TW201242969A - A pharmaceutical composition which improves the solubility and its preparation method - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing prasugrel and its salt, and its preparation method, the pharmaceutical composition improves the solubility of prasugrel and its salts at high PH by using of solid dispersion technology, inclusion technology or adding surfactants.

Description

201242969 VI. Description of the Invention: [Technical Field] The present invention relates to a peony composition containing prasugrel and a salt thereof, and a process for the preparation thereof, in particular, by using a solid dispersion technique, a clathrate technique or a surface The active agent technique enhances the composition of the dissolution of prasugrel and its salts at higher pH conditions and methods for their preparation. [Prior Art] 曰 袼 袼 袼 pra (prasugrel), its chemical name is 5-[(lRS)-2_cyclopropene~ 氡 基 ))-2-oxoethyl]-4, 5, 6, 7 -tetrahydrothiophene [3, 2-C] 比1 - Ί 赠 赠 (5 - (2-cy c 1 opropy 1 -1 - ( 2- f 1 uoroPHeny 1) X〇ethyl)-4 , 5, 6, 7-tetrahydrothieno[3, 2-c]pyridin '2'yl acetate) 〇

o

Sub-type · C2 〇 H2 〇 FN 〇 3S, molecular weight: 373.44. W is a kind of oral platelet inhibitor, anticoagulant. This phase was originally developed for patients with acute coronary δ彳iE requiring percutaneous coronary intervention, including those requiring stenting. The results of the study showed that β ‘no prasugrel was more effective than clopidogrel in reducing non-fatal heart disease and death caused by tb π and hurricane, which significantly reduced the risk of stent thrombosis. "...-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- At present, prasugrel hydrochloride (Efi (10) has been marketed in Europe, USA, its specifications are 5mg, 1〇mg, diamond-shaped tablets, slightly soluble in pH 1 to 4, very slightly soluble in pH 5, pH 6 Insoluble in 7 to a single load of 6 〇 '1 〇 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 维持 。 。 。 。 。 。 The bioavailability of sputum. According to the FDA review, when the prasugrel hydrochloride or prasugrel domain is administered alone, the bioavailability is similar; when the mu receptor antagonist is used together, the pH in the stomach increases. The bioavailability of the pragage base is significantly lower than that of the hydrochloride. It is known from the solubility of prasugrel hydrochloride and lagagrel that the solubility of prasugrel in PHI i 7 is poor, while the fat-soluble domain The base is stronger than the hydrochloride. Therefore, if the Wragre domain is improved, the dissolution rate of the high domain can be smothered. Solid separation refers to the drug with molecules, gel g, amorphous, crystallite, etc.: uniform a dispersion system formed by dispersing in a certain solid substance. It can increase the solubility and dissolution rate of poorly soluble drugs (4), thereby improving the bioavailability of the drug. The solid dispersion is intermediate production' can be made into capsules and flakes according to the needs, which is beneficial to the further industrial production of pharmaceutical preparations. Surfactants have both hydrophilic and lipophilic amphiphilic properties, improve the drug's bioavailability by improving the wettability of the drug 'preventing drug particle coalescence and micelle solubilization' to increase the dissolution of hydrophobic drugs. The types of surfactants can be roughly divided into four types, anionic surface active hydrazine, 95203 4 201242969 cationic surfactants, amphoteric surfactants and nonionic surfactants. The inclusion compound refers to a drug molecular structure. a unique form of complex formed by the inclusion of all or part of a molecular cavity in another substance. The inclusion is mainly a physical process, and the formation conditions depend on the Van der Waals force between the two molecules, the dispersion force, and the dipole Gravity. There are many methods used to prepare clathrates, such as coprecipitation, grinding, sonication, freeze-drying, etc. The inclusion properties are mainly cyclodextrin, cyclodextrin derivatives and urea. The cyclodextrin is commonly used in α, /5 and r. The cyclodextrin inclusion technology is widely used in pharmacy, mainly It is used for effectively increasing the solubility of a poorly soluble drug, increasing the stability of an unstable drug, masking a pungent odor of a drug, etc. SUMMARY OF THE INVENTION An object of the present invention is to provide a pharmaceutical composition containing prasugrel and a salt thereof, wherein The prasugrel and its salts are present in the composition in molecular, ionic, crystalline, or amorphous form, wherein the pharmaceutical composition is capable of increasing the dissolution of prasugrel and its salts at higher pH conditions. The dissolution rate is similar to or higher than prasugrel hydrochloride; the pH range is 1. 0 < ρ Η < 7. 0; the composition contains a surfactant; the prasugrel And a salt thereof is present in the form of a clathrate comprising cyclodextrin and a derivative thereof, said cyclodextrin being selected from -CD or HP-/3-CD, preferably /3-CD, Among them, prasugrel and its salt are the same as /9-CD

11 is better than! The quality of the product I is; the first is better than the _ more than 5 95203 201242969 1:1 to 1:5. The solid dispersion form is present, wherein it is selected from the group consisting of poly-dimensional 〇 43 type = sexual carrier material, the hydrophilic carrier material or cyclodextrin and its bio-ethylene glycol, mannitol, cellulose and/ The alcohol, more preferably preferably PVP, cellulose and/or prasugrel, preferably K12 or pvp is 1:1 to its = the weight ratio of the carrier material is selected from 1: 1 to 1:20, to 1.10, more preferably 1:3 to 1:5; the pharmaceutical composition of the second is a solid preparation characterized by: (2) Γ: particle size range: 9〇% The drug has a particle size of less than or equal to 75 Å; the agent contains a quantitative surfactant. The circumference is less than 2 = the diameter of the circumference is less than or equal to 5_; the particle size norm is selected from + _ purely less than or equal to 5 _; the surface active olefin type or, and poloxamer, the second type, the disc, the poly More preferably, the ratio of + to 12 is less than or equal to 1:20', and preferably less than or equal to 1:20. 2; The solid preparation package can be Qi! The filler is selected from the group consisting of mannose, vitamins, lactose or the like. , second, the cellulose group Yang; the material phase body (four) = material and microcrystalline slip agent selected from the stearic acid metal m * 1 slip agent's run and function, stearic acid, ammoniated vegetable oil, Slip--oxygen-cutting is preferably a colloidal dioxygenate or a substance; according to the weight of the solid preparation, the composition of the stagnation of the town is 100M' phase (four) dioxotomy. The 95203 6 201242969 ratio is 0. 5% to 1% _, the weight percentage method of the magnesium stearate is provided by providing a preparation of the inclusion compound, selected from the group consisting of a coprecipitation method, a kneading method, and an ultrasonic method.隹 is a coprecipitation method, a kneading method or a chilling succinct and a potting or kneading method; wherein the inclusion material used is a ring paste of the present invention and its derivative 'is most preferably e-CD; Another object is to provide a preparation of the solid dispersion 鲈, VIII, self-agent method, melting method, solvent-melting method or grinding method, = /, solvent material grinding method, more preferably secret agent method; The solvent is propylene carbonate, ethanol, decyl alcohol, ethyl acetate, dichlorohydrazine, chloroform, DMF ^ / and 乙峻' is preferably propylene, ethanol, sterol, acetic acid And / or two chaotic burning A 'is more preferably propan-_ and / or ethanol. The simple drug-micronized treatment showed that the dissolution of the drug was improved under the conditions of ΡΗ4·5, ρΗ6.8, but there was still a gap compared with the (d) salt micronized preparation, so other methods were needed. The object of the present invention is achieved by the following technical solutions: 1. Preparation of solid dispersion The hydrophilic carrier materials mentioned in the present invention include PVP, polyethylene glycol type surfactant, mannitol cellulose and cyclodextrin. Fine and its derivatives. PVP materials are classified into pvp_K12, pVp_K_17, PVP_K25' PVP-K29/32, PVP-K90, PVPP and copolyvidone according to their different viscosities. Be

- Poly-sterol used as a solid body, according to molecular weight, not I 7 95203 201242969 PEG 4000, PEG 6000, PEG 12000, PEG 20000. The surfactant used is classified into a cationic, anionic, and amphoteric surfactant according to the charged charge. Among them, the anionic surfactant comprises sodium decyl sulfate sodium 'stearate sodium stearate, sodium diethyl succinate, sodium dodecyl benzene sulfonate and bile salts. Nonionic surfactants include Span, Tween, Polyoxyethylene, Poloxamer, and the like. Due to the poor solubility of the drug, the preparation of the solid dispersion requires the use of a non-aqueous solvent. The invention has studied the common organic solvents such as acetone, ethanol, dioxane, methanol, chloroform, ethyl acetate, methanol, DMF and diethyl ether. (1) Solvent preparation of solid dispersion: carrier material and drug = The ratio of material is 1: 1 to 1: 20, respectively, adding appropriate organic solvent, sandalwood, dissolved, and the solution is evenly mixed, rotary evaporation, water bath 25_65t:, evaporation 〇 'empty drying 5-30h, temperature is % Rn〇r ^ ^ ^ · 'Real... Spoon a~60c, after drying, grind 60 mesh _120 mesh sieve 0 (2) Spray drying method to prepare off the rhyme: take the feed ratio from 1:1 to 1:2η eight, He shake and music will dissolve The dissolution ratio is trm preparation = dispersion: · carrier material and drug shot co-grinding, taking out, solid dispersion in a two-ball mill or colloid mill can be prepared into tablets, capsules, in which tablets or capsules are prepared, granules诏4 stone powder, polyethylene glycol, saponin saponin, magnesium stearate, sodium sulphate mixture, using 詈炎 u soil base bowl for sheet 4 or (4) 0.1% to ^ ^ ^ ^ 95203 8 201242969 solution Agents, including croscarmellose sodium, crospovidone, sulphonyl f powder sodium Fillers include starch, modified starch, mannitol, and cellulose. 2. Surfactant is added to the pharmaceutical composition. It is found that the dissolution rate of the preparations of the respective preparations of the hydrochloric acid is relatively improved, and the dissolution rate is lower than that under the condition of pH 6 8 . Prasugrel hydrochloride can achieve the same or higher dissolution rate of the micronized powder preparation by adding a certain proportion of the active agent to make the dissolution rate of the micronized raw material at a high pH value. It is well known to those skilled in the art and is classified into an anionic surfactant sodium lauryl sulfate and a bile salt; a nonionic surfactant Tween, a Span, a polyoxyethylene type, and a poloxamer. In the screening process: in the surfactant for use, the effect of solubilizing prasugrel is preferably 'more preferably, the twelve sulphur-based sulphur is most preferably sodium lauryl sulfate. Drug = granule = The present invention has also been studied. The particle size of the drug is found to be equal to ... m, preferably A is beneficial to the music, and the grain is out of range. The particle size range of the drug is less than one, most preferably:: = more preferably less than or equal to Preferably, the drug is less than or equal to 1:10, and the drug is the same as the drug. Were screened 'better side effect = = small "in 1:20 or less fortunate Shang Yi in good: 2. ...ΐ. Filled with Jin Gan, Alcohol, Temple Powder..............-: Microcrystalline cellulose, s 95203 9 201242969 A microcrystalline cellulose in sugar and hydroquinone The composition of the composition/species is preferably mannose|| and the lubricant is one of stearic acid gold eyebrow powder, colloidal cerium oxide, stearic acid, hydrogenated vegetable oil, slip; g dioxotomy, The composition of the magnesium stearate preferably has a colloidal ratio of 0% to 5%, and the weight of the fine powder (4) as described in the object is 100. L is 3%, more preferably 0 to 2%. The percentage of heavy stems of k magnesium is 0.5% and 1%. The preparation process of the hard fat can be carried out by all the components, including the living h riding granulation technique, together with the lubricant, and then by using the _ selected, surfactant, pre-released in the agent, and then by tableting or directly Filling, the month + solid can be first mixed with microcrystalline fiber π, 、,, 'Jing or with micro-powder gel, sifted and then mixed with music, dry granulation. The preparation step of Μ 丹 丹 can also be used for granulation. By wet granulation, all the ingredients except the lubricant, Baotuo, the linguistic component and the surfactant are mixed together, and purified with purified water, '''drying, or surface active The agent is added to purified water, and used as a moisturizing agent and a granule to be dried. After mixing the lubricant, compress or add capsules. It is also possible to use direct 杵 “ ", _ sound film method: mixing all ingredients except lubricant, after sifting and mixing the spoon, adding lubricant, and finally directly compressing or directly adding into the capsule. Preparation of inclusion compound (1) Preparation of inclusion complex by saturated aqueous solution: Dissolve saturated solution of inclusion material, control the temperature of 4 times, mix (4) mixed acetone, 10 95203 201242969 into saturated solution, constant temperature mixing 8h, cooled and solidified, the turbid liquid was filtered through a Buchner funnel, and diethyl ether was used as a good solvent. After washing the filter cake, the water and the organic solvent were removed by drying under reduced pressure. (2) Preparation of inclusion compound by grinding method: inclusion material was placed In the mortar, add appropriate amount of water, firstly grind the mixture, then grind the micronized drug in a mortar, grind it into a paste, dry, wash, and dry under reduced pressure. The inclusion material is /3-cyclodextrin. Derivatives of refined (stone-CD) and/or 3-cyclodextrin thereof, preferably cyclodextrin. The solvent is acetone, absolute ethanol, dichlorosilane, decyl alcohol, chloroform, etc. Meanwhile, the present invention also Investigated the use of heterogeneous systems, but It is found that the inclusion effect is poor. The prasugrel solid dispersion and the clathrate prepared by the invention are all preparation intermediates, and can also be prepared into corresponding capsules or tablets. Solid dispersion or inclusion compound As a preparation intermediate, the prepared capsule or tablet may contain a filler, and is selected from the group consisting of mannitol, starch, modified starch, microcrystalline cellulose, sorbitol, and vegetable sugar. In addition to the active ingredient and the filler, the medicinal solid The unit dosage form may contain various other conventional excipients such as disintegrants and minor amounts of lubricants. Lubricants include metal stearate (magnesium, calcium, sodium), stearic acid, hydrazine, hydrogenated castor oil, talcum powder And colloidal silica dioxide. Disintegration agent includes sodium carboxymethyl starch, croscarmellose sodium, cross-linked polyvinylpyrrolidone (PVPP), low-substituted hydroxypropyl cellulose, modified corn starch, pre-adhesive Starch and natural starch. The preparation step of the prasugrel solid dispersion and the inclusion compound can be prepared by using the H-pressing tablet or the dry granulation step. 11 95203 201242969 The present invention is Gray and hydrophilic carrier materials are materials 5, using surfactant addition method, solid dispersion technology and inclusion compound technology to improve the dissolution of prasugrel domain and its salt preparation at high pH, thereby improving the purification The bioavailability of the Lagrangian domain at a high pH has the following advantages: (1) The preparation of a prasugrel domain-based preparation by a method of adding a surfactant, a solid dispersion technique, and an inclusion technique can improve the Pula The bioavailability of the Greg domain at higher pH can be increased to near or higher dissolution with prasugrel hydrochloride at higher pH values, thereby increasing bioavailability. (2) Prepared The prasugrel solid dispersion and the clathrate are intermediate products, and can be further prepared into capsules, tablets and the like as needed, which is advantageous for further industrial production of the pharmaceutical preparation. The present invention is specifically described by the following examples, which are merely illustrative of the technical solutions of the present invention and are not intended to limit the scope of the invention. Example 1 : pharmaceutical composition: drug (prasugrel) 5 g sodium dodecyl sulfate sodium 〇 mannitol 73 g microcrystalline cellulose 50 g croscarmellose sodium cellulose 7. 5 g hydroxypropyl fluorenyl cellulose 3 g 12 95203 201242969 Stearic acid town 1. 5g Procedure: Micronized the drug (prasugrel), mixed with sodium dodecyl sulfate with the drug, added the prescribed amount of micro-powder gelatin, and added microcrystalline cellulose in equal increments. Mannitol, croscarmellose sodium, hydroxypropylmethylcellulose were mixed, passed through a 60 mesh sieve 5 times, and finally added magnesium stearate (pretreated by 60 mesh sieve) and uniformly mixed, and compressed. Example 2: Pharmaceutical composition: Drug (prasugrel) Sodium sulfonate sodium 5 g Mannitol 71.5 g Microcrystalline cellulose 50 g Cross-linked carboxymethyl cellulose sodium 7. 5 g Hydroxypropyl cellulose 3 g Micro powder 1.5g Magnesium stearate 1.5g Procedure: The powder (prasugrel) is micronized and mixed with other excipients other than surfactants and lubricants. The prescribed amount of sodium lauryl sulfate is dissolved in an appropriate amount of purified water as a wetting agent. The mixture was added to the mixed auxiliary material to prepare a soft material, which was sieved through a 30-mesh sieve, dried, and 40-mesh, and then mixed with magnesium stearate and tableted. Embodiment 3: • ..... - * - · - - - - - -. - - - . * * - - -....... -* , ... - . . _ _· „ _ • Each _ _ — 13 95203 201242969 Pharmaceutical composition: Drug (prasugrel) 5g Poloxamer 5g Mannitol 70g Microcrystalline cellulose 50g Cross-linked carboxymethyl cellulose sodium 7.5g Hydroxypropyl cellulose 3g micro-powder gelatin 3g magnesium stearate 1.5g Step: Micronized the drug (prasugrel) and mix it with other excipients and lubricants. Dissolve the prescription poloxamer in an appropriate amount of purified water. As a wetting agent, it is added to the mixed auxiliary material to prepare a soft material, which is sieved through a 30 mesh sieve, dried, and 40 mesh whole grains are mixed with magnesium stearate and compressed. Example 4 Pharmaceutical composition: Drug: Carrier 1:1 1:3 1:5 1:8 1 : 10 Drug (prasugrel) 2g 2g 2g 2g 2g PYPK30 2g 6g l〇g 16g 20g Acetone 30ml 30ml 45ml 60ml 90ml Anhydrous ethanol 5ml 10ml 15ml 20ml 30ml Steps: Weigh the prescribed amount of the drug (prasugrel) dissolved in acetone, PVPK30 as the carrier material, dissolved in absolute ethanol, mixed with acetone and ethanol. Evenly, water bath 14 95203 201242969 40 ° C rotary evaporation, 40 ° C vacuum drying for 24 h, grinding through 80 mesh sieve, that is, * prasugrel solid dispersion. Example 5 pharmaceutical composition: drug: carrier 1:1 1 :3 1:5 1:8 1 : 10 Drug (prasugrel) 2g 2g 2g 2g 2g PVPK30 2g 6g l〇g 16g 20g Acetone 30ml 30ml 45ml 60ml 90ml Anhydrous ethanol 5m 1 10ml 15ml 20ml 30ml PVPP 24g 40g 45g 60g 84g Steps: Weigh the prescribed amount of the drug (prasugrel) dissolved in acetone, PVPK30 as the carrier material, dissolved in absolute ethanol, add PVPK30 alcohol solution to the acetone solution, mix well. Mix the solution as a binder, add PVPP The dispersion was uniform, the water bath was rotary evaporated at 40 ° C, dried under vacuum at 40 ° C for 24 h, and ground through a 80 mesh sieve to obtain a solid dispersion of prasugrel. Example 6 Pharmaceutical composition: Drug (prasugrel) 2 g Acetone 100 ml PVPK30 20g absolute ethanol 50ml Steps: Weigh the prescribed amount of the drug (prasugrel) dissolved in acetone, PVPK30 as the carrier material, dissolved in absolute ethanol, the two solvents are mixed, spray dried to obtain 15 95203 201242969 Lagree solid dispersion. Example 7 Pharmaceutical composition: Drug (prasugrel) lg Propionate with 50ml PEG6000 3g Procedure: Weigh the prescribed amount of PEG6000, dissolved in acetone at 40 ° C, add the drug after cooling, quickly stir until homogeneous, cooling After the analysis. Example 8 Pharmaceutical composition: Drug (prasugrel) lg Mannitol 15g Procedure: Weigh the prescribed amount of micronized drug (prasugrel) and mannitol, place in a ball mill, grind for 6 hours, take out, pass 80 mesh sieve, That is, a solid dispersion of prasugrel is obtained. Lg l〇g 5g Example 9 Pharmaceutical composition Drug mannitol microcrystalline cellulose Step: Weigh the prescribed amount of drug (prasugrel), mannitol and microcrystalline cellulose, 16 95203 201242969 placed in a ball mill, ground for 6 h, Remove and pass through a 80 mesh sieve to obtain a solid dispersion of prasugrel. Example 10 Pharmaceutical composition: Drug: Solvent drug: cold-CD (1:1) Drug: /3-CD (1:3) Drug: /3-CD (1:5) Drug (prasugrel) 5g 2g Lg Acetone 80ml 40ml 20ml yS-CD 5g 6g 5g Water 140ml 176ml 140ml Step: At 40 °C, /3-CD is configured as a saturated solution, the drug (prasugrel) is dissolved in acetone, and it is dripped into cold-CD saturation. In the solution, it was dispersed for 8 h and the temperature was maintained at 40 °C. The mixture was cooled and solidified, suction filtered, washed with diethyl ether, and dried to obtain a praflazole inclusion compound. Example 11 Pharmaceutical composition: Drug: Solvent drug: yS-CD (1:1) Drug: /3-CD (1:2) Drug: 0-CD (1:3) Drug:/5-CD (1: 5) Drug (prasugrel) 2g lg 0. 665g 0. 526g yS-CD 2g 2g 1.995g 2. 63g water 6m 1 6m 1 5. 99ml 7. 89ml Step: Weigh the prescription - CD in the mortar Add three times the amount of water, weigh the drug (prasugrel) and grind it in a mortar and grind it into a paste. Drying, washing and drying give a prasugrel inclusion complex. Test Example 1 * — * * — — . - - - — « — * —* * — * . . . - _. .. .. . . . 17 95203 201242969 Preparation of solid dispersion by solvent method using PVP as carrier material (Drug: Carrier = 1: 10), the in vitro dissolution evaluation method is: (1) Weigh a solid dispersion containing 5 mg of the equivalent domain, and measure the dissolution rate (Appendix XC first method) to 1000 ml PH4. 5 phosphate buffer is the dissolution medium, the rotation speed is 50 rpm, according to the law, 5 ml of solution is taken at 5 min, lOmin, 15 min, 20 min, 30 min, filtered, and 5 ml of dissolution medium is added, and the filtrate is taken as the test solution. Liquid phase determination. (2) Weigh a solid dispersion containing 5 mg of the equivalent domain, and measure the dissolution method (Appendix XC first method), using 1000 ml of PH6.8 phosphate buffer solution as the dissolution medium, and the rotation speed is 50 rpm. Operation, 5ml solution was taken at 5miη, 15min, 30min, 45min, 60min, filtered, and 5ml of dissolution medium was added at the same time. The filtrate was taken as the test solution and sent to the liquid chamber for determination. (3) Preparation of positive drug (prasugrel hydrochloride) tablet prescription as follows: prasugrel hydrochloride 5. 49 g mannitol 79.51 g microcrystalline cellulose 50 g croscarmellose sodium 7.5 g hydroxypropyl thioglycol 3 g powder Silicone 3g magnesium stearate 1.5g Step: Micronized the drug, sequentially added microcrystalline cellulose, mannitol cross-linked carboxymethyl cellulose, mixed with acryl cellulose, 60 18 95203 201242969 The sieve was sieved 5 times, and finally magnesium stearate (pretreatment through a 60 mesh sieve) was added and uniformly mixed, and tableted. The dissolution evaluation of Examples 1-11 was carried out in sequence using the above evaluation system, and the dissolution results showed that the dissolution of the prasugrel-based solid preparation at a high pH value was remarkably improved, and Example 1 and Example 5 are shown here. The dissolution data of the product of Example 10 and the positive drug (prasugrel hydrochloride) tablet at pH 4.5 and pH 6.8 are not repeated here. Evaluation of Dissolution in pH 4.5 Phosphate Buffer·· Table 1: Comparison of Prasugrel Hydrochloride with the Product of Example 1

Omin 5min lOmin 15 min 20 min 30 min prasugrel hydrochloride 0 16. 71 26. 66 32.45 36.78 43.42 Example 1 Product 0 [25. 73 53. 76 56, 93 59.15 60.28 Table 2: Prasugrel hydrochloride and the product of Example 5 Comparison

Omin 5min lOmin 15 min 20 min 30 min prasugrel hydrochloride 0 16. 71 26.66 32.45 36.78 43.42 Example 5 product (prasugrel: carrier = 1:1) 0 15.43 27.47 35. 71 49.77 52.00 Example 5 product (prasugrel: Vector = 1: 3) 0 41.30 46.66 49.91 59.45 61.96 Example 5 Product Γprasugrel: vehicle = 1:5) 0 58.51 62. 89 63.97 64.12 66.70 Example 5 product f瞽Lagre: carrier = 1:8) 0 60.13 64.57 65.92 67.45 68.37 Example 5 Product f: saragrelide: vehicle = 1: 10) 0 65.98 71.73 72.14 72.57 73.86 19 95203 201242969 Table 3: Comparison of prasugrel hydrochloride with the product of the example ι

Omin 5rain lOmin 15 min 20 min 30rain prasugrel hydrochloride 0 16.71 26.66 32.45 36.78 43. 42 Example 10 product (prasugrel: /S-CD=l:l) 0 22.6 29.48 36.46 39. 46 41.18 Example 10 product Lagrele: /3-CD=l:3) 0 52.16 61.6 64.1 64.89 68.67 Example 10 product (prasugrel:; 8-CD=l:5) 0 36.83 45. 09 52.23 55.88 61.32 pH 6. 8 phosphate buffer Dissolution evaluation in: Table 4: Comparison of prasugrel hydrochloride with the product of Example 1

Omin 5min 15 min 30 min 45 min 60 min prasugrel hydrochloride 0 13.69 21.03 23.99 25.13 25. 62 Example 1 product 0 17.31 24.92 29.57 34. 32 36.97 Table 5: Comparison of prasugrel hydrochloride with the product of example 5

Omin 5 min 15 min 30 min 45 min 60 min prasugrel hydrochloride 0 13.69 21.03 23.99 25.13 25.62 Example 5 product (prasugrel: carrier = 1:1) 0 11.67 15. 12 19.36 24.72 25.86 Example 5 product (prasugrel: carrier = 1:3) 0 17.82 25.51 29.09 34.57 35.80 Product of Example 5 (prasugrel:carrier = 1:5) 0 20.58 26. 42 32.90 36.12 40.97 Example 5 product (prasugrel: carrier = 1:8) 0 21.08 28.59 34.58 37. 05 42.72 Example 5 product (prasugrel: vehicle = 1:10) 0 25.6 33.76 37.27 39.48 47. 47 20 95203 201242969 Table 6: Comparison of prasugrel hydrochloride with the product of example 10

Orain 5 min 15 min 30 min 45 min 60 min prasugrel hydrochloride 0 13.69 21.03 23. 99 25. 13 25.62 Example 10 product (prasugrel: /S-CD = 1:1) 0 14. 87 22. 43 25.66 26. 87 26.84 Example 10 product (prasugrel:; S-CD = 1:3) 0 15.74 25.41 28.76 29.31 30.15 Example 10 product (prasugrel: /3-0) = 1:5) 0 16.74 26. 24 27.28 28.37 29. 27 [Simple description of the diagram] No [Main component symbol description] None 21 95203

Claims (1)

201242969 VII. Patent Application Range: 1. A pharmaceutical composition comprising prasugrel and a salt thereof, wherein the Pragley and its salt are present in the composition in molecular, ionic, crystalline, or amorphous form. 2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is capable of increasing the dissolution of prasugrel and its salt at a higher pH. 3. The pharmaceutical composition of claim 2, wherein the dissolution is similar to or higher than prasugrel hydrochloride. 4. The pharmaceutical composition according to claim 2, wherein the pH range is 1. 0 < ρ Η < 7. 0. 5. The pharmaceutical composition according to claim 2, wherein the composition contains a surfactant. 6. The pharmaceutical composition according to claim 5, wherein the surfactant is sodium dodecyl sulfate. 7. The pharmaceutical composition of claim 2, wherein the prasugrel and its salt are present in the form of a clathrate. 8. The pharmaceutical composition according to claim 7, wherein the inclusion compound comprises a cyclodextrin and a derivative thereof. 9. The pharmaceutical composition of claim 8, wherein the cyclodextrin is selected from the group consisting of 0-CD or HP-/3-CD. 10. The pharmaceutical composition of claim 8, wherein the cyclodextrin is selected from the group consisting of /5-CD. 11. The pharmaceutical composition according to claim 9, wherein the quality ratio of the Prag 1 95203 201242969 Ray and its salt to the CD is 1:0.5 to 1:30. 12. The pharmaceutical composition according to claim 9, wherein the quality ratio of the Pragley and its salt to the call-CD is 1:1 to 1:15. 13. The pharmaceutical composition according to claim 9, wherein the quality ratio of the Pragley and its salt to /3-CD is from 1:1 to 1:5. 14. The pharmaceutical composition of claim 2, wherein the Pragel and its salt are in the form of a solid dispersion. 15. The pharmaceutical composition described in the scope of claim [n] wherein the composition further comprises a hydrophilic carrier material. 16. The pharmaceutical composition of claim π, wherein the hydrophilic carrier material is selected from the group consisting of povidone (PVP), polyethylene glycol, mannitol, cellulose, and/or cyclodextrin. Its derivatives. The pharmaceutical composition according to claim 15, wherein the hydrophilic carrier material is selected from the group consisting of PVPs, celluloses, and/or mannitol. The pharmaceutical composition according to claim 15, wherein the hydrophilic carrier material is selected from the group consisting of PVP-K12 or PVP-K30. 19. The pharmaceutical composition according to claim 15, wherein the weight ratio of the prasugrel and its salt to the carrier material is selected from the group consisting of 1: 丨 to :: 2 〇. 20. The pharmaceutical composition of claim 15, wherein the weight ratio of the prasugrel and its salt to the carrier material is selected from the group consisting of 1:1 to 丨:1〇. 21. The pharmaceutical composition of claim 15, wherein the weight ratio of the prasugrel and its salt to the carrier material is selected from the group consisting of 1:3 to i:5. 22. A method for preparing a pharmaceutical composition according to item 14 of the patent scope, which is a method of melting a solution, a melting method, a solvent, and a method. 95203 2 201242969 23. A method of preparing a pharmaceutical composition as claimed in claim 14 which is selected from a solvent method or a grinding method. 24. A method of preparing a pharmaceutical composition as claimed in claim 14 which is selected from the group consisting of a solvent method. 25. The method of claim 22, wherein the solvent is selected from the group consisting of propylene glycol, ethanol, decyl alcohol, ethyl acetate, dichlorohydrazine, gas imitation, foot or / and yoke. 26. The method of claim 22, wherein the solvent is selected from the group consisting of acetone or/and ethanol. 27. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is a solid preparation. 28. The pharmaceutical composition according to claim 27, wherein the solid preparation is: U) a particle size range of the drug: 90% of the drug particle size is less than or equal to 75 fim; (2) a certain amount in the preparation Surfactant. 29. The pharmaceutical composition according to claim 28, wherein the particle size range of the drug: 90% of the drug has a particle size of 5 Å or less. 30. The pharmaceutical composition according to claim 28, wherein the particle size range of the drug: 9% by weight of the drug particle size is less than or equal to m. The pharmaceutical composition according to claim 28, wherein the drug has a particle size range of 9% by weight or less of the drug particle size of 5 or less. 32. Patent application (4) The pharmaceutical composition described in item 28, wherein the surface is homogeneous; selected from the group consisting of sodium sulfonate, bile salt, Tween, Span, 95203 3 201242969 polyoxyethylene type or \ and Polo Sham. 33. The pharmaceutical composition of claim 28, wherein the surfactant is sodium dodecyl sulfate. The pharmaceutical composition according to claim 28, wherein the mass ratio of the prasugrel and the salt thereof to the surfactant is 1:20 or less. The pharmaceutical composition according to claim 28, wherein the mass ratio of the prasugrel and its salt to the surfactant is 1:10 or less. 36. The pharmaceutical composition of claim 28, wherein the mass ratio of the prasugrel and its salt to the surfactant is less than or equal to 1:2. 37. The pharmaceutical composition of claim 27, wherein the solid preparation comprises a filler. 38. The pharmaceutical composition of claim 37, wherein the filler is selected from the group consisting of mannitol, starch, modified starch, microcrystalline cellulose, lactose or a composition of acid hydrogen. 39. The pharmaceutical composition of claim 37, wherein the filler is selected from the group consisting of mannitol and microcrystalline cellulose. 40. The pharmaceutical composition of claim 27, wherein the solid preparation comprises a lubricant. The pharmaceutical composition according to claim 40, wherein the lubricant is selected from the group consisting of metal stearate, stearic acid, hydrogenated vegetable oil, talc or a composition of colloidal dioxide. The pharmaceutical composition according to claim 40, wherein the lubricant is selected from the group consisting of colloidal cerium oxide and magnesium stearate. 43. The pharmaceutical composition of claim 41, wherein 0% to 5% by weight of the solids of the formula 4 95203 201242969 is 100%. _ state of the weight percentage of the dioxide dioxide 44. Patent scope The weight of the preparation is im / the pharmaceutical composition, wherein the solids are (10) to 3%. The weight percentage of the colloidal dioxygen cut 45. The weight of the formulation of the 41st patent application range is the paint composition of the cockroach, wherein the solid content is 0% to 2%. , ... the weight percentage of the colloidal cerium oxide 46. Patent application No. 41, the singular composition of the stalks', wherein the weight percentage of the magnesium stearate is 〇· 5% to 1%. 47.1 The method of preparing a clathrate according to the seventh aspect of the patent, wherein the method for preparing the clathrate is selected from the group consisting of a co-precipitation method, a kneading method, an ultrasonic method, a freeze drying method or a spray drying method. 48. A method of preparing a pharmaceutical composition according to item 7 of the patent application, which is selected from the group consisting of a coprecipitation method or a kneading method. S 5 95203 201242969 IV. Designated representative map: There is no schema in this case (1) The representative representative map of this case is: (). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: This case does not represent the chemical formula 95203