WO2011072474A1 - 双环醇双层渗透泵控释片剂及其制备方法 - Google Patents

双环醇双层渗透泵控释片剂及其制备方法 Download PDF

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WO2011072474A1
WO2011072474A1 PCT/CN2010/001817 CN2010001817W WO2011072474A1 WO 2011072474 A1 WO2011072474 A1 WO 2011072474A1 CN 2010001817 W CN2010001817 W CN 2010001817W WO 2011072474 A1 WO2011072474 A1 WO 2011072474A1
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Prior art keywords
layer
controlled release
osmotic pump
drug
bicyclol
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PCT/CN2010/001817
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English (en)
French (fr)
Inventor
郭旻彤
吕昭云
李燕
潘显道
杨超莲
李强
王晓梅
兰培
赵立敏
刘玉娟
刘艳
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北京协和药厂
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Priority to KR1020127001104A priority Critical patent/KR101392007B1/ko
Priority to JP2012540258A priority patent/JP2013511564A/ja
Priority to EP10836913.3A priority patent/EP2471521B1/en
Publication of WO2011072474A1 publication Critical patent/WO2011072474A1/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
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • 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
    • 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
    • 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
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat

Definitions

  • the invention relates to a controlled release dosage form of a drug bicyclol for treating hepatitis, in particular to a double-layer osmotic pump controlled release preparation and a preparation method thereof.
  • the osmotic pump tablet is a new type of controlled release tablet, which is used to compress a drug and a high osmotic pressure penetration enhancer or other auxiliary material into a solid core, and a layer of a controlled rate semi-permeable membrane, and then a laser in the core.
  • One or more release orifices are opened on the coating film.
  • the moisture in the gastrointestinal tract enters the core through the semipermeable membrane to dissolve the drug into a saturated solution or suspension, and the dissolution of the osmotic pressure auxiliary material causes the solution in the tablet membrane to be a hypertonic solution.
  • There is a large osmotic pressure difference inside and outside the membrane so that the water continues to enter the membrane, and the drug solution or suspension is continuously pumped through the drug delivery orifice.
  • Osmotic pump controlled release tablets currently have two main forms in clinical applications, one is a multi-chamber osmotic pump controlled release tablet, and the other is a single-chamber primary osmotic pump controlled release tablet.
  • Single-chamber osmotic pump controlled release tablets are generally used in water-soluble drugs.
  • the core of the tablet contains only one layer of drug and a penetration enhancer with high osmotic pressure.
  • the coating film is composed of high molecular polymer and is wrapped on the surface of the core. There are one or two drug delivery orifices on the coating film.
  • Multi-chamber osmotic pump controlled release tablets are suitable for the preparation of water-soluble or poorly soluble drugs.
  • the core of the film is usually a two-layer tablet.
  • the drug-containing layer is composed of drugs, penetration enhancers and other excipients. After the water is formed, the drug solution or drug suspension is formed.
  • the boosting layer is composed of an inorganic salt and a polymer having an expanding action. When moisture enters the core assisting layer, the polymer swells and pushes the drug solution or the drug suspension of the drug-containing layer to discharge the sheet.
  • dual-chamber osmotic pump controlled release drug release is closer to zero-order release, but due to the difficulty of dual-chamber controlled release process and prescription design, there are currently not many products on the market.
  • Oral osmotic pump preparation can avoid the fluctuation of blood concentration of common oral preparations, reduce the number of medications and toxic side effects of drugs, improve the compliance and safety of patients' medications; compared with sustained release preparations, oral osmotic pump controlled release preparations
  • the release of the drug is more stable, closer to zero-order release, and the release behavior is not affected by gastrointestinal variables such as gastrointestinal peristalsis frequency, pH and gastrointestinal emptying time, thereby reducing individual differences in the drug.
  • Bicyclol is an innovative drug with independent intellectual property rights developed by the Institute of Materia Medica of the Chinese Academy of Medical Sciences for the treatment of elevated levels of aminotransferases caused by chronic hepatitis.
  • Bicyclol has a short half-life and requires three doses per day for clinical treatment, which is extremely inconvenient for chronic hepatitis B patients who require long-term medication.
  • the oral release of bicyclol is faster, and the individual differences are large, which affects the clinical therapeutic effect.
  • the double-ring yeast is made into an osmotic pump sheet, and the bicyclic alcohol can be released slowly and at a constant rate to achieve a zero-order release requirement, thereby reducing the peak-to-valley ratio of the drug blood concentration and reducing the adverse reaction of the ordinary tablet;
  • the release behavior of bicyclol osmotic pump controlled release tablets is not affected by factors such as environmental pH, gastrointestinal motility and food, which can reduce individual differences.
  • the bicyclol alcohol has low solubility, which affects its absorption and utilization.
  • the slow and constant release of bicyclol osmotic pump tablets can significantly improve the absorption of bicyclol and improve the clinical efficacy of bicyclol. Summary of the invention
  • Another object of the present invention is to provide a method for preparing a bicyclic alcohol double-layer osmotic pump controlled release tablet.
  • the invention provides a bicyclic alcohol double-layer osmotic pump controlled release tablet with osmotic pressure as a main release power and a preparation method thereof.
  • the technical scheme of the invention is realized in the following manner: preparing a double-layer osmotic pump controlled release tablet by using bicyclol as a raw material, the core of the tablet contains two layers, wherein one layer is a drug-containing layer, and the active drug is bicyclol and high. Other auxiliary materials such as molecular polymer and/or binder are mixed; the other layer is a boost layer composed of high molecular weight polymer, pigment, binder and other auxiliary materials.
  • the core of the double-layer controlled release tablet is made up of a drug-containing layer and a boosting laminate, and then the prepared two-layer film is coated with a semi-permeable film by coating, and the drug-containing layer is formed by laser or other suitable method. Make one or more release orifices.
  • the weight percentage of each component of the bicyclic alcohol double-layer osmotic pump controlled release tablet obtained by the invention is:
  • the controlled release tablet core of the present invention comprises a drug-containing layer and a boosting layer, wherein the auxiliary material for controlling release in the drug-containing layer is a polymer material, and one or more may be added according to the demand of the drug release drug.
  • the polymer material is preferably a polyoxyethylene polymer, hydroxypropylmethylcellulose or povidone. Experiments have shown that the molecular weight of the polyoxyethylene polymer is from 100,000 to 300,000, and the molecular weight of povidone is from 30,000 to 70,000. Better quality.
  • the inorganic salt is preferably sodium chloride.
  • the excipients for controlling release in the booster layer are one or more of polyoxyethylene polymer, hydroxypropylmethylcellulose, sodium chloride, povidone, and mixtures thereof.
  • suitable polyoxyethylene polymers have a molecular weight of 5 million to 7.5 million.
  • the tablet core may be added with other pharmaceutically known excipients, including binders, lubricants, glidants, and coloring, in addition to the main excipients.
  • binders binders, lubricants, glidants, and coloring
  • the controlled release coating film of the bicyclol osmotic pump controlled release tablet is prepared by spraying the coating liquid onto the double layer core, and the coating liquid is mainly composed of a film material and a solvent, and a plasticizer and/or a plasticizer may be added as needed. Or porogen.
  • Suitable coating materials include one of cellulose acetate, ethyl cellulose or a mixture thereof.
  • Plasticizers include: one or more of methyl phthalate, ethyl phthalate, triethyl citrate, polyethylene glycol, and mixtures thereof. More preferably, the polyethylene glycol has a molecular weight of from 200 to 8,000, and more preferably, the polyethylene glycol has a molecular weight of from 400 to 4,000.
  • the porogen comprises: one or more of glycerin, propylene glycol, polyethylene glycol, saccharides, and mixtures thereof; wherein the saccharide may be a pharmaceutically well-known monosaccharide, disaccharide or a mixture thereof such as sucrose or glucose. .
  • the coating liquid is prepared using a suitable solvent, and the solvent may be one or more selected from the group consisting of acetone, water, ethanol, dichloromethane, methanol, and isopropanol, and a mixture thereof.
  • the coating liquid may be added with other pharmaceutically known excipients as needed, including a binder, a lubricant, a coloring agent, an opacifier, and a surface.
  • One or more of the active agents are examples of the active agents.
  • the controlled release tablet of the bicyclic alcohol osmotic pump obtained by the invention is mainly released through the release pores on the insoluble coating film, and the release pores are located on the surface of the drug-containing layer, and the drug release is required according to the release rate.
  • the small holes may be one or several; the drug release holes may be obtained by laser drilling or other mechanical punching methods, wherein the laser drilling method is a mature and feasible method for industrialized continuous production.
  • the preparation of the two-layer tablet can be carried out by tableting after granulation, or can be directly compressed by using a powder. Experiments show that both methods can obtain a controlled release tablet with good appearance and quality.
  • the controlled release film can also be coated with a moisture-proof garment after punching, thereby finally obtaining a commercial product with good aesthetic quality and quality.
  • the bicyclol is made into an osmotic pump tablet.
  • the controlled release tablet absorbs moisture in the gastrointestinal tract, and on the one hand, the polymer containing the drug layer absorbs water and transforms into a fluid, and the activity
  • the drug forms a suspension, and at the same time, the volume of the polymer of the boosting layer is increased after water absorption, and the drug pushing the drug-containing layer is uniformly released from the drug releasing pore.
  • the active ingredient of bicyclol controlled-release tablets can be released at a constant rate and achieve zero-order release.
  • the drug release behavior is not affected by environmental pH, gastrointestinal motility and food, and has good correlation in vivo and in vitro.
  • Bicyclol osmotic pump tablets can reduce the difference of drug peak wave trough blood concentration, reduce the adverse reactions of ordinary tablets, enhance the absorption of the poorly soluble drug bicyclol, reduce individual differences, and improve the clinical efficacy of bicyclol.
  • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In order to further illustrate the innovation embodied in the bicyclic alcohol double-layer osmotic pump controlled release tablet of the present invention and the preparation method thereof, the present invention will be further described below in conjunction with specific embodiments, but the protection of the present invention is not limited to the implementation. The content described in the example. Example 1:
  • the total weight of the drug-containing layer is 240mg.
  • Preparation of drug-containing layer Mix the prescribed amount of bicyclol and other auxiliary materials except magnesium stearate, and add appropriate amount of ethanol to make granules. Dry at room temperature or in a drying facility.
  • booster layer Mix the prescribed amount of polyoxyethylene with other excipients other than magnesium stearate, and add appropriate amount of ethanol to granulate.
  • Isolation coat A layer of brown-red moisture-proof film coat is wrapped around the prepared coated double-layer film.
  • Example 2 A layer of brown-red moisture-proof film coat is wrapped around the prepared coated double-layer film.
  • the total weight of the drug-containing layer is 240mg.
  • Preparation of the drug-containing layer The prescribed amount of bicyclol and other excipients other than magnesium stearate are uniformly mixed, and an appropriate amount of ethanol is added for granulation. Dry at room temperature or in a drying facility.
  • the dried main layer is sieved and then thoroughly mixed with the prescribed amount of magnesium stearate.
  • Preparation of the booster layer Mix the prescribed amount of polyoxyethylene with other excipients other than magnesium stearate, and add an appropriate amount of ethanol to granulate.
  • the sieved layer is sifted and then thoroughly mixed with the prescribed amount of magnesium stearate.
  • the tablet was prepared on a double laminator using the prepared drug-containing layer and the booster layer as required.
  • the prepared bilayer tablets are coated in a coating apparatus to an appropriate weight gain.
  • the coated two-layer tablet is dried to remove the remaining solvent.
  • Isolation coat A layer of brown-red moisture-proof film coat is wrapped around the prepared coated double-layer sheet.
  • Example 3 A layer of brown-red moisture-proof film coat is wrapped around the prepared coated double-layer sheet.
  • the total weight of the drug-containing layer is 635mg.
  • Polyoxyethylene 140mg is polyoxyethylene 140mg
  • Example 4 In the same manner as in Example 2, the drug-containing layer and the boosting layer were prepared and then the two-layer sheet was pressed, and finally the semi-permeable film coating, the laser drilling and the moisture-proof barrier layer were coated.
  • Example 4 In the same manner as in Example 2, the drug-containing layer and the boosting layer were prepared and then the two-layer sheet was pressed, and finally the semi-permeable film coating, the laser drilling and the moisture-proof barrier layer were coated.
  • the total weight of the drug-containing layer is 80mg.
  • the total weight of the booster layer is 45. 3mg semipermeable membrane coating Cellulose acetate 3. 9g
  • Example 5 In the same manner as in Example 2, the drug-containing layer and the boosting layer were prepared and then the two-layer sheet was pressed, and finally the semi-permeable film coating, the laser drilling and the moisture-proof barrier layer were coated.
  • Example 5 In the same manner as in Example 2, the drug-containing layer and the boosting layer were prepared and then the two-layer sheet was pressed, and finally the semi-permeable film coating, the laser drilling and the moisture-proof barrier layer were coated.
  • the total weight of the drug-containing layer is 240mg.
  • Preparation of the drug-containing layer The prescribed amount of the double-ring drunk is mixed with other excipients other than magnesium stearate, and then thoroughly mixed with the prescribed amount of stearic acid.
  • Preparation of the booster layer The prescribed amount of polyoxyethylene and other excipients other than magnesium stearate are uniformly mixed and then thoroughly mixed with the prescribed amount of magnesium stearate.
  • the tablet was prepared on a double laminator using the prepared drug-containing layer and the booster layer as required. 4) Coating the prepared two-layer sheet in a coating device to an appropriate weight gain.
  • Example 6 Animal Pharmacokinetic Experiment
  • the bicyclol osmotic pump controlled release tablets prepared in Example 2 were subjected to single and multiple oral administration of Beagle dogs.
  • Pharmacokinetic studies. The pharmacokinetic study of Beagle dogs demonstrates that the controlled release tablets of the present invention have long-lasting controlled release characteristics.
  • Test animals Male and female Beagle dogs, each weighing 5. 8-6. 6kg.
  • Test methods Randomly divided into 2 groups, 3 in each group, with cross-administration, one week between two oral administrations, and plasma background determination before administration.
  • the amount of bicyclol normal tablets was 75m g / time / only, and the controlled release tablets were 75m g / time / only.
  • blood samples were taken at different time points for measurement, and the pharmacokinetic parameters were calculated according to the blood concentration data.
  • Table 1 Beagle dogs single oral bicyclol controlled release tablets and ordinary tablets after blood plasma pharmacokinetic parameters statistical moment parameters unit controlled release tablets ordinary tablets

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Description

双环醇双层渗透泵控释片剂及其制备方法 技术领域
本发明涉及一种治疗肝炎的药物双环醇的控释剂型， 特别是双层渗透泵控释制剂及其制备方法。 背景技术
渗透泵片是一种新型的控释片剂，它是将药物及具高渗透压的渗透促进剂或其它辅料压制成一固体片 芯， 外包一层控速半渗透膜， 然后用激光在片芯包衣膜上开一个或一个以上的释药小孔。 口服后胃肠道中 的水分通过半透膜进入片芯， 使药物溶解成饱和溶液或混悬液， 具有髙渗透压辅料的溶解使得片剂膜内的 溶液为高渗溶液。膜内外存在很大的渗透压差使得水分持续进入膜内， 药物溶液或悬浮液则通过释药小孔 持续泵出。
渗透泵控释片目前在临床应用中主要有两种形式， 一种为多室渗透泵控释片，一种为单室初级渗透泵 控释片。 单室渗透泵控释片一般多应用于水溶性的药物， 片芯仅包含一层药物和具有高渗透压的促渗剂， 包衣膜由高分子聚合物组成， 包裹在片芯的表面， 在包衣膜上有一个或两个释药小孔。 多室渗透泵控释片 适用于制备水溶性或难溶性药物， 其片芯通常为双层片， 含药层由药物、 促渗剂和其他辅料组成， 遇水后 形成药物溶液或药物混悬液； 助推层由无机盐和具有膨胀作用的聚合物组成， 当水分进入片芯助推层后聚 合物吸水膨胀推动含药层的药物溶液或药物混悬液排出片体。与单室渗透泵控释片相比， 双室渗透泵控释 片药物释放更加接近于零级释药， 但是由于双室控释片工艺和处方设计的困难， 目前上市的产品不多。
口服渗透泵制剂可以避免普通口服制剂血药浓度波动大的现象， 减少用药次数和药物的毒副反应， 提 高患者用药的顺应性和安全性；与缓释制剂相比， 口服渗透泵控释制剂释药更加平稳，更加接近零级释放， 且释药行为不受胃肠道可变因素（如胃肠蠕动频率， pH和胃肠排空时间）的影响， 从而减小药物的个体差 异性。
双环醇是由中国医学科学院药物研究所研制的具有自主知识产权的创新药物，用于慢性肝炎所致的氨 基转移酶升高的治疗。双环醇半衰期短， 临床治疗时需每日服药 3次， 对于需要长期服药的慢性乙肝患者 极为不便。 此外， 双环醇口服释药较快， 个体差异较大， 影响临床治疗作用的发挥。
本发明将双环酵制成渗透泵片， 双环醇可以缓慢恒速释出， 达到零级释放要求， 这样就可以减小药物 血药浓度的峰谷比， 减小普通片剂的不良反应； 此外， 双环醇渗透泵控释片药物释药行为不受环境 pH值、 胃肠蠕动和食物等因素的影响， 能够减少个体差异。 双环醇溶解度较低， 影响其吸收利用， 双环醇渗透泵 片缓慢恒速释放的特点可以明显改善双环醇的吸收， 提高双环醇的临床疗效。 发明内容
本发明的目的是提供一种双环醇渗透泵控释片。
本发明的另一个目的是提供一种双环醇双层渗透泵控释片的制备方法。 本发明提供了一种以渗透压为主要释药动力的双环醇双层渗透泵控释片及其制备方法。
本发明的技术方案是以下述方式实现的： 以双环醇为原料药制备双层渗透泵控释片， 片芯含有两层，. . 其中一层为含药层， 由活性药物双环醇与高分子聚合物和 /或粘合剂等其他辅料混合而成； 另外一层为助 推层， 由高分子聚合物、 色素、 粘合剂等其他辅料组成。 双层控释片的片芯由含药层和助推层压片而成， 然后经过包衣给制备的双层片包裹上一层半透膜，通过激光或其他合适的方法在含药层打一个或一个以上 的释药小孔。 本发明得到的双环醇双层渗透泵控释片各个组分的重量百分比为:
双环醇 1 - 40%
片芯含药层中起控释作用的辅料 20 - 70%
片芯助推层中起控释作用的辅料 20 - 70%
其他辅料 余量 本发明所述控释片片芯包括含药层和助推层， 其中含药层中起控释作用的辅料为高分子材料， 根据药 物释药的需求可以加入一种或多种无机盐及其他辅料， 以及它们的混合物。高分子材料优选为聚氧乙烯聚 合物、羟丙甲基纤维素、 聚维酮， 实验表明， 聚氧乙烯聚合物的分子量为 10万到 30万， 聚维酮的分子量 为 30000到 70000时制剂质量更优。 无机盐优选为氯化钠。
助推层中起控释作用的辅料为聚氧乙烯聚合物、 羟丙甲基纤维素、 氯化钠、 聚维酮的一种或多种， 以 及它们的混合物。 实验表明， 适宜的聚氧乙烯聚合物的分子量为 500万到 750万。
为提高物料的可压性， 改善片剂的外观， 达到合适的性能指标， 片芯中除主要辅料以外还可以加入药 学上周知的其他辅料， 包括粘合剂、 润滑剂、 助流剂、 着色剂、 填充剂、 助悬剂、 稳定剂、 增溶剂、 吸收 促进剂、 表面活性剂、 溶剂的一种或多种。 双环醇渗透泵控释片的控释衣膜是由包衣液喷涂到双层片芯上经干燥而成， 包衣液主要由膜材和溶剂 组成， 根据需要还可以加入增塑剂和 /或致孔剂。
适宜的包衣材料包括醋酸纤维素、 乙基纤维素的一种或者它们的混合物。
增塑剂包括： 邻苯二甲酸甲酯、 邻苯二甲酸乙酯、 柠檬酸三乙酯、 聚乙二醇的一种或多种， 以及它们 的混合物。 更优选的聚乙二醇的分子量为 200到 8000, 更优选的聚乙二醇的分子量为 400到 4000。
致孔剂包括： 甘油、 丙二醇、 聚乙二醇、 糖类的一种或多种， 以及它们的混合物； 其中糖类可以采用 庶糖、 葡萄糖等药学上周知的单糖、 二糖以及它们的混合物。
包衣液采用适宜的溶剂配制， 溶剂可以采用丙酮、水、 乙醇、二氯甲垸、 甲醇、 异丙醇的一种或多种， 以及它们的混合物。 为了得到合适的包衣颜色， 或者改善包衣液的附着性能等质量指标， 包衣液中根据需要可以加入药学 上周知的其他辅料， 包括粘合剂、 润滑剂、 着色剂、 遮光剂、 表面活性剂的一种或多种。
本发明得到的双环醇渗透泵控释片， 其药物的释放主要通过不溶性衣膜上的释药小孔释出， 释药小孔 位于含药层的表面， 根据释药速度的需要， 释药小孔可以为一个或几个； 释药小孔可以采用激光打孔或者 其他机械打孔的方法获得， 其中激光打孔的方法是一种成熟的可以实现工业化连续生产的可行的方法。
本发明的双环醇双层渗透控释片的制备方法可以概括成以下步骤：
A.双层片的制备； B.控释膜包衣； C.控释膜打孔。其中双层片的制备可以釆用制粒后压片， 也可以釆 用粉末直接压片， 实验表明， 两种方式均能获得美观、 质量合格的控释片剂。
为了片剂美观及防潮的需要， 控释膜打孔后还可以包防潮衣， 从而最终得到美观、 质量合格的商业化 产品。
本发明将双环醇制成渗透泵片， 当双环醇控释片进入到体内后， 控释片在胃肠道内吸收水分， 一方面 含药层的高聚物吸水后转变为流体状， 与活性药物形成混悬液的形式， 同时助推层的高聚物吸水后体积不 断增加， 推动含药层的药物均匀从释药小孔释放。双环醇控释片的有效成份可以缓 ft恒速释出， 达到零级 释放， 药物释药行为不受环境 pH值、 胃肠蠕动和食物等因素的影响， 体内外相关性好。 双环醇渗透泵片 能够减小药物波峰波谷血药浓度差异， 减小普通片剂的不良反应， 增强难溶性药物双环醇的吸收， 减少个 体差异， 提高双环醇的临床疗效。 具体实施方式 为进一步说明本发明的双环醇双层渗透泵控释片剂及其制备方法所体现的创新性，下面结合具体实施 对本发明作进一步的说明， 但本发明的权利保护并不仅限于实施例所描述的内容。 实施例 1:
含药层
双环醇 75mg
聚氧乙烯 134mg
PVP K30 24mg
氯化钠 5mg
硬脂酸镁 2mg
含药层总重 240mg 助推层
聚氧乙烯 64mg
PVP K30 lOmg 氯化钠 35mg
氧化铁红 0. 6mg
硬脂酸镁 0. 4mg
助推层总重 llOmg 包衣
醋酸纤维素 3. 9g
PEG 4000 0. 2g
95%丙酮 /水 1000ml 制备方法：
1) 含药层的制备：将处方量的双环醇和除硬脂酸镁外其他辅料混合均匀，加入适量的乙醇制粒。在 室温或干燥设备中干燥。
2) 将干燥的主药层过筛， 然后与处方量的硬脂酸镁充分混合。
3) 助推层的制备： 将处方量的聚氧乙烯和除硬脂酸镁外其他辅料混合均匀， 加入适量的乙醇制粒。
在室温或干燥设备中干燥。
4) 将干燥好的助推层过筛， 然后与处方量的硬脂酸镁充分混合。
5) 在双层压片机上用制备好的含药层和助推层按照片重要求压片。
6) 在包衣设备中对制备好的双层片包衣到适当的增重。
7) 对包衣好的双层片干燥以除去剩余的溶剂。
8) 打孔： 对包衣片含药层表面进行激光打孔。
9) 隔离衣包衣： 在制备好的包衣双层片外包裹一层棕红色防潮薄膜衣。 实施例 2:
含药层
双环醇 75mg
聚氧乙烯 139mg
羟丙甲基纤维素 24mg
硬脂酸镁 2mg
含药层总重 240mg 助推层
聚氧乙烯 64mg 羟丙甲基纤维素 10mg
氯化钠 35mg
氧化铁红 0. 6mg
硬脂酸镁 0. 4mg
助推层总重 UOmg 半透膜包衣
醋酸纤维素 95g
PEG 3350 5g
二氯甲烷 /甲醇（2 : 10) 2000ml 制备方法：
) 含药层的制备： 将处方量的双环醇和除硬脂酸镁外其他辅料混合均匀， 加入适量的乙醇制粒。 在室温 或干燥设备中干燥。
) 将干燥的主药层过筛， 然后与处方量的硬脂酸镁充分混合。
) 助推层的制备： 将处方量的聚氧乙烯和除硬脂酸镁外其他辅料 混合均匀， 加入适量的乙醇制粒。
在室温或干燥设备中干燥。
) 将干燥好的助推层过筛， 然后与处方量的硬脂酸镁充分混合。
) 在双层压片机上用制备好的含药层和助推层按照片重要求压片。
) 在包衣设备中对制备好的双层片包衣到适当的增重。
) 对包衣好的双层片干燥以除去剩余的溶剂。
) 打孔： 对包衣片含药层表面进行激光打孔。
) 隔离衣包衣： 在制备好的包衣双层片外包裹一层棕红色防潮薄膜衣。 实施例 3:
含药层
双环醇 165mg
聚氧乙烯 393mg
HPMC 70mg
硬脂酸镁 7mg
含药层总重 635mg 助推层 聚氧乙烯 140mg
羟丙甲基纤维素 20mg
氯化钠 71mg
氧化铁红 1. 5mg
硬脂酸镁 2. 5mg
助推层总重 235mg 半透膜包衣
醋酸纤维素 95g
PEG 5g
二氯甲烧 /甲醇 （2: 10) 2000ml 制备方法：
同实例 2,先制备含药层和助推层然后压制双层片，最后为半透膜包衣、激光打孔和防潮隔离层包衣。 实施例 4:
含药层
双环醇 25mg
聚氧乙烯 45mg
PVP K30 8mg
氯化钠 lmg
硬脂酸镁 lmg
含药层总重 80mg 助推层
聚氧乙烯 30mg
PVP K30 3mg
氯化钠 12mg
氧化铁红 0. 2mg
硬脂酸镁 0. lmg
助推层总重 45. 3mg 半透膜包衣 醋酸纤维素 3. 9g
PEG 0. 2g
95%丙酮 /水 1000ml 制备方法：
同实例 2,先制备含药层和助推层然后压制双层片，最后为半透膜包衣、激光打孔和防潮隔离层包衣。 实施例 5:
含药层
双环醇 75mg
聚氧乙烯 144mg
HPMC 19mg
硬脂酸镁 2mg
含药层总重 240mg 助推层
聚氧乙烯 68mg
HPMC 10mg
氯化钠 31mg
氧化铁红 0. 6mg
硬脂酸镁 0. 4mg
助推层总重 HOmg 半透膜包衣
醋酸纤维素 3. 9g
PEG 4000 0. 2g
95%丙酮 /水 1000ml
制备方法：
) 含药层的制备： 将处方量的双环醉和除硬脂酸镁外其他辅料混合均匀， 然后与处方量的硬脂酸樣充分 混合。
) 助推层的制备： 将处方量的聚氧乙烯和除硬脂酸镁外其他辅料混合均匀， 然后与处方量的硬脂酸镁充 分混合。
) 在双层压片机上用制备好的含药层和助推层按照片重要求压片。 4) 在包衣设备中对制备好的双层片包衣到适当的增重。
5) 对包衣好的双层片干燥以除去剩余的溶剂。
6) 打孔： 对包衣片含药层表面进行激光打孔。
7) 隔离衣包衣： 在制备好的包衣双层片外包裹一层棕红色防潮薄膜衣。 实施例 6动物药代动力学实验 为了验证双环醇渗透泵控释片在动物体内控释释放特性， 对实施例 2制备得到的双环醇渗透泵控释片 进行了 Beagle犬单次和多次口服药代动力学研究。 Beagle犬的药代动力学研究证明了本专利发明的控释 片具有长效控释特征。
试验动物： 雌雄 Beagle犬各三只， 体重 5. 8—6. 6kg。
试验方法： 随机分为 2组， 每组 3只， 采用交叉给药， 两次口服给药之间清洗一周， 并于给药前进行血浆 本底测定。双环醇普通片剂量为 75mg/次 /只， 控释片为 75mg/次 /只， 给药后分别于不同时间点采集血样进 行测定， 并根据血药浓度数据计算药代动力学参数。 表 1 Beagle犬单次口服双环醇控释片和普通片后血桨药代动力学参数 统计矩参数 单位 控释片 普通片
AUC(O-t) mg/L*h 1.19 ±0.59 1.40±0.27
AUC(O-oo) mg/L*h 2.30 ±1.67 1.52±0.32
MRT(O-t) h 9.09 ±3.61 5.54±1.76
MRT(O-oo) h 26.81 ±28.24 7.74±2.68
tl/2z h 16.67 ±21.62 5.91±3.90
Tmax h 6.17 ±4.58 0.31±0.13
Cmax ug/L 157.86 ±45.13 703.21±177.10 附图说明 图 1 Beagle犬单次口服双环醇普通片和按照实施例 2方法制备的控释片的血药浓度-时间曲线
8
替换页 （细则第 26条)

Claims

权 利 要 求 书
1. 一种含有双环醇的双层渗透泵控释制剂， 其特征在于， 含有双环醇和药学可接受的辅料， 其结构包含 含药层和助推层双层片芯， 片芯外包不溶性半透膜， 膜上具有一个或几个释药小孔。
2.如权利要求 1所述的双环醇渗透泵控释片， 含有双环醇的量为 0. lmg到 250mg; 适宜的范围为 25mg到 200mgi 更适宜的范围为 50mg到 150mg。
3.如权利要求 1所述的双环醇渗透泵控释片，其特征在于双层片芯中含药层所用的主要辅料为高分子材料 和 /或无机盐： 高分子材料优选为聚氧乙烯聚合物、 羟丙甲基纤维素、 羟丙基纤维素、 聚维酮的一种或多 种， 更优选的聚氧乙烯聚合物的分子量为 10万到 30万， 聚维酮的分子量为 30000到 70000; 无机盐优选 为氯化钠和氯化钾。
4.如权利要求 1所述的双环醇渗透泵控释片，其特征在于双层片芯中助推层所用的主要辅料为高分子材料 和 /无机盐： 高分子材料优选为聚氧乙烯聚合物、 羟丙甲基纤维素、 羟丙基纤维素、 聚维酮的一种或多种， 高分子材料更优选的聚氧乙烯聚合物的分子量为 500万到 750万； 无机盐优选为氯化钠和氯化鉀。
5.如权利要求 1至 4中任一权利要求所述的双环醇渗透泵控释片，其特征在于片芯中除主要辅料以外根据 需要可以加入药学上周知的其他辅料包括粘合剂、 润滑剂、 助流剂、 着色剂、 填充剂、 助悬剂、 稳定剂、 增溶剂、 吸收促进剂、 表面活性剂、 溶剂的一种或多种。
6.如权利要求 1所述的双环醇渗透泵控释片， 其特征在于片芯外包不溶性控释衣膜， 该控释衣膜由包衣液 喷涂到双层片芯上经干燥而成， 所述的包衣液主要由膜材和溶剂组成， 还包括增塑剂和 /或致孔剂； 所述 的膜材包括： 醋酸纤维素、 乙基纤维素的一种或者它们的混合物； 所述的增塑剂包括： 邻苯二甲酸甲酯、 邻苯二甲酸乙酯、 柠檬酸三乙酯、 聚乙二醇的一种或多种， 以及它们的混合物， 适宜的聚乙二醇的分子量 为 200到 8000， 更加适宜的聚乙二醇的分子量为 400到 4000; 所述的致孔剂包括： 水溶性聚合物如羟丙 甲基纤维素和羟丙基纤维素、甘油、 丙二醇、 聚乙二醇、 糖类的一种或多种， 以及它们的混合物， 适宜的 糖类包括庶糖、葡萄糖等药学上周知的单糖、二糖以及它们的混合物；所述的溶剂包括： 丙酮、水、 乙醇、 二氯甲垸、 甲醇、 异丙醇的一种或多种， 以及它们的混合物。
7.如权利要求 1或 6中任一权利要求所述的双环醇渗透泵控释片，包衣液中根据需要可以加入药学上周知 的其他辅料， 包括粘合剂、 润滑剂、 着色剂、 遮光剂、 表面活性剂的一种或多种。
8.如权利要求 1所述的双环醇渗透泵控释片， 其特征在于不溶性衣膜上具有一个或几个释药小孔， 该释药 小孔位于含药层的表面， 采用激光打孔或者其他机械打孔的方法获得， 最适宜的方法为激光打孔的方法。
9.一种制备权利要求 1所述的双环醇渗透泵控释片的方法， 其特征在于包含双层片的制备、控释膜包衣和 控释膜打孔三个步骤， 其中双层片的制备方法采用制粒后压片或者粉末直接压片法， 控释膜打孔后根据需 要可以包防潮衣。
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