WO2016161991A2 - 一种硫酸氢氯吡格雷固体制剂及其制备方法 - Google Patents

一种硫酸氢氯吡格雷固体制剂及其制备方法 Download PDF

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WO2016161991A2
WO2016161991A2 PCT/CN2016/090137 CN2016090137W WO2016161991A2 WO 2016161991 A2 WO2016161991 A2 WO 2016161991A2 CN 2016090137 W CN2016090137 W CN 2016090137W WO 2016161991 A2 WO2016161991 A2 WO 2016161991A2
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hydrogen sulfate
clopidogrel hydrogen
solid preparation
preparation
prescription
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PCT/CN2016/090137
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French (fr)
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WO2016161991A3 (zh
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蔡燕霞
谭岳尧
叶冠豪
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深圳信立泰药业股份有限公司
山东信立泰药业有限公司
惠州信立泰药业有限公司
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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
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical preparations.
  • the invention relates to a solid preparation of clopidogrel hydrogen sulfate and a preparation method thereof.
  • Clopidogrel hydrogen sulfate (CAS: 135046-48-9) is a clopidogrel sulfate, English name Clopidogrel Hydrogen Sulfate, chemical name: (s)- ⁇ -(2-chlorophenyl)-6,7 - Dihydrothieno[3,2-c]pyridine-5(4H)acetic acid methyl ester hydrogensulfate.
  • Clopidogrel hydrogen sulfate is an anti-platelet aggregation agent. The product was developed by the French pharmaceutical company Sanofi-Aventis and first marketed in the United Kingdom and the United States in 1998. Clopidogrel hydrogen sulfate entered China in 2001 and is used clinically to prevent atherothrombotic thrombosis. .
  • the domestic clopidogrel hydrogen sulfate preparation products mainly include Plavix of Sanofi-Aventis and Taijia of Shenzhen Xinlitai Pharmaceutical Co., Ltd.
  • Clopidogrel hydrogen sulfate is unstable under moist heat conditions, so the conventional wet granulation-tableting method is not suitable for the preparation of clopidogrel hydrogen sulfate.
  • a dry preparation process is commonly used to prepare clopidogrel hydrogen sulfate preparation.
  • the clopidogrel hydrogen sulfate bulk drug is easy to absorb moisture, and the electrostatic phenomenon of the powder is serious, if the solid preparation is prepared by the direct compression process, on the one hand, the liquidity of the total mixed powder is not suitable for direct compression.
  • sticking occurs during the tableting process, so that the production cannot be carried out smoothly.
  • the preparation of the clopidogrel hydrogen sulfate solid preparation usually requires a granulation process, and the fluidity is not
  • the powder of the active ingredient having a good particle size distribution is prepared into particles suitable for tableting.
  • the prior art mainly uses two methods of granulation, dry granulation and melt granulation.
  • Patent CN1935119A discloses a process for preparing a solid preparation of clopidogrel hydrogen sulfate by a dry granulation process, and the obtained solid preparation has the characteristics of high stability.
  • the electrostatic phenomenon of clopidogrel hydrogen sulfate powder is serious, the mixing effect in the mixing process is not ideal, and the uniformity of the active ingredient is not good.
  • a qualified preparation can be prepared by means of prescription improvement, the preparation process is Whole Physically not optimal.
  • the melt granulation process uses a lower melting point auxiliary as a binder, and is formed by melting and agglomerating and bonding, and forms particles after cooling. This method can effectively improve the uniformity of the raw materials in the granules, but is melted for the clopidogrel hydrogen sulfate product. Granules, because the active ingredient has the characteristics of a compound which is easy to stick, so that the development of the product melt granulation process needs to simultaneously ensure that the obtained particles are favorable for the subsequent tableting process.
  • Patent CN101690719 discloses a series of solid preparations of clopidogrel hydrogen sulfate prepared by using PEG6000 as a binder by melt granulation at a temperature of 50-90 ° C in a sandwich pot or a fluidized bed, which improves the original process.
  • the uniformity of the auxiliary materials can effectively alleviate the sticking phenomenon, and the obtained solid preparation has high stability.
  • the batch granulation process of the melt granulation process is relatively large, that is, the unit mass of clopidogrel hydrogen sulfate requires more excipient dispersion, and it is known that the process still needs to be improved.
  • the object of the present invention is to overcome the deficiencies of the prior art and provide a solid preparation of clopidogrel hydrogen sulfate prepared by a melt granulation process, wherein the obtained granules have a high content of a raw material drug, and the obtained preparation has good uniformity and a smooth surface.
  • the difference in tablet weight is small, and the dissolution performance is in line with clinical drug requirements.
  • a solid preparation of clopidogrel hydrogen sulfate comprising internal phase particles comprising clopidogrel hydrogen sulphate, a filler, a disintegrant and a binder, and an external adjuvant, the clopidogrel hydrogen sulfate solid preparation Using a melt granulation process, characterized in that the D90 of clopidogrel hydrogen sulfate is 30-100 ⁇ m, the binder is PEG6000, and when the mass fraction of clopidogrel hydrogen sulfate is 1, the binder use The amount is 0.1 to 0.5 parts.
  • the invention is based on controlling the particle size (D90) of clopidogrel hydrogen sulfate and the amount of PEG6000 as a binder.
  • the clopidogrel hydrogen sulfate of the present invention is based on clopidogrel hydrogen sulfate. .
  • the particle size (D90) of clopidogrel hydrogen sulfate was controlled to be 30-100 ⁇ m, the amount of binder PEG6000 can be effectively reduced, and the amount of excipients can be further reduced. It has good properties, is easy to mix with external auxiliary materials, and has no sticking phenomenon during the subsequent tableting process.
  • the obtained tablets have the characteristics of good uniformity, smooth surface and small difference in tablet weight, and the dissolution properties are in line with the requirements of clinical medication.
  • the large particle size of clopidogrel hydrogen sulfate tends to prepare particles having a large particle size, and the dissolution rate of the preparation is The effect of too little binder will also affect the granulation effect, making the particles loose and easily broken into powder, which is not conducive to the subsequent preparation process; while the smaller clopidogrel hydrogen sulfate particle size corresponds to the use of more bonding.
  • the agent more internal adjuvants are needed, and the small particle size of clopidogrel hydrogen sulfate tends to prepare small particle size internal phase particles, and there are more powders, which is also unfavorable for the subsequent preparation process; for the melt granulation process
  • the particle size (D90) of clopidogrel hydrogen sulfate is controlled to be 30-100 ⁇ m, it can be prepared according to the amount of the appropriate amount of the binder PEG6000, while effectively increasing the content of clopidogrel hydrogen sulfate in the granule.
  • Moderate particle size a narrow particle size distribution, which helps optimize the subsequent mixing and tableting process, the resulting tablets conformed to the requirements of clinical application Clopidogrel bisulfate.
  • the particle size (D90) of clopidogrel hydrogen sulfate is 40 to 90 ⁇ m, and more preferably the particle size (D90) of clopidogrel hydrogen sulfate is 50 to 80 ⁇ m.
  • the solid preparation of clopidogrel hydrogen sulfate according to the present invention may adopt a common crystal form of clopidogrel hydrogen sulfate, such as crystal form I, crystal form II, etc. reported in the prior art, and preferably crystal form I reported in the prior art, that is, crystal
  • the X-ray powder diffraction pattern of the type has diffraction peaks at 2 ⁇ angles of 9.28°, 10.96°, 14.88°, 15.55°, 18.54°, 19.02°, 20.65°, 23.24°, 23.92°, 25.59°.
  • the amount of the binder PEG6000 can be reduced, and the amount of other internal adjuvants can be controlled to a suitable range, thereby increasing the clopidogrel hydrogen sulfate in the particles.
  • the content is further improved on the basis of the granulation effect.
  • the mass fraction of clopidogrel hydrogen sulfate is 1, the mass part of the binder may be 0.1 to 0.5; preferably, when the mass fraction of clopidogrel hydrogen sulfate is 1, the mass part of the binder It can be from 0.15 to 0.35.
  • the inner phase particles of the clopidogrel hydrogen sulfate solid preparation of the invention have less auxiliary materials, and the content of clopidogrel hydrogen sulfate is higher, which effectively improves the efficiency of molten granulation.
  • the internal phase particles also include a filler and a disintegrant.
  • the filler in the inner phase particles is selected from one or more of microcrystalline cellulose, lactose, pre-treated starch, etc., mixed in any ratio, preferably one or two of microcrystalline cellulose and lactose. Mix above and above in any ratio. Specifically, when the mass fraction of clopidogrel hydrogen sulfate is 1, the mass fraction of the filler may be 0.03 to 0.1.
  • the disintegrant in the internal phase particles is selected from one or more selected from the group consisting of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, and the like. Mix of proportions. Specifically, when the mass fraction of clopidogrel hydrogen sulfate is 1, the mass fraction of the disintegrant may be 0.2 to 0.5.
  • a preferred internal phase particle formulation of the present invention is as follows:
  • a preferred internal phase particle formulation of the present invention is as follows:
  • a preferred internal phase particle formulation of the present invention is as follows:
  • Clopidogrel hydrogen sulfate 1 Microcrystalline cellulose 0.05 PEG6000 0.2 Cross-linked povidone 0.4
  • a preferred internal phase particle formulation of the present invention is as follows:
  • a preferred internal phase particle formulation of the present invention is as follows:
  • the molten granulation may be a device commonly used in the prior art, preferably a sandwich pan or a fluidized bed granulator, and the temperature of the material in the granulation process is controlled at 50 to 80 ° C.
  • the obtained particles have uniform particle size particles, few fine powders or only a small amount of fine powder, and the active ingredients have high uniformity and good fluidity.
  • the solid preparation of clopidogrel hydrogen sulfate according to the present invention further includes an external auxiliary material including a filler, a disintegrating agent, a stabilizer, and a lubricant.
  • the filler is selected from one or a mixture of two or more of microcrystalline cellulose, lactose, pregelatinized starch, and the like in any ratio. Specifically, when the mass fraction of clopidogrel hydrogen sulfate is 1, the mass part of the filler may be 0.3 to 1.0.
  • the disintegrating agent is selected from one or more selected from the group consisting of crospovidone, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, and the like. Mix of proportions. Specifically, when the mass fraction of clopidogrel hydrogen sulfate is 1, the mass fraction of the disintegrant may be 0.1 to 0.5.
  • the stabilizer is sucrose stearate. Specifically, when the mass fraction of clopidogrel hydrogen sulfate is 1, The mass fraction of the stabilizer may be 0.02 to 0.08.
  • the lubricant is selected from one or a mixture of two or more of magnesium stearate, hydrogenated castor oil, talc, and the like in any ratio. Specifically, when the mass fraction of clopidogrel hydrogen sulfate is 1, the mass part of the lubricant may be 0.03 to 1.0.
  • a preferred formulation of the clopidogrel hydrogen sulfate solid formulation of the present invention is as follows:
  • a preferred formulation of the clopidogrel hydrogen sulfate solid formulation of the present invention is as follows:
  • a preferred formulation of the clopidogrel hydrogen sulfate solid formulation of the present invention is as follows:
  • a preferred formulation of the clopidogrel hydrogen sulfate solid formulation of the present invention is as follows:
  • a preferred formulation of the clopidogrel hydrogen sulfate solid formulation of the present invention is as follows:
  • Another object of the present invention is to provide a preparation method of the solid preparation of clopidogrel hydrogen sulfate according to the present invention, which is suitable for the formulation characteristics, and is beneficial to exerting the advantages of the prescription and realizing the improvement of the hydrogen chloride in the inner phase particles.
  • step 2) The inward mixed powder obtained in the step 1) is added to a melt granulation apparatus, and granulated at 50 to 80 ° C for 10 to 30 minutes to obtain internal phase particles.
  • step 1) can be mixed by a conventional mixing device, preferably by a column type lifting mixer.
  • step 2) is controlled at 10 to 30 minutes to facilitate the preparation of internal phase particles in accordance with the subsequent formulation process.
  • preparation method comprises the following steps:
  • step 2) adding the inward mixed powder obtained in the step 1) to the melt granulation apparatus, and granulating at 50 to 80 ° C for 10 to 30 minutes to obtain internal phase particles;
  • the steps 1) and 3) can be mixed by conventional mixing equipment, preferably by column type lifting.
  • the mixing machine equipment is mixed; the granulation time of step 2) is controlled to be 10-30 min to facilitate the preparation of the internal phase particles in accordance with the subsequent preparation process, since the inner phase particles obtained in the step 2) have a moderate particle size, uniform particles and no fine powder or It only contains a small amount of fine powder, so that the total mixing particles in the preparation of step 3) can be quickly mixed with the external auxiliary materials in a short time, and the mixing effect is good;
  • the molten granulating device in the step 2) is a sandwich pot or a stream.
  • the bed granulator; the tableting pressure of the step 4) is preferably 3 to 5 kgf, and based on the beneficial effect of the internal phase particles, no sticking phenomenon occurs during the tableting process.
  • the solid preparation of clopidogrel hydrogen sulfate may be further subjected to a coating treatment using a conventional coating process selected from commonly used commercially available or self-made coating materials such as Opadry. , hypromellose and the like.
  • the present invention has the following outstanding advantages and beneficial effects:
  • a solid preparation of clopidogrel hydrogen sulfate is prepared, which is prepared by a melt granulation process, and the obtained granules have high content of raw materials, and the obtained preparation has the characteristics of good uniformity, smooth surface, small difference in tablet weight, and dissolution property. Both meet the requirements of clinical use, and when using a specific crystal form, the effect is better;
  • a preparation method of the solid preparation of clopidogrel hydrogen sulfate according to the present invention is very suitable for the prescription characteristics, is beneficial to exerting the advantages of the prescription, and achieving the purpose of increasing the content of clopidogrel hydrogen sulfate in the internal phase particles, And further realize the optimal preparation process, and finally prepare a solid preparation of clopidogrel hydrogen sulfate with high qualified rate and conforming to clinical use.
  • the BT-1001 intelligent powder property testing instrument was used to detect the angle of repose of the obtained clopidogrel hydrogen sulfate internal phase particles;
  • the inward mixed powder obtained in the step 1) is added to a fluidized bed granulator, and granulated at 50 to 60 ° C for 10 to 30 minutes to obtain internal phase particles (residence angle 37 °), and the obtained particles are uniform and have no fine powder;
  • the inward mixed powder obtained in the step 1) is added to a fluidized bed granulator, and granulated at 50 to 60 ° C for 10 to 30 minutes to obtain internal phase particles (the angle of repose is 38°), and the obtained particles are uniform and have no fine powder;
  • the inward mixed powder obtained in the step 1) is added to a fluidized bed granulator, and granulated at 50 to 60 ° C for 10 to 30 minutes to obtain internal phase particles (the angle of repose is 38°), and the obtained particles are uniform and have no fine powder;
  • a preferred formulation of the clopidogrel hydrogen sulfate solid formulation of the present invention is as follows:
  • the inward mixed powder obtained in the step 1) is added to a fluidized bed granulator, and granulated at 50 to 60 ° C for 10 to 30 minutes to obtain internal phase particles (residence angle 40 °), the obtained particles are uniform, and a small amount of fine powder exists. However, it has no effect on the subsequent process;
  • step 2) The inward mixed powder obtained in the step 1) is added to a fluidized bed granulator, and granulated at 50 to 60 ° C for 10 to 30 minutes to obtain internal phase particles (residence angle 39 °), the obtained particles are uniform, and a trace amount of fine powder is present. No impact on subsequent processes;
  • the inward mixed powder obtained in the step 1) is added to a fluidized bed granulator, and granulated at 50 to 60 ° C for 10 to 30 minutes to obtain internal phase particles (the angle of repose is 36°), and the obtained particles are uniform and have no fine powder.
  • the obtained particle diameter is significantly larger than that of the internal phase particles obtained in Examples 1-5;
  • the inward mixed powder obtained in the step 1) is added to a fluidized bed granulator, and granulated at 50 to 60 ° C for 10 to 30 minutes to obtain internal phase particles (residence angle 45 °), and the granulation effect is poor.
  • the obtained particles are more Fine powder
  • the inward mixed powder obtained in the step 1) is added to a fluidized bed granulator, and granulated at 50 to 60 ° C for 10 to 30 minutes to obtain internal phase particles (the angle of repose is 38°), and the obtained particles are obtained in comparison with the examples 1-5.
  • the particles are slightly smaller, the particles are uniform, and there are few fine powders;
  • the dissolution rate of the clopidogrel sulfate tablets obtained in Examples 1-5 and Comparative Examples 1 and 3 was respectively measured by the Chinese Pharmacopoeia (2010 edition) Appendix XC dissolution measurement method second pulp method. as follows:
  • the dissolution rate was similar to that of the tablets obtained in Examples 1-5, but since the particle size of the drug substance used was small, it was required to increase the binder and the internal phase auxiliary material in the preparation of the internal phase particles. The amount is used to optimize the granulation effect, so that the content of the active ingredient in the inner phase particles is low, and the granulation efficiency is far less than that of Examples 1-5.
  • the clopidogrel hydrogen sulfate tablets obtained in Examples 1-5 were packaged and placed under high temperature and high humidity conditions (RH 75%, 40 ° C), and the total impurity content was observed.
  • the results were as follows:
  • Example 1 0.3 0.3 0.4
  • Example 2 0.3 0.4 0.4
  • Example 3 0.3 0.4 0.4
  • Example 4 0.3 0.3 0.4

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Abstract

提供了一种硫酸氢氯吡格雷固体制剂，采用熔融制粒工艺制备，所得颗粒中原料药含量高，所得制剂具有均匀性好，片表面光滑，片重差异小等特点，且溶出性能均符合临床用药要求，且当使用特定晶型时，效果更佳。

Description

一种硫酸氢氯吡格雷固体制剂及其制备方法 技术领域
本发明属于药物制剂领域，特别的，本发明涉及一种硫酸氢氯吡格雷固体制剂及其制备方法。
背景技术
硫酸氢氯吡格雷(CAS:135046-48-9)，是氯吡格雷的硫酸盐，英文名Clopidogrel Hydrogen Sulfate，化学名为：(s)-α-(2-氯苯基)-6,7-二氢噻吩并[3,2-c]吡啶-5(4H)乙酸甲酯硫酸氢盐。硫酸氢氯吡格雷是一种抗血小板聚集剂。该产品由法国制药企业赛诺菲-安万特公司研制，并于1998年首次在英国和美国上市，硫酸氢氯吡格雷于2001年进入中国，临床上用于预防动脉粥样硬化血栓形成事件。目前，国内的硫酸氢氯吡格雷制剂产品主要有赛诺菲-安万特公司的波立维(Plavix)和深圳信立泰药业股份有限公司的泰嘉。
Figure PCTCN2016090137-appb-000001
硫酸氢氯吡格雷在湿热条件下不稳定，因此常规湿法制粒-压片的方法并不适用于硫酸氢氯吡格雷制剂中，目前常用干法制剂工艺制备硫酸氢氯吡格雷制剂。然而，由于硫酸氢氯吡格雷原料药容易吸潮，且粉体静电现象较为严重，如果采用直接压片工艺制备固体制剂，则一方面因总混粉末流动性不佳而不适合直接压片，另一方面也会因化合物本身的特性及处方的原因而在压片过程中发生粘冲，使得生产无法顺利进行，因此制备硫酸氢氯吡格雷固体制剂通常需要经过制粒工序，将流动性不佳、粒径分布较宽的有效成分粉体制备成适于压片的颗粒。现有技术主要采用干法制粒和熔融制粒两种制粒方法。
专利CN1935119A公开了一种干法制粒工艺制备硫酸氢氯吡格雷固体制剂的工艺，所得固体制剂具有稳定性高的特点。但是，由于硫酸氢氯吡格雷粉体静电现象较为严重，在混合过程中的混合效果不够理想，使得有效成分均匀性不佳，尽管通过处方改进等措施可以制备得到合格的制剂，但是制剂工艺在整 体上并非最优。
熔融制粒工艺以熔点较低的辅料为粘合剂，通过熔融后聚集粘合形成，冷却后形成颗粒，该方法可以有效提高颗粒中原辅料均匀性，但是对于硫酸氢氯吡格雷产品的熔融制粒，由于有效成分具有容易粘冲的化合物特性，使得开发该产品熔融制粒工艺需要同时兼顾保证所得颗粒有利于后续压片工艺。专利CN101690719公开了一系列硫酸氢氯吡格雷固体制剂，以PEG6000为粘合剂，采用熔融制粒法在50～90℃的温度下在夹层锅或流化床中制备得到，该工艺提高了原辅料混合均匀度，有效缓解了粘冲现象，所得固体制剂稳定性高。但是，该熔融制粒工艺的批次用料比较多，即单位质量硫酸氢氯吡格雷需要较多的辅料分散，可知其工艺依然有待提高。
《中国药学杂志》2011年第46卷第2期第117页公开了一种硫酸氢氯吡格雷的熔融制粒工艺，采用PEG6000作为粘合剂，采用熔融制粒的方法制备，该方法有效解决了粘冲的问题，且所得固体制剂脆碎度和片重差异小，溶出符合临床用药要求。文献随后对熔融粘合剂用量对制粒效果的影响情况进行陈述，认为粘合剂用量太少，难以制备成颗粒，而太多的粘合剂使用则易造成颗粒硬且易成团块，影响制剂溶出。但是，该熔融制粒工艺的批次用料仍然偏多，其工艺依然有提高的空间。
因此，减少熔融制粒工艺的批次用料量，提高颗粒中原料药含量，从整体上优化制剂工艺，并最终制备得到符合临床用药要求的硫酸氢氯吡格雷固体制剂，是现有技术没有解决的技术问题。
发明内容
本发明的目的在于克服现有技术的不足，提供了一种硫酸氢氯吡格雷固体制剂，采用熔融制粒工艺制备，所得颗粒中原料药含量高，所得制剂具有均匀性好，片表面光滑，片重差异小等特点，且溶出性能均符合临床用药要求。
本发明的以上目的通过如下技术手段实现：
一种硫酸氢氯吡格雷固体制剂，包含内相颗粒和外加辅料，所述内相颗粒包含硫酸氢氯吡格雷、填充剂、崩解剂和粘合剂，所述硫酸氢氯吡格雷固体制剂采用熔融制粒工艺，其特征在于所述硫酸氢氯吡格雷的D90为30～100μm，所述粘合剂为PEG6000，当硫酸氢氯吡格雷的质量份为1时，所述粘合剂的用 量为0.1～0.5份。
本发明的发明点在于控制硫酸氢氯吡格雷的粒径(D90)及作为粘合剂的PEG6000的用量，如未特别说明，本发明所述硫酸氢氯吡格雷均以硫酸氢氯吡格雷计。
现有技术公开的熔融制粒方案，为了保证制粒效果和溶出性能，需要加入较大量的粘合剂，并且对应加入大量内加辅料，使得硫酸氢氯吡格雷尽可能的包裹、分散在颗粒中，影响了制剂效率。为了提高制剂效率，我们做了大量的实验以在尽可能增加颗粒中硫酸氢氯吡格雷含量，进而提高制剂效率。研发过程中我们惊奇的发现，当控制硫酸氢氯吡格雷的粒径(D90)为30～100μm时，可以有效减少粘合剂PEG6000的用量，并进一步减少辅料的用量，所得颗粒粒径均匀流动性好，易于与外加辅料混合，且在后续压片过程中无粘冲现象，所得片剂具有均匀性好，片表面光滑，片重差异小等特点，且溶出性能均符合临床用药要求。具体的，粘合剂在一定范围内用量越大，对应使用的内加辅料越多，越有利于制备得到合格的颗粒；硫酸氢氯吡格雷粒径增大可以一定程度上减少粘合剂的用量，但是当粒径增大到一定程度时，则不再对应粘合剂用量的下降，另外，大粒径的硫酸氢氯吡格雷趋于制备得到大粒径的颗粒，对制剂溶出速率有影响，过少的粘合剂用量也会影响制粒效果，使得颗粒松散，易破碎出现粉末，不利于后续制剂工艺；而偏小的硫酸氢氯吡格雷粒径则对应使用更多的粘合剂，需要的内加辅料也更多，小粒径的硫酸氢氯吡格雷也趋于制备得到小粒径内相颗粒，并存在较多粉末，同样不利于后续制剂工艺；对于熔融制粒工艺，当控制硫酸氢氯吡格雷的粒径(D90)为30～100μm时，可以对应适量的粘合剂PEG6000的用量，在有效提高颗粒中硫酸氢氯吡格雷含量的同时，制备得到的颗粒粒径适中、粒径分布窄有助于实现后续混合及压片工艺的优化，所得片剂各项指标符合硫酸氢氯吡格雷的临床用药要求。优选的，所述硫酸氢氯吡格雷的粒径(D90)为40～90μm，更优选硫酸氢氯吡格雷的粒径(D90)为50～80μm。
本发明所述硫酸氢氯吡格雷固体制剂可以采用常用的硫酸氢氯吡格雷晶型，如现有技术报道的I晶型、II晶型等，优选现有技术报道的I晶型，即晶型的X-射线粉末衍射谱图在2θ角为9.28°，10.96°，14.88°，15.55°，18.54°，19.02°，20.65°，23.24°，23.92°，25.59°处存在衍射峰。
在控制硫酸氢氯吡格雷的粒径在前述范围的基础上，可以降低粘合剂PEG6000的用量，并将其他内加辅料的用量控制在合适的范围，进而提高硫酸氢氯吡格雷在颗粒中的含量，进而在保证制粒效果的基础上，提高制粒效率。具体的，当硫酸氢氯吡格雷的质量份为1时，粘合剂的质量份可为0.1～0.5；优选的，当硫酸氢氯吡格雷的质量份为1时，粘合剂的质量份可为0.15～0.35。
本发明所述硫酸氢氯吡格雷固体制剂的内相颗粒中所用辅料更少，硫酸氢氯吡格雷的含量更高，有效提高了熔融制粒效率。所述内相颗粒还包括填充剂和崩解剂。
所述内相颗粒中的填充剂选自微晶纤维素、乳糖、预交化淀粉等中的一种或两种以上以任意比例的混合，优选微晶纤维素、乳糖中的一种或两种以上以任意比例的混合。具体的，当硫酸氢氯吡格雷的质量份为1时，填充剂的质量份可为0.03～0.1。
所述内相颗粒中的崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠等中的一种或两种以上以任意比例的混合。具体的，当硫酸氢氯吡格雷的质量份为1时，崩解剂的质量份可为0.2～0.5。
本发明的一个优选的内相颗粒处方，如下：
项目 质量份
硫酸氢氯吡格雷 1
微晶纤维素 0.05
PEG6000 0.2
低取代羟丙纤维素 0.3
交联聚维酮 0.1
本发明的一个优选的内相颗粒处方，如下：
项目 质量份
硫酸氢氯吡格雷 1
乳糖 0.06
PEG6000 0.3
交联羧甲基纤维素钠 0.3
本发明的一个优选的内相颗粒处方，如下：
项目 质量份
硫酸氢氯吡格雷 1
微晶纤维素 0.05
PEG6000 0.2
交联聚维酮 0.4
本发明的一个优选的内相颗粒处方，如下：
项目 质量份
硫酸氢氯吡格雷 1
微晶纤维素 0.05
PEG6000 0.15
低取代羟丙纤维素 0.3
交联聚维酮 0.1
本发明的一个优选的内相颗粒处方，如下：
项目 质量份
硫酸氢氯吡格雷 1
乳糖 0.1
PEG6000 0.35
交联羧甲基纤维素钠 0.3
所述熔融制粒可采用现有技术常用的设备，优选夹层锅或流化床制粒机，制粒工艺中物料温度控制在50～80℃。所得颗粒粒径颗粒均匀，几无细粉或仅含有少量细粉，有效成分均匀性高，流动性好。
本发明所述硫酸氢氯吡格雷固体制剂的还包括外加辅料，所述外加辅料包括填充剂、崩解剂、稳定剂、润滑剂。
具体的，所述填充剂选自微晶纤维素、乳糖、预胶化淀粉等中的一种或两种以上以任意比例的混合。具体的，当硫酸氢氯吡格雷的质量份为1时，填充剂的质量份可为0.3～1.0。
所述崩解剂选自交联聚维酮、羟丙纤维素、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠等中的一种或两种以上以任意比例的混合。具体的，当硫酸氢氯吡格雷的质量份为1时，崩解剂的质量份可为0.1～0.5。
所述稳定剂为蔗糖硬脂酸酯。具体的，当硫酸氢氯吡格雷的质量份为1时， 稳定剂的质量份可为0.02～0.08。
所述润滑剂选自硬脂酸镁、氢化蓖麻油、滑石粉等中的一种或两种以上以任意比例的混合。具体的，当硫酸氢氯吡格雷的质量份为1时，润滑剂的质量份可为0.03～1.0。
本发明的一个优选的硫酸氢氯吡格雷固体制剂处方，如下：
Figure PCTCN2016090137-appb-000002
本发明的一个优选的硫酸氢氯吡格雷固体制剂处方，如下：
Figure PCTCN2016090137-appb-000003
本发明的一个优选的硫酸氢氯吡格雷固体制剂处方，如下：
Figure PCTCN2016090137-appb-000004
Figure PCTCN2016090137-appb-000005
本发明的一个优选的硫酸氢氯吡格雷固体制剂处方，如下：
Figure PCTCN2016090137-appb-000006
本发明的一个优选的硫酸氢氯吡格雷固体制剂处方，如下：
Figure PCTCN2016090137-appb-000007
Figure PCTCN2016090137-appb-000008
本发明的另一目的在于提供一种本发明所述硫酸氢氯吡格雷固体制剂的制备方法，该制备方法很好的契合处方特性，有利于发挥处方优势，实现提高内相颗粒中硫酸氢氯吡格雷含量的目的，并进一步实现制剂工艺最优，最终制备得到合格率高、符合临床用药的硫酸氢氯吡格雷的固体制剂，所述制备方法包含如下步骤：
1)将处方量的硫酸氢氯吡格雷与内加辅料混合20～30min，得到内向混粉；
2)将步骤1)所得内向混粉加入熔融制粒设备中，在50～80℃下制粒10～30min得到内相颗粒。
上述步骤中的原、辅料种类、性质、用量，及所用设备种类均与前一目的中所述对应一致；其中步骤1)中可采用常规的混合设备混合，优选采用立柱式提升混合机混合，步骤2)的制粒时间控制在10～30min有利于制备得到符合后续制剂工艺的内相颗粒。
进一步的，所述制备方法包含如下步骤：
1)将处方量的硫酸氢氯吡格雷与内加辅料混合20～30min，得到内向混粉；
2)将步骤1)所得内向混粉加入熔融制粒设备中，在50～80℃下制粒10～30min得到内相颗粒；
3)将步骤2)所得内向颗粒与处方量的外加辅料混合10～20min，得到总混颗粒；
4)将步骤3)所得总混颗粒压片，制备得到硫酸氢氯吡格雷固体制剂。
上述步骤中的原、辅料种类、性质、用量，及所用设备种类均与前一目的中所述对应一致；其中步骤1)和步骤3)中可采用常规的混合设备混合，优选采用立柱式提升混合机设备混合；步骤2)的制粒时间控制在10～30min有利于制备得到符合后续制剂工艺的内相颗粒，由于步骤2)所得内相颗粒粒径适中、颗粒均匀且几无细粉或仅含有少量细粉，使得在制备步骤3)所述总混颗粒时可以与外加辅料实现较短时间内快速混合，混合效果好；所述步骤2)中的熔融制粒设备为夹层锅或流化床制粒机；步骤4)的压片压力优选3～5kgf，基于内相颗粒的有益效果，在压片过程中无粘冲现象发生。
所述硫酸氢氯吡格雷固体制剂可以进一步进行包衣处理，所述包衣工艺采用常规的包衣工艺，所述包衣材料选自常用的市售或自制的包衣材料，如欧巴代、羟丙甲纤维素等。
本发明与现有技术相比具有如下突出的优点及有益效果：
1、提供了一种硫酸氢氯吡格雷固体制剂，采用熔融制粒工艺制备，所得颗粒中原料药含量高，所得制剂具有均匀性好，片表面光滑，片重差异小等特点，且溶出性能均符合临床用药要求，且当使用特定晶型时，效果更佳；
2、一种本发明所述硫酸氢氯吡格雷固体制剂的制备方法，该制备方法很好的契合处方特性，有利于发挥处方优势，实现提高内相颗粒中硫酸氢氯吡格雷含量的目的，并进一步实现制剂工艺最优，最终制备得到合格率高、符合临床用药的硫酸氢氯吡格雷的固体制剂。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但发明的实施方式不限于此。
实施例采用BT-1001智能粉体特性测试仪器对所得硫酸氢氯吡格雷内相颗粒进行休止角检测；
实施例采用现有技术报道的硫酸氢氯吡格雷I型结晶。
实施例1
处方：
Figure PCTCN2016090137-appb-000009
Figure PCTCN2016090137-appb-000010
制备步骤：
1)将处方量的硫酸氢氯吡格雷(D90＝67μm)与内加辅料混合20～30min，得到内向混粉；
2)将步骤1)所得内向混粉加入流化床制粒机中，在50～60℃下制粒10～30min得到内相颗粒(休止角37°)，所得颗粒均匀，几无细粉；
3)将步骤2)所得内向颗粒与处方量的外加辅料混合10～20min，得到总混颗粒；
4)将步骤3)所得总混颗粒压片，制备得到硫酸氢氯吡格雷固体制剂(75mg规格)。
压片过程中未出现粘冲现象，所得硫酸氢氯吡格雷固体制剂片面光滑。
实施例2
处方：
Figure PCTCN2016090137-appb-000011
制备步骤：
1)将处方量的硫酸氢氯吡格雷(D90＝60μm)与内加辅料混合20～30min，得到内向混粉；
2)将步骤1)所得内向混粉加入流化床制粒机中，在50～60℃下制粒10～30min得到内相颗粒(休止角38°)，所得颗粒均匀，几无细粉；
3)将步骤2)所得内向颗粒与处方量的外加辅料混合10～20min，得到总混颗粒；
4)将步骤3)所得总混颗粒压片，制备得到硫酸氢氯吡格雷固体制剂(75mg规格)。
压片过程中未出现粘冲现象，所得硫酸氢氯吡格雷固体制剂片面光滑。
实施例3
处方：
Figure PCTCN2016090137-appb-000012
制备步骤：
1)将处方量的硫酸氢氯吡格雷(D90＝73μm)与内加辅料混合20～30min，得到内向混粉；
2)将步骤1)所得内向混粉加入流化床制粒机中，在50～60℃下制粒10～30min得到内相颗粒(休止角38°)，所得颗粒均匀，几无细粉；
3)将步骤2)所得内向颗粒与处方量的外加辅料混合10～20min，得到总混颗粒；
4)将步骤3)所得总混颗粒压片，制备得到硫酸氢氯吡格雷固体制剂(75mg规格)。
压片过程中未出现粘冲现象，所得硫酸氢氯吡格雷固体制剂片面光滑。
实施例4
处方：
本发明的一个优选的硫酸氢氯吡格雷固体制剂处方，如下：
Figure PCTCN2016090137-appb-000013
制备步骤：
1)将处方量的硫酸氢氯吡格雷(D90＝91μm)与内加辅料混合20～30min，得到内向混粉；
2)将步骤1)所得内向混粉加入流化床制粒机中，在50～60℃下制粒10～30min得到内相颗粒(休止角40°)，所得颗粒均匀，存在少量细粉，但对后续工艺无影响；
3)将步骤2)所得内向颗粒与处方量的外加辅料混合10～20min，得到总混颗粒；
4)将步骤3)所得总混颗粒压片，制备得到硫酸氢氯吡格雷固体制剂(75mg规格)。
压片过程中未出现粘冲现象，所得硫酸氢氯吡格雷固体制剂片面光滑。
实施例5
处方：
Figure PCTCN2016090137-appb-000014
Figure PCTCN2016090137-appb-000015
制备步骤：
1)将处方量的硫酸氢氯吡格雷(D90＝48μm)与内加辅料混合20～30min，得到内向混粉；
2)将步骤1)所得内向混粉加入流化床制粒机中，在50～60℃下制粒10～30min得到内相颗粒(休止角39°)，所得颗粒均匀，存在微量细粉，对后续工艺无影响；
3)将步骤2)所得内向颗粒与处方量的外加辅料混合10～20min，得到总混颗粒；
4)将步骤3)所得总混颗粒压片，制备得到硫酸氢氯吡格雷固体制剂(75mg规格)。
压片过程中未出现粘冲现象，所得硫酸氢氯吡格雷固体制剂片面光滑。
对比实施例1
Figure PCTCN2016090137-appb-000016
Figure PCTCN2016090137-appb-000017
制备步骤：
1)将处方量的硫酸氢氯吡格雷(D90＝116μm)与内加辅料混合20～30min，得到内向混粉；
2)将步骤1)所得内向混粉加入流化床制粒机中，在50～60℃下制粒10～30min得到内相颗粒(休止角36°)，所得颗粒均匀，几无细粉，但是通过目测即可看出所得颗粒粒径明显大于实施例1-5所得内相颗粒粒径；
3)将步骤2)所得内向颗粒与处方量的外加辅料混合10～20min，得到总混颗粒；
4)将步骤3)所得总混颗粒压片，制备得到硫酸氢氯吡格雷固体制剂(75mg规格)。
压片过程中未出现粘冲现象，所得硫酸氢氯吡格雷固体制剂片面光滑。
对比实施例2
Figure PCTCN2016090137-appb-000018
制备步骤：
1)将处方量的硫酸氢氯吡格雷(D90＝23μm)与内加辅料混合20～30min，得到内向混粉；
2)将步骤1)所得内向混粉加入流化床制粒机中，在50～60℃下制粒10～30min得到内相颗粒(休止角45°)，采用该处方制粒效果不佳，所得颗粒存在较 多细粉；
3)将步骤2)所得内向颗粒与处方量的外加辅料混合10～20min，得到总混颗粒；
4)将步骤3)所得总混颗粒压片，在压片工艺开始不久即出现粘冲现象，所得硫酸氢氯吡格雷固体制剂的片面模糊，经多次调整压片工艺参数仍无法解决粘冲的问题。
对比实施例3
采用与对比实施例2相同批次的原料药，通过增加粘合剂并调整其他内相辅料的用量及加入方式，以期达到优化制粒效果的目的，并进一步解决压片过程中的粘冲问题。
Figure PCTCN2016090137-appb-000019
制备步骤：
1)将处方量的硫酸氢氯吡格雷(D90＝23μm)与内加辅料混合20～30min，得到内向混粉；
2)将步骤1)所得内向混粉加入流化床制粒机中，在50～60℃下制粒10～30min得到内相颗粒(休止角38°)，所得颗粒较实施例1-5所得颗粒略小，颗粒均匀，几无细粉；
3)将步骤2)所得内向颗粒与处方量的外加辅料混合10～20min，得到总混颗粒；
4)将步骤3)所得总混颗粒压片，制备得到硫酸氢氯吡格雷固体制剂(75mg规格)。
压片过程中未出现粘冲现象，所得硫酸氢氯吡格雷固体制剂片面光滑。
实施例6
采用《中国药典》(2010版)附录XC溶出度测定方法第二法浆法分别对实施例1-5及对比实施例1、3所得硫酸氢氯吡格雷片剂的溶出度进行检测，所得结果如下：
项目 30min溶出度(％)
实施例1 97
实施例2 95
实施例3 97
实施例4 95
实施例5 95
对比实施例1 86
对比实施例3 98
可以看出，实施例1-5所得片剂在30min内可以实现溶出度在90％以上，符合临床用药要求；
对于对比实施例1，由于其采用粒径偏大的原料药，使得其内相颗粒粒径偏大，所得片剂的溶出速度明显慢于实施例1-5所得片剂。
对于对比实施例3，其溶出度与实施例1-5所得片剂相仿，但是由于其采用的原料药粒径偏小，使得其在制备内相颗粒时需要通过增加粘合剂及内相辅料用量以优化制粒效果，使得内相颗粒中有效成分含量较低，制粒效率远不及实施例1-5。
实施例7
稳定性考察
将实施例1-5所得硫酸氢氯吡格雷片剂包装后置于高温高湿条件下(RH75％，40℃)条件下，并观察总杂含量变化情况，结果如下：
项目 0天(％) 15天(％) 30天(％)
实施例1 0.3 0.3 0.4
实施例2 0.3 0.4 0.4
实施例3 0.3 0.4 0.4
实施例4 0.3 0.3 0.4
实施例5 0.3 0.4 0.4
可以看出，本发明实施例1-5所得制剂在储存过程中具有较高的稳定性。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 一种硫酸氢氯吡格雷固体制剂，包含内相颗粒和外加辅料，所述内相颗粒包含硫酸氢氯吡格雷、填充剂、崩解剂和粘合剂，所述硫酸氢氯吡格雷固体制剂采用熔融制粒工艺，其特征在于所述硫酸氢氯吡格雷的D90为30～100μm，所述粘合剂为PEG6000，当硫酸氢氯吡格雷的质量份为1时，所述粘合剂的用量为0.1～0.5份。
  2. 根据权利要求1所述的硫酸氢氯吡格雷固体制剂，其特征在于所述硫酸氢氯吡格雷的D90为40～90μm。
  3. 根据权利要求1或2任意一项所述的硫酸氢氯吡格雷固体制剂，其特征在于所述硫酸氢氯吡格雷的D90为50～80μm，所述硫酸氢氯吡格雷的X-射线粉末衍射谱图在2θ角为9.28°，10.96°，14.88°，15.55°，18.54°，19.02°，20.65°，23.24°，23.92°，25.59°处存在衍射峰。
  4. 根据权利要求1-3任意一项所述的硫酸氢氯吡格雷固体制剂，其特征在于所述内相颗粒中的填充剂为微晶纤维素、乳糖、预交化淀粉中的一种或两种以上以任意比例的混合，所述内相颗粒中的崩解剂为交联聚维酮、低取代羟丙基纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或两种以上以任意比例的混合，当硫酸氢氯吡格雷的质量份为1时，所述崩解剂的质量份为0.2～0.5，所述填充剂的质量份为0.03～0.1，所述粘合剂的用量为0.15～0.35份。
  5. 根据权利要求1所述的硫酸氢氯吡格雷固体制剂，其特征在于所述内相颗粒处方为如下处方的任意一个：
    处方一
    项目 质量份 硫酸氢氯吡格雷 1 微晶纤维素 0.05 PEG6000 0.2 低取代羟丙纤维素 0.3 交联聚维酮 0.1
    处方二
    项目 质量份 硫酸氢氯吡格雷 1 乳糖 0.06
    PEG6000 0.3 交联羧甲基纤维素钠 0.3
    处方三
    项目 质量份 硫酸氢氯吡格雷 1 微晶纤维素 0.05 PEG6000 0.2 交联聚维酮 0.4
    处方四
    项目 质量份 硫酸氢氯吡格雷 1 微晶纤维素 0.05 PEG6000 0.15 低取代羟丙纤维素 0.3 交联聚维酮 0.1
    处方五
    Figure PCTCN2016090137-appb-100001
  6. 根据权利要求1-5任意一项所述的硫酸氢氯吡格雷固体制剂，其特征在于所述外加辅料包括填充剂、崩解剂、稳定剂、润滑剂，所述填充剂为微晶纤维素、乳糖、预胶化淀粉中的一种或两种以上以任意比例的混合，所述崩解剂为交联聚维酮、羟丙纤维素、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或两种以上以任意比例的混合，所述稳定剂为蔗糖硬脂酸酯，所述润滑剂为硬脂酸镁、氢化蓖麻油、滑石粉中的一种或两种以上以任意比例的混合，当硫酸氢氯吡格雷的质量份为1时，所述填充剂的质量份为0.3～1.0，所述 崩解剂的质量份为0.1～0.5，所述稳定剂的质量份为0.02～0.08，所述润滑剂的质量份为0.03～1.0。
  7. 根据权利要求1所述的硫酸氢氯吡格雷固体制剂，其特征在于所述硫酸氢氯吡格雷固体制剂的处方为如下处方的任意一个：
    处方一
    Figure PCTCN2016090137-appb-100002
    处方二
    Figure PCTCN2016090137-appb-100003
    处方三
    Figure PCTCN2016090137-appb-100004
    Figure PCTCN2016090137-appb-100005
    处方四
    Figure PCTCN2016090137-appb-100006
    处方五
    Figure PCTCN2016090137-appb-100007
    Figure PCTCN2016090137-appb-100008
  8. 一种制备如权利要求1-7任意一项所述硫酸氢氯吡格雷固体制剂的制备方法，包括如下步骤：
    1)将处方量的硫酸氢氯吡格雷与内加辅料混合20～30min，得到内向混粉；
    2)将步骤1)所得内向混粉加入熔融制粒设备中，在50～80℃下制粒10～30min得到内相颗粒。
  9. 根据权利要求8所述的硫酸氢氯吡格雷固体制剂的制备方法，包括如下步骤：
    1)将处方量的硫酸氢氯吡格雷与内加辅料混合20～30min，得到内向混粉；
    2)将步骤1)所得内向混粉加入熔融制粒设备中，在50～80℃下制粒10～30min得到内相颗粒；
    3)将步骤2)所得内向颗粒与处方量的外加辅料混合10～20min，得到总混颗粒；
    4)将步骤3)所得总混颗粒压片，制备得到硫酸氢氯吡格雷固体制剂。
  10. 根据权利要求9所述的硫酸氢氯吡格雷固体制剂的制备方法，其特征在于所述步骤1)和步骤3)中采用立柱式提升混合机设备混合；所述步骤2)中的熔融制粒设备为夹层锅或流化床制粒机；所述步骤4)的压片压力优选3～5kgf，所述制备方法进一步包含包衣的步骤。
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