摘要
熔融高速搅拌法制备缓释微丸以其特有的工艺特点，近年来越来越多地受到人们的关注，是制备缓释微丸有效的生产方法之一。在最简单的形式中，起始物料在混合器中混合，随着过程的继续，由于摩擦产生的热而使温度升高，粘合剂融化作为液体粘合剂。通过进一步地混合碰撞，颗粒结聚，最终形成微丸。关于熔融高速搅拌法制备微丸已有文献报道，为了给生产提供依据、提高药物制剂的生产水平，本文以自制的高速搅拌制粒机对模型药物的微丸制备工艺及其对产品质量的影响进行了较为全面的考察和研究。
本实验在参照了有关资料的基础上，自制了适用于实验室研究及小批量生产的高速搅拌制粒机，本装置操作方便，易于控制，容易清洗。本次实验的目的是进行盐酸普萘洛尔复方制剂的研究。由于各种条件的限制，最终只形成了普萘洛尔缓释微丸，氢氯噻嗪制成了普通片而不是微丸。
不同药物由于粉体性质如结晶形状、流动性、粘结能力等的不同，往往不同药物用同一处方或制丸工艺不同时，成丸效果不同。而组成微丸的辅料种类、数量和性质不同会极大地影响微丸的成型及微丸的质量。针对模型药物的性质，选择了硫酸钙为稀释剂，氢化蓖麻油为粘合剂。
此次工艺的进行分为三个阶段。第一阶段：采用高速搅拌制粒机制备了普萘洛尔空白丸心。对其制备工艺及影响因素(粘合剂的种类、转桨速度、载药量、混合时间等)进行了考察，并进行了优化，选出了较佳的工艺参数。投料量为100g，其中粘合剂是硫酸钙量的26％，温度为87℃，转速为350rpm，制备时间为6min，制备
沈阳药科大学硕士学位论文 摘要
出了圆整、密实、堆密度大的空白丸心。
第二阶段在同一设备中将其制备工艺与包衣技术相结合，将普
素洛尔与粘合剂的混合物以一定的速度喷洒到空白丸心上，使其形
成含药量适宜的药丸。对其影响因素进行了考察，最终选定了包衣
温度为 87．3 C，转速为 250rpm，空白丸心与普蔡洛尔与粘合剂的量
比为 50：40：15。
第三阶段将阻滞材料包在含药丸上，形成12小时的缓释微丸。
对影响缓释微丸释放的各种因素进行了考察，选定的包衣材料（硫
酸钙：氢化蓖麻油）的量比为1：l，包衣量为含药丸量的50％。
采用相似因子祛研究了普蒂洛尔缓释微丸的稳定性，结果表明
缓释微丸在高温、高湿、光照及加速实验条件下基本稳定，经家犬
体内药动学研究表明，缓释微丸的Tmx为3．54 ’J’时，tl／2为3．2 ’J’时，
相对生物利用度为235．1％。
论文的第二部分是氢氯噬嗓普通片的制备研究。对处方进行了
正交设计，筛选出最佳处方，达到预期要求，在30分钟氢氯噬嗓的
溶出达到80％，对影响其释放的各种因素进行了考察。并采用HPLC
法对普蔡洛尔和氢氯噬嗓两种成分进行了初步的分析研究。
本次实验研究了缓释微丸的成丸过程，采用了一种适用于模型
药物的制备方法，达到了预期的要求。可以看出，熔融高速搅拌制
丸法制各缓释微丸效果良好，为将来的工业化大生产提供了可行的
参考。
Melt pelletization in a high speed mixer has its unique character, one of the techniques which manufacture pelletized products. Pellets are of great interest to the people more and more. It is one of the common and effective methods in producing sustained-release pellets. In its simplest form, melt pelletization proceeds by mixing the starting materials with a binder which is solid at ambient temperature and melts or softens at relative low temperatures. By operation of the mixture, the temperature is raised because of the development of heat caused by friction. The binder melts and acts like a liquid binder. By further agigation wet agglomerates are formed. Melt pelletization in a high shear mixer has been reported before, to provide basis for pharmaceutical industry and raising the level of pharmaceutical products, the process variable and effects of these parameters on the performance of the end products were investigated using self-made high shear mixer in the article.
Based on previous experiments,a laboratory scale high speed mixer was self-made. It is convenient to operate the mixer and control the mixing process. It is easy to clean this equipment. The purpose of the present work was about the studies on the compound recipe Propranolol sustained-release pellets. Because of some reasons we prepared
Propranolol sustained-release pellets and Hydrochlorothiazide conventional tables not pellets.
Drugs have different micromeritics property for example crystal state, flowbility, binding force, if they are manufactured based on the same formulation or the same process technology, the performance of the pellet is different. The different types, amounts and properties of the experients affect the possibility of the pellets and the quality of the pellets. Based on the property of the model drug, we selected Calcium Sulfate as dilute, Hydrogenated Castor Oil as binder.
There were three phases in the process. The first phase: the variables (the different kinds of binder, the impeller speed, product load, and massing time) 100g product load, 87centigrade product temperature, 350rpm impeller speed, the massing time was 7min.The results showed that pellets made had advantages of good sphericity, high strength and high bulk density.
The second phase was used combing melt pelletization in the same high-shear mixer with coating technique to obtain pellets with high drug content inside. The mixer containing Propranolol and binder was sprayed on the surface. The variables were investigated and the optimal parameters of process were found under certain condition. They were 86.5 centigrade coating temperature, 350rpm impeller speed. The amount radio of pellets and Propranolol and binder was 50:40:15.
The last phase was the coating process which was performed by coating hydrophobic and hydrophilic materials to obtain 12 hour sustained-release pellets. The results indicated that the ideal sustain-release behavior and good release reproductivity were achieved using coating formulation .The amount radio of Calcium Sulfate and Hydrogenated Castor Oil was 1:1, the total amount of coating materials was 50 percent of the amount of the drug pellets.
The stability of Propranolol sustained-release pellets were studied
ABSTRACT
using the method of fit factor. The drug content and release stability of sustained-release pellets were good under the condition of high temperature, high humidity and strong light. The pharmacokinetics of pellets in dogs indicated that the Tmax was 3.54h, t1/2 was 3.2h, and relative bioavaility was 235.1%.
The second part of this paper was about the preparation of Hydrochlorothiazide. The formulation variables were optimizated by orthogonal design. The release of Hydrochlorothiazide in 30min was 80 percent of the total amount and this formulation was equivalent to the standard. HPLC method were used to detect Propranolol and Hydrochlorothiazide.
This article discussed the form mechanism of pellet and adopted a process that was applicable to the model drug. The results in t
引文
(1) Isaac Ghebre-Sellassie. Pharmaceutical pelletization technology, MARCEL DEKKER, INC, 1989:3-7
(2) Special Delivery:Advances in drug therapy. The Research News,University of Michigan, 1996:552-556
(3) H.Bechgaard and G.H.Nielson. Controlled release multiple unites and single-unit dosea. Drug Dev Ind Pharm, 1978,4:53-67
(4) R.J.Lautz and M.J.Robinson,U.S.patent 3,146,167 (August 1964)
(5) N.Nakahara,U.S.Patent 3,277,520 (June 1966)
(6) N.Moriya,U.S.Patent 3,579,719 (May 1971)
(7) N.Moriya,U.S.Patent 3,584,334 (June 1971)
(8) 陆彬，药物新剂型与新技术．人民卫生出版社，北京，1998，289-300
(9) 高原，王洪光，张汝华等．熔融高速搅拌混合法制粒的研究进展，中国药学杂志，1999，34(3)：149-151
(10) 张钧寿．缓／控释制剂的国外研究动向，中国新药杂志，1996，5(3)，161-163
(11) 周自永，王世祥．新编常用药物手册(第二版)，北京，金盾出版社出版，1992，231-232
(12) P. Holm. Effect of impeller and chopper design on the granulation in a high speed mixer. Drug Der Ind Pharm, 1987,13(9-11):1675-1701
(13) Torben Schaefer, Christina Mathiesen. Melt pelletization in a high shear mixer Ⅶ effect of product temperature. Int J Pharm, 1996,134:105-117
(14) Torben Schaefer. Equipment for wet granulation, Acta Pharm. Suec, 1988, 25:205-228
(15) Paul Wan SiaHeng,Tin Wui Wong, Jian Jun Shu etc.A new method for the control of the size pellets in the melt pelletization process with a high shear mixer. Chem Pharm Bull,1999,47(5):633-638
(16) Paul Wan Sia Heng, Tin Wui Wong, Lai Wah Chan etc. Influence of production variables on the sphericity of melt pellets. Chem Pharm Bull, 2000,48:420-424
(17) Torben Schaefer, Christina Mathiesen. Melt pelletization in a high shear mixer Ⅷ effect of binder viscosity. Int J Pharm, 1996,139:125-138
(18) D.Vornovicb, M.Moneghini, B.Perissutti etc. Preparation in high-shear mixer of sustained-release pellets by melt pelletization. Int J Pharm, 2000, 203:235-244
(19) Torben Schaefer, Per Holm, H.Gjelstrup Kristensen etc. Melt pelletization in a high shear mixer. V effects of process variables and binder. Acta Pharm Nord, 1992,4(3): 133-140
(20) Torben Schaefer, Melt pelletization in a high shear mixer. Ⅵ Agglomeration of a cohesive power. Int J Pharm, 1996, 132:221-230
(21) Torben Schaefer, Birgitte Taagegaard, Lars Juul Thomsen etc. Melt pelletization in a high shear mixer ⅳ Effect of process variable in a laboratory scale mixer. Eur J Pharm Sci, 1993, 1:125-131
(22) Torben Schaefer, Christina Mathiesen. Melt pelletization in a high shear mixer ⅸ Effects of binder particle size. Int J Pharm, 1996, 139:139-148
(23) 陈挺，陈庆华．盐酸苯丙醇胺微丸的制备工艺研究，中国医药工业杂志，1999，30(8)：345-347
(24) John W. Skoug,Martin V. Mikelsons,Cynthia N.Vigneron etc,Qualitative evalution of the mechanism of release of matrix sustained release dosage forms by measurement of polymer release, J Control Rel,1993,27:227-229
(25) Celia M.McTaggart, John A.Ganley, Alfred Sickmueller etc. The evalution of formulation and processing condition of a melt granulation process, Int J Pharm, 1984, 19:139:184
(26) L.Juul Thomsen, T. Schaefer, J.M.-Sonnergaard etc. Prolonged release matrix pellets prepared by melt pelletization Ⅰ .Process variables, Drug Dev Ind Pharm,1993,19(15):1867-1887
(27) Torben Schaefer, Per Holm, H.Gjelstrup Kristensen etc. Melt pelletization in a high shear mixer Ⅲ Effects of lactose quality. Acta Pharm Nord, 1992,4(4):245-252
(28) 平其能，现代药剂学，北京医药科技出版社，1998，411-412
(29) 夏锦辉，刘昌孝．固体制剂的体外溶出度的统计学评价分析．中国药学杂志，2000，35(2)：130-131
(30) M.V.R. Velasco-De-Paola, M.I.R.M.Santoro, M.N.Gai etc. dissolution kinetics evalution of controlled-release tablets containing propranolol hydrochloride, Drug Der Ind Pharm. 1999,25 (4),535-541
(31) Gurvinder singh Rekhi, Sunil S.Jambhekar. Bioavailability and in-vitro/invivo correlation for propranolol hydrochloride extended-release bead products prepared using aquous polymerie dispersions,J Pharm Pharmacol, 1996,48:1276-1284
(32) 党全训．氢氯噻噙及其片剂的反相高效液相色谱法，药物分析杂志，1991，11(3)，141-143
(33) 陈杏梅．紫外分光光度法测定氢氯噻嗪片的含量，中国药学杂志，1990，25(9)，543-544
(34) 美国药典23版，749-750，1327-1332
(35) 邱怡虹，郑良元，沈勤炎．双波长分光光度法测定复方氢氯噻嗪片的含量，中国药科大学学报，1987，18(2)：130-132
(36) 金有郁．药物不良反应(第二版)，北京，人民卫生出版社，1996，101-102
(37) 中华人民共和国药典委员会，临床用药须知，北京，化学工业出版社，1995，323-324
(38) 康学军，王玉，陈世卿等．反相高效液相法测定血浆中普萘洛尔的浓度，中国药科大学学报，1994，25(3)：153-155
(39) 盐酸普萘洛尔缓释片与常释片的生物利用度比较研究．魏广力，肖淑华，刘昌孝，药学学报，1999，34(8)：627-630
(40) KEVIN M.HEDEEN. Rapid high-performance liquid chromatographic method for the determination of propranolol levels in canine and feline plasma. J Chrom, 1991,572:239-245
(41) Gurvinder Singh Rekhi, Sunil S.Jambhekar, Paul F. Souney. A fluorimetric liquid chromatographic method for the determination of propranolol in human serum/plasma. J Pharm Bio Analysis, 1995,13:1499-1505