二氟尼柳缓释制剂的研究
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摘要
二氟尼柳(Diflunisal)为水杨酸衍生物非甾体抗炎药(NSAIDs),具有优良的镇痛消炎作用,临床上用于治疗风湿性关节炎、类风湿性关节炎、骨关节炎、扭伤、劳损和镇痛。普通片常规给药方法为每日三次,给药次数多,且易造成血药浓度的波动和增加不良反应的发生,因此有必要制成缓控释制剂,以减少给药次数和保持平稳的血药浓度。本文以HPMC为凝胶骨架材料,结合其它辅料,制备了日服一次的二氟尼柳缓释片。
建立了紫外分光光度法,用于二氟尼柳基本理化性质、片剂释放度和含量的测定；建立了高效液相色谱法,用于检测体内血药浓度。以上方法准确可靠,方便快捷,很好地满足了本研究中的各项分析要求。
在处方前研究中,测定了二氟尼柳在不同介质中的溶解度,以缓释片在0-12hr药物的释放度为判定标准,考察了处方因素、工艺因素及释放条件对释放的影响；在此基础上应用L。(33)正交设计试验优化处方,筛选出最优处方,制成了日服一次的缓释片剂；二氟尼柳缓释片的初步稳定性试验显示,其对光、热、水分、空气等均较稳定,含量、释放度均无明显变化。
在释药机理的研究中,考察了几个影响较大的因素对缓释片释药的影响,最终判断缓释片的释药机理为non-Fickian扩散机制,即为药物扩散和骨架溶蚀协同作用的结果,其中扩散机制起主要支配作用。
以二氟尼柳普通片为参比制剂,进行了家犬的体内药动学研究。建立了高效液相色谱法,测定了二氟尼柳的血药浓度。药动学参数计算结果表明,二氟尼柳在自制片中与市售片中的Tmax分别为6.00±0.00h和2.08±0.49h；Cmax分别55.98±2.71μg·mL-1和91.81±6.41μg·mL-1：AUC0-t分别为911.45±99.67μg·h·mL-1和926.04±82.08μg·h·mL-1；相对生物利用度为95.20%,经统计分析法对AUC0-t、Cmax进行评价,自制二氟尼柳缓释与参比制剂AUC0-48生物等效,Cmax生物不等效。
Diflunisal, a non-steroidal salicylic acid derivatives class maked analgesic and antiphlogistic activeities. It has been mainly used for rheumatoid arthritis、osteoarthritis、sprain、strain and analgesia.For plain tablets, the usual administration was 3times daily. Frequent adminstrations led to fluctuation in blood concentration and high incidence of adverse effects. Therefore it was necessary to prepare a kind of sustained release preparations. Combining with other filers, a sustained release tablet(SRT) of once daily administration was prepared by using hydroxypropyl methyl-cellulose as basic matrix material.
According to the literature, UV spectrophotomatry was developed for in vitro assay of physicochemical properties, content and drug release. High-performance liquid chromatograpy (HPLC) was applied in the determination of plasma concentration in dogs. The method was quick and accurate which could meet the requirement of the analysis.
In the preformulation studies, the drug solubility in various mediums was determined. The influences of formulation, manufacture and release condition on the drug release were investigated with the accumulative drug release over 12 h as standard. Basing on the results of single-factor tests, orthogonal design test was carried out to optimize the formulation and the optimal tablet administrated once a day was screened. Stability studies of diflunisal-SRT showed that light, temperature, moisture and air had little effect on the content and release behavior of drug.
To study the mechanism of drug release, some factors which greatly influence the drug release were investigated. Finally drug release mechanism was confirmed as non-Fickian diffusion, which was the combination result of diffusion and erosion and mainly by diffusion.
Using diflunisal tablets as control, in vivo pharmacokinetics of prolong-released gel skeleton tablets prepared in this work in Beagle dogs was investigated. An appropriate HPLC method was developed for measuring the concentration of diflunisal in blood.
Pharmacokinetics parameters showed that Tm. of diflunisal in prolong-released gel skeleton tablets prepared in this work and controlled tablet were 5.17±1.33h and 2.17±0.68h;Cmax were 83.59±45.46μg·mL-1 and 96.21±14.61μg·mL-1; AUC(o-t) were 1287.35±819.80μg·h·mL-1 and 988.83±222.57μg·h·mL-1;relative bioavailability was 124.42%. In terms of the statistical analysis of AUC0-∞,it is concluded that the two preparations are inbioequivalence. The AUC0-∞of prepared prolong-released gel skeleton tablets is higher than it of the controlled tablets.
建立了紫外分光光度法,用于二氟尼柳基本理化性质、片剂释放度和含量的测定；建立了高效液相色谱法,用于检测体内血药浓度。以上方法准确可靠,方便快捷,很好地满足了本研究中的各项分析要求。
在处方前研究中,测定了二氟尼柳在不同介质中的溶解度,以缓释片在0-12hr药物的释放度为判定标准,考察了处方因素、工艺因素及释放条件对释放的影响；在此基础上应用L。(33)正交设计试验优化处方,筛选出最优处方,制成了日服一次的缓释片剂；二氟尼柳缓释片的初步稳定性试验显示,其对光、热、水分、空气等均较稳定,含量、释放度均无明显变化。
在释药机理的研究中,考察了几个影响较大的因素对缓释片释药的影响,最终判断缓释片的释药机理为non-Fickian扩散机制,即为药物扩散和骨架溶蚀协同作用的结果,其中扩散机制起主要支配作用。
以二氟尼柳普通片为参比制剂,进行了家犬的体内药动学研究。建立了高效液相色谱法,测定了二氟尼柳的血药浓度。药动学参数计算结果表明,二氟尼柳在自制片中与市售片中的Tmax分别为6.00±0.00h和2.08±0.49h；Cmax分别55.98±2.71μg·mL-1和91.81±6.41μg·mL-1：AUC0-t分别为911.45±99.67μg·h·mL-1和926.04±82.08μg·h·mL-1；相对生物利用度为95.20%,经统计分析法对AUC0-t、Cmax进行评价,自制二氟尼柳缓释与参比制剂AUC0-48生物等效,Cmax生物不等效。
Diflunisal, a non-steroidal salicylic acid derivatives class maked analgesic and antiphlogistic activeities. It has been mainly used for rheumatoid arthritis、osteoarthritis、sprain、strain and analgesia.For plain tablets, the usual administration was 3times daily. Frequent adminstrations led to fluctuation in blood concentration and high incidence of adverse effects. Therefore it was necessary to prepare a kind of sustained release preparations. Combining with other filers, a sustained release tablet(SRT) of once daily administration was prepared by using hydroxypropyl methyl-cellulose as basic matrix material.
According to the literature, UV spectrophotomatry was developed for in vitro assay of physicochemical properties, content and drug release. High-performance liquid chromatograpy (HPLC) was applied in the determination of plasma concentration in dogs. The method was quick and accurate which could meet the requirement of the analysis.
In the preformulation studies, the drug solubility in various mediums was determined. The influences of formulation, manufacture and release condition on the drug release were investigated with the accumulative drug release over 12 h as standard. Basing on the results of single-factor tests, orthogonal design test was carried out to optimize the formulation and the optimal tablet administrated once a day was screened. Stability studies of diflunisal-SRT showed that light, temperature, moisture and air had little effect on the content and release behavior of drug.
To study the mechanism of drug release, some factors which greatly influence the drug release were investigated. Finally drug release mechanism was confirmed as non-Fickian diffusion, which was the combination result of diffusion and erosion and mainly by diffusion.
Using diflunisal tablets as control, in vivo pharmacokinetics of prolong-released gel skeleton tablets prepared in this work in Beagle dogs was investigated. An appropriate HPLC method was developed for measuring the concentration of diflunisal in blood.
Pharmacokinetics parameters showed that Tm. of diflunisal in prolong-released gel skeleton tablets prepared in this work and controlled tablet were 5.17±1.33h and 2.17±0.68h;Cmax were 83.59±45.46μg·mL-1 and 96.21±14.61μg·mL-1; AUC(o-t) were 1287.35±819.80μg·h·mL-1 and 988.83±222.57μg·h·mL-1;relative bioavailability was 124.42%. In terms of the statistical analysis of AUC0-∞,it is concluded that the two preparations are inbioequivalence. The AUC0-∞of prepared prolong-released gel skeleton tablets is higher than it of the controlled tablets.
引文
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[5]Brogden RN,Heel RC, Pakes GE,et al.Diflunisal:a review of its pharmacological properties and therapeutic use in pain and muscu-loskeletal strains and sprains and pain in osteoarthritis. Drugs,1980,19(2):84-106
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[24]董志超,蒋雪涛.羟丙基甲基纤维素在凝胶骨架片中的应用.国外医药-合成药、生化药、制剂分册,1994,14(1)：41-44
[25]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(12)920-924
[26]刘清飞,罗国安,王义明.缓控释制剂释放度相似性评价方法的应用进展[J].中国药学杂志,2006,41(15)：1121-1124
[27]姜红,金少红.固体药物制剂的溶出度比较[J].中国药事,2000,14(5)：326-328
[28]夏锦辉,刘昌孝.固体药物制剂的体外溶出度的统计学评价分析[J].中国药学杂志,2000,35(2)：130-131
[29]陈家鼎,刘宛如.概率统计讲义.高等教育出版社.
[30]吴涛.硫酸沙丁胺醇渗透泵型控释片及其人工神经网络辅助处方设计的研究.沈阳药科大学博士学位论文
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[32]Adrian Bodea, Sorin E.Leucuta.Optimization of hydrophilic matrix tablets using a D-optimal design. Int.J.Pharm.1998,153:247-255
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[34]陆兵,徐国杰,张汝华.偏离度-缓控释制剂处方优化的指标.中国医药工业杂志,1999,30(8)：348-351
[35]Jeffrey W. Moore, Henry H. Flanner, Mathematical comparison of dissolution profiles. Pharm. Tech.1996,6:64-74
[36]夏锦辉,刘昌孝.固体药物制剂的体外溶出度的统计学评价分析.中国要学杂志,2000,35(2)：130-131
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[2]Tempero KF, Cirillo VJ, Steelman SL.Diflunisal:a review of pharmacokinetic and pharmacodynamic properties, drug inter-actions and special tolerability studies in humans [J].Br J ClinPharmacal,1997:4,31S.
[3]孟繁浩,王立升,贾伟儒.非甾体抗炎药二氟尼柳的合成.精细化工,2002,19(5)：252-253
[4]唐法娣,王砚.国产与进口二氟尼柳的实验性镇痛和抗炎作用的比较.中国新药与临床杂志,2002,21(8)：484-487
[5]Brogden RN,Heel RC, Pakes GE,et al.Diflunisal:a review of its pharmacological properties and therapeutic use in pain and muscu-loskeletal strains and sprains and pain in osteoarthritis. Drugs,1980,19(2):84-106
[6]汪年松,唐令诠.二氟尼柳的研究进展.中华综合医学,2002,3(5)：405-408.
[7]梁诚.二氟尼柳开发前景广阔.中国医药情报,2004,10(1)：26-27.
[8]陆彬.药物新剂型与新技术[M].北京：人民卫生出版社,1998,253-322
[9]Cheng K,Zhu JB,Song XX,et al.Study on hydroxypropyl methylcellulose donut-shaped tablets [J]. Drug Dev Ind Pharm,1999,25(9):1067-1071
[10]李腊蕊,朱家壁.口服固体缓控释制剂研究进展[J].中国药科大学学报,2006,37(1)：14-17
[11]Wan LSC, Heng PWS, Wong LF. Relationship between swelling and drug release in a hydrophilic matrix[J]. Drug Dev. Ind. Pharm,1993,19(10):1201-1210
[12]Bettini R, Colombo P, Masssimo G, et al. Swelling and drug release in hydrogel matrices: polymer viscosity and matrix porosity effects[J]. Euro. J. Pharm. Sci.,1994,2(3):213-219
[13]Colombo P, Bettini R, Masssimo G, et al. Drug diffusion front movement is important in drug release control from swellable matrix tablets [J]. J. Pharm. Sci.,1995,84(8):991-997
[14]徐冬羽,屠锡德.口服亲水凝胶骨架片的研究进展[J].药学进展,2002,26(1)：10-15
[15]肖秋生,蒋永培.羟丙甲基纤维素控释、缓释骨架片研究进展[J].西北药学杂志,2000,15(3)：133-135
[16]陈慧云,王建华,徐世荣.高分子材料纤维素醚类衍生物在缓释制剂辅料中的应用[J].材料导报,2005,19(7)：48-50,60
[17]吕丹,裴元英.羟丙基甲基纤维素—卡波普缓释凝胶亲水凝胶骨架片的研制和释药影响因素的考察[J].中国药学杂志,2001,36(9)：603-606
[18]平其能,胡一桥,周建平,等。现代药剂学,第一版[M]。北京：中国医药工业出版社,2001
[19]毕殿洲.药剂学,北京人民卫生出版社,2000年,13
[20]P.Colombo, P.catellani, N.A.Peppaset al. Swelling characteristics of hydrophilic matrices for controlled released; new dimensionless number to describe the swelling and release behavior.Int.J.Pharm.1992,88:99-109
[21]Thomas D. Reynolds, Stevin H. Gehrke, Ajaz S. Hussain et al. Polymer erosion and drug release characterization of hydroxypropyl methylcellulose matrices. J. Pharm.Sci.1998, 87(9):1115-1122
[22]F.Veiga, T.Salsa & E.Plna.Influence of technological variables on the release of theophylline from hydrophilic matrix tablets. Drug Dev.Ind.Pharm.1997,23(6):547-551
[23]T.Salsa, F.Veiga & M.E.Plna. Oral controlled-rel ease dosage forms. I. Cellulose ether polymer in hydrophilic matrices. Drug Dev.Ind.Pharm.1997,23(9):928-938
[24]董志超,蒋雪涛.羟丙基甲基纤维素在凝胶骨架片中的应用.国外医药-合成药、生化药、制剂分册,1994,14(1)：41-44
[25]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(12)920-924
[26]刘清飞,罗国安,王义明.缓控释制剂释放度相似性评价方法的应用进展[J].中国药学杂志,2006,41(15)：1121-1124
[27]姜红,金少红.固体药物制剂的溶出度比较[J].中国药事,2000,14(5)：326-328
[28]夏锦辉,刘昌孝.固体药物制剂的体外溶出度的统计学评价分析[J].中国药学杂志,2000,35(2)：130-131
[29]陈家鼎,刘宛如.概率统计讲义.高等教育出版社.
[30]吴涛.硫酸沙丁胺醇渗透泵型控释片及其人工神经网络辅助处方设计的研究.沈阳药科大学博士学位论文
[31]M.C. Bonferoni, S.Rossi & F.Ferrari er al.On the employment of λ carrageenan in a matrix system Ⅲ.Optimization of λ a carrageen an-HPMC hydrophilic matrix.J.Controlled Release.1998,51:231-239
[32]Adrian Bodea, Sorin E.Leucuta.Optimization of hydrophilic matrix tablets using a D-optimal design. Int.J.Pharm.1998,153:247-255
[33]G.J.Xu, F.Fang & R.H.Zhang et al. A research on aspirin sustained-release formulation.Drug Dev.Ind.Pharm.1997,23(8):741-747
[34]陆兵,徐国杰,张汝华.偏离度-缓控释制剂处方优化的指标.中国医药工业杂志,1999,30(8)：348-351
[35]Jeffrey W. Moore, Henry H. Flanner, Mathematical comparison of dissolution profiles. Pharm. Tech.1996,6:64-74
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