新型辅料卡伯波在口服固体缓释制剂中的应用研究
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摘要
本文以烟酸（nicotinic acid，niacin）为水溶性模型药物，研究了Carbopol在口
服缓释制剂中的应用。先对Carbopol在不同介质中的膨胀性和粘性进行了基础
研究，并与HPMC K4M作比较。系统考察了各种处方因素和溶出条件对释药速
率的影响，探索了缓释片的释药机制；对比研究了在缓释制剂中应用Carbopol
的三种制备工艺：包括粉末直接压片法、快速搅拌制粒法和Carbopol颗粒外加
法，重点考察了Carbopol颗粒外加法工艺，在此基础上筛选了与国外制剂具有
相似体外释放度的处方，考察了其稳定性。最后以进口制剂作对照，对自制烟酸
缓释片进行了兔体内的生物利用度试验。
Carbopo1934P、974P与971P为三种可口服的药用高分子材料，在人工胃液
和人工肠液中的膨胀度有明显差异，在不同介质中粘度测定结果表明：Carbopol
受pH及离子强度的影响较大，而HPMC K4M相对较小。
在处方因素考察中发现Carbopol的型号、含量以及处方中所有的填充剂，均
对主药的释药速率有影响，而Carbopol的粒度、压片压力对释放度影响不明显。
在考察溶出方法和溶出介质时，发现使用蓝法或桨法体外释放度有明显的不同；
溶出介质的pH及离子强度，对主药的释药速率影响较大。
对制备工艺的研究表明，Carbopol颗粒外加法与其它两种工艺比较，工艺
简单，操作方便，缓释效果与粉末压片法接近，比快速搅拌制粒法好。抗湿性实
验表明Carbopol颗粒外加法制备的片剂表面易吸潮，薄膜包衣后片剂硬度增大，
但释药速率基本不变。
在处方筛选中发现，Carbopol与HPMC联用后缓释效果比单用明显增强，通
过红外光谱可知两者在pH4.0-6.8的溶液中可能形成内在复合物；对筛选的处方
进行加速稳定性实验，结果表明光照、高温、高湿均使释药速率有所减慢，外观
及含量无明显变化：三个月加速实验表明，缓释片内在质量稳定。
采用离子对色谱法建立了血浆中烟酸的测定方法，用兔子进行了进口片与
自制片的药代动力学研究。结果表明自制片与进口片的达峰时间和达峰浓度无显
著性差异，其相对生物利用度为116.8％，两者生物等效。
Nicotinic acid (niacin) was used as a water-soluble drug model to investigate the
application of Carbopol on sustained release oral matrix tablets. Carbopol934P. 974P
and 971 P are the oral pharmaceutical grades of Carbomer and currently being utilized
as polymeric matrices for controlling drug release in pharmaceutical dosage forms.
The swelling and adhesiveness of Carbopol in different mediums were
investigated .The result indicated the swelling of Carbopol was significantly different
in simulated gastric fluid(SGF) and simulated intestic fluid(SIF).The adhesiveness of
Carbopol was strongly affected by pH and ionic strength compared with HPMCK4m.
The influence of composition factors and dissolution conditions on in vitro
dissolution behavior was evaluated. The result showed dissolution rate was affected
by the content and type of Carbopol, filler, dissolution method, pH and ionic strength
of dissolution medium, but the particle size of Carbopol and hardness of tablets had
little influence.
A novel wet granulation method- Carbopol extragranular addition was studied in
details. It is a simple and manageable process compared with general wet granulation
and has the advantage of avoiding agglomeration of Carbopol during granulation.
The formulation of sustained release nicotinic acid tablet (SRNAT) using the
combination of Carbopol974P and HPMCK4m was screened. It has similar in vitro
dissolution characteristics to the imported tablet.
Pharmacokinetic studies were carried out in six healthy rabbits after a single oral
administration of the self-prepared and imported SRNAT in a randomized crossover
way. The results demonstrated that the two preparations were bioequivalent.
服缓释制剂中的应用。先对Carbopol在不同介质中的膨胀性和粘性进行了基础
研究，并与HPMC K4M作比较。系统考察了各种处方因素和溶出条件对释药速
率的影响，探索了缓释片的释药机制；对比研究了在缓释制剂中应用Carbopol
的三种制备工艺：包括粉末直接压片法、快速搅拌制粒法和Carbopol颗粒外加
法，重点考察了Carbopol颗粒外加法工艺，在此基础上筛选了与国外制剂具有
相似体外释放度的处方，考察了其稳定性。最后以进口制剂作对照，对自制烟酸
缓释片进行了兔体内的生物利用度试验。
Carbopo1934P、974P与971P为三种可口服的药用高分子材料，在人工胃液
和人工肠液中的膨胀度有明显差异，在不同介质中粘度测定结果表明：Carbopol
受pH及离子强度的影响较大，而HPMC K4M相对较小。
在处方因素考察中发现Carbopol的型号、含量以及处方中所有的填充剂，均
对主药的释药速率有影响，而Carbopol的粒度、压片压力对释放度影响不明显。
在考察溶出方法和溶出介质时，发现使用蓝法或桨法体外释放度有明显的不同；
溶出介质的pH及离子强度，对主药的释药速率影响较大。
对制备工艺的研究表明，Carbopol颗粒外加法与其它两种工艺比较，工艺
简单，操作方便，缓释效果与粉末压片法接近，比快速搅拌制粒法好。抗湿性实
验表明Carbopol颗粒外加法制备的片剂表面易吸潮，薄膜包衣后片剂硬度增大，
但释药速率基本不变。
在处方筛选中发现，Carbopol与HPMC联用后缓释效果比单用明显增强，通
过红外光谱可知两者在pH4.0-6.8的溶液中可能形成内在复合物；对筛选的处方
进行加速稳定性实验，结果表明光照、高温、高湿均使释药速率有所减慢，外观
及含量无明显变化：三个月加速实验表明，缓释片内在质量稳定。
采用离子对色谱法建立了血浆中烟酸的测定方法，用兔子进行了进口片与
自制片的药代动力学研究。结果表明自制片与进口片的达峰时间和达峰浓度无显
著性差异，其相对生物利用度为116.8％，两者生物等效。
Nicotinic acid (niacin) was used as a water-soluble drug model to investigate the
application of Carbopol on sustained release oral matrix tablets. Carbopol934P. 974P
and 971 P are the oral pharmaceutical grades of Carbomer and currently being utilized
as polymeric matrices for controlling drug release in pharmaceutical dosage forms.
The swelling and adhesiveness of Carbopol in different mediums were
investigated .The result indicated the swelling of Carbopol was significantly different
in simulated gastric fluid(SGF) and simulated intestic fluid(SIF).The adhesiveness of
Carbopol was strongly affected by pH and ionic strength compared with HPMCK4m.
The influence of composition factors and dissolution conditions on in vitro
dissolution behavior was evaluated. The result showed dissolution rate was affected
by the content and type of Carbopol, filler, dissolution method, pH and ionic strength
of dissolution medium, but the particle size of Carbopol and hardness of tablets had
little influence.
A novel wet granulation method- Carbopol extragranular addition was studied in
details. It is a simple and manageable process compared with general wet granulation
and has the advantage of avoiding agglomeration of Carbopol during granulation.
The formulation of sustained release nicotinic acid tablet (SRNAT) using the
combination of Carbopol974P and HPMCK4m was screened. It has similar in vitro
dissolution characteristics to the imported tablet.
Pharmacokinetic studies were carried out in six healthy rabbits after a single oral
administration of the self-prepared and imported SRNAT in a randomized crossover
way. The results demonstrated that the two preparations were bioequivalent.
引文
1．傅崇东，徐惠南 卡波姆在药剂中的应用研究进展国外医药—合成药 生化药 制剂分册1999，20(2)：121-125
2．郑建津 沈慧凤 Carbopol及其在缓控释制剂中的应用研究概况 上海医药工业研究院硕士论文(1999)
3．唐磊 卢振海 水凝胶体系—分册二 卡伯波树脂用于医药制剂产品(1999) BFGoodrich公司编译
4．陈新谦 金有豫 新编药物学(14版)P273，人民卫生出版社
5. Physician's Desk Reference,Medical Economics Production Company,Inc.USA
6．蒋雪涛 卡波姆及其应用性能 上海市1999年药用辅料推广会议论文
7. Gul MK and Zhu J Formulation and in vitro evaluation of ibuprofen-Carbopol 974PNF controlled release matrix tablet III:influence of co-excipients on release rate of the drug.J.Controlled.Rel.1998,54:185-190
8. Goskonda VR,Reddy IK,Durrani MJ et al Solid-state stability assessment of controlled release tablets containing Carbopo1971P J.Controlled.Rel.1998,54:87-93
9. Durrani MJ,Andrews A,Whitaker R.et al Studies on drug release kinetics from carbomer matrices.Drug Dev.Ind.Pharm.1994,20(5):2439-2447
10. Durrani MJ,Whitaker R,Manji PA A Novel Wet Granulation Method for Carbopol resin I:Extragranular Addition Drug Dev.Ind.Pharm.1997,23(12):1201-1205
11. Pillay V,Fassihi R Evaluation and comparison of dissolution data derived from different modified release dosage forms:an alternative method J.Contrlled.Rel 1998,55:45-55
12．任麒 吴梦菲 郑建津等 几种常用辅料在制剂工艺中的应用 上海市1999年药用辅料推广会议论文
13 Neau SU, Chow MY,Durrani MJ Fabrication and characterization of extruded and spheronized beads containing Carbopo1974PNF resin Int.J.Pharm.1996,131:47
14 Sheen PC,Sabol PJ,Alcorn GJ.et al Aqueous film coating studies of sustained release nicotinic acid pellets:an in-vitro evaluation.Drug Dev.Ind.Pharm.1992,18(8):851-860
15 Khullar P.,Khar RK and Agarwal SP Evaluation of hydrogel-based controlled-release niacin tablets.Drug Dev.Ind.Pharm.1998,24(5):479-483
16 U.S.patent 5,268,181
17 Knopp RH et al Equivalent efficacy of a time release form of niacin (Niaspan)given once-a-night versus plain niacin in the management of hyperlipidemia Metabolism 1998,47(9):1097-1104
18 Guyton JR, Goldberg AC, Kreisberg RA et al Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia Am.J.Cardiol.1998,82(6):737-743
19 Britton ML,Brandberry CJ,Letassy NA,et al ASHP therapeutic position statement on the safe use of niacin in the management of dyslipidemias.Am.J.Health-Syst.Pharm.1997,54(12):2815-2819
20 Perez-Macros B, Ford JL, Armstrong DJ et al Influence of pH on the release of Propranold Hydrochloride from matrices containing Hydroxypropylmethylcellulose K4m and Carbopo1974 J.Pharm.Sci.1996,85(3):330-333
21 Moore JW and Flanner HH Mathematical comparison of dissolution profiles Pharm.Tech.1996,(6):64-74 2000,35(2):130-131
22 夏锦辉 刘昌孝 固体药物制剂的体外溶出度统计学评价分析 中国药学杂志2000，35(2)：130-131
23 Miyanchi Y.,Noritoshi,Sano.et al Simultaneous determination of nicotinic acid and its two metabolites in human plasma using solid-phase extraction in combination with high performance liquid chromatography Int.J.Vitam.Nutr.Res.1993,63(2):145-149
24 Beeker B.Hummel K.A new method for the detection of nicotinic acid in plasma. Araneim-Forsch 1990,40(5):573-575
25 Mawatari K,Ihana F,Waatanabe M.Determination of nicotinic acid and nicotinamide in human serum by HPLC with postcolumn ultraviolet-irradiation and fluorescence detection.Anal.Sci.1991,7(5):733-736
26 Tsurta Y.,Kohashi K.,Ishida S.Determination of nicotinic acid in serum by HPLC with florescence detection J.Chromatogr.1984,309(2):309-3015
27 Pelzer M.Northcott S. and Hanson G. An improved method for the determination of nicotinic acid in human plasma by high-performance liquid chromatography.J.Liq.Chromatogr.1993,16(12):2563-2570
28 Neuvonen PJ,Roivas L,Laine K.et al The bioavailability of sustained release nicotinic acid formulations Br.J.Clin.Pharmac.1991,32:473-476
29 Hegen N,Seibert V and Hegen M High -performance liquid chromatographic determination of free nicotinic acid and its metabolite,nicotinuric acid,in plasma and urine. Clin. Chem. 1978, 24(10):1740-1743
30 Ahuja A, Khar RK, Ali J.Mucoadhesive drug delivery systems. Drug Dev.Ind.Pharm, 1997, 23(5):489-515
2．郑建津 沈慧凤 Carbopol及其在缓控释制剂中的应用研究概况 上海医药工业研究院硕士论文(1999)
3．唐磊 卢振海 水凝胶体系—分册二 卡伯波树脂用于医药制剂产品(1999) BFGoodrich公司编译
4．陈新谦 金有豫 新编药物学(14版)P273，人民卫生出版社
5. Physician's Desk Reference,Medical Economics Production Company,Inc.USA
6．蒋雪涛 卡波姆及其应用性能 上海市1999年药用辅料推广会议论文
7. Gul MK and Zhu J Formulation and in vitro evaluation of ibuprofen-Carbopol 974PNF controlled release matrix tablet III:influence of co-excipients on release rate of the drug.J.Controlled.Rel.1998,54:185-190
8. Goskonda VR,Reddy IK,Durrani MJ et al Solid-state stability assessment of controlled release tablets containing Carbopo1971P J.Controlled.Rel.1998,54:87-93
9. Durrani MJ,Andrews A,Whitaker R.et al Studies on drug release kinetics from carbomer matrices.Drug Dev.Ind.Pharm.1994,20(5):2439-2447
10. Durrani MJ,Whitaker R,Manji PA A Novel Wet Granulation Method for Carbopol resin I:Extragranular Addition Drug Dev.Ind.Pharm.1997,23(12):1201-1205
11. Pillay V,Fassihi R Evaluation and comparison of dissolution data derived from different modified release dosage forms:an alternative method J.Contrlled.Rel 1998,55:45-55
12．任麒 吴梦菲 郑建津等 几种常用辅料在制剂工艺中的应用 上海市1999年药用辅料推广会议论文
13 Neau SU, Chow MY,Durrani MJ Fabrication and characterization of extruded and spheronized beads containing Carbopo1974PNF resin Int.J.Pharm.1996,131:47
14 Sheen PC,Sabol PJ,Alcorn GJ.et al Aqueous film coating studies of sustained release nicotinic acid pellets:an in-vitro evaluation.Drug Dev.Ind.Pharm.1992,18(8):851-860
15 Khullar P.,Khar RK and Agarwal SP Evaluation of hydrogel-based controlled-release niacin tablets.Drug Dev.Ind.Pharm.1998,24(5):479-483
16 U.S.patent 5,268,181
17 Knopp RH et al Equivalent efficacy of a time release form of niacin (Niaspan)given once-a-night versus plain niacin in the management of hyperlipidemia Metabolism 1998,47(9):1097-1104
18 Guyton JR, Goldberg AC, Kreisberg RA et al Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia Am.J.Cardiol.1998,82(6):737-743
19 Britton ML,Brandberry CJ,Letassy NA,et al ASHP therapeutic position statement on the safe use of niacin in the management of dyslipidemias.Am.J.Health-Syst.Pharm.1997,54(12):2815-2819
20 Perez-Macros B, Ford JL, Armstrong DJ et al Influence of pH on the release of Propranold Hydrochloride from matrices containing Hydroxypropylmethylcellulose K4m and Carbopo1974 J.Pharm.Sci.1996,85(3):330-333
21 Moore JW and Flanner HH Mathematical comparison of dissolution profiles Pharm.Tech.1996,(6):64-74 2000,35(2):130-131
22 夏锦辉 刘昌孝 固体药物制剂的体外溶出度统计学评价分析 中国药学杂志2000，35(2)：130-131
23 Miyanchi Y.,Noritoshi,Sano.et al Simultaneous determination of nicotinic acid and its two metabolites in human plasma using solid-phase extraction in combination with high performance liquid chromatography Int.J.Vitam.Nutr.Res.1993,63(2):145-149
24 Beeker B.Hummel K.A new method for the detection of nicotinic acid in plasma. Araneim-Forsch 1990,40(5):573-575
25 Mawatari K,Ihana F,Waatanabe M.Determination of nicotinic acid and nicotinamide in human serum by HPLC with postcolumn ultraviolet-irradiation and fluorescence detection.Anal.Sci.1991,7(5):733-736
26 Tsurta Y.,Kohashi K.,Ishida S.Determination of nicotinic acid in serum by HPLC with florescence detection J.Chromatogr.1984,309(2):309-3015
27 Pelzer M.Northcott S. and Hanson G. An improved method for the determination of nicotinic acid in human plasma by high-performance liquid chromatography.J.Liq.Chromatogr.1993,16(12):2563-2570
28 Neuvonen PJ,Roivas L,Laine K.et al The bioavailability of sustained release nicotinic acid formulations Br.J.Clin.Pharmac.1991,32:473-476
29 Hegen N,Seibert V and Hegen M High -performance liquid chromatographic determination of free nicotinic acid and its metabolite,nicotinuric acid,in plasma and urine. Clin. Chem. 1978, 24(10):1740-1743
30 Ahuja A, Khar RK, Ali J.Mucoadhesive drug delivery systems. Drug Dev.Ind.Pharm, 1997, 23(5):489-515