多索茶碱渗透泵型控释片和缓释骨架片的研究
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摘要
本文以多索茶碱作为模型药物，在考察各辅料、药物及包衣膜基本性
质的基础上，选用聚氧乙烯（PEO）、羧甲基纤维素钠（CMCNa）、羟丙基甲
基纤维素（HPMC）及KCl、NaCl等为辅料与药物制成具有含药层和推挽层
的双层片心，以醋酸纤维素（CA）/聚乙二醇6000（PEG6000）为包衣材料，制
备了多索茶碱渗透泵型控释片，并以HPMC作为骨架材料制备了多索茶碱
缓释骨架片。
本文对多索茶碱渗透泵型控释片作了系统研究。首先考察了影响本品
释药的因素。其中，含药层载药量、促渗透聚合物用量、推挽层片重等因
素对释药有较明显的影响；含药层片重、促渗透聚合物的种类、推挽层组
成及一定范围内的释药孔径对释药影响不大。利用正交试验，选定包衣膜
厚度、增塑剂PEG的用量及分子量三个因素三个水平，以药物释放度及
其与时间的相关系数两个指标的综合评分作为评价指标，优化筛选了包衣
膜处方，通过调节增塑剂PEG的用量、包衣膜的厚度等因素，使本品在12
或24小时内保持零级释药。同时对该片剂的释药机制作了初步考察，膜
内外渗透压差和推挽层产生的推动力是药物释放的主要动力。初步稳定性
试验结果表明，在高温高湿条件下，本品外观变化较大，应40℃以下密闭
保存。
考察了影响多索茶碱缓释骨架片释药的因素。结果表明，HPMC的种
类和用量、填充剂乳糖的用量对其释药有显著影响，通过调节HPMC的用
量，可使本品在12或24小时内保持连续缓慢释放。初步稳定性试验结果
表明，在高温高湿条件下，本品质量稳定。
本文以国产多索茶碱速释片作为对照，对多索茶碱缓释骨架片和渗透
泵型控释片进行了人体相对生物利用度和药动学初步研究。结果表明：单
剂量口服多索茶碱300mg，三种制剂（速释片、缓释骨架片和渗透泵型控
释片）的药—时曲线下面积分别为5.67、5.51、6.01（μg/ml）·h，达峰时间分
别为1.5、4.0、5.7h，最大血药浓度分别为2.57、0.69、0.48μg/ml。缓释
沈阳药科大学硕士学位论文 摘要
骨架片对速释片的相对生物利用度为97．2％，渗透泵型控释片为105．9％，
两种制剂具有良好的体内外相关性。
In this paper doxophylline was selected as the model drug to prepare the
osmotic pump tablet and matrix tablet. On the basis of the pre-formulation
research about the properties of doxophylline, excipients and cellulose acetate
(CA) free film, polyethylene oxide (PEO),carboxymethylcellulose sodium
(CMCNa), hydroxypropylmethylcellulose (HPMC), potassium chloride and
sodium chloride were used to make the two-layer tablet core coated with the CA
coating comprising with 10% polyethylene glycol 6000 (PEG6000).And HPMC
was selected as the matrix material to prepare the sustained-release tablet.
The system research of the doxophylline osmotic pump controlled-release
tablet was made mainly. The effect of some factors on the drug release from the
osmotic pump tablet was investigated. The result was the content of drug in the
core tablet, the content variation of osmopolymers and the mass of the push-pull
layer had significant influence on the drug release; but the sort of osmopolymers,
the mass of the drug layer, the composition of the push-pull layer and the size of
orifice for drug delivery had not. According to the experimental design of
orthogonal test, coating thickness, the PEG sorts and content variation in the
coating solution were selected as the causal factors. The linear correlation
coefficient of the accumulative drug release amount and time (r) and the
accumulative drug release amount (F%) were used as the evaluation standard to
optimize the coating formulation. The zero-order release of the drug from the
osmotic pump tablet could sustain to 12 or 24 hours with the thickness of
coating varying. The result of the drug release mechanism study indicated that
the drug release was mainly modulated by the osmotic pressure difference
between inside and outside of the coating and the swelling force of the push-pull
layer of the core tablet. The osmotic pump tablets were unstable under high
temperature or humidity circumstance.
The effect of some factors on the drug release from the HPMC sustained-
release matrix tablet was investigated. The result was the viscosity and content
variation of HPMC and the content variation of additive had significant
influence on the drug release. The drug release from the matrix tablet could
sustain to 12 or 24 hours with the content of HPMC varying. The matrix tablets
were stable under high temperature or humidity circumstance.
Using the immediate release tablet as the reference, the pharmacokinetics
3
of doxophylline sustained-release tablet and osmotic pump controlled-release
tablet were studied, The result indicated that after p.o. 300mg doxophylline,
AUC~.,. of the three formulations in turn were 5.67, 5.51, 6.01 (~ig/ml)h; Tm
were 1.5, 4.0, 5.7 h; Cm were 2.57, 0.69, 0.48 ~tg/ml. The relative bioavailability
of the sustained-release tablet was 97.2% and that of the osmotic pump
controlled-release tablet was 105.9%. The drug release from the two kinds of
tablets was equal in vitro and in vivo.
质的基础上，选用聚氧乙烯（PEO）、羧甲基纤维素钠（CMCNa）、羟丙基甲
基纤维素（HPMC）及KCl、NaCl等为辅料与药物制成具有含药层和推挽层
的双层片心，以醋酸纤维素（CA）/聚乙二醇6000（PEG6000）为包衣材料，制
备了多索茶碱渗透泵型控释片，并以HPMC作为骨架材料制备了多索茶碱
缓释骨架片。
本文对多索茶碱渗透泵型控释片作了系统研究。首先考察了影响本品
释药的因素。其中，含药层载药量、促渗透聚合物用量、推挽层片重等因
素对释药有较明显的影响；含药层片重、促渗透聚合物的种类、推挽层组
成及一定范围内的释药孔径对释药影响不大。利用正交试验，选定包衣膜
厚度、增塑剂PEG的用量及分子量三个因素三个水平，以药物释放度及
其与时间的相关系数两个指标的综合评分作为评价指标，优化筛选了包衣
膜处方，通过调节增塑剂PEG的用量、包衣膜的厚度等因素，使本品在12
或24小时内保持零级释药。同时对该片剂的释药机制作了初步考察，膜
内外渗透压差和推挽层产生的推动力是药物释放的主要动力。初步稳定性
试验结果表明，在高温高湿条件下，本品外观变化较大，应40℃以下密闭
保存。
考察了影响多索茶碱缓释骨架片释药的因素。结果表明，HPMC的种
类和用量、填充剂乳糖的用量对其释药有显著影响，通过调节HPMC的用
量，可使本品在12或24小时内保持连续缓慢释放。初步稳定性试验结果
表明，在高温高湿条件下，本品质量稳定。
本文以国产多索茶碱速释片作为对照，对多索茶碱缓释骨架片和渗透
泵型控释片进行了人体相对生物利用度和药动学初步研究。结果表明：单
剂量口服多索茶碱300mg，三种制剂（速释片、缓释骨架片和渗透泵型控
释片）的药—时曲线下面积分别为5.67、5.51、6.01（μg/ml）·h，达峰时间分
别为1.5、4.0、5.7h，最大血药浓度分别为2.57、0.69、0.48μg/ml。缓释
沈阳药科大学硕士学位论文 摘要
骨架片对速释片的相对生物利用度为97．2％，渗透泵型控释片为105．9％，
两种制剂具有良好的体内外相关性。
In this paper doxophylline was selected as the model drug to prepare the
osmotic pump tablet and matrix tablet. On the basis of the pre-formulation
research about the properties of doxophylline, excipients and cellulose acetate
(CA) free film, polyethylene oxide (PEO),carboxymethylcellulose sodium
(CMCNa), hydroxypropylmethylcellulose (HPMC), potassium chloride and
sodium chloride were used to make the two-layer tablet core coated with the CA
coating comprising with 10% polyethylene glycol 6000 (PEG6000).And HPMC
was selected as the matrix material to prepare the sustained-release tablet.
The system research of the doxophylline osmotic pump controlled-release
tablet was made mainly. The effect of some factors on the drug release from the
osmotic pump tablet was investigated. The result was the content of drug in the
core tablet, the content variation of osmopolymers and the mass of the push-pull
layer had significant influence on the drug release; but the sort of osmopolymers,
the mass of the drug layer, the composition of the push-pull layer and the size of
orifice for drug delivery had not. According to the experimental design of
orthogonal test, coating thickness, the PEG sorts and content variation in the
coating solution were selected as the causal factors. The linear correlation
coefficient of the accumulative drug release amount and time (r) and the
accumulative drug release amount (F%) were used as the evaluation standard to
optimize the coating formulation. The zero-order release of the drug from the
osmotic pump tablet could sustain to 12 or 24 hours with the thickness of
coating varying. The result of the drug release mechanism study indicated that
the drug release was mainly modulated by the osmotic pressure difference
between inside and outside of the coating and the swelling force of the push-pull
layer of the core tablet. The osmotic pump tablets were unstable under high
temperature or humidity circumstance.
The effect of some factors on the drug release from the HPMC sustained-
release matrix tablet was investigated. The result was the viscosity and content
variation of HPMC and the content variation of additive had significant
influence on the drug release. The drug release from the matrix tablet could
sustain to 12 or 24 hours with the content of HPMC varying. The matrix tablets
were stable under high temperature or humidity circumstance.
Using the immediate release tablet as the reference, the pharmacokinetics
3
of doxophylline sustained-release tablet and osmotic pump controlled-release
tablet were studied, The result indicated that after p.o. 300mg doxophylline,
AUC~.,. of the three formulations in turn were 5.67, 5.51, 6.01 (~ig/ml)h; Tm
were 1.5, 4.0, 5.7 h; Cm were 2.57, 0.69, 0.48 ~tg/ml. The relative bioavailability
of the sustained-release tablet was 97.2% and that of the osmotic pump
controlled-release tablet was 105.9%. The drug release from the two kinds of
tablets was equal in vitro and in vivo.
引文
1． F.Theeuwes. Elementary osmotic pump . J Pharm Sci. 1975,64(12) : 1987-1991
2． S.Rose, J.F.Nelson, A continuous long-term injector. Aust J Exp Biol.1955, 33:415-423
3． Ger offen 72-2201357
4． A.Amkraut, J.B.Eckenhoff, K.Nichols. Osmotic delivery of peptides and macromolecules . Adv Drug Delivery Rev.1990,4(2) :1255~1266
5． R.K.Verma, B.Mishra, S.Garg. Osmotically controlled oral drug delivery. Drug Dev Ind Pharm.2000, 26(7) :695~708
6． K.Okimoto, R.A.Rajewski, VJ.Stella. Release of testosterone from an osmotic pump tablet utilizing (SBE)7m-β-cyclodextrin as both a solubilizing and an osmotic pump agent, J Central Release.1999,58:29~38
7． K.Okimoto, M.Miyake, N.Ohnishi, et al. Design and evaluation of an osmotic pump tablet (OPT) for prednisolone, a poorly water soluble drug, using (SBE)7m-β-CD. Pharm Res.1998,15(10) :1562~1568
8． us patent 4765989
9． us patent 5160744
10． us patent 5024843
11． us patent 4200098
12． us patent 4298003
13． us patent 4455143
14． us patent 4439196
15． us patent 4475196
16． Belg BE 86-903516
17． us patent 5198229
18． 潘卫三，甘勇．双室渗透泵控释制剂的研究进展．沈阳药科大学学报．2000，17 (2) ：147-151
19． wo 92-9201445
20． G.Santus, R.W.Baker. Osmotic drug delivery: a review of the patent literature. J Control
Release. 1995, 35:1～21
21．刘春胜，何秀峰，王云萍等．多索茶碱及其片剂的高效液相色谱分析．药学学报．1996；31(2)：156～160
22．付世江，霍宝方，孙吉臻等．口服多索茶碱片Ⅰ期临床试验研究．中国临床药理学杂志．1998，14(4)：222～226
23．郭辉，徐小莹，何丽一等．多索茶碱在大鼠体内的药代动力学．药学学报．1997，32(2)：81～84
24．黎洪珊，柳翠敬．渗透泵制剂的研究进展．国外医药—合成药生化药制剂分册．1999；20(1)：9～13
25. S.Janicki, R.Cichon, Z.Jedras, et al. Gastrointestinal therapeutic system delivering of a water insoluble drug: isosorbide dinitrate (ISDN). Pharmazie.1987,42:95～96
26. us patent 5082668
27．吴涛，潘卫三，庄殿友等．口服渗透泵制剂的研究进展．中国药学杂志．1999，34(2)：76～78
28. us patent 5607696
29．赵春顺．沈阳药科大学硕士学位论文．
30. L.S.C.Wan, P.W.S.Heng, L.F. Wong. Relationship between swelling and drug release in a hydrophilic matrix. Drug Dev Ind Pharm.1993,19(10): 1201～1210
31. J.L.Jensen, L.E.Aplel,J.H.Clair, et al. Variables that affect the mechanism of drug release from osmotic pumps coated weth acrylate/methacrylate copolymer latexes. J Pharm Sci. 1995,84(5):530～533
32. Jian-Hwa Guo. Effects of plasticizers on water permeation and mechanical properties of cellulose acetate: antiplasticization in slightly plasticized polymer film. Drug Dev Ind Pharm.1993,19(13):1541～1555
33．卢元东，王登明，徐惠南．中国药学杂志．1994，29(5)：284～289
34．吴涛，潘卫三，陈济民等．药用高分子控释膜的研究进展．中国药学杂志．1999，34(5)：289～291
35．吴涛．沈阳药科大学博士学位论文．
36．平其能主编．现代药剂学．北京．中国医药科技出版社．1998，393
37．陆彬主编．药物新剂型与新技术．北京．人民卫生出版社．1998，265
38. F. Langenbucher. Linearization of dissolution rate curves by the Weibull distribution. J Pharm Pharmac. 1972, 24:979～982
39. P.M.Sathe, Y. Tsong, V.P.Shah. In-vitro dissolution profile comparison: statistics and analysis, model dependent approach. Pharm Res. 1996,13(12): 1799～1803
40. J.W. Marger, D.Chilko, S.Howard. On the analysis of dissolution data. Drug Dev Ind Pharm. 1986,12(7):969～992
41．夏锦辉，刘昌孝．固体药物制剂的体外溶出度的统计学平均分析．中国药学杂志．2000(2)：130～131
42. M.A. Ramadan, R.Tawashi. The effect of hydrodynamic conditions delivery orifice size on the rate of drug release from the elementary osmotic pump system(EOP). Drug Dev Ind Pharm. 1987,13(2):235～248
43．鲁纯素主编．物理化学(第三版)．北京，人民卫生出版社．1995，90
44．董志超，蒋雪涛．羟丙基甲基纤维素的性质对药物亲水性骨架片溶出度的影响．药学学报，1994，29(2)：920～924
45．苏杰，张钧寿，吴葆金．亲水凝胶在药物制剂中的应用．药学进展，1999，23(3)：143～146
46. M.V. Velasco, J.L.Ford, P. Rowe, et al. Influence of drug: hydroxypropylmethylcellulose ratio, drug and polymer particle size and compression force on the release of diclofenac sodium from HPMC tablets. J Contral Release,1999, 57:75～85
47．平其能主编．现代药剂学．北京．中国医药科技出版社．1998，182
48．董志超．羟丙基甲基纤维素在凝胶骨架片的应用．国外医药—合成药 生化药 制剂分册．1993，14(1)：41～44
49. A.Lagana, M.Bizzarri, A. Marino, et al. Solid phase extraction and high performance liquid chromatographic determination of doxophylline in plasma. Biomed Chrom.1990, 4(5):205～207
50. F. Tagliaro, R.Dorlzzi,A.Frigerlo, et al. Non-extraction HPLC method for simultaneous measurement of dyphylline and doxophylline in serum. Clin Chem.1990, 36(1):113～115
51. D.Westerlund. Direct injection of plasma into column liquid chromatographic systems. Chromatographia. 1987,24:155～164
52．姚银秀，彭文兴，李焕德．口服两种多索茶碱片的生物等效性研究．中国药科大学学报．1998，29(5)：353～355
2． S.Rose, J.F.Nelson, A continuous long-term injector. Aust J Exp Biol.1955, 33:415-423
3． Ger offen 72-2201357
4． A.Amkraut, J.B.Eckenhoff, K.Nichols. Osmotic delivery of peptides and macromolecules . Adv Drug Delivery Rev.1990,4(2) :1255~1266
5． R.K.Verma, B.Mishra, S.Garg. Osmotically controlled oral drug delivery. Drug Dev Ind Pharm.2000, 26(7) :695~708
6． K.Okimoto, R.A.Rajewski, VJ.Stella. Release of testosterone from an osmotic pump tablet utilizing (SBE)7m-β-cyclodextrin as both a solubilizing and an osmotic pump agent, J Central Release.1999,58:29~38
7． K.Okimoto, M.Miyake, N.Ohnishi, et al. Design and evaluation of an osmotic pump tablet (OPT) for prednisolone, a poorly water soluble drug, using (SBE)7m-β-CD. Pharm Res.1998,15(10) :1562~1568
8． us patent 4765989
9． us patent 5160744
10． us patent 5024843
11． us patent 4200098
12． us patent 4298003
13． us patent 4455143
14． us patent 4439196
15． us patent 4475196
16． Belg BE 86-903516
17． us patent 5198229
18． 潘卫三，甘勇．双室渗透泵控释制剂的研究进展．沈阳药科大学学报．2000，17 (2) ：147-151
19． wo 92-9201445
20． G.Santus, R.W.Baker. Osmotic drug delivery: a review of the patent literature. J Control
Release. 1995, 35:1～21
21．刘春胜，何秀峰，王云萍等．多索茶碱及其片剂的高效液相色谱分析．药学学报．1996；31(2)：156～160
22．付世江，霍宝方，孙吉臻等．口服多索茶碱片Ⅰ期临床试验研究．中国临床药理学杂志．1998，14(4)：222～226
23．郭辉，徐小莹，何丽一等．多索茶碱在大鼠体内的药代动力学．药学学报．1997，32(2)：81～84
24．黎洪珊，柳翠敬．渗透泵制剂的研究进展．国外医药—合成药生化药制剂分册．1999；20(1)：9～13
25. S.Janicki, R.Cichon, Z.Jedras, et al. Gastrointestinal therapeutic system delivering of a water insoluble drug: isosorbide dinitrate (ISDN). Pharmazie.1987,42:95～96
26. us patent 5082668
27．吴涛，潘卫三，庄殿友等．口服渗透泵制剂的研究进展．中国药学杂志．1999，34(2)：76～78
28. us patent 5607696
29．赵春顺．沈阳药科大学硕士学位论文．
30. L.S.C.Wan, P.W.S.Heng, L.F. Wong. Relationship between swelling and drug release in a hydrophilic matrix. Drug Dev Ind Pharm.1993,19(10): 1201～1210
31. J.L.Jensen, L.E.Aplel,J.H.Clair, et al. Variables that affect the mechanism of drug release from osmotic pumps coated weth acrylate/methacrylate copolymer latexes. J Pharm Sci. 1995,84(5):530～533
32. Jian-Hwa Guo. Effects of plasticizers on water permeation and mechanical properties of cellulose acetate: antiplasticization in slightly plasticized polymer film. Drug Dev Ind Pharm.1993,19(13):1541～1555
33．卢元东，王登明，徐惠南．中国药学杂志．1994，29(5)：284～289
34．吴涛，潘卫三，陈济民等．药用高分子控释膜的研究进展．中国药学杂志．1999，34(5)：289～291
35．吴涛．沈阳药科大学博士学位论文．
36．平其能主编．现代药剂学．北京．中国医药科技出版社．1998，393
37．陆彬主编．药物新剂型与新技术．北京．人民卫生出版社．1998，265
38. F. Langenbucher. Linearization of dissolution rate curves by the Weibull distribution. J Pharm Pharmac. 1972, 24:979～982
39. P.M.Sathe, Y. Tsong, V.P.Shah. In-vitro dissolution profile comparison: statistics and analysis, model dependent approach. Pharm Res. 1996,13(12): 1799～1803
40. J.W. Marger, D.Chilko, S.Howard. On the analysis of dissolution data. Drug Dev Ind Pharm. 1986,12(7):969～992
41．夏锦辉，刘昌孝．固体药物制剂的体外溶出度的统计学平均分析．中国药学杂志．2000(2)：130～131
42. M.A. Ramadan, R.Tawashi. The effect of hydrodynamic conditions delivery orifice size on the rate of drug release from the elementary osmotic pump system(EOP). Drug Dev Ind Pharm. 1987,13(2):235～248
43．鲁纯素主编．物理化学(第三版)．北京，人民卫生出版社．1995，90
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