WO2021072773A1 - 一种奥利司他胶囊及其制备方法 - Google Patents

一种奥利司他胶囊及其制备方法 Download PDF

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WO2021072773A1
WO2021072773A1 PCT/CN2019/112028 CN2019112028W WO2021072773A1 WO 2021072773 A1 WO2021072773 A1 WO 2021072773A1 CN 2019112028 W CN2019112028 W CN 2019112028W WO 2021072773 A1 WO2021072773 A1 WO 2021072773A1
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Prior art keywords
orlistat
leucine
capsule
add
propylene carbonate
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PCT/CN2019/112028
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English (en)
French (fr)
Inventor
张贵民
陈小伟
李泽
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山东新时代药业有限公司
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Priority to PCT/CN2019/112028 priority Critical patent/WO2021072773A1/zh
Priority to CN201980042418.XA priority patent/CN114555061B/zh
Publication of WO2021072773A1 publication Critical patent/WO2021072773A1/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a capsule containing orlistat and a preparation method thereof.
  • the World Health Organization defines abnormal or excessive fat accumulation that can damage health as overweight and obesity.
  • a body mass index (BMI) ⁇ 25 kg/m 2 is considered overweight, and a body mass index ⁇ 30 kg/m 2 is considered obesity.
  • Orlistat is currently the first and only non-central nervous system weight loss drug. It is now generally believed that excessive fat intake is one of the main causes of obesity. Therefore, controlling the digestion of triglycerides by lipase through drugs has become an effective way to lose weight. The drug selectively inhibits the action of pancreatic lipase in the gastrointestinal tract, thereby reducing the absorption of fat in the diet by 30%, thereby reducing weight.
  • the pharmacological activity of orlistat is dose-dependent.
  • the therapeutic dose of orlistat (120mg/d, taken with meals) combined with a low-calorie balanced diet can reduce 30% of the fat absorption in the diet and achieve weight loss Objectives, and further reduce the occurrence of risk factors for diseases associated with obesity.
  • Orlistat is white or almost white, crystalline powder; it is easily soluble in methanol and ethanol, soluble in chloroform, and almost insoluble in water; melting point 42°C ⁇ 46°C.
  • Orlistat was developed by Roche Pharmaceuticals and was first marketed in New Zealand under the trade name Xenical ® , and was launched in the US in 1999. In 2009, my country approved the import of Orlistat capsules. At present, Chongqing Huasen Pharmaceutical, Hangzhou Sino-American Huadong Pharmaceutical, Shandong New Times Pharmaceutical, Zhejiang Hisun Pharmaceutical and other companies orlistat capsules or tablets are on the market.
  • Orlistat has a low melting point and poor stability, and related substances increase rapidly during storage.
  • US6004996 discloses a preparation method of orlistat preparation, which is prepared by preparing active ingredients into pellets and then filling them into hard capsules, including 50% of the active ingredients, and auxiliary materials are mainly used as diluents and extruding Spheronized microcrystalline cellulose, sodium lauryl sulfate as a solubilizer, povidone K 30 as a binder, and talc as a lubricant are prepared into 0.25-2mm pellets with an extruder, and then packed Into a hard capsule.
  • the orlistat preparation produces heat during production, which leads to significant increase in related substances and poor stability.
  • composition containing tetrahydro-streptobacterin discloses a composition containing orlistat, which combines orlistat, stabilizer (polyvinyl) Ketones, lactose, hypromellose, hypromellose) and pharmaceutical excipients (surfactants, diluents, disintegrants, talc), pellets are prepared by extrusion spheronization to control the size of these particles The diameter is in the range of 0.25mm to 2mm, and then prepared into suitable oral solid preparations-capsules, tablets or bagged dosage forms to solve the problem of adhesion and adhesion during the process. Extrusion and spheronization equipment is required in production, and during the capsule filling process, the free orlistat on the surface melts and sticks due to frictional heating.
  • Chinese patent CN201811027763.X relates to an orlistat soft capsule and its preparation method.
  • the content is mainly composed of orlistat, polysorbate 80 and vitamin E polyethylene glycol succinate; the film is composed of fish gelatin and glycerin And purified water.
  • a large amount of Tween 80 is used in the formulation of the invention.
  • Polysorbate Tween 80 is hygroscopic, and peroxides will be generated when stored for too long, which is not conducive to the stability of the formulation. Tween 80 will emit pungent and pungent fumes when it is heated and decomposed.
  • the high water content in the rubber of soft capsules affects the stability of the preparation.
  • Chinese patent CN201110370659.2 discloses a preparation containing orlistat and a preparation method thereof.
  • the preparation contains a coating layer of orlistat.
  • the tablets or blank pellets are prepared after the orlistat coating layer is formed on the surface.
  • the orlistat preparation can effectively solve the sticking problem caused by the melting of orlistat during the production process, and at the same time, the preparation maintains better stability and dissolution.
  • due to the poor stability of orlistat related substances are likely to increase during the melting of the drug.
  • Chinese patent CN201010005285.X discloses a tablet containing orlistat cyclodextrin inclusion compound, the tablet is composed of orlistat cyclodextrin inclusion compound, disintegrant and other pharmaceutically acceptable excipients composition.
  • Chinese patent CN201610884801.8 provides a co-crystal of orlistat and amino acids and a pharmaceutical composition containing the co-crystal. The co-crystal has a higher melting point, can reduce the requirements for drying conditions in the preparation process of the raw material drug and the preparation, has a higher dissolution rate, and accelerates the onset of the drug.
  • Chinese patent CN201710321107.X discloses a slimming tablet containing orlistat, which utilizes low-temperature hot-melt extrusion and cutting processes to prepare orlistat tablets.
  • Chinese patent CN201310032613.9 uses supercritical technology to micronize raw materials, and at the same time coats the surface of orlistat with a layer of inert material, which successfully solves the problem of low dissolution of preparations prepared by the prior art and solves the problem of tablet compression. Sticky punch problem during the process.
  • Chinese patent CN201310753213.7 uses an aqueous solvent below 10°C as a wetting agent, which solves the stability of orlistat during the granulation process, but it will still cause stickiness and shock during the drying of the granules, capsule filling or tableting. Orlistat is degraded.
  • orlistat raw materials are ground at -5°C to 0°C to produce oral solid preparations with high dissolution rate.
  • the dissolution of preparations is poor, and related substances will increase significantly during the preparation and storage process.
  • the purpose of the present invention is to provide an orlistat capsule with simple preparation process, rapid dissolution and good stability.
  • the present invention reduces the particle size of the raw material and improves the hydrophilicity of the drug by forming a composite crystal of orlistat and excipients; using leucine and propylene carbonate as stabilizers to jointly solve the preparation and storage process of orlistat In the stability.
  • an orlistat capsule which is composed of a complex crystal formed by orlistat, hydroxypropyl cellulose, leucine and propylene carbonate, and pharmaceutically acceptable excipients.
  • the mass ratio of each component in the composite crystal is as follows: orlistat 1, hydroxypropyl cellulose 0.2-0.6,
  • the weight ratio of each component in the composite crystal is as follows: orlistat 1, hydroxypropyl cellulose 0.4, leucine 0.1, and propylene carbonate 0.02.
  • the composite crystal particle size distribution D90 in the orlistat capsule is 250 ⁇ m-90 ⁇ m, more preferably 180 ⁇ m.
  • the pharmaceutically acceptable excipients can be selected by those skilled in the art according to the prior art, and may include, for example, fillers, disintegrants and lubricants.
  • the filler can be selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, and powdered cellulose;
  • the disintegrant can be selected, for example, from crospovidone, sodium starch glycolate, and cross-linked.
  • the lubricant can be selected from one or more of magnesium stearate, zinc stearate or sodium fumarate stearate, for example.
  • the orlistat capsule specifically contains the following components by weight: 100 parts of orlistat complex crystals, 30-50 parts of fillers, 5-15 parts of disintegrants, and 1-5 parts of lubricants
  • the orlistat capsule specifically contains the following components by weight: 100 parts of orlistat complex crystals, 40 parts of fillers, 10 parts of disintegrants, and 2.5 parts of lubricants.
  • Another aspect of the present invention provides a method for preparing orlistat capsules, which specifically includes the following steps:
  • Orlistat complex crystals and other pharmaceutically acceptable excipients are mixed uniformly, and capsules are filled to obtain the product.
  • the mass-volume ratio of the orlistat to the polar solvent and the non-polar solvent is 1:1-10:5-50; g/mL/mL.
  • the mass-volume ratio of orlistat to polar solvent and non-polar solvent is 1:6:10; g/mL/mL.
  • the polar solvent is one or more of ethanol, methanol, and acetonitrile;
  • the non-polar solvent is one or more of n-hexane, heptane, and ether.
  • the stirring condition is 3000 to 5000 rpm.
  • the cooling temperature is -5°C to -15°C.
  • the crystallization time is 4-10h.
  • the orlistat composite particles prepared by the present invention have good fluidity
  • the prepared orlistat capsule has a simple preparation process
  • the prepared preparation has good stability and rapid dissolution.
  • Components 120 g of orlistat, 48 g of hydroxypropyl cellulose, 12 g of leucine, 2.4 g of propylene carbonate, 72.96 g of microcrystalline cellulose, 18.24 g of crospovidone, and 4.56 g of magnesium stearate.
  • step (2) Mix the orlistat complex crystals prepared in step (1) with microcrystalline cellulose, crospovidone, and magnesium stearate uniformly, and fill the capsules to obtain it.
  • Components 120 g of orlistat, 60 g of hydroxypropyl cellulose, 15.60 g of leucine, 3.00 g of propylene carbonate, 89.37 g of siliconized microcrystalline cellulose, 23.83 g of sodium starch glycolate, and 5.96 g of zinc stearate.
  • step (2) Mix the orlistat complex crystals prepared in step (1) with silicified microcrystalline cellulose, sodium starch glycolate, and zinc stearate uniformly, and fill the capsules to obtain it.
  • Components 120 g of orlistat, 36 g of hydroxypropyl cellulose, 8.4 g of leucine, 1.8 g of propylene carbonate, 58.17 g of starch, 11.63 g of low-substituted hydroxypropyl cellulose, and 3.32 g of talc.
  • step (2) Mix the orlistat complex crystals prepared in step (1) with starch, low-substituted hydroxypropyl cellulose, and talc evenly, and fill the capsules to obtain it.
  • Orlistat 120g hydroxypropyl cellulose 72g, leucine 18g, propylene carbonate 3.6g, powdered cellulose 60g, microcrystalline cellulose 46.80g, croscarmellose sodium 32.04g , Magnesium stearate 10.68g.
  • step (2) Mix the orlistat complex crystals prepared in step (1) with powdered cellulose, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, and fill the capsules to obtain .
  • Orlistat 120g hydroxypropyl cellulose 24g, leucine 6g, propylene carbonate 1.2g, powdered cellulose 45.36g, crospovidone 3g, sodium carboxymethyl starch 4.56g, hard Zinc fatty acid 1.51g.
  • step (2) Mix the orlistat complex crystals prepared in step (1) with powdered cellulose, crospovidone, sodium carboxymethyl starch, and zinc stearate uniformly, and fill the capsules to obtain it.
  • Components 120 g of orlistat, 120 g of hydroxypropyl cellulose, 18 g of leucine, 3.6 g of propylene carbonate, 148.50 g of microcrystalline cellulose, 54 g of crospovidone, 21.60 g of magnesium stearate.
  • step (2) Mix the orlistat complex crystals prepared in step (1) with microcrystalline cellulose, crospovidone, and magnesium stearate uniformly, and fill the capsules to obtain it.
  • Orlistat 120g hydroxypropyl cellulose 12g, leucine 2.4g, propylene carbonate 0.60g, silicified microcrystalline cellulose 33.75g, sodium starch glycolate 2.70g, zinc stearate 0.68g.
  • step (2) Mix the orlistat complex crystals prepared in step (1) with silicified microcrystalline cellulose, sodium starch glycolate, and zinc stearate uniformly, and fill the capsules to obtain it.
  • Components 120 g of orlistat, 72 g of hydroxypropyl cellulose, 18 g of leucine, 3.6 g of propylene carbonate, 106.8 g of powdered cellulose, 32.04 g of sodium starch glycolate, and 10.68 g of zinc stearate.
  • Orlistat complex crystals are mixed evenly with powdered cellulose, sodium starch glycolate, and zinc stearate, and then filled into capsules to obtain.
  • Components 120 g of orlistat, 24 g of hydroxypropyl cellulose, 6 g of leucine, 1.2 g of propylene carbonate, 45.36 g of microcrystalline cellulose, 7.56 g of sodium starch glycolate, and 1.51 g of zinc stearate.
  • Orlistat complex crystals, microcrystalline cellulose, sodium starch glycolate, and zinc stearate are mixed uniformly, and capsules are filled to obtain it.
  • Orlistat 120g Leucine 12g, Propylene Carbonate 2.4g, Microcrystalline Cellulose 70g, Sodium Carboxymethyl Starch 20g,
  • Zinc stearate 4g Zinc stearate 4g.
  • Orlistat complex crystals, microcrystalline cellulose, sodium starch glycolate, and zinc stearate are mixed uniformly, and capsules are filled to obtain it.
  • Components 120 g of orlistat, 24 g of hydroxypropyl cellulose, 43 g of microcrystalline cellulose, 7.5 g of sodium starch glycolate, and 1.5 g of zinc stearate.
  • Orlistat complex crystals, microcrystalline cellulose, sodium starch glycolate, and zinc stearate are mixed uniformly, and capsules are filled to obtain it.
  • Components 120 g of orlistat, 48 g of hydroxypropyl cellulose, 12 g of leucine, 2.4 g of propylene carbonate, 70 g of cellulose lactose complex, 20 g of sodium starch glycolate, and 4 g of zinc stearate.
  • Orlistat complex crystals are mixed evenly with powdered cellulose, sodium starch glycolate, and zinc stearate, and then filled into capsules to obtain.
  • Components 120g orlistat, 93.6g microcrystalline cellulose 101, 12g povidone K29/32, 7.2g sodium carboxymethyl starch,
  • Components 120g orlistat, 120g microcrystalline cellulose, 120g poloxamer 215, 40g colloidal silicon dioxide.
  • the orifice plate with a certain diameter is continuously extruded to obtain a strip-shaped semi-solid intermediate
  • Orlistat L-leucine co-crystal 12g microcrystalline cellulose 8.5 ⁇ 9.2g, sodium carboxymethyl starch 1.0 ⁇ 1.3g, crospovidone 1.1 ⁇ 1.5g, lauryl sulfate Sodium 0.2 ⁇ 0.3g, proper amount of povidone K30, make 100 tablets in total.
  • 4Filling capsules According to the calculated theoretical filling quantity, fill the dry particles into No. 0 capsules (mainly composed of gelatin, titanium dioxide, lemon yellow, and bright blue).
  • Liquor Liquor, granulate, dry, add magnesium stearate, mix well, press tablets, and get ready.
  • the orlistat soft capsule including content and rubber
  • the content components are 120 parts of orlistat, 8040 parts of polysorbate, and 200 parts of vitamin E polyethylene glycol succinate
  • the film is composed of fish gelatin, glycerin and purified water in a weight ratio of 2:1:3.
  • the fish gelatin is prepared by the following method:
  • step B Add the fish scale powder obtained in step A to deionized water at a temperature of 55°C and soak for 2 hours, the solid-to-liquid ratio of the deionized water to the fish scale powder is 1g:8ml, pick up, drain, and then put it in the treatment solution for processing 2h, the treatment liquid is composed of polysorbate 80 and vitamin E polyethylene glycol succinate in a weight ratio of 3:2, the solid-to-liquid ratio of the treatment liquid to the fish scale powder is 1g:2ml, and then the concentration is 1mol /L citric acid solution soaked for 2h, the solid-liquid ratio of the citric acid solution and the fish scale powder is 1g:4ml, adjust the pH to 5, pick up and drain to obtain fish scale gel;
  • step C Place the fish scale gel obtained in step B for 15 minutes in a treatment solution composed of polysorbate 80 and vitamin E polyethylene glycol succinate in a weight ratio of 3:2, and the treatment solution is coagulated with fish scales.
  • the solid-liquid ratio of the glue is 1g:2ml, pick it up and soak it in deionized water at 75°C for 3h, filter, take the filter residue, repeat twice, combine the filter residue, freeze concentration, the freezing concentration condition is: pre-cooling temperature The temperature is 6°C, the stirring speed is 160r/min, and the temperature of the refrigerant is -12°C.
  • step S2 Heat vitamin E polyethylene glycol succinate to 95°C for 60 minutes, cool to 43°C, add it to the mixture I obtained in step S1 for homogeneous emulsification, cool to 30°C, keep warm, and under -0.09MPa vacuum conditions Degas for 60min to get the contents;
  • step S4 the glue produced in step S3 is pressed into the film under the condition of 85°C, and the film is loaded on the automatic rotary capsule making machine,
  • the conditions for preparing the soft capsule are: control the temperature of the pellets to be 35-40°C, the rotational speed of the roller mold to be about 3 revolutions/min, control the environmental humidity to be 30-40%, and the temperature to be 22 ⁇ 2°C, control each soft capsule to contain 0.12g orlistat to obtain soft capsules;
  • step S5 the soft capsule obtained in step S4 was shaped in a dry air at 20°C for 4 hours, and the pellets were washed with anhydrous ethanol, and the pellets were washed and blow-dried to obtain the result.
  • Components prepared 10,000 tablets: 1000 g of microcrystalline cellulose, 400 g of lactose, 100 g of sodium carboxymethyl starch, 20 g of magnesium stearate, and 1200 g of orlistat.
  • microcrystalline cellulose, lactose, sodium carboxymethyl starch, and magnesium stearate are mixed uniformly and compressed to obtain blank tablets; orlistat is heated and melted at 50°C, and the molten liquid is coated on the blank tablets to obtain.
  • Test example 1 The fluidity of orlistat compound particles
  • the size of the angle of repose reflects the fluidity of the particles.
  • the angle of repose is required to be less than 40°. Examples 1-9 are all prepared by the co-crystallization process of raw and auxiliary materials, with good crystal roundness and good particle fluidity, which is convenient for subsequent preparation of preparations.
  • Test example 2 Dissolution test
  • Examples 1-9 dissolve quickly; Comparative Example 1 does not contain hydroxypropyl cellulose, and the co-crystal composite has poor hydrophilicity and slow dissolution; Comparative Example 2 does not contain leucine and propylene carbonate , The dissolution is slightly worse than the examples; Comparative Example 3 adopts the raw and auxiliary material co-pulverization process, and the dissolution is slow; Comparative Examples 4-10 have poor dissolution rates.
  • Test example 3 Test of related substances
  • the control solution Take the control solution and adjust the detection sensitivity so that the peak height of the main component chromatographic peak is 10%-20% of the full scale. Then accurately measure the test solution and the control solution for injection separately, and record the chromatogram until the retention time of the main component peak is 5 times. If there are impurity peaks in the chromatogram of the test solution (excluding the peaks of auxiliary materials), the peak area of a single impurity shall not be greater than 0.2 times (0.2%) of the main peak area of the control solution, and the sum of the impurity peak areas shall not be greater than 1 of the main peak area of the control solution. Times (1.0%).
  • Comparative Example 1 does not contain hydroxypropyl cellulose, but due to the stabilizing agent of leucine and propylene carbonate. Exist, the related substances change little; Comparative Example 2 does not contain leucine and propylene carbonate, and the related substances change slightly; Comparative Example 3 adopts the co-pulverization process of raw and auxiliary materials, the raw materials are in powder form, and the related substances are relatively large; The proportion of 4-10 related substances is relatively large, and the related substances in the accelerated test have a large change. Therefore, the orlistat capsule prepared by the present invention has good stability.

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Abstract

一种药物制剂领域技术，公开了一种奥利司他的胶囊及其制备方法。通过奥利司他与羟丙基纤维素，白氨酸和碳酸丙烯酯形成复合物的方法减小原料粒径，提高药物的亲水性和流动性以及稳定性，解决奥利司他制备，存储过程中的稳定性；制备工艺简单，制得的奥利司他胶囊溶出迅速、稳定性好。

Description

一种奥利司他胶囊及其制备方法 技术领域
本发明属于药物制剂技术领域，具体而言，涉及一种含有奥利司他的胶囊及其制备方法。
 背景技术
世界卫生组织将可损害健康的异常或过量脂肪累积定义为超重和肥胖，身体质量指数（BMI）≥25kg/m 2时为超重，身体质量指数≥30kg/m 2时为肥胖。
据世界卫生组织调查，截至2015年1月全球十八岁以上成人中，超重和肥胖人群占52%左右。肥胖所带来的负面影响已经超过了酗酒和抽烟，并被世界卫生组织列为世界四大医学社会问题之一。肥胖可导致心血管、呼吸、内分泌、消化、生殖及中枢神经系统等风险。肥胖患者较正常人更易罹患冠心病、高血压、高脂血症、糖尿病、脑血管意外、骨关节炎、睡眠呼吸暂停等疾病。有些调查还显示肥胖与某些癌症的高发有关。与同龄的正常体重个体相比，相对于各种原因的死亡，肥胖患者的死亡风险率增加。
奥利司他是目前第一个而且是唯一的非中枢神经系统减重药物。现在普遍认为摄入脂肪过多的是引起肥胖的主要原因之一，因此，通过药物控制脂肪酶对甘油三酯的消化就成为行之有效的减肥途径。该药通过选择性抑制胃肠道胰脂肪酶的作用，进而减少饮食中脂肪的吸收达30%，从而减轻体重。
奥利司他的药理学活性呈剂量依赖性，治疗剂量的奥利司他（120mg/d，进餐时服用）结合微低热量平衡膳食，可减少膳食中30%的脂肪吸收，实现降低体重的目的，并进一步减少与肥胖伴发疾病危险因素的发生。
奥利司他为白色或类白色，结晶性粉末；在甲醇、乙醇中极易溶解，在三氯甲烷中易溶，在水中几乎不溶；熔点42℃～46℃。化学名：（S）-2-甲酰氨-4-甲基-戊酸（S）-1-[[（2S，3S）-3-已基-4-氧-氧杂环丁基]甲基]-十二烷基酯，分子式：C29H53NO5，分子量：495.75；结构式：
Figure 510200dest_path_image001
奥利司他由罗氏制药研发，首先在新西兰上市，商品名Xenical ®，1999年在美国上市。2009年我国批准奥利司他胶囊进口，目前国内还有重庆华森制药、杭州中美华东制药、山东新时代药业、浙江海正药业等企业奥利司他胶囊或片剂上市销售。
奥利司他熔点较低，稳定性差，存储过程中有关物质增加迅速。US6004996公开了一种奥利司他制剂的制备方法，其是将活性成分制备成小丸后装入硬质胶囊中而成，其中包括50％的活性成分，辅料主要是用作稀释剂和挤出滚圆的微晶纤维素，作增溶剂的十二烷基硫酸钠，作为粘合剂的聚维酮K 30以及用作润滑剂的滑石粉，用挤出机制备成0.25-2mm小丸，然后装入硬质胶囊。但是该奥利司他制剂生产时产热，导致有关物质增大明显，稳定性较差。
原研企业罗氏申请的中国专利《含有四氢一制胰脂菌素的组合物》(申请号98800369.4)公开了一种含有奥利司他的组合物，将奥利司他、稳定剂(聚维酮、乳糖、羟丙甲纤维素、羟丙纤维素)和药用赋形剂(表面活性剂、稀释剂、崩解剂、滑石粉)，采用挤出滚圆法制备小丸，控制这些微粒的粒径在0.25mm～2mm范围，再制备成合适的口服固体制剂-胶囊、片剂或袋装剂型，以解决工艺过程中出现粘连和粘结问题。生产中需要挤出、滚圆设备，而且在胶囊充填过程中，因摩擦发热导致表面游离的奥利司他融化而粘连。
中国专利CN201811027763.X涉及一种奥利司他软胶囊及其制备方法，内容物主要由奥利司他、聚山梨酯80和维生素E聚乙二醇琥珀酸酯组成；胶片由鱼明胶、甘油和纯化水组成。该发明处方中使用大量的吐温80，聚山梨酯吐温80聚有吸湿性，贮存时间过长会产生过氧化物，不利于制剂的稳定性。吐温80加热分解时会发出辛辣和刺激性的烟气。软胶囊胶皮中水分较高，影响制剂的稳定性。
中国专利CN201110370659.2公开了一种含奥利司他的制剂及其制备方法，该制剂含有奥利司他包衣层，所述的制剂是通过将奥利司他熔融液，包衣在空白片或空白小丸表面形成所述的奥利司他包衣层后制备而成。该奥利司他制剂可以有效解决了生产过程中因奥利司他融化而导致的粘冲问题，同时制剂保持了较好的稳定性和溶出度。但是由于奥利司他的稳定性较差，药物熔融过程中易导致有关物质增加。
中国专利CN201010005285.X公开了一种含有奥利司他环糊精包合物的片剂，该片剂由奥利司他环糊精包合物、崩解剂以及其他药学上可接受的辅料组成。中国专利CN201610884801.8提供一种奥利司他与氨基酸的共晶体及包含该共晶体的药物组合物。所述的共晶体具有较高的熔点，可降低原料药与制剂的制备过程中对干燥条件的要求，并具有较高的溶出度，加快药物起效。中国专利CN201710321107.X公开了一种含有奥利司他的减肥片剂，利用低温热熔挤出和切割工艺，用于制备奥利司他片剂。中国专利CN201310032613.9选用超临界技术进行微粉化原料，同时将奥利司他表面涂覆一层惰性材料，成功地解决了现有技术制备的制剂溶出度较低的问题，以及解决了压片过程中粘冲问题。中国专利CN201310753213.7采用低于10℃的含水溶剂作为润湿剂，解决了制粒过程中奥利司他的稳定性，但在颗粒干燥、胶囊充填或压片过程中仍会导致粘冲和奥利司他降解。中国专利CN201710321107.X，将奥利司他原料经-5℃～0℃低温研磨，制成的口服固体制剂溶出度高。鉴于奥利司他本身的特性，制剂溶出较差，制备和存储过程中有关物质会有明显的增加，现有部分技术解决了溶出问题，或解决制剂制备过程中有关物质增加问题，但均未能有效解决奥利司他制剂存储过程中的稳定性的问题，而且溶出度仍需要提高，来满足治疗要求。
 技术问题
鉴于现有技术的不足，本发明的目的在于提供一种制备工艺简单、溶出迅速、稳定性好的奥利司他胶囊。
 技术解决方案
本发明通过奥利司他与辅料形成复合物结晶的方法减小原料粒径，提高药物的亲水性；以白氨酸、碳酸丙烯酯为稳定剂，共同解决奥利司他制备、存储过程中的稳定性。
为达到上述目的，本发明通过以下技术方案实现：
本发明一方面提供一种奥利司他胶囊，其由奥利司他、羟丙基纤维素、白氨酸和碳酸丙烯酯形成的复合物结晶和药学上可接受的辅料组成。
优选地，所述复合物结晶中各组分的质量比如下：奥利司他1、羟丙基纤维素0.2-0.6、
白氨酸  0.05-0.15、碳酸丙烯酯0.01-0.03。
进一步优选地，所述复合物结晶中各组分质量比如下：奥利司他1、羟丙基纤维素0.4、白氨酸0.1、碳酸丙烯酯0.02。
优选地，所述的奥利司他胶囊中的复合物结晶粒度分布D90为250µm-90µm，进一步优选为180µm。
所述药学上可接受的辅料是本领域技术人员根据现有技术可以选择的，例如可以包括填充剂、崩解剂和润滑剂。其中填充剂例如可以选自微晶纤维素、硅化微晶纤维素、粉状纤维素中的一种或几种；崩解剂例如可以选自交联聚维酮、羧甲淀粉钠、交联甲基纤维素钠中的一种或几种；润滑剂例如可以选自硬脂酸镁、硬脂酸锌或硬脂酸富马酸钠中的一种或几种。
优选地，所述奥利司他胶囊具体含有以下重量份的组份：奥利司他复合物结晶100份，填充剂30-50份，崩解剂5-15份，润滑剂   1-5份
进一步优选地，所述奥利司他胶囊具体含有以下重量份的组份：奥利司他复合物结晶100份、填充剂40份、崩解剂10份、润滑剂2.5份。
本发明另一个方面提供一种奥利司他胶囊的制备方法，具体包括以下步骤：
（1）将奥利司他、羟丙基纤维素、白氨酸、碳酸丙烯酯加入极性溶剂中，缓慢搅拌至完全溶解；搅拌条件下加入非极性溶剂，降温析晶，过滤，干燥，即得奥利司他复合物结晶；
（2）奥利司他复合物结晶与药学上可接受的其它辅料混合均匀，充填胶囊，即得。
优选地，所述奥利司他与极性溶剂、非极性溶剂的质量体积比为1:1~10：5~50；g/mL/mL。
进一步优选地，所述奥利司他与极性溶剂、非极性溶剂的质量体积比为1:6:10；g/mL/mL。
优选地，所述的极性溶剂为乙醇、甲醇、乙腈中的一种或几种；所述的非极性溶剂为正己烷、庚烷、乙醚中的一种或几种。
优选地，所述搅拌条件为3000～5000rpm。
优选地，所述降温温度为-5～-15℃。
优选地，所述析晶时间为4～10h。
 有益效果
与现有技术相比，本发明制备的奥利司他复合物颗粒流动性好，制备的奥利司他胶囊制备工艺简单，制成制剂的稳定性好，溶出迅速。
 本发明的实施方式
现通过以下实施例来进一步描述本发明制剂的制备过程和实施效果，但本发明的保护范围并不局限于以下实施例。
实施例 1
组分：奥利司他120g、羟丙基纤维素48g、白氨酸12g、碳酸丙烯酯2.4g、微晶纤维素72.96g、交联聚维酮18.24g、硬脂酸镁4.56g。
制备工艺：
（1）将奥利司他、羟丙基纤维素、白氨酸、碳酸丙烯酯加入720mL乙醇中，缓慢搅拌至完全溶解；3500rpm搅拌条件下加入3600mL正己烷，降温至-10℃析出结晶7h，过滤，30℃真空干燥，即得奥利司他复合物结晶，粒度分布D 90为180µm；
（2）将步骤（1）制得的奥利司他复合物结晶与微晶纤维素、交联聚维酮、硬脂酸镁混合均匀，充填胶囊，即得。
实施例 2
组分：奥利司他120g、羟丙基纤维素60g、白氨酸15.60g、碳酸丙烯酯3.00g、硅化微晶纤维素89.37g、羧甲淀粉钠23.83g、硬脂酸锌5.96g。
制备工艺：
（1）将奥利司他、羟丙基纤维素、白氨酸、碳酸丙烯酯加入960mL甲醇中，缓慢搅拌至完全溶解；3200rpm搅拌条件下加入4800mL庚烷，降温至-12℃析出结晶9h，过滤，30℃真空干燥，即得奥利司他复合物结晶，粒度分布D 90为200µm；
（2）将步骤（1）制得的奥利司他复合物结晶与硅化微晶纤维素、羧甲淀粉钠、硬脂酸锌混合均匀，充填胶囊，即得。
实施例 3
组分：奥利司他120g、羟丙基纤维素36g、白氨酸8.4g、碳酸丙烯酯1.8g、淀粉58.17g、低取代羟丙基纤维素11.63g、滑石粉3.32g。
制备工艺：
（1）将奥利司他、羟丙基纤维素、白氨酸、碳酸丙烯酯加入480mL乙腈中，缓慢搅拌至完全溶解；4000rpm搅拌条件下加入2400mL乙醚，降温至-6℃析出结晶6h，过滤，30℃真空干燥，即得奥利司他复合物结晶，粒度分布D 90为150µm；
（2）将步骤（1）制得的奥利司他复合物结晶与淀粉、低取代羟丙基纤维素、滑石粉混合均匀，充填胶囊，即得。
实施例 4
组分：奥利司他120g、羟丙基纤维素72g、白氨酸18g、碳酸丙烯酯3.6g、粉状纤维素60g、微晶纤维素46.80g、交联羧甲基纤维素钠32.04g、硬脂酸镁10.68g。
制备工艺：
（1）将奥利司他、羟丙基纤维素、白氨酸、碳酸丙烯酯加入60mL甲醇与60mL乙腈混合溶剂中，缓慢搅拌至完全溶解；3000rpm搅拌条件下加入6000mL乙醚，降温至-15℃析出结晶10h，过滤，30℃真空干燥，即得奥利司他复合物结晶，粒度分布D 90为250µm；
（2）将步骤（1）制得的奥利司他复合物结晶与粉状纤维素、微晶纤维素、交联羧甲基纤维素钠、硬脂酸镁混合均匀，充填胶囊，即得。
实施例 5
组分：奥利司他120g、羟丙基纤维素24g、白氨酸6g、碳酸丙烯酯1.2g、粉状纤维素45.36g、交联聚维酮3g、羧甲基淀粉钠4.56g、硬脂酸锌1.51g。
制备工艺：
（1）将奥利司他、羟丙基纤维素、白氨酸、碳酸丙烯酯加入120mL甲醇溶剂中，缓慢搅拌至完全溶解；5000rpm搅拌条件下加入200mL正己烷和400mL庚烷的混合溶剂，降温至-5℃析出结晶4h，过滤，30℃真空干燥，即得奥利司他复合物结晶，粒度分布D 90为90µm；
（2）将步骤（1）制得的奥利司他复合物结晶与粉状纤维素、交联聚维酮、羧甲基淀粉钠、硬脂酸锌混合均匀，充填胶囊，即得。
实施例 6
组分：奥利司他120g、羟丙基纤维素120g、白氨酸18g、碳酸丙烯酯3.6g、微晶纤维素148.50g、交联聚维酮54g、硬脂酸镁21.60g。
制备工艺：
（1）将奥利司他、羟丙基纤维素、白氨酸、碳酸丙烯酯加入1800mL乙醇中，缓慢搅拌至完全溶解；3200rpm搅拌条件下加入7200mL正己烷，降温至-6℃析出结晶8h，过滤，30℃真空干燥，即得奥利司他复合物结晶，粒度分布D 90为230µm；
（2）将步骤（1）制得的奥利司他复合物结晶与微晶纤维素、交联聚维酮、硬脂酸镁混合均匀，充填胶囊，即得。
实施例 7
组分：奥利司他120g、羟丙基纤维素12g、白氨酸2.4g、碳酸丙烯酯0.60g、硅化微晶纤维素33.75g、羧甲淀粉钠  2.70g、硬脂酸锌0.68g。
制备工艺：
（1）将奥利司他、羟丙基纤维素、白氨酸、碳酸丙烯酯加入60mL甲醇中，缓慢搅拌至完全溶解；4500rpm搅拌条件下加入240mL庚烷，降温至-10℃析出结晶5h，过滤，30℃真空干燥，即得奥利司他复合物结晶，粒度分布D 90为120µm；
（2）将步骤（1）制得的奥利司他复合物结晶与硅化微晶纤维素、羧甲淀粉钠、硬脂酸锌混合均匀，充填胶囊，即得。
实施例 8
组分：奥利司他120g、羟丙基纤维素72g、白氨酸18g、碳酸丙烯酯3.6g、粉状纤维素106.8g、羧甲淀粉钠32.04g、硬脂酸锌10.68g。
制备工艺：
（1）将奥利司他、羟丙基纤维素、白氨酸、碳酸丙烯酯加入120mL乙腈中，缓慢搅拌至完全溶解；1000rpm搅拌条件下加入6000mL乙醚，降温至-10℃析出结晶9h，过滤，干燥，即得奥利司他复合物结晶，粒度分布D 90为330µm；
（2）奥利司他复合物结晶与粉状纤维素、羧甲淀粉钠、硬脂酸锌混合均匀，充填胶囊，即得。
实施例 9
组分：奥利司他120g、羟丙基纤维素24g、白氨酸6g、碳酸丙烯酯1.2g、微晶纤维素45.36g、羧甲淀粉钠7.56g、硬脂酸锌1.51g。
制备工艺：
（1）将奥利司他、羟丙基纤维素、白氨酸、碳酸丙烯酯加入120mL甲醇中，缓慢搅拌至完全溶解；8000rpm搅拌条件下加入600mL庚烷，降温至-10℃析出结晶4h，过滤，干燥，即得奥利司他复合物结晶，粒度分布D 90为35µm；
（2）奥利司他复合物结晶与微晶纤维素、羧甲淀粉钠、硬脂酸锌混合均匀，充填胶囊，即得。
 工业实用性
对比例 1
组分：奥利司他120g、白氨酸12g、碳酸丙烯酯2.4g、微晶纤维素70g、羧甲淀粉钠20g、
硬脂酸锌4g。
制备工艺：
（1）将奥利司他、白氨酸、碳酸丙烯酯加入720mL甲醇中，缓慢搅拌至完全溶解；4000rpm搅拌条件下加入3600mL庚烷，降温至-10℃析出结晶6h，过滤，干燥，即得奥利司他复合物结晶，经检测粒度分布D 90为150µm；
（2）奥利司他复合物结晶与微晶纤维素、羧甲淀粉钠、硬脂酸锌混合均匀，充填胶囊，即得。
对比例 2
组分：奥利司他120g、羟丙基纤维素24g、微晶纤维素43g、羧甲淀粉钠7.5g、硬脂酸锌1.5g。
制备工艺：
（1）将奥利司他、羟丙基纤维素加入120mL甲醇中，缓慢搅拌至完全溶解；5000rpm搅拌条件下加入600mL庚烷，降温至-10℃析出结晶7h，过滤，干燥，即得奥利司他复合物结晶，经检测粒度分布D 90为90µm；
（2）奥利司他复合物结晶与微晶纤维素、羧甲淀粉钠、硬脂酸锌混合均匀，充填胶囊，即得。
对比例 3
组分：奥利司他120g、羟丙基纤维素48g、白氨酸12g、碳酸丙烯酯2.4g、纤维素乳糖复合物70g、羧甲淀粉钠20g、硬脂酸锌4g。
制备工艺：
（1）将奥利司他、羟丙基纤维素、白氨酸、碳酸丙烯酯混合均匀，加液态二氧化碳低温粉碎，粒度分布D90为73.2µm；
（2）奥利司他复合物结晶与粉状纤维素、羧甲淀粉钠、硬脂酸锌混合均匀，充填胶囊，即得。
对比例 4
组分：120g奥利司他、93.6g微晶纤维素101、12g聚维酮K29/32、7.2g羧甲基淀粉钠、
7.2g十二烷基硫酸钠、100g纯化水。    
制备工艺：
（1）称取原辅料加至湿法制粒机中制软材，混合180s，加水时间为30s，粒化时间为30s，加入润湿剂时不开切割桨；
（2）Φ0.8mm挤出网，25r/min挤出；
（3）800r/min滚圆40s；
（4）流化床干燥参数：物料温度均小于30℃。
对比例 5
组分：120g奥利司他、120g微晶纤维素、120g泊洛沙姆215、40g胶态二氧化硅。 
制备工艺：
（1）取奥利司他，微晶纤维素，粉碎，过100目筛，备用；
（2）取处方量奥利司他，微晶纤维素，聚合物，胶态二氧化硅置湍流混合器中，混合，约4分钟；
（3）将混合物料以一定速率持续进料，在45℃的熔体温度下于双螺杆挤出机通过
一定孔径的孔板持续挤出，得条状半固体中间体；
（4）按一定厚度切割（3）得到的条状中间体，得到奥利司他片剂；
（5）以具有高防潮性能的PVDC/铝箔为包装材料，对（4）所得奥利司他片剂进行包装。
对比例 6
(1)1:1奥利司他L-亮氨酸共晶的制备
取0.496gⅡ型奥利司他(0.001mol)，置于100mL三颈烧瓶中，40℃水浴轻轻搅拌下缓慢滴加正辛醇，直至固体完全溶解；然后置于40℃下搅拌过夜后冷却至室温，缓慢滴加0.197mg/L-亮氨酸(0.0015mol)的饱和正辛醇溶液；再置于40℃下于振荡器中成熟3天；最后在冰浴条件下静置2天后真空过滤析出的固体，将析出的固体置于真空箱中70℃下干燥4小时，得白色片状结晶0.617g，总收率为98.4％。
（2）含奥利司他与L-亮氨酸共晶胶囊的制备
组分：奥利司他L-亮氨酸共晶12g，微晶纤维素8.5～9.2g，羧甲基淀粉钠1.0～1.3g，交联聚维酮1.1～1.5g，十二烷基硫酸钠0.2～0.3g，聚维酮K30适量，共制成100粒。
制备方法：
①混合：预先将十二烷基硫酸钠、交联聚维酮、羧甲淀粉钠、微晶纤维素过80目筛，得细粉备用；然后按处方量称取十二烷基硫酸钠、交联聚维酮、羧甲淀粉钠和微晶纤维素细粉以及共晶；先将十二烷基硫酸钠、交联聚维酮、羧甲淀粉钠混合均匀，再加入微晶纤维素和共晶混合均匀，过80目筛两遍，即得混匀的粉末。
②制粒与干燥：往混匀的粉末中缓慢加入含10％聚维酮K30的50％乙醇溶液，制软材，20目挤压过筛制湿颗粒，湿颗粒置60℃鼓风干燥箱中烘干6小时，取出过20目筛整粒。
③颗粒含量测定：按质量标准中含量测定方法进行，测定干燥颗粒中奥利司他含
量，计算理论装量。
④灌装胶囊：按计算出的理论装量，将干燥颗粒灌装入0号胶囊(主要由明胶、钛白粉、柠檬黄、亮蓝构成)中。
对比例 7
调整SQW-25低温研磨混合(炼)机至-2℃后，将0.72kg奥利司他原料投入。维持设备的研磨温度，控制研磨频率40HZ，研磨3min。取研磨制得的奥利司他粉末120g与二氧化硅0.19g、羧甲淀粉钠0.94g、微晶纤维素3.75g和硬脂酸镁0.0625g，混合均匀；填充胶囊，即得。
对比例 8
1.奥利司他片处方
1.1包合物配方：奥利司他12.4g(0.025mol)、α-环糊精24.325g(0.025mol)、50％乙醇溶液1500ml。
1.2压片配方
包合物10份、微晶纤维素87份、羧甲基淀粉钠2份、硬脂酸镁1份。
2.制备工艺
(1)将处方量的α-环糊精溶于处方量的50％乙醇中，加入处方量的奥利司他，然后加热混合液，当奥利司他变为油状，继续加热至40℃，然后使用超声匀质机，频率为20kHz，60W，保温超声46min制得均匀混合溶液。
(2)开启冻干机对产品进行预冻，以2℃/min 将制品温度降至约-40℃以下，保温4小时左右，待产品完全冻结实后，开启冷凝器使温度降至-40℃以下，开始抽真空进行冻干，然后逐步升高温度至-5℃，使样品中水分基本冻干，继续升温至30℃左右，保温约8h，冻干结束得本品。
(3)将奥利司他包合物和微晶纤维素、羟丙基纤维素混匀，加入2％聚维酮乙醇溶
液，制粒，干燥，加入硬脂酸镁，混匀，压片，即得。
对比例 9
组分：所述奥利司他软胶囊，包括内容物和胶皮，所述内容物组分为奥利司他120份、聚山梨酯8040份和维生素E聚乙二醇琥珀酸酯200份；所述胶片由鱼明胶、甘油和纯化水按重量比2:1:3组成。
（1）所述鱼明胶由以下方法制得：
A将清洗干燥后的罗非鱼鱼鳞粉碎至10目，得鱼鳞粉末；
B将步骤A得到的鱼鳞粉末加入温度为55℃的去离子水浸泡2h，所述去离子水与鱼鳞粉末的固液比为1g:8ml，捞起，沥干，接着放入处理液中处理2h，所述处理液由聚山梨酯80和维生素E聚乙二醇琥珀酸酯按重量比3:2组成，所述处理液与鱼鳞粉末的固液比为1g:2ml，接着加入浓度为1mol/L的柠檬酸溶液浸泡2h，所述柠檬酸溶液与鱼鳞粉末的固液比为1g:4ml，调节pH值为5，捞起沥干，得鱼鳞凝胶；
C将步骤B得到的鱼鳞凝胶放置处理液中处理15min，所述处理液由聚山梨酯80和维生素E聚乙二醇琥珀酸酯按重量比3:2组成，所述处理液与鱼鳞凝胶的固液比为1g:2ml，捞起放入温度为75℃的去离子水中浸泡3h，过滤，取滤渣，重复2遍，合并滤渣，冷冻浓缩，所述冷冻浓缩条件为：预冷温度为6℃，搅拌速度为160r/min，冷媒温度为-12℃，即得。
（2）奥利司他软胶囊制备方法制备方法：
S1将奥利司他加热至43℃溶解，接着将聚山梨酯80热至43℃，加入溶解后的奥利司他中搅拌均匀，得混合液I；
S2将维生素E聚乙二醇琥珀酸酯加热至95℃保温60min，降温至43℃，加入步骤S1得到的混合液I中均质乳化，降温至30℃保温，并在-0.09MPa真空条件下脱气60min，得内容物；
S3将鱼明胶加入纯化水中，加热至70℃搅拌至完全溶解，加入甘油，加热至70℃搅拌均匀，过滤，60℃静置保温1h，得胶浆；
S4将步骤S3制得的胶浆在85℃的条件下压制胶片，将胶片装上自动旋转制囊机，
注入步骤S2制得的内容物，所述制备软胶囊的条件为：控制压丸温度为35～40℃，滚模转速3转/分钟左右，控制环境湿度为30～40％，温度为22±2℃，控制每粒软胶囊含有奥利司他0.12g，得软胶囊；
S5将步骤S4得到的软胶囊在20℃的干燥风定形4h，用无水乙醇进行洗丸，洗丸后吹干，即得。
对比例 10
组分（制备10000片）：微晶纤维素1000g，乳糖400g，羧甲基淀粉钠100g，硬脂酸镁20g，奥利司他1200g。
制备工艺：
处方量微晶纤维素、乳糖、羧甲基淀粉钠、硬脂酸镁混合均匀，压片，得空白片；奥利司他50℃加热熔化，将熔融液在空白片上包衣，即得。
试验例 1 ：奥利司他复合物颗粒流动性
取本发明实施例1-9制备的奥利司他复合物颗粒，用粉体特性测试仪测定休止角，结果见表1。
Figure 863821dest_path_image002
休止角的大小反应颗粒流动性的好坏，休止角越小，颗粒流动性越好，胶囊充填过程中片重差异也会越小。一般为保证胶囊充填的顺利进行，要求休止角小于40°，实施例1-9均采用原辅料共析晶工艺制备，结晶圆整度好，颗粒流动性均较好，便于后续制剂的制备。
试验例 2 ：溶出度试验
色谱柱：Agilent XDB C 8（150mm×4.6mm，3μm），流动相：乙腈-水（86:14:0.05），流速：2mL/min，检测波长：200nm，进样量：100μL。理论板数按奥利司他峰计算不低于3000。
取各实施例和对比例制备的样品，分别于0个月、加速六个月（在温度40°C±2°C、相对湿度75%±5%的条件下放置6个月）测量溶出度，照溶出度测定法（中国药典2015年版四部通则0931第二法），以0.5%十二烷基硫酸钠pH5.5磷酸缓冲液500mL为溶出介质，转速为每分钟50转，依法操作，分别于5、10、15、30分钟时，取溶液适量，滤过，取续滤液作为供试品溶液；另取奥利司他对照品适量，精密称定，加乙腈适量使溶解，用溶出介质定量稀释制成每1mL中约含0.24mg的溶液，作为对照品溶液。精密量取供试品溶液与对照品溶液各100μl，分别注入液相色谱仪，记录色谱图。按外标法以峰面积计算每胶囊的溶出量。
Figure 662013dest_path_image003
Figure 392071dest_path_image004
Figure 858954dest_path_image005
从表2可以看出，实施例1-9溶出迅速；对比例1不含羟丙基纤维素，共结晶复合物亲水性差，溶出较慢；对比例2不含白氨酸和碳酸丙烯酯，溶出较实施例稍差一些；对比例3为采用原辅料共粉碎工艺，溶出较慢；对比例4-10溶出速度均较差。
试验例 3 ：有关物质试验
色谱柱：Agilent XDB C 8（250mm×4.6 mm，3μm），流动相：乙腈-水-磷酸（86:14:0.05），流速：1.5mL/min，检测波长：200nm，进样量：50μL。理论板数按奥利司他峰计算不低于3000。
分别于0个月、加速六个月（按市售包装，在温度40°C±2°C、相对湿度75%±5%的条件下放置6个月）取各实施例和对比例制备的样品细粉适量（约相当于奥利司他25mg），精密称定，置50mL量瓶中，加乙腈超声溶解并稀释至刻度，摇匀，置玻璃离心管中离心，取上清液作为供试品溶液；精密量取1mL，置100mL量瓶中，加流动相稀释至刻度，摇匀，作为对照溶液。取对照溶液进样，调节检测灵敏度，使主成分色谱峰的峰高为满量程的10％～20％。再精密量取供试品溶液与对照溶液分别进样，记录色谱图至主成分峰保留时间的5倍。供试品溶液的色谱图中如有杂质峰（扣除辅料峰），单个杂质峰面积不得大于对照溶液主峰面积的0.2倍（0.2％），各杂质峰面积的和不得大于对照溶液主峰面积的1倍（1.0％）。
Figure 383476dest_path_image006
Figure 668964dest_path_image007
从表3可以看出，实施例1-9有关物质较小，加速6个月有关物质增加不明显；对比例1不含羟丙基纤维素，但由于稳定剂白氨酸、碳酸丙烯酯的存在，有关物质变化不大；对比例2不含白氨酸和碳酸丙烯酯，有关物质变化稍大一些；对比例3为采用原辅料共粉碎工艺，原料呈粉末状，有关物质较大；对比例4-10有关物质较大，而且加速试验有关物质变化较大。所以，本发明制备的奥利司他胶囊具有很好的稳定性。

Claims (9)

  1. 一种奥利司他胶囊，其特征在于：其由奥利司他、羟丙基纤维素、白氨酸和碳酸丙烯酯形成的复合物结晶和药学上可接受的辅料组成。
  2. 如权利要求1所述奥利司他胶囊，其特征在于，所述复合物结晶中各组分质量比如下：奥利司他1、羟丙基纤维素0.2-0.6、白氨酸0.05-0.15、碳酸丙烯酯0.01-0.03。
  3. 如权利要求1所述奥利司他胶囊，其特征在于：所述的奥利司他胶囊中的复合物结晶粒度分布D90为250µm-90µm。
  4. 一种制备如权利要求1所述奥利司他胶囊的方法，其特征在于，具体包括以下步骤：
    （1）将奥利司他、羟丙基纤维素、白氨酸、碳酸丙烯酯加入极性溶剂中，缓慢搅拌至完全溶解；搅拌条件下加入非极性溶剂，降温析晶，过滤，干燥，即得奥利司他复合物结晶；
    （2）奥利司他复合物结晶与药学上可接受的其它辅料混合均匀，充填胶囊，即得。
  5. 如权利要求4所述的方法，其特征在于：所述奥利司他与极性溶剂、非极性溶剂的质量体积比为1:1~10:5~50，g/mL/mL。
  6. 如权利要求4所述的方法，其特征在于：所述的极性溶剂为乙醇、甲醇、乙腈中的一种或几种；所述的非极性溶剂为正己烷、庚烷、乙醚中的一种或几种。
  7. 如权利要求4所述的方法，其特征在于：所述搅拌条件为3000～5000rpm。
  8. 如权利要求4所述的方法，其特征在于：所述降温温度为-5～-15℃。
  9. 如权利要求4所述的方法，其特征在于：所述析晶时间为4～10h。
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