WO2011134369A1 - 提高普拉格雷溶出度的药物组合物及其制备方法 - Google Patents

提高普拉格雷溶出度的药物组合物及其制备方法 Download PDF

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WO2011134369A1
WO2011134369A1 PCT/CN2011/073162 CN2011073162W WO2011134369A1 WO 2011134369 A1 WO2011134369 A1 WO 2011134369A1 CN 2011073162 W CN2011073162 W CN 2011073162W WO 2011134369 A1 WO2011134369 A1 WO 2011134369A1
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Prior art keywords
pharmaceutical composition
composition according
prasugrel
group
salt
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PCT/CN2011/073162
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English (en)
French (fr)
Inventor
岑均达
张春红
张起
吕爱锋
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孙远
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Priority to EP11774360.9A priority Critical patent/EP2564847B1/en
Priority to JP2013506469A priority patent/JP5887040B2/ja
Priority to US13/643,197 priority patent/US9050328B2/en
Priority to CN201180015701.7A priority patent/CN102811718B/zh
Publication of WO2011134369A1 publication Critical patent/WO2011134369A1/zh
Priority to HK12110932.6A priority patent/HK1170166A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present invention relates to a pharmaceutical composition comprising prasugrel and a salt thereof, and a process for the preparation thereof, in particular to improving the prasugrel and its salt by using a solid dispersion technique, an inclusion compound technique or a surfactant technique A composition for dissolution at pH conditions and a method for preparing the same.
  • Background technique
  • Prasugrel is an oral platelet inhibitor, anticoagulant. This product was originally developed for patients with acute coronary syndrome requiring percutaneous coronary intervention, including those requiring stenting. Studies have shown that prasugrel is more effective than clopidogrel in reducing death from nonfatal heart disease and stroke, and significantly reducing the risk of stent thrombosis.
  • prasugrel hydrochloride (US20080166893) in 2006, and proposed a dosing regimen in the patent.
  • prasugrd hydrochloride (Efient) has been marketed in Europe and the United States. Its specifications are 5mg, 10mg, rhombohedral tablets, slightly soluble in ⁇ 1 ⁇ 4, very slightly soluble in pH 5, pH 6 Insoluble in ⁇ 7, single-load dose 60mg, 10mg maintenance dose, and should take 75 ⁇ 325mg every day aspirin.
  • Prasugrel hydrochloride has a higher bioavailability than the base at higher intragastric pH.
  • the bioavailability is similar when prasugrel hydrochloride or prasugrel base is administered alone;
  • the pH in the stomach increases, and the bioavailability of the prasugrel base is significantly lower than that of the hydrochloride.
  • a solid dispersion refers to a dispersion system in which a drug is uniformly dispersed in a solid carrier material in a state of molecular, colloidal, amorphous, or microcrystalline. Solid dispersion technology can increase the solubility and dissolution of poorly soluble drugs, thereby increasing the bioavailability of the drug.
  • the solid dispersion is an intermediate product, and can be further prepared into a capsule, a tablet or the like as needed, which is advantageous for further industrial production of the pharmaceutical preparation.
  • Surfactants have both hydrophilic and lipophilic amphiphilic properties. By improving the wettability of the drug, preventing the aggregation of drug particles, and solubilizing the micelles, the dissolution of the hydrophobic drug can be improved, thereby improving the biological activity of the drug. Utilization.
  • the types of surfactants can be broadly classified into four types, anionic surfactants, cationic surfactants, amphoteric surfactants, and nonionic surfactants.
  • An inclusion complex refers to a unique form of a complex formed by the molecular structure of a drug being wholly or partially incorporated into the molecular cavity of another substance.
  • the cooperation of the package 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 attraction between the dipoles.
  • There are many methods for preparing the clathrate such as coprecipitation, grinding, sonication, freeze-drying, and the like.
  • the substances having inclusion properties are mainly cyclodextrin, cyclodextrin derivatives and urea.
  • the cyclodextrin is usually three kinds of ⁇ , ⁇ and ⁇ .
  • the cyclodextrin inclusion technology has been widely used in pharmaceutics, and is mainly used to effectively increase the solubility of poorly soluble drugs, increase the stability of unstable drugs, and mask the pungent odor of drugs. Summary of the invention
  • It is an object of the present invention to provide a pharmaceutical composition comprising prasugrel and a salt thereof, wherein the prasugrel and its salt are present in the composition in molecular, ionic, crystalline, or amorphous form, wherein:
  • the pharmaceutical composition is capable of increasing prasugrel and its salts at higher pH conditions Dissolution
  • the dissolution is similar to or higher than prasugrel hydrochloride
  • the pH range is 1.0 ⁇ pH 7.0;
  • Said composition contains a surfactant
  • the prasugrel and its salt are in the form of a clathrate, the clathrate comprises a cyclodextrin and a derivative thereof, and the cyclodextrin is selected from ⁇ -CD or ⁇ - ⁇ -CD, preferably ⁇ -CD, wherein the mass ratio of prasugrel and its salt to ⁇ -CD is 1:0.5 to 1:30, preferably 1:1 to 1:15, more preferably 1:1 to 1:5.
  • the prasugrel and its salt are in the form of a solid dispersion, wherein the composition further comprises a hydrophilic carrier material selected from the group consisting of povidone (PVP) and polyethylene glycol. a class, mannitol, cellulose and/or cyclodextrin and derivatives thereof, preferably PVP, cellulose and/or mannitol, more preferably PVP, most preferably PVP-K12 or PVP-K30;
  • PVP povidone
  • the weight ratio of gre and its salt to the carrier material is selected from 1:1 to 1:20, preferably from 1:1 to 1:10, more preferably from 1:3 to 1:5;
  • the particle size range of the drug 90% of the drug particle size is less than or equal to 75 ⁇ ;
  • the particle size range is less than or equal to 50 ⁇ m ; the particle size range is less than or equal to ⁇ , preferably less than or equal to 5 ⁇ ; the surfactant is selected from the group consisting of sodium decyl sulfate, bile salt, Tween, and the disc.
  • the solid preparation package may contain a filler, and the filler is selected from the group consisting of mannitol, starch, modified starch, Microcrystalline cellulose, lactose or/and calcium hydrogen phosphate, preferably a combination of mannitol and microcrystalline cellulose; the solid preparation comprises a lubricant selected from the group consisting of metal stearate and stearic acid.
  • a hydrogenated vegetable oil, talc or/and colloidal silica preferably a composition of colloidal silica, magnesium stearate; the weight of said colloidal silica based on 100% by weight of the solid preparation The percentage is 0% to 5%, preferably 0% to 3%, more Preferably 0% ⁇ 2%; based on 100% by weight of the solid preparation, the weight percentage of magnesium stearate is 0.5% ⁇ : 1%;
  • Another object of the present invention is to provide a method of preparing the inclusion compound, the method
  • the method is selected from the group consisting of a coprecipitation method, a kneading method, an ultrasonic method, a freeze drying method or a spray drying method, preferably a coprecipitation method, a kneading method or a freeze drying method, more preferably a coprecipitation method or a kneading method; wherein the inclusion material used is a cyclodextrin And its derivatives, preferably ⁇ -CD and its derivatives, most preferably ⁇ -CD;
  • another object of the present invention is to provide a process for preparing the solid dispersion selected from the group consisting of a solvent method, a melting method, and a solvent - a melting method or a grinding method, preferably a solvent method or a grinding method, more preferably a solvent method; wherein the solvent is selected from the group consisting of acetone, ethanol,
  • the simple drug-micronized treatment showed that the dissolution of the drug was improved at pH 4.5 and pH 6.8, but there was still a gap compared with the hydrochloride micronized preparation, so other methods were needed.
  • the hydrophilic carrier materials mentioned in the present invention include PVPs, polyethylene glycols, surfactants, mannitol, celluloses and cyclodextrins and derivatives thereof.
  • PVP materials are classified into PVP-K12, PVP-K-17, PVP-K25, PVP-K29/32, PVP-K90, PVPP and copolyvidone according to their viscosity.
  • Polyethylene glycol used as a solid dispersion is classified into PEG4000, PEG6000, PEG12000, and PEG20000 depending on the molecular weight.
  • the surfactant used is classified into a cationic, anionic, zwitterionic surfactant according to the charge.
  • the anionic surfactant comprises sodium dodecyl sulfate, sodium stearate, sodium cetyl sulfate, sodium diethyl succinate, sodium dodecylbenzenesulfonate and bile salts.
  • Nonionic surfactants include Span, Tween, Polyoxyethylene, Poloxamer, and the like.
  • a non-aqueous solvent is required to prepare the solid dispersion.
  • the present invention has been studied on common organic solvents such as acetone, ethanol, dichloromethane, methanol, chloroform, ethyl acetate, methanol, DMF, and diethyl ether.
  • the obtained solid dispersion can be prepared into tablets, capsules, granules and the like, wherein a tablet or capsule can be prepared, and a glidant and a lubricant can be added, including talc, polyethylene glycol, colloidal silica, and hard.
  • a mixture of magnesium citrate and sodium lauryl sulfate in an amount of 0.1% to 5% by weight of the tablet or capsule and may be added to a disintegrating agent, including croscarmellose sodium, crospovidone, carboxymethyl Based on sodium starch, fillers may be added including starch, modified starch, mannitol, and microcrystalline cellulose.
  • the dissolution of the prasugrel hydrochloride preparation was compared with the dissolution of the raw material, and the dissolution was more obvious.
  • the dissolution was lower than that of prasugrel hydrochloride, and a certain proportion of surface activity was added.
  • the agent can make the dissolution rate of the micronized raw material at the high pH value, and can achieve the same or higher dissolution rate as the hydrochloride salt micronized preparation.
  • Surfactants are well known to those skilled in the art and are classified into anionic surfactants sodium lauryl sulfate, bile salts; nonionic surfactants Tweens, Span, polyoxyethylene, poloxamers. .
  • anionic surfactants sodium lauryl sulfate, bile salts nonionic surfactants Tweens, Span, polyoxyethylene, poloxamers.
  • the effect of solubilizing prasugrel is sodium lauryl sulfate, bile salt, poloxamer, more preferably sodium lauryl sulfate and bile salt. Most preferred is sodium lauryl sulfate.
  • the present invention has also been studied for the particle size of the drug.
  • the drug particle size range is 75 ⁇ m or less, preferably less than 50 ⁇ m ⁇ , more preferably ⁇ or less, and most preferably 5 ⁇ or less.
  • the present invention also screens, and finds that the ratio of the ratio of the drug to the surfactant is less than or equal to 1:20, and the solubilization effect on the drug is better, and the range is preferably less than or equal to 1:10, more preferably. Less than or equal to 1:2.
  • the filler is a combination of one or more of mannitol, starch, modified starch, microcrystalline cellulose, lactose, and calcium hydrogen phosphate, preferably a combination of mannitol and microcrystalline cellulose.
  • the lubricant is a combination of one or more of a metal stearate, stearic acid, hydrogenated vegetable oil, talc, colloidal silica, preferably a combination of colloidal silica and magnesium stearate.
  • the weight percentage of the micro-silica gel is 0% to 5%, preferably 0% to 3%, more preferably Choose 0 ⁇ 2%.
  • the weight percentage of magnesium stearate is from 0.5% to 1%.
  • the preparation process of the method may be a dry granulation technique, in which all components except the lubricant, including the active ingredient and the surfactant, are pre-mixed together, and then the lubricant is added by screening, compressing, sieving the particle size, The capsules are then filled by tableting or directly. If the surfactant is oily, the semi-solid may be first mixed with microcrystalline cellulose or with micro-silica gel, sieved, mixed with the drug, and dry granulated.
  • the preparation process can also be wet granulation.
  • wet granulation all the ingredients except the lubricant, including the active ingredient and the surfactant, are mixed together, wetted and dried with purified water, and the surfactant can also be added to the purified water as a wetting agent. Agent, granulation is dry. After mixing the lubricant, compress or fill the capsule.
  • the inclusion material is a derivative of ⁇ -cyclodextrin ( ⁇ -CD) and ⁇ -cyclodextrin, preferably ⁇ -cyclodextrin.
  • the solvent is acetone, absolute ethanol, dichloromethane, methanol, chloroform or the like.
  • the present invention also studied the inclusion of a heterogeneous system, but found that the inclusion effect was poor.
  • the prasugrel solid dispersion and the clathrate prepared by the present invention are all intermediates of the preparation, and can also be prepared into corresponding capsules or tablets.
  • the solid dispersion or clathrate is used as a preparation intermediate, and the capsule or tablet prepared may contain a filler, and mannitol, starch, modified starch, microcrystalline cellulose, sorbitol, and sucrose are used.
  • the pharmaceutically acceptable solid unit dosage form can contain various other conventional excipients such as disintegrating agents and minor amounts of lubricants.
  • Lubricants include stearic acid metals Salt (magnesium, calcium, sodium), stearic acid, wax, hydrogenated castor oil, talc and colloidal silica.
  • Disintegrators include sodium carboxymethyl starch, croscarmellose sodium, crosslinked polyvinylpyrrolidone (PVPP), low substituted hydroxypropyl cellulose, modified corn starch, pregelatinized starch and natural starch.
  • the preparation process of the prasugrel solid dispersion and the clathrate can be carried out by a powder direct compression process or a dry granulation process.
  • the invention uses prasugrel and a hydrophilic carrier material as materials, and adopts a method of adding a surfactant, a solid dispersion technique and an inclusion compound technique respectively to improve the prasugrel base and the salt preparation thereof at a high pH value.
  • the dissolution rate thereby increasing the bioavailability of prasugrel bases at high pH, has the following advantages:
  • the preparation of prasugrel base preparation by the method of adding surfactant, solid dispersion technology and inclusion technique can improve the bioavailability of prasugrel base at higher pH value, and can improve to The near or higher dissolution of Lagrelide hydrochloride at higher pH values, thereby increasing bioavailability.
  • the prepared 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.
  • Example 1 The present invention will be specifically described with reference to the embodiments, and the embodiments of the present invention are only intended to illustrate the technical solutions of the present invention, and do not limit the essence of the present invention.
  • Example 1
  • the drug is micronized, mixed with sodium dodecyl sulfate and mixed with a prescription amount of micro-silica gel, and microcrystalline cellulose, mannitol, croscarmellose sodium, and the like are sequentially added in equal amounts.
  • the hydroxypropylmethylcellulose was mixed, passed through a 60 mesh sieve 5 times, and finally magnesium stearate (pretreated by a 60 mesh sieve) was added and mixed uniformly, and tableted.
  • Example 2 Example 2:
  • the drug is micronized and mixed with other excipients other than surfactants and lubricants.
  • the prescribed amount of sodium lauryl sulfate was dissolved in an appropriate amount of purified water as a wetting agent. Adding to the mixed auxiliary material, preparing soft material, granulating through 30 mesh sieve, drying, 40 mesh whole granules, mixing magnesium stearate, and pressing.
  • Example 3
  • the drug is micronized and mixed with other excipients other than surfactants and lubricants.
  • the prescribed amount of poloxamer is dissolved in an appropriate amount of purified water as a wetting agent. Add to the mixed excipients, make - soft materials, pass 30 mesh sieve granules, and dry.
  • magnesium stearate was mixed and compressed.
  • the prescribed amount of the drug (prasugrel) is dissolved in acetone, and PVPK30 is the carrier material.
  • ⁇ -CD was dissolved in a saturated solution, and the drug (prasugrel) was dissolved in acetone.
  • the mixture was added dropwise to a ⁇ -CD saturated solution under stirring for 8 hours to maintain a temperature of 40 °C.
  • the mixture was cooled and solidified, suction filtered, washed with diethyl ether, and dried to give a prasugrel inclusion compound.
  • the positive drug prasugrel hydrochloride was micronized, and then microcrystalline cellulose, mannitol, croscarmellose sodium, hydroxypropylmethylcellulose were added in an equal amount, passed through a 60 mesh sieve 5 times, and finally added hard. Magnesium citrate (pretreatment by 60 mesh sieve) is uniformly mixed and compressed.
  • Example 1-11 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 rate of the prasugrel base solid preparation at a high pH value was remarkably improved.
  • the dissolution data of the product of Example 1, Example 5, and Example 10 and the positive drug (prasugrel hydrochloride) tablets at pH 4.5 and pH 6.8 are not described herein.

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Description

提高普拉格雷溶出度的药物组合物及其制备方法
技术领域
本发明涉及一种含有普拉格雷及其盐的药物组合物及其制备方 法， 尤其涉及通过采用固体分散体技术、 包合物技术或表面活性剂技 术提高了普拉格雷及其盐在较高 pH值条件下的溶出度的组合物及其 制备方法。 背景技术
普拉格雷 （prasugrd ) , 其化学名为 5-[(lRS)-2-环丙基 -1-(2-氟苯 基 )-2-氧代乙基 ]-4,5,6,7-四氢噻吩 [3,2-c]吡啶 -2-基醋酸酯 ( 5-(2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno [3,2-
Figure imgf000002_0001
分子式： C2QH2QFN03S， 分子量： 373.44。
普拉格雷是一种口服的血小板抑制剂， 抗凝血药物。 本品最初开 发用于需要经皮冠状动脉介入治疗的急性冠状动脉综合症的患者， 包 括需要进行支架置人术的患者。 研究结果显示普拉格雷比氯吡格雷更 能有效地降低非致死性心脏病和卒中导致的死亡， 明显降低支架内血 栓风险。
礼来公司于 2006 年申请了普拉格雷盐酸盐的相关专利 (US20080166893 ) , 并在专利中提出了给药方案。 目前， 盐酸普拉格 雷薄膜包衣片（prasugrd, Efient)已在欧洲， 美国上市， 其规格为 5mg、 10mg， 菱形片， 在 ρΗ 1〜4中微溶， pH 5中极微溶， pH 6〜7中不溶， 单次负荷剂量 60mg， 10mg维持剂量， 同时每天还应服用 75〜325mg 阿司匹林。盐酸普拉格雷在较高的胃内 pH下同碱基相比， 有较高的生 物利用度。 根据 FDA-review相关报道， 单独服用盐酸普拉格雷或普拉 格雷碱基时， 生物利用度相近； 当同服？?1或112受体拮抗剂合用时， 胃内 pH升高， 普拉格雷碱基的生物利用度明显低于盐酸盐。 由盐酸普 拉格雷及普拉格雷的溶解性可知， 普拉格雷在 pH 1〜7中溶解性均比 盐酸盐差， 而脂溶性碱基较盐酸盐较强。 所以如果提高碱基的生物利 用度， 可以提高碱基在不同 pH下的溶出度。
固体分散体是指药物以分子、 胶态、 无定形、 微晶等状态均匀分 散在某一固态载体物质中所形成的分散体系。 采用固体分散体技术可 以增加难溶性药物的溶解度和溶出度， 从而提高药物的生物利用度。 固体分散体为中间产物， 可以根据需要进一步制成胶囊剂、 片剂等， 有利于药物制剂的进一步工业化生产。
表面活性剂具有既亲水又亲油的两亲性， 通过改善药物的润湿性， 防止药物粒子聚结， 以及胶束增溶作用， 可提高疏水性药物的溶出度， 从而提高药物的生物利用度。 表面活性剂的种类大体可以分为四类， 阴离子型表面活性剂， 阳离子型表面活性剂， 两性表面活性剂以及非 离子型表面活性剂。
包合物是指一种药物分子结构被全部或部分包合入另一种物质的 分子腔中而形成的独特形式的络合物。 包合作用主要是一物理过程， 形成条件取决于两分子间的范德华力， 分散力， 偶极子间引力。 制备 包合物所采用的方法很多， 如共沉淀法、 研磨法、 超声法、 冷冻干燥 法等。 具有包合性能的物质主要有环糊精、 环糊精衍生物和尿素等。 环糊精常见的为 α、 β和 γ三种。 环糊精包合技术在药剂学中的应用日 益广泛， 主要用于有效增加难溶性药物溶解度， 增加不稳定性药物的 稳定性， 掩蔽药物刺激性气味等。 发明内容
本发明的目的在于提供一种含有普拉格雷及其盐的药物组合物， 其中所述的普拉格雷及其盐以分子、 离子、 晶体、 或无定型的形式存 在于组合物中， 其中：
所述药物组合物能够提高普拉格雷及其盐在较高 pH值条件下的 溶出度；
所述的溶出度与盐酸普拉格雷相近或比之更高；
所述的 pH范围为 1.0<pH 7.0;
所述的组合物含有表面活性剂；
所述的普拉格雷及其盐以包合物形式存在， 所述的包合物含有环 糊精及其衍生物， 所述的环糊精选自 β-CD或 ΗΡ-β-CD, 优选 β-CD, 其中普拉格雷及其盐同 β-CD的质量比为 1 : 0.5〜1 : 30，优选 1:1〜1:15， 更优选 1:1〜1:5。
所述的普拉格雷及其盐以固体分散体形式存在， 其中所述的组合 物还含有亲水性载体材料， 该亲水性载体材料选自聚维酮 （PVP) 类、 聚乙二醇类、 甘露醇、 纤维素类和 /或环糊精及其衍生物， 优选 PVP 类、 纤维素类和 /或甘露醇， 更优选 PVP 类， 最优选 PVP-K12 或 PVP-K30; 其中普拉格雷及其盐同载体材料的重量比选自 1:1〜1:20， 优选 1:1〜1:10， 更优选 1:3〜1:5；
所述的药物组合物为固体制剂， 其特征为：
( 1 ) 药物的粒径范围： 90%的药物粒径小于等于 75μιη;
( 2 ) 在制剂中含有一定量的表面活性剂。
其中所述的粒径范围小于等于 50μιη; 所述的粒径范围小于等于 ΙΟμιη, 优选小于等于 5μιη; 所述的表面活性剂选自十二垸基硫酸钠、 胆盐， 吐温类、 司盘、 聚氧乙烯型或 /和泊洛沙姆， 优选十二垸基硫 酸钠、 胆盐或 /和泊洛沙姆， 更优选十二垸基硫酸钠； 其中普拉格雷及 其盐同表面活性剂的质量比小于等于 1:20， 优选小于等于 1:10， 更优 选小于等于 1:2; 所述的固体制剂包可含填充剂， 所述的填充剂选自甘 露醇、 淀粉、 改性淀粉、 微晶纤维素、 乳糖或 /和磷酸氢钙， 优选甘露 醇与微晶纤维素的组合物； 所述的固体制剂包含润滑剂， 所述的润滑 剂选自硬脂酸金属盐、 硬脂酸、 氢化植物油、 滑石粉或 /和胶态二氧化 硅，优选胶态二氧化硅、硬脂酸镁的组合物；按固体制剂的重量为 100% 计， 所述的胶态二氧化硅的重量百分比为 0%〜5%， 优选 0% ~ 3%， 更 优选 0%〜2%； 按固体制剂的重量为 100%计， 所述的硬脂酸镁的重量 百分比为 0.5%〜： 1%;
本发明的另一目的在于提供一种制备所述的包合物的方法， 该方 法选自共沉淀法、 捏合法、 超声法、 冷冻干燥法或喷雾干燥法优选共 沉淀法、 捏合法或冷冻干燥法， 更优选共沉淀法或捏合法； 其中采用 的包合材料为环糊精及其衍生物，优选 β-CD及其衍生物，最优选 β-CD; 本发明的另一目的在于提供一种制备所述固体分散体的方法， 其 选自溶剂法、 熔融法、 溶剂 -熔融法或研磨法， 优选溶剂法或研磨法， 更优选溶剂法； 其中所述溶剂选自丙酮、 乙醇、 甲醇、 乙酸乙酯、 二 氯甲垸、 氯仿、 DMF 或 /和乙醚， 优选丙酮、 乙醇、 甲醇、 乙酸乙酯 或 /和二氯甲垸， 更优选丙酮或 /和乙醇。
单纯的采用药物微粉化处理后发现， 药物在 pH4.5， pH6.8条件下 溶出度有所提高， 但是与盐酸盐微粉化制剂相比仍有差距， 故需采用 其他的方法。
本发明目的通过以下技术方案实现的：
1、 固体分散体制备
本发明所提及的亲水性载体材料包括 PVP类， 聚乙二醇类， 表面 活性剂， 甘露醇， 纤维素类和环糊精及其衍生物。 PVP类材料， 按照 粘度不同，分为 PVP-K12, PVP-K-17, PVP-K25， PVP-K29/32, PVP-K90, PVPP以及共聚维酮。被用作固体分散体的聚乙二醇， 按照分子量的不 同， 分为 PEG4000, PEG6000, PEG12000, PEG20000。 所使用的表面 活性剂， 按照所带电荷分为阳离子型、 阴离子型、 两性离子表面活性 剂。 其中， 阴离子型号表面活性剂包含十二垸基硫酸钠， 硬脂酸钠， 十六醇硫酸钠， 二乙基琥珀酸磺酸钠， 十二垸基苯磺酸钠以及胆盐。 非离子型表面活性剂包含司盘类， 吐温类， 聚氧乙烯型， 泊洛沙姆等。
由于药物溶解性差， 制备固体分散体需采用非水溶剂。 本发明对 常用有机溶剂如： 丙酮、 乙醇、 二氯甲垸、 甲醇、 氯仿、 乙酸乙酯、 甲醇， DMF、 乙醚进行了研究。
( 1 ) 溶剂法制备固体分散体： 取载体材料和药物投料比为 1:1〜
1:20, 分别加入适当有机溶剂搅拌溶解， 溶液混合均匀， 旋转蒸发， 水 浴 25-65°C， 蒸发 0.1-5h， 真空干燥 5-30h， 温度为 25-60°C， 干燥后研 磨过 60目 -120目筛。
(2) 喷雾干燥法制备固体分散体： 取载体材料和药物投料比为
1:1〜1:20， 分别加入适当有机溶剂搅拌溶解， 将溶解后的有机溶剂混 合均匀后喷雾干燥。
(3 )研磨法制备固体分散体： 取载体材料和药物投料比为 1:1〜 1:20， 混匀， 置于研钵， 球磨机或胶体磨中， 共研磨， 取出， 过 80-100 目筛。
所得的固体分散体可制备成片剂、 胶囊剂、 颗粒剂等， 其中制备 片剂或胶囊剂， 可加入助流剂和润滑剂， 包括滑石粉， 聚乙二醇， 胶 体二氧化硅， 硬脂酸镁， 十二烷基硫酸钠的混合物， 用量为片重或胶 囊的 0.1%〜5%,可加入崩解剂， 包括交联羧甲基纤维素钠， 交联聚维 酮， 羧甲基淀粉钠， 可加入填充剂包括淀粉、 改性淀粉、 甘露醇、 微 晶纤维素。
2、 药物组合物中加入表面活性剂
单纯的采用原料微粉化处理后发现， 同盐酸普拉格雷制剂溶出度 进行比较， 溶出度提高较明显， 而在 pH6.8条件下溶出度低于盐酸普 拉格雷， 通过加入一定比例的表面活性剂， 使微粉化原料的溶出度在 高 pH值下， 能达到同盐酸盐微粉化制剂相同或是更高的溶出度。
表面活性剂为本领域技术人所熟知的， 分为阴离子表面活性剂十 二烷基硫酸钠、 胆盐； 非离子型表面活性剂 吐温类、 司盘、 聚氧乙烯 型、 泊洛沙姆。 本发明在筛选过程中发现所用的表面活性剂中， 对于 普拉格雷增溶的效果优选十二烷基硫酸钠、 胆盐、 泊洛沙姆， 更优选 十二烷基硫酸钠和胆盐， 最优选十二烷基硫酸钠。
对于药物粒径， 本发明亦进行了研究。 药物粒径发现药物粒径越 小， 越有利于药物的溶出。 药物粒径范围小于等于 75μιη， 优选小于等 于 50μιη， 更优选小于等于 ΙΟμιη, 最优选小于等于 5μιη。
关于表面活性剂用量， 本发明亦进行了筛选， 实验发现药物同表 面活性剂用量比例范围小于等于 1:20， 对药物的增溶效果比较好， 该 范围内优选小于等于 1:10,更优选小于等于 1:2。
填充剂为甘露醇、 淀粉、 改性淀粉、 微晶纤维素、 乳糖、 磷酸氢 钙中的一种或几种的组合物， 优选甘露醇与微晶纤维素的组合物。
润滑剂为硬脂酸金属盐、 硬脂酸、 氢化植物油、 滑石粉、 胶态二 氧化硅中的一种或几种的组合物， 优选胶态二氧化硅、 硬脂酸镁的组 合物。所述的微粉硅胶的重量百分比为 0%〜5%， 优选 0%〜3%， 更优 选 0〜2%。 硬脂酸镁的重量百分比为 0.5%~1%。
该方法的制备工艺可以为干法制粒技术， 把除润滑剂外的所有成 分， 包括活性成分和表面活性剂， 预先混合在一起， 然后通过用筛选、 压缩、 筛分颗粒大小， 加入润滑剂， 再通过压片或直接填充胶囊。 如 果表面活性剂为油状， 半固体可以先用微晶纤维素或用微粉硅胶混合， 过筛后再同药物混合， 干法制粒。
制备工艺也可以为湿法制粒。 通过湿法制粒， 把除润滑剂外的所 有成分， 包括活性成分和表面活性剂， 混合在一起， 用纯化水进行润 湿、 干燥， 亦可以将表面活性剂加入纯化水中， 以其作为润湿剂， 制 粒干燥。 润滑剂混合后， 压片或填充胶囊。
还可以采用直接进行压片法： 混合除了润滑剂外的所有成分， 进 行过筛混合均匀后， 加入润滑剂， 最后直接压片或直接填充入胶囊中。
3、 包合物制备
( 1 )饱和水溶液法制备包合物： 配置包合材料的饱和溶液， 控制 溶液温度为 40°C， 将药物溶于丙酮， 搅拌下， 滴入到饱和溶液中， 恒 温搅拌 8h， 冷却析固， 将混浊液用布氏漏斗过滤， 选用乙醚作为良溶 剂， 洗涤滤饼后， 减压干燥除去水分及有机溶剂。
(2)研磨法制备包合物： 包合材料置于研钵中， 加入适量水， 先 将研磨均匀后， 将微粉化药物置于研钵中共研磨， 研磨成糊状， 干燥， 洗涤， 减压干燥。
其中所述包合材料为 β-环糊精 （β-CD) 及其 β_环糊精的衍生物， 优选 β_环糊精。 所述溶剂为丙酮、 无水乙醇、 二氯甲垸、 甲醇、 氯仿 等。
同时， 本发明也研究了采用非均相体系包合， 但结果发现包合效 果较差。
通过本发明制备得到的普拉格雷固体分散体及包合物， 均为制剂 中间体， 亦可制备成相应的胶囊剂或片剂。
将固体分散体或包合物作为制剂中间体， 制备的胶囊剂或片剂可 含有填充剂， 选用甘露醇， 淀粉， 改性淀粉， 微晶纤维素， 山梨糖醇， 蔗糖。 除活性成分和填充剂以外， 药用固体单元剂型可以含有多种其 他常规的赋形剂， 如崩解剂和少量的润滑剂。 润滑剂包括硬脂酸金属 盐（镁、 钙、 钠）， 硬脂酸， 蜡， 氢化蓖麻油， 滑石粉和胶质二氧化硅。 崩解剂包括羧甲基淀粉钠， 交联羧甲基纤维素钠， 交联聚乙烯吡咯烷 酮 （PVPP), 低取代羟丙基纤维素， 改性玉米淀粉、 预胶化淀粉和天 然淀粉。
普拉格雷固体分散体及包合物的制剂工艺， 可以采用粉末直接压 片工艺， 或干法制粒工艺进行制备。
本发明是以普拉格雷和亲水性载体材料为材料， 分别采用加入表 面活性剂的方法、 固体分散体技术以及包合物技术， 提高普拉格雷碱 基及其盐制剂在高 pH值中的溶出度， 从而提高普拉格雷碱基在高 pH 值的生物利用度， 该发明具有以下优点：
( 1 )采用加入表面活性剂的方法、 固体分散体技术及包合技术制 备普拉格雷碱基制剂，可以提高普拉格雷碱基在较高 pH值中的生物利 用度，可以提高到和普拉格雷盐酸盐在较高 pH值中的将近或更高的溶 出度， 从而提高生物利用度。
(2)制备的普拉格雷固体分散体及包合物为中间产物， 可以根据 需要进一步制成胶囊剂、 片剂等， 有利于药物制剂的进一步工业化生 产。 具体实施方式
以下将结合实施例具体说明本发明， 本发明的实施例仅用于说明 本发明的技术方案， 并非限定本发明的实质。 实施例 1
药物组合物：
药物 （普拉格雷
十二烷基硫酸钠 10g
甘露醇 73g
微晶纤维素 50g
交联羧甲基纤维 7.5g
羟丙甲基纤维素 3g
硬脂酸镁 1.5g 工艺：
将药物 （普拉格雷）微粉化处理， 同十二烷基硫酸钠同药物混合， 加入处方量微粉硅胶， 等量递增依次加入微晶纤维素、 甘露醇、 交联 羧甲基纤维素钠、 羟丙甲基纤维素混合， 过 60目筛 5次， 最后加入硬 脂酸镁 （过 60目筛预处理） 混合均匀， 压片。 实施例 2:
药物组合物：
药物 （普拉格雷） 5g
十二烷基硫酸钠 5g
甘露醇 71.5g
微晶纤维素 50g
交联羧甲基纤维素钠 7.5g
羟丙甲基纤维素 3g
微粉硅胶 1.5g
硬脂酸镁 1.5g
工艺：
将药物 （普拉格雷） 微粉化处理， 同除表面活性剂、 润滑剂外其 它辅料混合均匀。 将处方量十二烷基硫酸钠溶解于适量纯化水中， 以 其作为润湿剂。 加入至混合后的辅料中， 制备软材， 过 30目筛制粒， 烘干， 40目整粒后混入硬脂酸镁 ， 压片。 实施例 3 :
药物组合物：
药物 （普拉格雷） 5g
泊洛沙姆 5g
甘露醇 70g
微晶纤维素 50g
交联羧甲基纤维素钠 7.5g
羟丙甲基纤维素 3g
微粉硅胶 3g 硬脂酸镁 1.5g
工艺：
将药物 （普拉格雷） 微粉化处理， 同除表面活性剂、 润滑剂外其 它辅料混合均匀。 将处方量泊洛沙姆 ί 解于适量纯化水中， 以其作为 润湿剂。 加入至混合后的辅料中， 制 -软材， 过 30目筛制粒， 烘干，
40目整粒后混入硬脂酸镁， 压片。 实施例 4
药物组合物 ：
Figure imgf000010_0002
工艺:
称取处方量药物 （普拉格雷） 溶于丙酮中， PVPK30为载体材料， 溶于无水乙醇中， 将丙酮和乙醇混合均匀， 水浴 40°C旋转蒸发， 40°C 真空干燥 24h， 研磨过 80目筛， 即得普拉格雷固体分散体。
Figure imgf000010_0001
Figure imgf000010_0003
工艺:
称取处方量药物 （普拉格雷） 溶于丙酮中， PVPK30为载体材料， 溶于无水乙醇中， 将 PVPK30醇溶液加入至丙酮溶液中， 混合均匀。 以混合溶液作粘合剂， 加入 PVPP中， 分散均匀， 水浴 40°C旋转蒸发， 40°C真空干燥 24h， 研磨过 80目筛， 即得普拉格雷固体分散体。 实施例 6
药物组合 ^ 药物 （普拉格雷） 2g
丙酮 100ml
PVPK30 20g
无水乙翻 50ml
工艺：
称取处方量药物 （普拉格雷） 溶于丙酮中， PVPK30为载体材料，
：于无水乙醇中， 将两种溶剂混匀， 喷雾干燥得普拉格雷固体分散体' 实施例 7
药物组合物：
药物 （普拉格雷） lg
丙酮 50ml
PEG6000 3g
工艺：
称取处方量 PEG6000, 40°C条件下， 溶于丙酮中， 冷却后加入主 药， 迅速搅拌至均匀， 冷却后析固。 实施例 8
药物组合物：
药物 （普拉格雷） lg
甘露醇 15g
工艺：
称取处方量微粉化药 (普拉格雷） 和甘露醇， 置于球
6h， 取出， 过 80目筛 即得普拉格雷固体分散体。 药物组合物：
药物 （普拉格雷） lg
甘露醇 10g
微晶纤维素 5g
工艺：
称取处方量药物 （普拉格雷）、 甘露醇和微晶纤维素， 置于球磨机 中， 研磨 6h， 取出， 过 80目筛， 即得普拉格雷固体分散体。 实施例 10
药物组合物:
Figure imgf000012_0001
工艺：
40°C条件下， β-CD配置成饱和溶液， 药物 （普拉格雷） 溶解于丙 酮， 搅拌下滴入 β-CD饱和溶液中， 分散 8h， 保持温度 40°C。 冷却析 固， 抽滤， 用乙醚洗涤， 烘干即得普拉格雷包合物。 实施例 11
药物组合物:
Figure imgf000012_0002
工艺: 称取处方量 β-CD置于研钵中， 加入三倍量水， 称取药物（普拉格 雷） 置于研钵中共研磨， 研磨成糊状。 干燥， 洗涤， 烘干即得普拉格 雷包合物。 试验例 1
采用 PVP为载体材料，溶剂法制备固体分散体（药物：载体 =1 :10)， 体外溶出度评价方法为：
( 1 )称取含相当碱基 5mg药物的固体分散体，照溶出度测定方法 (附录 XC第一法）， 以 1000ml pH4.5磷酸缓冲液为溶出介质， 转速为 每分钟 50转， 依法操作， 于 5min， 10min， 15min， 20min, 30min取 溶液 5ml ， 滤过， 同时补充 5ml溶出介质， 取续滤液作为供试品溶液， 液相测定。
(2 )称取含相当碱基 5mg药物的固体分散体，照溶出度测定方法 (附录 XC第一法）， 以 1000ml pH6.8磷酸缓冲溶液为溶出介质， 转速 为每分钟 50转， 依法操作， 经 5min、 15min、 30min、 45min、 60min 取溶液 5ml ， 滤过， 同时补充 5ml溶出介质， 取续滤液作为供试品溶 液， 送于液相室测定。
( 3 )制备阳性药物 （盐酸普拉格雷） 片剂处方如下
盐酸普拉格雷 5.49g
甘露醇 79.51g
微晶纤维素 50g
交联羧甲基纤维素钠 7.5g
羟丙甲基纤维素 3g
微粉硅胶 3g
硬脂酸镁 1.5g
工艺：
将阳性药物盐酸普拉格雷微粉化处理， 依次加入微晶纤维素、 甘 露醇、 交联羧甲基纤维素钠、 羟丙甲基纤维素等量混合， 过 60目筛 5 次， 最后加入硬脂酸镁 （过 60目筛预处理） 混合均匀， 压片。
实施例 1-11的溶出度评价依次采用上述评价体系， 溶出度结果显 示， 普拉格雷碱基固体制剂在高 pH值下的溶出度明显提高， 在此陈列 实施例 1、 实施例 5、 实施例 10产物与阳性药物 （盐酸普拉格雷） 片 剂在 pH4.5及 pH6.8中溶出度对比数据， 其他的就不再赘述。
PH4.5磷酸缓冲液中的溶出度评价：
表 1 : 盐酸普拉格雷与实施例 1产物的对比
Figure imgf000014_0001
表 2 : 盐酸普拉格雷与实施例 5产物的对比
Figure imgf000014_0002
表 3 : 盐酸普拉格雷与实施例 10产物的对比
Omin 5min lOmin 15min 20min 3 Omin 盐酸普拉格雷 0 16.71 26.66 32.45 36.78 43.42 实施例 10产物
0 22.6 29.48 36.46 39.46 41.18
(普拉格雷： P-CD=1:1)
实施例 10产物
0 52.16 61.6 64.1 64.89 68.67
(普拉格雷: 0-CD=l:3)
实施例 10产物
0 36.83 45.09 52.23 55.88 61.32
(普拉格雷: i3-CD=l:5)
PH6.8磷酸缓冲液中的溶出度评价：
表 4: 盐酸普拉格雷与实施例 1 产物的对比
Omin 5min 15min 3 Omin 45min 60min 盐酸普拉格雷 0 13.69 21.03 23.99 25.13 25.62 实施例 1 产物 0 17.31 24.92 29.57 34.32 36.97
表 5: 盐酸普拉格雷与实施例 5产物的对比
Omin 5min 15min 3 Omin 45min 60min 盐酸普拉格雷 0 13.69 21.03 23.99 25.13 25.62 实施例 5产物
0 11.67 15.12 19.36 24.72 25.86
(普拉格雷:载体 =1:1)
实施例 5产物
0 17.82 25.51 29.09 34.57 35.80
(普拉格雷:载体 =1:3) 实施例 5产物
0 20.58 26.42 32.90 36.12 40.97
(普拉格雷:载体 =1:5)
实施例 5产物
0 21.08 28.59 34.58 37.05 42.72
(普拉格雷:载体 =1:8)
实施例 5产物
0 25.6 33.76 37.27 39.48 47.47
(普拉格雷:载体 =1:10) 表 6: 盐酸普拉格雷与实施例 10产物的对比
Omin 5min 15min 3 Omin 45min 60min 盐酸普拉格雷 0 13.69 21.03 23.99 25.13 25.62 实施例 10产物
0 14.87 22.43 25.66 26.87 26.84
(普拉格雷： P-CD=1:1)
实施例 10产物
0 15.74 25.41 28.76 29.31 30.15
(普拉格雷: 0-CD=l:3)
实施例 10产物
0 16.74 26.24 27.28 28.37 29.27
(普拉格雷: i3-CD=l:5)

Claims

权利要求书:
1、 一种含有普拉格雷及其盐的药物组合物， 其中所述的普拉格雷 及其盐以分子、 离子、 晶体、 或无定型的形式存在于组合物中。
2、 根据权利要求 1所述的药物组合物， 其中所述药物组合物能够 提高普拉格雷及其盐在较高 pH值条件下的溶出度。
3、 根据权利要求 2所述的药物组合物， 其中所述的溶出度与盐酸 普拉格雷相等或比之更高。
4、根据权利要求 2所述的药物组合物， 其中所述的 pH范围为 1.0
Figure imgf000017_0001
5、 根据权利要求 2所述的药物组合物， 其中所述的组合物含有表 面活性剂。
6、 根据权利要求 5所述的药物组合物， 其中所述的表面活性剂为 十二烷基硫酸钠。
7、 根据权利要求 2所述的药物组合物， 其中所述的普拉格雷及其 盐以包合物形式存在。
8、 根据权利要求 7所述的药物组合物， 其中所述的包合物含有环 糊精及其衍生物。
9、 根据权利要求 8 所述的药物组合物， 其中所述的环糊精选自 β-CD或 ΗΡ-β-CD, 优选 β-CDo
10、 根据权利要求 9所述的药物组合物， 其中普拉格雷及其盐同 环糊精的质量比为 1:0.5〜1:30， 优选 1:1〜1:15， 更优选 1:1〜1:5。
11、 根据权利要求 2所述的药物组合物， 其中所述的普拉格雷及 其盐以固体分散体形式存在。
12、 根据权利要求 11所述的药物组合物， 其中所述的组合物还含 有亲水性载体材料。
13、 根据权利要求 12所述的药物组合物， 其中所述的亲水性载体 材料选自聚维酮 （PVP) 类、 聚乙二醇类、 甘露醇、 纤维素类和 /或环 糊精及其衍生物， 优选 PVP类、 纤维素类和 /或甘露醇。
14、 根据权利要求 13所述的药物组合物， 其中所述的亲水性载体 材料选自 PVP-K12或 PVP-K30。
15、 根据权利要求 12所述的药物组合物， 其中普拉格雷及其盐同 载体材料的重量比选自 1:1〜1:20， 优选 1:1〜1:10， 更优选 1:3 ~ 1:5。
16、 一种制备如权利要求 11所述的药物组合物的方法， 其选自溶 剂法、 熔融法、 溶剂 -熔融法或研磨法， 优选溶剂法或研磨法， 更优选 溶剂法。
17、根据权利要求 16所述的方法，其中所述溶剂选自丙酮、 乙醇、 甲醇、 乙酸乙酯、 二氯甲垸、 氯仿、 DMF或 /和乙醚， 优选丙酮或 /和 乙醇。
18、 根据权利要求 2所述的药物组合物， 其中所述的药物组合物 为固体制剂。
19、 根据权利要求 18所述的药物组合物， 其中所述的固体制剂特 征为：
( 1 ) 药物的粒径范围： 90%的药物粒径小于等于 75μιη， 优选小 于等于 50μιη， 更优选小于等于 ΙΟμιη, 更优选小于等于 5μιη;
(2) 在制剂中含有一定量的表面活性剂。
20、 根据权利要求 19所述的药物组合物， 其中所述的表面活性剂 选自十二垸基硫酸钠、 胆盐， 吐温类、 司盘、 聚氧乙烯型或 /和泊洛 沙姆， 优选十二垸基硫酸钠。
21、 根据权利要求 19所述的药物组合物， 其中普拉格雷及其盐同 表面活性剂的质量比小于等于 1:20， 优选小于等于 1:10， 更优选小于 等于 1:2。
22、 根据权利要求 18所述的药物组合物， 其中所述的固体制剂包 含填充剂。
23、 根据权利要求 22所述的药物组合物， 其中所述的填充剂选自 甘露醇、 淀粉、 改性淀粉、 微晶纤维素、 乳糖或 /和磷酸氢钙， 优选甘 露醇与微晶纤维素的组合物。
24、 根据权利要求 18所述的药物组合物， 其中所述的固体制剂包 含润滑剂。
25、 根据权利要求 24所述的药物组合物， 其中所述的润滑剂选自 硬脂酸金属盐、 硬脂酸、 氢化植物油、 滑石粉或 /和胶态二氧化硅， 优 选胶态二氧化硅和硬脂酸镁的组合物。
26、 根据权利要求 25所述的药物组合物， 其中按固体制剂的重量 为 100%计，所述的胶态二氧化硅的重量百分比为 0%〜5%，优选 0%〜 3% , 更优选 0%〜2%。
27、 根据权利要求 25所述的药物组合物， 其中按固体制剂的重量 为 100%计， 所述的硬脂酸镁的重量百分比为 0.5%〜1%。
28、 一种制备如权利要求 7所述的药物组合物的方法， 该方法选 自共沉淀法、 捏合法、 超声法、 冷冻干燥法或喷雾干燥法， 优选共沉 淀法或捏合法。
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