WO2016044976A1 - 一种双层包衣的环孢素a缓释微丸制剂及其制备方法 - Google Patents

一种双层包衣的环孢素a缓释微丸制剂及其制备方法 Download PDF

Info

Publication number
WO2016044976A1
WO2016044976A1 PCT/CN2014/087085 CN2014087085W WO2016044976A1 WO 2016044976 A1 WO2016044976 A1 WO 2016044976A1 CN 2014087085 W CN2014087085 W CN 2014087085W WO 2016044976 A1 WO2016044976 A1 WO 2016044976A1
Authority
WO
WIPO (PCT)
Prior art keywords
sustained
release
cyclosporin
coating
preparation
Prior art date
Application number
PCT/CN2014/087085
Other languages
English (en)
French (fr)
Inventor
徐希明
姜冬梅
余江南
朱源
Original Assignee
江苏大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江苏大学 filed Critical 江苏大学
Priority to CN201480001191.1A priority Critical patent/CN104717963B/zh
Priority to PCT/CN2014/087085 priority patent/WO2016044976A1/zh
Publication of WO2016044976A1 publication Critical patent/WO2016044976A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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

Definitions

  • the invention relates to a poorly soluble pharmaceutical oral sustained-release pellet preparation and a preparation method thereof, in particular to an oral cyclosporin A sustained-release pellet preparation and a preparation method thereof.
  • CsA cyclosporine A
  • cyclosporin A the main dosage forms of commercially available cyclosporin A include injections, oral liquids, and soft capsules. Due to the poor water solubility of the drug, a large amount of solubilizing agent, Cremophor EL, has been added to the clinically used cyclosporin A injection, which is easy to cause cholestasis, allergic reaction, liver and kidney toxicity.
  • cyclosporin A has a regular cyclic structure with a large molecular weight, so that its water solubility and intestinal permeability are poor; 2) P-glycoprotein (P-gp) is present on the cell membrane, which can pump cyclosporine A out of the cell in an energy-dependent manner; (3) the first-pass effect of the liver. Therefore, increasing the solubility and bioavailability of cyclosporin A has become a hot spot in cyclosporin A research.
  • the invention adopts the sustained-release pellet technology to achieve the purpose of "double release” of sustained release and sustained release, and prepares the poorly soluble drug cyclosporine A sustained-release pellet.
  • the preparation process is simple and convenient for industrial production.
  • the results of in vitro and in vivo experiments showed that the sustained release effect of cyclosporin A sustained-release pellets was obvious.
  • the invention adopts the method of double-layer coating of the pill, and prepares a cyclosporin A sustained-release pellet which is convenient for industrialization and has a sustained release effect.
  • a cyclosporin A sustained-release pellet preparation which is characterized in that it is obtained by coating two layers of blank pill, the inner layer coating is an immediate release layer, the outer layer coating is a sustained release layer, and the immediate release layer is coated.
  • the coating liquid is dissolved in ethanol by mass parts of cyclosporine A, polyvinylpyrrolidone K300.67-3 parts, poloxamer 1880.067-1 parts, polyethylene glycol 4000.1-1 parts and fine powder silica gel 0.18-1 parts.
  • Solution composition the sustained-release layer coating liquid is dissolved in 1 part by mass of ethyl cellulose, 0-0.2 parts of diethyl phthalate, 40000.1-0.3 parts of polyethylene glycol and 0.12-1 parts of silica gel of micro-powder. Composition of ethanol solution.
  • cyclosporin A sustained-release pellet preparation described above, wherein the blank peptide is a blank sugar pellet or a blank microcrystalline cellulose pellet.
  • the above cyclosporin A sustained-release pellet preparation, the poloxamer 188 can be replaced by Tween 80.
  • the cyclosporin A sustained-release pellet preparation described above may be replaced by talc.
  • the ethyl cellulose may be replaced by cellulose acetate.
  • the above oral cyclosporin A sustained release pellet preparation which may be a capsule.
  • FIG. 1 A method for preparing the above oral cyclosporin A sustained-release pellet preparation, and the process flow thereof is shown in FIG. Includes the following steps:
  • Step 1 weigh 80g-150g blank pill, placed in Mini250 extrusion spheronization fluidizing coating machine, preheating for 30min;
  • Step 2 preparing the immediate release layer coating liquid according to the above prescription amount, magnetically stirring until uniform, and coating the blanking pill 100-300ml immediate release layer coating liquid, the coating parameters are: spheron rotation speed 400-1000 rpm, material temperature 30 -35 ° C, taken out after the package, dried at 50 ° C for 2 h, that is, cyclosporin A immediate release pellets;
  • Step 3 Prepare the sustained-release layer coating solution according to the above prescription amount, stir it magnetically until uniform, and apply the cyclosporin A immediate release pellet prepared in step 2 to coat 100-300 ml sustained-release layer coating solution.
  • the coating parameters are: The spheronization speed is 400-1000 rpm, the material temperature is 30-35 ° C, the coating is taken out, and dried at 50 ° C for 2 h to obtain an oral cyclosporin A sustained-release pellet preparation.
  • the invention adopts the sustained-release pellet technology to prepare the poorly-dissolving drug cyclosporine A sustained-release pellets, and achieves the purpose of “double release medicine” for immediate release and sustained release.
  • the in vitro release curve of cyclosporin A immediate release pellets is shown in Fig. 2. It can be seen from Fig. 2 that within 60 min, the release of cyclosporin A immediate release pellets reached 90% in vitro, which is significantly higher than that of the drug substance;
  • In vitro release curve of cyclosporine A sustained-release pellets as shown in Figure 3, the cumulative release rates of cyclosporine A at 2, 6, 12, and 24 h were 12%, 45%, 83%, and 93%, respectively. Slow release characteristics.
  • the cyclosporin A sustained-release pellets prepared by the invention have a lower peak-to-valley phenomenon of blood drug concentration and a higher compliance with the patient than the control preparation.
  • the cyclosporine A sustained-release pellets and the control preparation were orally administered in dogs, and the drug-time curve was determined, as shown in Fig. 4, and the pharmacokinetic parameters are shown in Table 1. The results showed that C max was significantly decreased, T max , t 1/2 and MRT were significantly prolonged, and the sustained release effect was obvious.
  • the preparation method adopted by the invention is simple, no special equipment is needed, the auxiliary materials are easy to obtain, the price is cheap, the influencing factors in the preparation process are few, the reproducibility is good, and the industrial production is easy.
  • FIG. 1 is a block diagram showing the process of preparing a cyclosporin A sustained-release pellet according to the present invention
  • FIG. 2 is a graph showing the in vitro release profile of cyclosporin A immediate release pellets prepared by the present invention
  • Figure 3 is a graph showing the in vitro release profile of the cyclosporin A sustained-release pellets prepared by the present invention
  • Figure 4 is a graph showing the time of oral administration of cyclosporine A sustained-release pellets and control preparations
  • cyclosporine A (Fujian Kerui Pharmaceutical Co., Ltd.); polyvinylpyrrolidone k30 (Shanghai Changwei Pharmaceutical Materials Co., Ltd.); polyethylene glycol 400, polyethylene glycol 4000, diethyl phthalate Ester, Tween 80 (Zhongguo Group Chemical Reagent Co., Ltd.); ethyl cellulose (Shanghai Kalakang Coating Technology Co., Ltd.); anhydrous ethanol (Chengdu Kelon Reagent Chemical Plant); Polosham 188 (BASF China Co., Ltd.; micro-silica gel (Guangzhou Hongyuan Food Additive Co., Ltd.); blank sugar pill, blank microcrystalline cellulose pill (Hangzhou Chengyuan Biotechnology Co., Ltd.); talcum powder (Anhui Ante Biochemical Co., Ltd.); acetic acid Cellulose (Shanghai Hercept Chemical Co., Ltd.).
  • cyclosporine A4g Polyvinylpyrrolidone k304g, polyethylene glycol 4000.8g, poloxamer 1880.8g, micronized silica gel 1g, magnetically stir and dissolve with 100ml 40% (v/v, the same below) ethanol solution, and package After the coating is completed, the coating is taken out and dried at 50 ° C for 2 hours to obtain a cyclosporin A immediate release pellet.
  • the cyclosporin A immediate release pellet was subjected to in vitro drug release test, and the results are shown in Fig. 2.
  • cyclosporine A6g Polyvinylpyrrolidone k304g, polyethylene glycol 4001.2g, poloxamer 1880.9g, fine powder silica gel 1.5g, magnetically dissolved with 100ml of 60% ethanol aqueous solution, and coated. After the coating is completed, it is taken out and dried at 50 ° C for 2 hours to obtain cyclosporin A immediate release pellets.
  • the cyclosporin A immediate release pellet was subjected to in vitro drug release test, and the results are shown in Fig. 2.
  • cyclosporin A10g Polyvinylpyrrolidone k3010g, polyethylene glycol 4001g, Tween 801.8g, talc powder 3g, magnetically stir and dissolve with 200ml of 60% ethanol aqueous solution, coat, remove after coating, dry at 50 °C 2h, the cyclosporin A immediate release pellets were obtained.
  • the cyclosporin A immediate release pellet was subjected to in vitro drug release test, and the results are shown in Fig. 2.
  • cyclosporin A8g Polyvinylpyrrolidone k3016g, polyethylene glycol 4001.8g, poloxamer 1882.8g, micronized silica gel 2g, dissolved in 180ml of 65% ethanol aqueous solution magnetically, coated, after the coating was completed, After drying at 50 ° C for 2 h, cyclosporin A immediate release pellets were obtained.
  • the cyclosporin A immediate release pellet was subjected to in vitro drug release test, and the results are shown in Fig. 2.
  • cyclosporin A4g Polyvinylpyrrolidone k3012g, polyethylene glycol 4002.5g, poloxamer 1883.8g, micronized silica gel 4g, magnetically stir and dissolve with 250ml 35% ethanol aqueous solution, coat, remove after coating After drying at 50 ° C for 2 h, cyclosporin A immediate release pellets were obtained. The cyclosporin A immediate release pellet was subjected to in vitro drug release test, and the results are shown in Fig. 2.
  • cyclosporin A12g Polyvinylpyrrolidone k3012g, polyethylene glycol 4001.2g, poloxamer 1880.8g, micronized silica gel 2.5g, magnetically stir and dissolve with 150ml 55% ethanol aqueous solution, coat, take out after coating After drying at 50 ° C for 2 h, cyclosporin A immediate release pellets were obtained. The cyclosporin A immediate release pellet was subjected to in vitro drug release test, and the results are shown in Fig. 2.
  • cyclosporin A6g weighed cyclosporine A6g, polyvinylpyrrolidone k309g, polyethylene glycol 4006g, poloxamer 1886g, micronized silica gel 2.5g, magnetically dissolved with 300ml of 60% ethanol aqueous solution, coated, coated and removed, 50 After drying at °C for 2 h, cyclosporin A immediate release pellets were obtained. The cyclosporin A immediate release pellet was subjected to in vitro drug release test, and the results are shown in Fig. 2.
  • cyclosporin A8g Polyvinylpyrrolidone k309g, polyethylene glycol 4004g, poloxamer 1883g, fine powder silica gel 1.5g, dissolved in 300ml of 60% ethanol water magnetically, coated, after the coating was completed, 50 After drying at °C for 2 h, cyclosporin A immediate release pellets were obtained. The cyclosporin A immediate release pellet was subjected to in vitro drug release test, and the results are shown in Fig. 2.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

一种环孢素A缓释微丸制剂，由空白素丸经两层包衣而得。速释层包衣液由环孢素A1份、聚乙烯吡咯烷酮（PVP）K30 0.67-3份、泊洛沙姆188 0.067-1份、聚乙二醇（PEG）400 0.1-1份、微粉硅胶0.18-1份，溶解于乙醇溶液；缓释层包衣液由乙基纤维素1份、邻苯二甲酸二乙酯0-0.2份、聚乙二醇4000 0.1-0.3份、微粉硅胶0.12-1份，溶解于乙醇组成。所述缓释微丸制剂以空白素丸为丸芯，将速释包衣与缓释包衣技术相结合，按照先速释后缓释的"双释药"原理，制备难溶性药物环孢素A缓释微丸，实现了缓释制剂口服先快速起效，再平稳缓慢释药的目的，并提供了该缓释微丸制剂的制备方法。

Description

一种双层包衣的环孢素A缓释微丸制剂及其制备方法 技术领域
本发明涉及一种难溶性药物口服缓释微丸制剂及其制备方法，特别涉及口服环孢素A缓释微丸制剂及其制备方法。
背景技术
第三代高效免疫抑制剂环孢素A(Cyclosporine A,CsA)是一种从丝状真菌培养液中分离出的的环肽。它是一种强效免疫抑制剂，已被广泛用于肾脏，肝脏，心脏，肺，胰腺等器官的移植以及自身免疫性疾病的治疗。
目前，市售的环孢素A的主要剂型包括注射剂、口服液和软胶囊剂。由于该药水溶性差，所以目前临床使用的环孢素A注射剂中加入了大量增溶剂——聚氧乙烯蓖麻油(Cremophor EL)，此辅料易导致胆汁淤积，过敏反应，肝肾毒性等。且口服环孢素A生物利用度是很低的，这主要由于以下原因：(1)环孢素A具有规则环状结构，分子量很大，以致其水溶性和肠道渗透性很差；(2)细胞膜上存在P-糖蛋白(P-glycoprotein,P-gp)，它能够能量依赖性地将环孢素A泵出细胞外；(3)肝的首过效应。因此，提高环孢素A的溶解度和生物利用度已成为环孢素A研究的热点。
国内外比较常用的增加难溶性药物溶解度的方法主要有三种：一是将难溶性药物微粉化；二是合成水溶性前体药物，三是将难溶性药物制备成水溶性的制剂。
目前，关于研究环孢素A的讨论很多，国内外专家提出了各种假想。(参见M.Rodriguez-Aller,B.Kaufmann,D.Guillarme,etal.In vivo characterisation of a novel water-soluble Cyclosporine A prodrug for the treatment of dry eye disease[J].European Journal of Pharmaceutics and Biopharmaceutics,2012(80):544–552.K.Mondon,M.Zeisser-Labouèbe,R.Gurny,M.Moller.Novel Cyclosporin A formulations using MPEG–hexyl-substituted polylactide micelles:A suitability study[J].European Journal of Pharmaceutics and Biopharmaceutics,2011(77):56–65.杨志强,许洁,潘萍,等.环孢素A-pH敏感性纳米粒的制备工艺和体外释药特性[J].中国新药杂志,2008,17(20):1783-1786.)这些方法都增加了环孢素A的溶解度或是提高了环孢素A的体内相对生物利用度。但是，他们几乎都不太适合工 业化生产。
近几年缓释微丸技术发展迅速，工艺成熟，操作简单。(参见徐希明，余江南，朱源，张正艮.盐酸坦索罗辛缓释微丸制剂及其制备方法[P].中国发明专利，CN200910233724.X.2010-4-21；朱家壁，杨燕，陈盛君.含硝苯地平和阿替洛尔的复方缓释微丸片及其制备方法[P].中国发明专利，CN200810025409.3.2008-9-10；何仲贵，孙英华，王永军，孙进.苦参素或苦参碱缓释微丸及其制备方法[P].中国发明专利，CN200710158669.3.2008-5-14.)上述方法显示，缓释微丸技术应用非常广泛。
本发明采用缓释微丸技术，达到了先速释后缓释的“双释药”目的，制备了难溶性药物环孢素A缓释微丸。制备操作简单，便于工业化生产。体内外实验结果显示，环孢素A缓释微丸缓释效果明显。
发明内容
本发明采用素丸双层包衣的方法，制备了一种便于工业化、缓释效果明显的环孢素A缓释微丸。
本发明的技术方案如下：
一种环孢素A缓释微丸制剂，其特征是它由空白素丸经两层包衣而得，内层包衣为速释层、外层包衣为缓释层，速释层包衣液由质量份环孢素A 1份、聚乙烯吡咯烷酮K300.67-3份、泊洛沙姆1880.067-1份、聚乙二醇4000.1-1份和微粉硅胶0.18-1份，溶解于乙醇溶液组成；缓释层包衣液由质量份乙基纤维素1份、邻苯二甲酸二乙酯0-0.2份、、聚乙二醇40000.1-0.3份和微粉硅胶0.12-1份，溶解于乙醇溶液组成。
上述的环孢素A缓释微丸制剂，所述的空白素丸为空白糖丸或空白微晶纤维素丸。
上述的环孢素A缓释微丸制剂，所述的泊洛沙姆188可用吐温80代替。
上述的环孢素A缓释微丸制剂，所述的微粉硅胶可用滑石粉代替。
上述的环孢素A缓释微丸制剂，所述的乙基纤维素可用醋酸纤维素代替。
上述的口服环孢素A缓释微丸制剂，它可以为胶囊剂。
一种制备上述的口服环孢素A缓释微丸制剂的方法，其工艺流程见图1，它 包括下列步骤：
步骤1、称取80g-150g空白素丸，置于Mini250挤出滚圆流化包衣机中，预热30min；
步骤2、按上述处方量配制速释层包衣液，磁力搅拌至均匀，将空白素丸包衣100-300ml速释层包衣液，包衣参数为：滚圆转速400-1000rpm，物料温度30-35℃，包以后取出，50℃干燥2h，即得环孢素A速释微丸；
步骤3、按上述处方量配制缓释层包衣液，磁力搅拌至均匀，将步骤2制备的环孢素A速释微丸包衣100-300ml缓释层包衣液，包衣参数为：滚圆转速400-1000rpm，物料温度30-35℃，包衣后取出，50℃干燥2h，即得口服环孢素A缓释微丸制剂。
有益效果
1、本发明采用缓释微丸技术，制备了难溶性药物环孢素A缓释微丸，达到了先速释后缓释的“双释药”目的。环孢素A速释微丸体外释药曲线见图2，由图2看出，60min内，环孢素A速释微丸体外释放就达到了90％，明显高于原料药；图3为环孢素A缓释微丸体外释药曲线，由图3看出，2、6、12、24h环孢素A累积释放率分别为12％、45％、83％、93％，具有明显的缓释特征。
2、本发明所制环孢素A缓释微丸相对对照制剂，减少了血药浓度峰谷现象，提高了病人用药顺应性。环孢素A缓释微丸及对照制剂经犬口服给药，测定药时曲线，见图4，药动学参数见表1。结果表明Cmax明显降低，Tmax、t1/2、MRT明显延长，缓释效果明显。
3、本发明所采用的制备方法简单，不需要特殊设备，辅料易得，价格便宜，制备过程影响因素少，重现性好，易于工业化生产。
附图说明
图1为本发明制备环孢素A缓释微丸的工艺流程方框图；
图2为本发明制备的环孢素A速释微丸体外释药曲线图；
图3为本发明制备的环孢素A缓释微丸体外释药曲线图；
图4为环孢素A缓释微丸及对照制剂犬口服给药的药时曲线图；
具体实施方式
以下所列实施例有助于本领域技术人员更好地理解本发明，但不以任何方式限制本发明。
以下实施例所用材料和仪器设备为：
实验材料：环孢素A(福建科瑞药业有限公司)；聚乙烯吡咯烷酮k30(上海昌为药用材料有限公司)；聚乙二醇400、聚乙二醇4000、邻苯二甲酸二乙酯、吐温80(国药集团化学试剂有限公司)；乙基纤维素(上海卡乐康包衣技术有限公司)；无水乙醇(成都市科龙试剂化工厂)；泊洛沙姆188(巴斯夫中国有限公司)；微粉硅胶(广州鸿源食品添加剂有限公司)；空白糖丸、空白微晶纤维素丸(杭州诚缘生物科技有限公司)；滑石粉(安徽安特生物化学有限公司)；醋酸纤维素(上海赫力思特化工有限公司)。
实验仪器：Mini250挤出滚圆流化包衣机(深圳信宜特制药设备有限公司)；5Q50-1J型蠕动泵(保定兰格恒流泵有限公司)；ZRS-8G智能溶出仪(天津天大天发有限公司)。
实施例1
称取空白糖丸80g，置于Mini250挤出滚圆流化包衣机中，预热30min。
分别称取环孢素A4g，聚乙烯吡咯烷酮k304g，聚乙二醇4000.8g，泊洛沙姆1880.8g，微粉硅胶1g，用100ml40％(v/v,下同)乙醇水溶液磁力搅拌溶解，进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A速释微丸。将该环孢素A速释微丸进行体外释药测试，结果见图2。
分别称取乙基纤维素3g，邻苯二甲酸二乙酯0.6g、聚乙二醇40000.9g，微粉硅胶3g，用150ml60％乙醇水溶液磁力搅拌溶解，取上述制备的环孢素A速释微丸进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A缓释微丸。将该环孢素A缓释微丸进行体外释药测试，结果见图3。
实施例2
称取空白糖丸90g，置于Mini250挤出滚圆流化包衣机中，预热30min。
分别称取环孢素A6g，聚乙烯吡咯烷酮k304g，聚乙二醇4001.2g，泊洛沙姆1880.9g，微粉硅胶1.5g，用100ml60％乙醇水溶液磁力搅拌溶解，进行包衣， 包衣完成后取出，50℃干燥2h，即得环孢素A速释微丸。将该环孢素A速释微丸进行体外释药测试，结果如图2。
分别称取乙基纤维素8g，邻苯二甲酸二乙酯0.8g，聚乙二醇40000.8g，微粉硅胶3g，用200ml40％乙醇水溶液磁力搅拌溶解，取上述制备的环孢素A速释微丸进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A缓释微丸。将该环孢素A缓释微丸进行体外释药测试，结果如图3。
实施例3
称取空白微晶纤维素丸100g，置于Mini250挤出滚圆流化包衣机中，预热30min。
分别称取环孢素A10g，聚乙烯吡咯烷酮k3010g，聚乙二醇4001g，吐温801.8g，滑石粉3g，用200ml60％乙醇水溶液磁力搅拌溶解，进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A速释微丸。将该环孢素A速释微丸进行体外释药测试，结果如图2。
分别称取醋酸纤维素5g，聚乙二醇40001g，微粉硅胶2g，用250ml无水乙醇磁力搅拌溶解，取上述制备的环孢素A速释微丸进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A缓释微丸。将该环孢素A缓释微丸进行体外释药测试，结果如图3。
实施例4
称取空白糖丸110g，置于Mini250挤出滚圆流化包衣机中，预热30min。
分别称取环孢素A8g，聚乙烯吡咯烷酮k3016g，聚乙二醇4001.8g，泊洛沙姆1882.8g，微粉硅胶2g，用180ml65％乙醇水溶液磁力搅拌溶解，进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A速释微丸。将该环孢素A速释微丸进行体外释药测试，结果如图2。
分别称取乙基纤维素6g，邻苯二甲酸二乙酯0.6g，聚乙二醇40001.8g，微粉硅胶2g，用150ml85％乙醇水溶液磁力搅拌溶解，取上述制备的环孢素A速释微丸进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A缓释微丸。将该环孢素A缓释微丸进行体外释药测试，结果如图3。
实施例5
称取空白糖丸120g，置于Mini250挤出滚圆流化包衣机中，预热30min。
分别称取环孢素A4g，聚乙烯吡咯烷酮k3012g，聚乙二醇4002.5g，泊洛沙姆1883.8g，微粉硅胶4g，用250ml35％乙醇水溶液磁力搅拌溶解，进行包衣，包衣完成后取出，50℃干燥2h，既得环孢素A速释微丸。将该环孢素A速释微丸进行体外释药测试，结果如图2。
分别称取乙基纤维素6g，邻苯二甲酸二乙酯0.3g，聚乙二醇40001.5g，微粉硅胶4g，用100ml90％乙醇水溶液磁力搅拌溶解，取上述制备的环孢素A速释微丸进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A缓释微丸。将该环孢素A缓释微丸进行体外释药测试，结果如图3。
实施例6
称取空白糖丸130g，置于Mini250挤出滚圆流化包衣机中，预热30min。
分别称取环孢素A12g，聚乙烯吡咯烷酮k3012g，聚乙二醇4001.2g，泊洛沙姆1880.8g，微粉硅胶2.5g，用150ml55％乙醇水溶液磁力搅拌溶解，进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A速释微丸。将该环孢素A速释微丸进行体外释药测试，结果如图2。
分别称取乙基纤维素5g，聚乙二醇40000.5g，微粉硅胶2g，用150ml80％乙醇水溶液磁力搅拌溶解，取上述制备的环孢素A速释微丸进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A缓释微丸。将该环孢素A缓释微丸进行体外释药测试，结果如图3。
实施例7
称取空白糖丸140g，置于Mini250挤出滚圆流化包衣机中，预热30min。
分别称取环孢素A6g，聚乙烯吡咯烷酮k309g，聚乙二醇4006g，泊洛沙姆1886g，微粉硅胶2.5g，用300ml60％乙醇水溶液磁力搅拌溶解，进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A速释微丸。将该环孢素A速释微丸进行体外释药测试，结果如图2。
分别称取乙基纤维素6g，邻苯二甲酸二乙酯0.9g，聚乙二醇40000.9g，微 粉硅胶3g，用150ml90％乙醇水溶液磁力搅拌溶解，取上述制备的环孢素A速释微丸进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A缓释微丸。将该环孢素A缓释微丸进行体外释药测试，结果如图3。
实施例8
称取空白糖丸150g，置于Mini250挤出滚圆流化包衣机中，预热30min。
分别称取环孢素A8g，聚乙烯吡咯烷酮k309g，聚乙二醇4004g，泊洛沙姆1883g，微粉硅胶1.5g，用300ml60％乙醇水磁力搅拌溶解，进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A速释微丸。将该环孢素A速释微丸进行体外释药测试，结果如图2。
分别称取乙基纤维素8g，邻苯二甲酸二乙酯1.6g，聚乙二醇40000.8g，微粉硅胶1g，用150ml95％乙醇水磁力搅拌溶解，取上述制备的环孢素A速释微丸进行包衣，包衣完成后取出，50℃干燥2h，即得环孢素A缓释微丸。将该环孢素A缓释微丸进行体外释药测试，结果如图3。
实施例9环孢素A缓释微丸体内药动学实验
1.1动物给药与血样处理
将6只成年雄性Beagle犬，体重13±1kg(南京亚东实验动物研究中心提供)随机分成两组，禁食12小时后，分别交叉单剂量口服相当于75mgCsA的新山地明、自制缓释微丸胶囊(采用实施例3所制得的微丸)。给药后分别于0.5、l、2、3、4、6、8、10、12、24h前肢静脉取血3mL。精密吸取全血样品1mL置于10mL具塞离心管中，加入10μg·mL-1内标(环孢素D)100μL，加入0.1mol·L-1氢氧化钠2mL，涡旋振荡2min，再加入农残级乙醚4mL，涡旋振荡5min，3000rpm离心15min，移取上层乙醚层至10mL离心试管中，40℃恒温水浴下N2吹干。加入500μL正己烷，200μL酸化甲醇溶液(甲醇：0.1mol·L-1盐酸＝3:1)，涡旋30s，3000rpm离心10min，取下清液用HPLC法测定药物浓度。
1.2药时曲线与相对生物利用度
环孢素A缓释微丸及对照制剂犬口服给药的药时曲线见图4。血药浓度数据经BAPP软件(中国药科大学药代中心提供)拟合药动学参数，参数数据均以Mean±SD表示，结果见表1。相对生物利用度F＝(AUCT/AUCR)x100％。从结 果可以看出，环孢素A缓释微丸的Tmax、t1/2、MRT、AUC均高于新山地明，说明环孢素A缓释微丸口服给药后的药物体内滞留时间增加，生物利用度提高，相对口服生物利用度为130.12％。
表1环孢素A缓释微丸及对照制剂犬口服给药后的药动学参数
Figure PCTCN2014087085-appb-000001

Claims (7)

  1. 一种环孢素A缓释微丸制剂，其特征是：它由空白素丸经两层包衣而得，内层包衣为速释层、外层包衣为缓释层，速释层包衣液由质量份环孢素A1份、聚乙烯吡咯烷酮K300.67-3份、泊洛沙姆1880.067-1份、聚乙二醇4000.1-1份和微粉硅胶0.18-1份，溶解于乙醇溶液组成；缓释层包衣液由质量份乙基纤维素1份、邻苯二甲酸二乙酯0-0.2份、、聚乙二醇40000.1-0.3份和微粉硅胶0.12-1份，溶解于乙醇溶液组成。
  2. 根据权利要求1所述的环孢素A缓释微丸制剂，其特征是：所述的空白素丸为空白糖丸或空白微晶纤维素丸。
  3. 根据权利要求1所述的环孢素A缓释微丸制剂，其特征是：所述的泊洛沙姆188以吐温80代替。
  4. 根据权利要求1所述的环孢素A缓释微丸制剂，其特征是：所述的微粉硅胶以滑石粉代替。
  5. 根据权利要求1所述的环孢素A缓释微丸制剂，其特征是：所述的乙基纤维素以醋酸纤维素代替。
  6. 根据权利要求1所述的环孢素A缓释微丸制剂，其特征是：它为胶囊剂。
  7. 一种制备权利要求1所述的环孢素A缓释微丸制剂的方法，其特征是它包括下列步骤：
    步骤1、称取80g-150g空白素丸，置于Mini250挤出滚圆流化包衣机中，预热30min；
    步骤2、按权利要求1所述处方量配制速释层包衣液，磁力搅拌至均匀，将空白素丸包衣100-300ml速释层包衣液，包衣参数为：滚圆转速400-1000rpm，物料温度30-35℃,包以后取出，50℃干燥2h，即得环孢素A速释微丸；
    步骤3、，按权利要求1所述处方量配制缓释层包衣液，磁力搅拌至均匀，将步骤2制备的环孢素A速释微丸包衣100-300ml缓释层包衣液，包衣参数为：滚圆转速400-1000rpm，物料温度30-35℃,包衣后取出，50℃干燥2h，即得口服环孢素A缓释微丸制剂。
PCT/CN2014/087085 2014-09-22 2014-09-22 一种双层包衣的环孢素a缓释微丸制剂及其制备方法 WO2016044976A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201480001191.1A CN104717963B (zh) 2014-09-22 2014-09-22 一种双层包衣的环孢素a缓释微丸制剂及其制备方法
PCT/CN2014/087085 WO2016044976A1 (zh) 2014-09-22 2014-09-22 一种双层包衣的环孢素a缓释微丸制剂及其制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2014/087085 WO2016044976A1 (zh) 2014-09-22 2014-09-22 一种双层包衣的环孢素a缓释微丸制剂及其制备方法

Publications (1)

Publication Number Publication Date
WO2016044976A1 true WO2016044976A1 (zh) 2016-03-31

Family

ID=53416686

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/087085 WO2016044976A1 (zh) 2014-09-22 2014-09-22 一种双层包衣的环孢素a缓释微丸制剂及其制备方法

Country Status (2)

Country Link
CN (1) CN104717963B (zh)
WO (1) WO2016044976A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113081970A (zh) * 2021-05-07 2021-07-09 聊城大学 一种环孢素固体分散体及其片剂制备方法
CN115039742A (zh) * 2022-05-24 2022-09-13 江苏宁录科技股份有限公司 一种草地贪夜蛾性信息素双重缓释诱芯及其制备方法
CN115645376A (zh) * 2022-10-26 2023-01-31 山东德州神牛药业有限公司 一种替米考星高效双层包衣微丸及其制备方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111346067B (zh) * 2020-03-11 2022-05-17 广东科泰鼎润药业科技有限公司 胍法辛的控释制剂及其制备方法
CN115590840A (zh) * 2022-09-14 2023-01-13 浙江中医药大学（Cn） 一种时空递释中药多组分组合微丸及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1625391A (zh) * 2002-02-01 2005-06-08 株式会社太平洋 包含环胞菌素的缓释药物组合物
WO2006110802A1 (en) * 2005-04-12 2006-10-19 Elan Pharma International Limited Nanoparticulate and controlled release compositions comprising cyclosporine
CN102166201A (zh) * 2011-04-25 2011-08-31 江苏大学 口服环孢素a缓释制剂及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1625391A (zh) * 2002-02-01 2005-06-08 株式会社太平洋 包含环胞菌素的缓释药物组合物
WO2006110802A1 (en) * 2005-04-12 2006-10-19 Elan Pharma International Limited Nanoparticulate and controlled release compositions comprising cyclosporine
CN102166201A (zh) * 2011-04-25 2011-08-31 江苏大学 口服环孢素a缓释制剂及其制备方法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113081970A (zh) * 2021-05-07 2021-07-09 聊城大学 一种环孢素固体分散体及其片剂制备方法
CN115039742A (zh) * 2022-05-24 2022-09-13 江苏宁录科技股份有限公司 一种草地贪夜蛾性信息素双重缓释诱芯及其制备方法
CN115039742B (zh) * 2022-05-24 2023-08-29 江苏宁录科技股份有限公司 一种草地贪夜蛾性信息素双重缓释诱芯及其制备方法
CN115645376A (zh) * 2022-10-26 2023-01-31 山东德州神牛药业有限公司 一种替米考星高效双层包衣微丸及其制备方法
CN115645376B (zh) * 2022-10-26 2023-10-31 山东德州神牛药业有限公司 一种替米考星高效双层包衣微丸及其制备方法

Also Published As

Publication number Publication date
CN104717963B (zh) 2016-12-14
CN104717963A (zh) 2015-06-17

Similar Documents

Publication Publication Date Title
WO2016044976A1 (zh) 一种双层包衣的环孢素a缓释微丸制剂及其制备方法
Li et al. Novel gelatin microcapsule with bioavailability enhancement of ibuprofen using spray-drying technique
CN106420633B (zh) 固体分散体及其制备方法和应用
Cao et al. Enhanced oral bioavailability of novel mucoadhesive pellets containing valsartan prepared by a dry powder-coating technique
CA3068609A1 (en) Compositions and methods for treatment of cystic fibrosis
JP2017500332A (ja) 経口医薬組成物
KR20040099298A (ko) ３－［（２－｛［４－（헥실옥시카보닐아미노－이미노-메틸）－페닐아미노］－메틸｝－１－메틸－１ｈ－벤즈이미다졸－５－카보닐）－피리딘－２－일－아미노］ 프로피온산 에틸에스테르의 경구 투여 형태
JP2011515444A (ja) 固体分散体の調製方法
WO2016038532A1 (en) Amorphous treprostinil diethanolamine
CN104414978A (zh) 一种含有埃索美拉唑镁的肠溶微丸
JP2003534296A (ja) 溶出性の改善されたプランルカスト固体分散系及びその製造方法
CN104069071B (zh) 一种双层包衣的水飞蓟宾缓释微丸及其制备方法
CN104224732B (zh) 一种口服骨架型环孢素a缓释微丸制剂及其制备方法
Lian-Dong et al. Preparation of rosiglitazone maleate sustained-release floating microspheres for improved bioavailability
Tripathy et al. Solid dispersion: A technology for improving aqueous solubility of drug
CN111467344A (zh) 一种拉西地平固体分散体及其制备方法
CN102552163B (zh) 一种酒石酸美托洛尔缓释微丸及其制备方法
CN108186590A (zh) 石杉碱甲缓释口崩片及其制备方法
US10675276B2 (en) Dosing preparation of dabigatran etexilate or a salt thereof and a preparation method thereof
CN103948558B (zh) 一种泊沙康唑双层渗透泵控释片及其制备方法
CN106806353A (zh) 艾拉莫德缓释胶囊及其制备方法
CN104248636A (zh) 一种西罗莫司制剂及其制备方法
CN102727446B (zh) 含难溶性药物的固体制剂及其制备方法
CN115212174B (zh) 一种载阿立哌唑长效缓释微球及其制备方法
CN106727317B (zh) 一种固体西罗莫司自微乳制剂及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14902669

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14902669

Country of ref document: EP

Kind code of ref document: A1