β, γ than bent trisodium salt composite Sha Ku.
Further, the present invention provides more husky than bent trisodium salt composite crystal form A or figured silk fabrics containing above-mentioned Valsartan sand libraryPharmaceutical composition more amorphous α, β, γ than bent trisodium salt composite Tan Shaku.
Further, the present invention provides above-mentioned Valsartan sand library is more husky than bent trisodium salt composite crystal form A or ValsartanLibrary it is more amorphous α, β, γ than bent trisodium salt composite preparing for preventing or chronic heart failure or hypertensionThe purposes of drug.
Valsartan sand library is than bent trisodium salt composite crystal form A
Powder x-ray diffraction collection of illustrative plates of the Valsartan sand library provided by the invention than bent trisodium salt composite crystal form A (usesCu-K α radiate) feature be：It it is 4.1 ° ± 0.2 °, 4.9 ° ± 0.2 °, 5.0 ° ± 0.2 °, 5.6 ° ± 0.2 °, 12.5 ° in 2 θ values± 0.2 °, 16.9 ° ± 0.2 °, 20.0 ° ± 0.2 ° is waited positions to be corresponding with characteristic diffraction peak.
In one embodiment, Valsartan sand library of the present invention is than the powder of bent trisodium salt composite crystal form AThe feature of X-ray diffracting spectrum (being radiated using Cu-K α) is：2 θ values for 4.1 ° ± 0.2 °, 4.9 ° ± 0.2 °, 5.0 ° ±0.2°、5.6°±0.2°、8.3°±0.2°、12.5°±0.2°、14.8°±0.2°、16.9°±0.2°、17.6°±0.2°、18.0 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.3 ° ± 0.2 °, 20.0 ° ± 0.2 °, 25.1 ° ± 0.2 °, 29.1 ° ± 0.2 ° is waited positionsIt is corresponding with characteristic diffraction peak.
In one embodiment, Valsartan sand library provided by the invention has such as than bent trisodium salt composite crystal form AFeature representated by powder x-ray diffraction collection of illustrative plates shown in FIG. 1.
In one embodiment, Valsartan sand library provided by the invention is than the crystal form of bent trisodium salt composite crystal form APurity (i.e. Valsartan sand library is than the mass percentage of bent trisodium salt composite crystal form A) is generally higher than 70%, preferably greater than80%, most preferably greater than 90%.The content can pass through powder x-ray diffraction method, differential scanning calorimetry (DSC) method or infraredAbsorption spectrometry etc. measures.
The present invention also provides a kind of preparation method of Valsartan sand library than bent trisodium salt composite crystal form A, this method packetsIt includes：
(1) Valsartan and Sha Ku ratio songs are dissolved in ethyl alcohol；
(2) alkaline sodium compound is dissolved in water；
(3) solution that step (2) obtains with the solution that step (1) obtains is mixed, adds in anti-solvent and solid is precipitated；
(4) solid be precipitated is detached；
(5) optionally, solid step (4) isolated is dry at 20~50 DEG C.
In above-mentioned steps (1), the Valsartan is the drug listed for many years, commercially viable to buy or be according toIt is prepared by the method known.For example, the preparation of Valsartan is described in US5399578 and EP0443983, these documents pass through referenceMode is incorporated into the application.The sand library can be made than song according to the method disclosed in patent document US5217996A, thisA little documents are incorporated into the application by reference.
In above-mentioned steps (1), Valsartan is generally 1 with husky library than the bent mol ratio that feeds intake:0.8~1.2, preferably 1:0.9~1.1.
In above-mentioned steps (1), the weight proportion of ethyl alcohol and Valsartan is generally 2:1~15:1, preferably 5:1~10:1.
In above-mentioned steps (2), alkaline sodium compound may be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide or ethyl alcoholSodium etc., preferably sodium hydroxide, sodium methoxide or sodium ethoxide.
In above-mentioned steps (2), the mol ratio that feeds intake of sodium and Valsartan in step (1) is generally in alkaline sodium compound2.8~5:1, preferably 2.9~3.5:1.
In above-mentioned steps (2), the weight ratio of water and alkaline sodium compound is generally 0.5:1~10:1, preferably 0.5~5:1.
In above-mentioned steps (3), " anti-solvent " refers to prepared compound poor solubility and can be mutual with ethyl alcohol or waterMolten solvent.These anti-solvents are selected from acetone, butanone, pentanone, cyclohexanone, Ethyl formate, methyl acetate, ethyl acetate, acetic acidIsopropyl ester, butyl acetate, ether, isopropyl ether, n-butyl ether, glycol monoethyl ether, glycol dimethyl ether, t-butyl methyl ether, firstBenzene, dimethylbenzene etc. or their mixture, wherein it is preferred that isopropyl acetate and ethyl acetate.The anti-solvent and step (3)The volume ratio of mixed solvent is generally 0.5:1~20:1.It can be standing or stirring that solid process, which is precipitated,.
In the step of above-mentioned preparation method (4), the routine side in the art such as filtering may be used in " separation "Method.
In the step of above-mentioned preparation method (5), the temperature of " drying " is generally 20~50 DEG C；Can with constant pressure and dry,It can also be dried under reduced pressure.
Valsartan sand library is more amorphous α than bent trisodium salt composite
The Valsartan sand library provided by the invention powder x-ray diffraction collection of illustrative plates more amorphous α than bent trisodium salt composite (makesWith Cu-K α radiate) feature be：Nearby there is peak for 4.5 °, 20.5 ° and 31.6 ° in 2 θ values.Wherein " near " general for 4.5 °Range for the range of ± 0.5 ° of range, preferably ± 0.3 °, more preferably ± 0.2 °；The range for being generally ± 2 ° for 20.5 °,It is preferred that the range of ± 1 ° of range, more preferably ± 0.5 °；For 31.6 ° generally ± 0.5 ° of range.
In one embodiment, Valsartan sand library provided by the invention is more amorphous α than bent trisodium salt composite hasFeature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 2.
Valsartan-Sha Kubi is bent in the Valsartan-Sha Kubi song trisodium salt composite mix of preparation provided by the inventionThe content (mass content) of the amorphous α of trisodium salt composite is generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.It will be appreciated by persons skilled in the art that Valsartan-Sha Kubi songs trisodium salt composite of the present invention is referred to changeWhat synthetic method was synthetically prepared contains impurity or the Valsartan other crystal forms of-Sha Kubi song trisodium salt composites or unbodied figured silk fabricsSha Tan-Sha Kubi song trisodium salt composites.
In one embodiment, water content during Valsartan sand library is more amorphous α than bent trisodium salt composite for 0.2~20%, in another embodiment, water content during Valsartan sand library is more amorphous α than bent trisodium salt composite for 2~15%, in another embodiment, water content during Valsartan sand library is more amorphous α than bent trisodium salt composite for 4~15%, in another embodiment, water content during Valsartan sand library is more amorphous α than bent trisodium salt composite for 5~15%, in another embodiment, water content during Valsartan sand library is more amorphous α than bent trisodium salt composite for 6~15%, in another embodiment, water content during Valsartan sand library is more amorphous α than bent trisodium salt composite for 7~15%.
The present invention also provides the preparation method that a kind of Valsartan sand library is more amorphous α than bent trisodium salt composite, this methodIncluding：
(1) Valsartan and Sha Ku ratio songs are dissolved in ethyl alcohol；
(2) alkaline sodium compound is dissolved in water；
(3) solution that step (2) obtains with the solution that step (1) obtains is mixed, adds in anti-solvent and solid is precipitated；
(4) solid be precipitated and the drying at 80~120 DEG C are detached.
In the step of above-mentioned preparation method (1), Valsartan is generally 1 with husky library than the bent mol ratio that feeds intake:0.8~1.2, preferably 1:0.9~1.1.
In the step of above-mentioned preparation method (1), the weight proportion of ethyl alcohol and Valsartan is generally 2:1~15:1, preferably 5:1~10:1.
In the step of above-mentioned preparation method (2), alkaline sodium compound may be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, firstSodium alkoxide or sodium ethoxide etc., preferably sodium hydroxide, sodium methoxide or sodium ethoxide.
In the step of above-mentioned preparation method (2), sodium mole is matched with feeding intake for Valsartan in step (1) in alkaline sodium compoundThan being generally 2.8~5:1, preferably 2.9~3.5:1.
In the step of above-mentioned preparation method (2), the weight ratio of water and alkaline sodium compound is generally 0.5:1~10:1, it is excellentSelect 0.5~5:1.
In the step of above-mentioned preparation method (3), " anti-solvent " refers to prepared compound poor solubility and can be withThe solvent that ethyl alcohol or water dissolve each other.These anti-solvents are selected from acetone, butanone, pentanone, cyclohexanone, Ethyl formate, methyl acetate, acetic acidEthyl ester, isopropyl acetate, butyl acetate, ether, isopropyl ether, n-butyl ether, glycol monoethyl ether, glycol dimethyl ether, tertiary butylMethyl ether, toluene, dimethylbenzene etc. or their mixture, wherein it is preferred that isopropyl acetate and ethyl acetate.The anti-solvent withThe volume ratio of the mixed solvent of step (3) is generally 0.5:1~20:1.Be precipitated solid process can be stand orStirring.
In the step of above-mentioned preparation method (4), the routine side in the art such as filtering may be used in " separation "Method.
In the step of above-mentioned preparation method (4), the temperature of " drying " is generally 80~150 DEG C, preferably 110~140℃；It can also be dried under reduced pressure with constant pressure and dry.
Valsartan sand library is more amorphous β than bent trisodium salt composite
The powder x-ray diffraction collection of illustrative plates of the amorphous β of Valsartan-Sha Kubi songs trisodium salt composite provided by the invention (makesWith Cu-K α radiate) feature be：Peak nearby is corresponding with for 4.0 ° and 20.5 ° in 2 θ values, in 2 θ values for 31.6 ° nearby without correspondencePeak.Wherein the specific location of " correspondence " is the vertex at peak.Wherein " near " for 4.0 ° of generally ± 0.5 ° of ranges, preferablyThe range of ± 0.3 ° of range, more preferably ± 0.2 °；It is more excellent for the range of 20.5 ° generally ± 2 ° of range, preferably ± 1 °The range of ± 0.5 ° of choosing；For 31.6 ° generally ± 0.5 ° of range.
In one embodiment, the amorphous β of Valsartan-Sha Kubi songs trisodium salt composite provided by the invention hasFeature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 3.
In one embodiment, the Valsartan-Sha Kubi song trisodiums salt composite mixing of preparation provided by the inventionThe content (mass content) of the amorphous β of Valsartan-Sha Kubi songs trisodium salt composite is generally higher than 70% in object, preferably greater than80%, most preferably greater than 90%.
It will be appreciated by persons skilled in the art that Valsartan-Sha Kubi songs trisodium salt composite of the present invention refers toBe the figured silk fabrics containing impurity or the other crystal forms of Valsartan-Sha Kubi song trisodium salt composites being synthetically prepared with chemical synthesis processSha Tan-Sha Kubi song trisodium salt composites.
In one embodiment, water content during Valsartan sand library is more amorphous β than bent trisodium salt composite for 0.2~20%, in another embodiment, water content during Valsartan sand library is more amorphous β than bent trisodium salt composite for 2~15%, in another embodiment, water content during Valsartan sand library is more amorphous β than bent trisodium salt composite for 4~15%, in another embodiment, water content during Valsartan sand library is more amorphous β than bent trisodium salt composite for 5~15%, in another embodiment, water content during Valsartan sand library is more amorphous β than bent trisodium salt composite for 6~15%, in another embodiment, water content during Valsartan sand library is more amorphous β than bent trisodium salt composite for 7~15%.
The present invention also provides the preparation method of the amorphous β of Valsartan-Sha Kubi songs trisodium salt composite a kind of, this methodIncluding：
(1) Valsartan and Sha Ku ratio songs are dissolved in ethyl alcohol；
(2) alkaline sodium compound is dissolved in water；
(3) solution that step (2) obtains with the solution that step (1) obtains is mixed, adds in anti-solvent and solid is precipitated；
(4) solid be precipitated, freeze-drying are detached.
In the step of above-mentioned preparation method (1), Valsartan is generally 1 with husky library than the bent mol ratio that feeds intake:0.8~1.2, preferably 1:0.9~1.1.
In the step of above-mentioned preparation method (1), the weight proportion of ethyl alcohol and Valsartan is generally 2:1~15:1, preferably 5:1~10:1.
In the step of above-mentioned preparation method (2), alkaline sodium compound may be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, firstSodium alkoxide or sodium ethoxide etc., preferably sodium hydroxide, sodium methoxide or sodium ethoxide.
In the step of above-mentioned preparation method (2), sodium mole is matched with feeding intake for Valsartan in step (1) in alkaline sodium compoundThan being generally 2.8~5:1, preferably 2.9~3.5:1.
In the step of above-mentioned preparation method (2), the weight ratio of water and alkaline sodium compound is generally 0.5:1~10:1, it is excellentSelect 0.5~5:1.
In the step of above-mentioned preparation method (3), " anti-solvent " refers to prepared compound poor solubility and energyThe solvent to dissolve each other with ethyl alcohol or water.These anti-solvents are selected from acetone, butanone, pentanone, cyclohexanone, Ethyl formate, methyl acetate, secondAcetoacetic ester, isopropyl acetate, butyl acetate, ether, isopropyl ether, n-butyl ether, glycol monoethyl ether, glycol dimethyl ether, tertiary fourthYlmethyl ether, toluene, dimethylbenzene etc. or their mixture, wherein it is preferred that isopropyl acetate and ethyl acetate.The anti-solvent0.5 is generally with the volume ratio of the mixed solvent of step (3):1~20:1.It can stand that solid process, which is precipitated, can alsoIt is stirring.
In the step of above-mentioned preparation method (4), the routine side in the art such as filtering may be used in " separation "Method.
In the step of above-mentioned preparation method (4), generally -70~-10 DEG C of the temperature of " freeze-drying ", preferably -60~-40 DEG C；Pressure is generally 0~50Pa, preferably 1~10Pa.
Valsartan sand library is more amorphous γ than bent trisodium salt composite
The powder x-ray diffraction collection of illustrative plates of the amorphous γ of Valsartan-Sha Kubi songs trisodium salt composite provided by the inventionThe feature of (being radiated using Cu-K α) is：Peak nearby is corresponding with for 4.5 ° and 20.5 ° in 2 θ values, in 2 θ values for 31.6 ° nearby without rightThe peak answered.Wherein the specific location of " correspondence " is the vertex at peak.Wherein " near " for 4.5 ° of generally ± 1 ° of ranges, preferablyThe range of ± 0.5 ° of range, more preferably ± 0.2 °；It is more excellent for the range of 20.5 ° generally ± 2 ° of range, preferably ± 1 °The range of ± 0.5 ° of choosing；For 31.6 ° generally ± 0.5 ° of range.
Further, the amorphous γ of Valsartan-Sha Kubi songs trisodium salt composite provided by the invention has such as Fig. 4 institutesThe feature representated by powder x-ray diffraction collection of illustrative plates shown.
The representative powder X-ray of the amorphous γ of Valsartan-Sha Kubi songs trisodium salt composite provided by the invention spreads outCollection of illustrative plates is penetrated to be listed in attached drawing (referring to Fig. 4)." representative powder x-ray diffraction collection of illustrative plates " refers to the powder X-ray of this crystal formDiffractive features meet this collection of illustrative plates display whole pattern, it is to be appreciated that during the test, due to by many factors (such asProcessing method, instrument, test parameter, test operation of sample etc. when the granularity of test sample, test) influence, same crystalline substanceThe characteristic diffraction peak intensity of powder x-ray diffraction collection of illustrative plates measured by type has certain difference.
Valsartan-Sha Kubi is bent in the Valsartan-Sha Kubi song trisodium salt composite mix of preparation provided by the inventionThe content (mass content) of the amorphous γ of trisodium salt composite is generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.It will be appreciated by persons skilled in the art that Valsartan-Sha Kubi songs trisodium salt composite of the present invention is referred to changeWhat synthetic method was synthetically prepared contains impurity or the Valsartan other crystal forms of-Sha Kubi song trisodium salt composites or unbodied figured silk fabricsSha Tan-Sha Kubi song trisodium salt composites.
Water content during Valsartan sand library provided by the invention is more amorphous γ than bent trisodium salt composite is 0.2~20%,In one embodiment, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 0.2~6%,In one specific embodiment, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 0.2~4%, anotherIn one specific embodiment, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 2~15%, anotherIn specific embodiment, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 4~15%, in another toolIn body embodiment, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 5~15%, another specificIn embodiment, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 6~15%, in another specific realityIt applies in scheme, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 7~15%.
The present invention also provides the preparation method of the amorphous γ of Valsartan-Sha Kubi songs trisodium salt composite a kind of, the partyMethod includes：
(1) Valsartan, Sha Ku are dissolved in than bent and alkaline sodium compound in ethyl alcohol；
(2) solid is precipitated in the solution obtained by concentration step (1)；
(3) solid that separating step (2) is precipitated；
(4) optionally, the separated solid obtained of drying steps (3).
In the step of above-mentioned preparation method (1), the Valsartan is the drug listed for many years, it is commercially viable buy orIt can be prepared according to known method.For example, the preparation of Valsartan is described in US5399578 and EP0443983, these documentsIt is incorporated into the application by reference.The sand library can be according to the side disclosed in patent document US5217996A than songMethod is made, these documents are incorporated into the application by reference.
In the step of above-mentioned preparation method (1), the alkaline sodium compound may be selected from sodium hydroxide, sodium carbonate, sodium ethoxideOr sodium tert-butoxide etc., preferably sodium hydroxide or sodium ethoxide.
In the step of above-mentioned preparation method (1), the Valsartan is generally 1 with husky library than the bent mol ratio that feeds intake:0.8~1.2, preferably 1:0.9~1.1.
In the step of above-mentioned preparation method (1), the mol ratio one that feeds intake of sodium and Valsartan in the alkaline sodium compoundAs be 2.8~5:1, preferably 2.9~3.5:1.
It is described to be dissolved in Valsartan, Sha Ku in ethyl alcohol than bent and alkaline sodium compound in the step of above-mentioned preparation method (1)Mode include by Valsartan, Sha Ku than song and alkaline sodium compound be dissolved in same ethyl alcohol and form ethanol solution or first by figured silk fabricsSha Tan, Sha Ku are partly or entirely dissolved in ethyl alcohol respectively than one or both of bent or alkaline sodium compound substance, then mix againIt closes, forms ethanol solution.
In the step of above-mentioned preparation method (2), the mode of the concentration includes：Directly concentrate；Or first concentrate, it adds anti-Solvent, then concentrate；Or anti-solvent is first added in, then concentrate.These concentrations can be applied alone, and can also be combined.It is wherein described anti-moltenAgent refers to, to prepared compound poor solubility and the solvent that can dissolve each other with ethanolic moiety or all, may be selected from ether, isopropylEther, n-butyl ether, t-butyl methyl ether, benzene,toluene,xylene, petroleum ether, n-hexane, normal heptane, isooctane etc. or theirs is mixedObject is closed, wherein it is preferred that t-butyl methyl ether, toluene, n-hexane, normal heptane or isooctane.The mode packet for adding in anti-solventIt includes：It is disposable to add in；Or be added portionwise, that is, it is concentrated after adding in anti-solvent, after concentrating remaining certain volume, is added in again anti-Solvent, then concentrate, repeat the operation for adding anti-solvent and concentration.
In the step of above-mentioned preparation method (2), the concentration can carry out under normal pressure, can also carry out under reduced pressure；Thickening temperature is generally 30 DEG C to solution boiling point.
In the step of above-mentioned preparation method (3), the conventional method in the art such as filtering may be used in the separation.
In the step of above-mentioned preparation method (4), the temperature of the drying is generally 30~70 DEG C；Can with constant pressure and dry,It can be dried under reduced pressure.
In one embodiment, the present invention provides a kind of Valsartan sand libraries comprising therapeutically effective amount to answer than bent trisodium saltClose the pharmaceutical composition or preparation of object crystal form A and pharmaceutic adjuvant.
In one embodiment, the present invention provides a kind of Valsartan sand libraries comprising therapeutically effective amount to answer than bent trisodium saltClose the pharmaceutical composition or preparation of the amorphous α of object and pharmaceutic adjuvant.
In one embodiment, the present invention provides a kind of Valsartan-Sha Kubi song trisodium salts comprising therapeutically effective amountThe pharmaceutical composition or preparation of the amorphous β of compound and pharmaceutic adjuvant.
In one embodiment, the present invention provides a kind of Valsartan-Sha Kubi song trisodium salts comprising therapeutically effective amountThe pharmaceutical composition or preparation of the amorphous γ of compound and pharmaceutic adjuvant.
Aforementioned pharmaceutical compositions or preparation can orally or not oral administrations.It is preferred that peroral dosage form, including tablet, capsule,Pill, granule, solution, syrup, dry suspensoid agent, suspension, powder, sustained release preparation or controlled release preparation etc..Wherein preferablyThe solid orally ingestibles such as tablet, capsule, granule, dry suspensoid agent and sustained release preparation or controlled release preparation, wherein more preferable pieceAgent and capsule.
The various dosage forms of aforementioned pharmaceutical compositions can be prepared according to the conventional method of pharmaceutical field.Such as it will treat effectiveThe Valsartan sand library of amount is more amorphous α, β, γ than bent trisodium salt composite than bent trisodium salt composite crystal form A or Valsartan sand library,Optionally with the active constituent of one or more therapeutically effective amounts, mix or contact with one or more pharmaceutic adjuvants, thenIt is made into required dosage form.
In one embodiment, Valsartan sand library provided by the invention is more husky than bent trisodium salt composite crystal form A or figured silk fabricsTan Shaku is more amorphous α than bent trisodium salt composite, amorphous β, amorphous γ are mixed or contacted with one or more pharmaceutic adjuvants,Then peroral dosage form, preferred tablet and capsule are made into.In the peroral dosage form, pharmaceutic adjuvant is selected from this field routinePharmaceutic adjuvant, including filler, disintegrant, adhesive, dispersant, lubricant or retention agent and all types of coating materialsDeng.
The filler generally comprises pregelatinized starch, starch, lactose, dextrin, calcium monohydrogen phosphate, calcium carbonate, mannitol, micro-Crystalline cellulose, sorbierite, glucose etc., they, which can be used alone, to be used in mixed way, wherein it is preferred that lactose, microcrystalline celluloseElement, pregelatinized starch, mannitol.
The disintegrant generally comprises cross-linked carboxymethyl cellulose sodium, sodium carboxymethylcellulose, sodium carboxymethyl starch, is crosslinked and gathersVinylpyrrolidone, starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose etc., they, which can be used alone, to mixIt uses, wherein preferably microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, lowReplace hydroxypropyl cellulose.
Described adhesive generally comprises microcrystalline cellulose, pre-paying starch, hydroxypropyl methyl cellulose, hydroxy propyl celluloseElement, povidone, crospovidone, starch slurry, Arabic gum, Macrogol 4000, polyvinyl alcohol, alginates, water, various concentrationEthanol solution, they, which can be used alone, to be used in mixed way, wherein it is preferred that crospovidone, povidone, hydroxypropyl firstBase cellulose, hydroxypropylcellulose.
The lubricant generally comprises magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, stearic acid richness horseSour potassium, palmitic acid, silica, stearmide, talcum powder, solid polyethylene glycol, glyceryl triacetate etc..They can be independentUsing that can also be used in mixed way, wherein it is preferred that silica, magnesium stearate, stearic acid, talcum powder.
If desired, other auxiliary materials can also be added into above-mentioned composition or preparation, as sweetener (such as aspartame,Steviosin etc.), colorant (such as lemon yellow, iron oxide various medicinal or food coloring), stabilizer (such as calcium carbonate, bicarbonateCalcium, sodium bicarbonate, sodium carbonate, calcium phosphate, calcium monohydrogen phosphate, glycine etc.), surfactant (such as Tween 80, dodecyl sulphateSodium etc.), coating material (such as Opadry, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic resin copolymer etc.).
In one embodiment, in aforementioned pharmaceutical compositions or preparation, Valsartan sand library is than bent trisodium salt compositeCrystal form A or Valsartan sand library it is more amorphous α, β, γ than bent trisodium salt composite particle diameter distribution control 90% be less than 100 μm, it is excellentChoosing is less than 50 μm, more preferably less than 10 μm.
In one embodiment, in above-mentioned unitary pharmaceutical composition or preparation, Valsartan sand library is answered than bent trisodium saltIt closes object crystal form A or Valsartan sand the library weight content more amorphous α, β, γ than bent trisodium salt composite and is generally 1mg to 2g, preferably10mg to 400mg, more preferable 50mg is between 200mg.
It is slower for preventing or treating preparing than bent trisodium salt composite that the present invention still further provides Valsartan sand libraryHeart failure or hypertension become the purposes of the drug of the illness of feature, and wherein chronic heart failure is reduced including ejection fractionHeart failure and the chronic heart failure etc. that retains of ejection fraction, hypertension is including primary etc..
In one embodiment, the present invention provides Valsartan sand library is more husky than bent trisodium salt composite crystal form A or figured silk fabricsTan Shaku is more amorphous α, β, γ than bent trisodium salt composite to be for prevention or chronic heart failure or hypertension in preparationThe purposes of the drug of the illness of feature.
The experiment proved that Valsartan sand library provided by the invention is than bent trisodium salt composite crystal form A or Valsartan sand library ratioAmorphous α, β, γ preparation method of bent trisodium salt composite is easy, and crystal form is easily controllable, stability and favorable solubility, suitable for useIn preparation.
The powder x-ray diffraction analysis of the above-mentioned crystal of the present invention is under environment temperature and ambient humidity, through Dutch paReceiving the Cu-K α radiation of section's X`Pert PRO type Powder X-ray Diffractometers, (wavelength is) measure what is completed." environment temperature "Usually 0~40 DEG C；" ambient humidity " is usually 30%~80% relative humidity.It is appreciated that during the test,Due to by many factors (processing method of sample, instrument, test parameter, test operation when the granularity of such as test sample, testDeng) influence, the characteristic diffraction peak position of the powder x-ray diffraction collection of illustrative plates measured by same crystal form or intensity have centainlyDifference.Under normal circumstances, the experimental error of 2 θ values of characteristic diffraction peak can be ± 0.2 ° in powder x-ray diffraction collection of illustrative plates.