407缓释片的研究
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摘要
407是由我国药学学者从植物中提取的一种生物碱，其理化性质稳定，该药作为镇痛药已被中国药典收载。但由于407的治疗浓度与失效浓度比较接近，其药效仅能维持2小时左右，镇痛的同时具有较强的催眠作用，有些患者不便白天服用。多年来，由于以上原因不同程度地限制了该药的临床应用。市场上有普通片剂，30mg／片一日三次，使用不便。407缓释片的研制不仅可以缓解癌痛、牙痛、痛经患者夜间疼痛问题从而提高他们的睡眠质量，使单方的制剂起到复方制剂的作用，并且减少了用药次数方便了患者，尤其是去除了普通片严重的血药浓度的“峰谷”现象，使药物的安全性、有效性和适应性显著提高。而且407的缓释制剂在国内外文献中尚无报道，拟申请中华人民共和国发明专利。
407缓释片包括速释和缓释两部分，速释部分进入体内后迅速崩解、溶出，快速地达到治疗浓度，发挥药效；缓释部分在体内续持释药，保持血药浓度在治疗浓度以上，维持药效。本文通过单因素实验，考察了原、辅料粒度、颗粒粒度、硬度等工艺因素及HPMC用量、酒石酸用量等处方因素对药物释放的影响，初步筛选了处方。并在此基础上通过正交实验设计优化了处方和工艺；建立了体外释放度测定方法，确立了体外释放的拟合模型；建立了407体内药物浓度的测定方法，进行了动物的体内药代动力学实验，运用3p87计算机程序对407的动物数据进行了模型和参数拟合。
单因素实验考察结果表明：原、辅料粒度在60—120目之间，粒度在16—20目之间，硬度在40—60N之间，药物从制剂中的释放行为基本一致；HPMC可显著影响药物的释放，随其用量的增加释放呈下降趋势；酒石酸的用量以30mg／片为
军事医学科学院在职硕士学位论文
中文摘要
最优。通过正交实验设计确立了407缓释部分的处方和工艺，单因数实验确立了
速释部分处方和工艺，两者复合后体外实验证明释放度符合设计要求。
本文还建立了准确可靠的质量控制方法。休外释放度的测定采用紫外分光光
度法，并考察了在人工胃液及蒸馏水两种不同溶出介质中的释放行为，在两种条
件下，所建立方法的精密度和回收率均符合要求。经验证本缓释片的体外释放属
于pH非依赖性。407缓释片体外释放度实验结果表明:
1 HPMC在处方中所占百分比对释放度有显著影响。较理想的缓释处方是HPMC
的百分比为40%，致酸剂的百分比为20%，其体外释放行为符合Higuchi方程，
厂0.9921。速释部分主要以乳糖、微晶纤维素、交联PVP为敷料，体外smin可完
全崩解，15min释放完全。
2缓释片的硬度对体外释放无显著影响;转篮的速度对体外释放也无显著影响
(转篮的速度在100r/mln时符合夜间服药的情况);由于加入了致酸剂在蒸馏水和
人二胃液中，溶液pH对主药的释放无显著影响。
结合实验室条件，建立了高效液相一紫外检测法测定动物血浆中药物浓度，
407在l一25oug/ml范围内线形关系良好，二0.9321，n=5。最低检测浓度为300ng/ml，
满足动物体内血药浓度测定要求。
以407普通片为对照品，进行了动物体内药动学实验，采用3p87药动学程序
进行模型分析和参数计算，表明自制407缓释片的体内药物动力学符合二室模型，
运用SAS程序进行统计分析，证明比格犬口服同等剂量的双层片和普通片时，
MRT、tl。、Tmax、Cmax无显著性差异，k，0=0.149074<普通片的0.22429、AUC(计
算)二58.861>胀ㄆ?1.855有显著性差异。在tl尼、Tmax、Cmax保持基本不变的
情况下，消除减慢说明407缓释片具有较好的缓释效果。
本文研制了407的一种新的缓释制剂，体外释放度实验表明407缓释片具有良
好的速释和缓释效果，体内药动学实验进一步证明了双层片具有良好的缓释特征，
本文为进一步研究和开发奠定基础。
407 is a kind of alkaloid that was extracted from the plant by the pharmaceutical specialist of our country and its physical and chemical feature is stable. The tablet of 407 has been recorded by pharmacopoeia of China. But now that its therapeutic and lost concentration is much similar, therapeutic result of drug can only maintain about 2 hours. At the same time 407 ceases pain, it has a strong hypnotic impact. Consequently some valetudinarians are inconvenient to take it in the daytime. For many yeas, 407 has been confined to take in any degree in the hospital. Now, common tablet sale on the market, its dose is 30mg/tablet, three times one day, but takes it inconveniently. Study on sustained-release tablet of 407 might not only cease to pain in the night that was given rise to cancer, toothache, menstrual pain and so on, but also enhance their quality of sleeping, reduce valetudinarians to take drug frequently, specially take out serious phenomena of "valley". Therefore, the safety, availability and adapta
tion of drug might be enhanced obviously. And than the sustained-release tablet of 407 has not been reported in the national and international literature, if successfully, we may apply on the monopoly.
In order to enhance drug's therapeutic effect permanently and rapidly, we develop sustained-release tablet of 407 that includes in rapid-released slice and sustained-release
slice. In this article, the sustained-release slice were based on HPMC, the rapid-release slice were based on cross-PVP. Some factors that may affect the drug dissolution, such as particle size of 407, granule size, hardness and amount of HPMC or L (+)-Tartaric acid were studied. It was shown that particle size of HPMC and 407, granule size, hardness has little effect on drug dissolution, but the amount of HPMC and L (+)-Tartaric acid affected dramatically. On the basis of single factor test, the better formulation and preparing technique were optimized through orthogonal design and dissolution behavior was also investigated. In this study a UV spectrum method to assay the amount of 407 released from the preparation in simulated gastric fluid and distilled water was established, and established the released mode of drug in vitro. A method of HPLC detect for the quantitative analysis of 407 in beagle dog plasma was set up with codeine as internal standard. Pharmacokinetic parameters were managed using 3p87 Pharmacokinetic program.
Single factors test shows that particle size of HPMC and 407, granule size, from 60 to 120 mu, hardness from 40 to 60 mu, have little effect on drug dissolution. The more amount of HPLC, the less amount of drug dissolved. The best suitable amount of L (+)-Tartaric acid is 30mg each tablet. The formulation and preparing technique were optimized through orthogonal design.
In this study a UV spectrum method to assay the amount of 407 released from the preparation in simulated gastric fluid and distilled water was established. And the result indicated that the drug dissolution from the preparation was pH-independent. Sustained-released tablet of 407 of test result in vitro show:
1 The amount of HPMC in the recipe has effect on discharge dramatically. The better recipe is that HPMC is forty percent, L (+)-Tartaric acid is twenty percent in the whole. The mode of drug release in vitro was suitable for Higuchi program, r=0.9921.
2 The hardness and speed of basket has little effect on drug dissolution; by reason that goes into L (+)-Tartaric acid in simulated gastric fluid and distilled water, the drug
dissolution from the preparation was pH-independent.
3 According to our lab condition, a method of HPLC detect for the quantitative analysis of 407 in beagle dog plasma was set up with codeine as internal standard. The standard curve was linear in the range of l-250um/ml, r=0.9321,n=5.the lowest detection define is 300ng/ml, and suitable for test demand.
Pharmacokinetic parameters were evaluated in vivo in 6 beagle dogs with 407 common tablets as reference standard. The data were managed using 3p87 Pharmacokinetic
407缓释片包括速释和缓释两部分，速释部分进入体内后迅速崩解、溶出，快速地达到治疗浓度，发挥药效；缓释部分在体内续持释药，保持血药浓度在治疗浓度以上，维持药效。本文通过单因素实验，考察了原、辅料粒度、颗粒粒度、硬度等工艺因素及HPMC用量、酒石酸用量等处方因素对药物释放的影响，初步筛选了处方。并在此基础上通过正交实验设计优化了处方和工艺；建立了体外释放度测定方法，确立了体外释放的拟合模型；建立了407体内药物浓度的测定方法，进行了动物的体内药代动力学实验，运用3p87计算机程序对407的动物数据进行了模型和参数拟合。
单因素实验考察结果表明：原、辅料粒度在60—120目之间，粒度在16—20目之间，硬度在40—60N之间，药物从制剂中的释放行为基本一致；HPMC可显著影响药物的释放，随其用量的增加释放呈下降趋势；酒石酸的用量以30mg／片为
军事医学科学院在职硕士学位论文
中文摘要
最优。通过正交实验设计确立了407缓释部分的处方和工艺，单因数实验确立了
速释部分处方和工艺，两者复合后体外实验证明释放度符合设计要求。
本文还建立了准确可靠的质量控制方法。休外释放度的测定采用紫外分光光
度法，并考察了在人工胃液及蒸馏水两种不同溶出介质中的释放行为，在两种条
件下，所建立方法的精密度和回收率均符合要求。经验证本缓释片的体外释放属
于pH非依赖性。407缓释片体外释放度实验结果表明:
1 HPMC在处方中所占百分比对释放度有显著影响。较理想的缓释处方是HPMC
的百分比为40%，致酸剂的百分比为20%，其体外释放行为符合Higuchi方程，
厂0.9921。速释部分主要以乳糖、微晶纤维素、交联PVP为敷料，体外smin可完
全崩解，15min释放完全。
2缓释片的硬度对体外释放无显著影响;转篮的速度对体外释放也无显著影响
(转篮的速度在100r/mln时符合夜间服药的情况);由于加入了致酸剂在蒸馏水和
人二胃液中，溶液pH对主药的释放无显著影响。
结合实验室条件，建立了高效液相一紫外检测法测定动物血浆中药物浓度，
407在l一25oug/ml范围内线形关系良好，二0.9321，n=5。最低检测浓度为300ng/ml，
满足动物体内血药浓度测定要求。
以407普通片为对照品，进行了动物体内药动学实验，采用3p87药动学程序
进行模型分析和参数计算，表明自制407缓释片的体内药物动力学符合二室模型，
运用SAS程序进行统计分析，证明比格犬口服同等剂量的双层片和普通片时，
MRT、tl。、Tmax、Cmax无显著性差异，k，0=0.149074<普通片的0.22429、AUC(计
算)二58.861>胀ㄆ?1.855有显著性差异。在tl尼、Tmax、Cmax保持基本不变的
情况下，消除减慢说明407缓释片具有较好的缓释效果。
本文研制了407的一种新的缓释制剂，体外释放度实验表明407缓释片具有良
好的速释和缓释效果，体内药动学实验进一步证明了双层片具有良好的缓释特征，
本文为进一步研究和开发奠定基础。
407 is a kind of alkaloid that was extracted from the plant by the pharmaceutical specialist of our country and its physical and chemical feature is stable. The tablet of 407 has been recorded by pharmacopoeia of China. But now that its therapeutic and lost concentration is much similar, therapeutic result of drug can only maintain about 2 hours. At the same time 407 ceases pain, it has a strong hypnotic impact. Consequently some valetudinarians are inconvenient to take it in the daytime. For many yeas, 407 has been confined to take in any degree in the hospital. Now, common tablet sale on the market, its dose is 30mg/tablet, three times one day, but takes it inconveniently. Study on sustained-release tablet of 407 might not only cease to pain in the night that was given rise to cancer, toothache, menstrual pain and so on, but also enhance their quality of sleeping, reduce valetudinarians to take drug frequently, specially take out serious phenomena of "valley". Therefore, the safety, availability and adapta
tion of drug might be enhanced obviously. And than the sustained-release tablet of 407 has not been reported in the national and international literature, if successfully, we may apply on the monopoly.
In order to enhance drug's therapeutic effect permanently and rapidly, we develop sustained-release tablet of 407 that includes in rapid-released slice and sustained-release
slice. In this article, the sustained-release slice were based on HPMC, the rapid-release slice were based on cross-PVP. Some factors that may affect the drug dissolution, such as particle size of 407, granule size, hardness and amount of HPMC or L (+)-Tartaric acid were studied. It was shown that particle size of HPMC and 407, granule size, hardness has little effect on drug dissolution, but the amount of HPMC and L (+)-Tartaric acid affected dramatically. On the basis of single factor test, the better formulation and preparing technique were optimized through orthogonal design and dissolution behavior was also investigated. In this study a UV spectrum method to assay the amount of 407 released from the preparation in simulated gastric fluid and distilled water was established, and established the released mode of drug in vitro. A method of HPLC detect for the quantitative analysis of 407 in beagle dog plasma was set up with codeine as internal standard. Pharmacokinetic parameters were managed using 3p87 Pharmacokinetic program.
Single factors test shows that particle size of HPMC and 407, granule size, from 60 to 120 mu, hardness from 40 to 60 mu, have little effect on drug dissolution. The more amount of HPLC, the less amount of drug dissolved. The best suitable amount of L (+)-Tartaric acid is 30mg each tablet. The formulation and preparing technique were optimized through orthogonal design.
In this study a UV spectrum method to assay the amount of 407 released from the preparation in simulated gastric fluid and distilled water was established. And the result indicated that the drug dissolution from the preparation was pH-independent. Sustained-released tablet of 407 of test result in vitro show:
1 The amount of HPMC in the recipe has effect on discharge dramatically. The better recipe is that HPMC is forty percent, L (+)-Tartaric acid is twenty percent in the whole. The mode of drug release in vitro was suitable for Higuchi program, r=0.9921.
2 The hardness and speed of basket has little effect on drug dissolution; by reason that goes into L (+)-Tartaric acid in simulated gastric fluid and distilled water, the drug
dissolution from the preparation was pH-independent.
3 According to our lab condition, a method of HPLC detect for the quantitative analysis of 407 in beagle dog plasma was set up with codeine as internal standard. The standard curve was linear in the range of l-250um/ml, r=0.9321,n=5.the lowest detection define is 300ng/ml, and suitable for test demand.
Pharmacokinetic parameters were evaluated in vivo in 6 beagle dogs with 407 common tablets as reference standard. The data were managed using 3p87 Pharmacokinetic
引文
1 中国药典．2000年版二部．P391-392
2 张静、平其能．口服择时释药系统 药学近展，1999年23卷第5期
3 张宁 口服缓控释制剂技术发展的新动向 国外医学药学分册 2000年8月第27卷第4期
4 胡良平等．现代统计学与SAS应用．军事医学科学出版社．北京．1996．4
5 Higuchi T. Rate of release of medicament from ointment base containing drug in suspension. J Pharm. Sci. 1961,50:874-876
6 郑俊民等．药用高分子材料学．中国医药科技出版社．P104
7 罗云等．交联聚维酮对乙酰氨基酚片的影响．中国医院药学杂志．1999年第19卷第11期P670
8 毕殿洲等．药剂学．人民卫生出版社．第四版．P57
9 Jantzen GM, Robinson JR. Medem Pharmaceutics, Banker GS&Rhode CT.3ed.New York:Marcel Dekker Inc, 1996:590-592
10 张金风，潭力等．HPLC测定人体血浆中罗痛定浓度及药代动力学研究．中国科大学学报．1998,29(1)：67-70．南京
11 魏树礼等．生物药剂学与药物动力学．北京医科大学／中国协和医科大学联合出版社．1997．北京
12 梁文权等．生物药剂学与药物动力学．人民卫生出版社．2000．北京
2 张静、平其能．口服择时释药系统 药学近展，1999年23卷第5期
3 张宁 口服缓控释制剂技术发展的新动向 国外医学药学分册 2000年8月第27卷第4期
4 胡良平等．现代统计学与SAS应用．军事医学科学出版社．北京．1996．4
5 Higuchi T. Rate of release of medicament from ointment base containing drug in suspension. J Pharm. Sci. 1961,50:874-876
6 郑俊民等．药用高分子材料学．中国医药科技出版社．P104
7 罗云等．交联聚维酮对乙酰氨基酚片的影响．中国医院药学杂志．1999年第19卷第11期P670
8 毕殿洲等．药剂学．人民卫生出版社．第四版．P57
9 Jantzen GM, Robinson JR. Medem Pharmaceutics, Banker GS&Rhode CT.3ed.New York:Marcel Dekker Inc, 1996:590-592
10 张金风，潭力等．HPLC测定人体血浆中罗痛定浓度及药代动力学研究．中国科大学学报．1998,29(1)：67-70．南京
11 魏树礼等．生物药剂学与药物动力学．北京医科大学／中国协和医科大学联合出版社．1997．北京
12 梁文权等．生物药剂学与药物动力学．人民卫生出版社．2000．北京
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