TP缓释片的研制及体内外相关性评价
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摘要
本课题以光学活性体TP为模型药物探讨在生物药剂学和药物动力学理论指导下进行缓释片研制的思路和方法。课题选用HPMC为基本骨架材料，预胶化淀粉为压片助剂，硬脂酸镁为润滑剂制备了能在体外持续释放12h的TP缓释片。在处方筛选和工艺优化的研究中，以不改变TP的光学活性为前提，以片剂的基本药剂学要求为指标，初步考察并确定了TP缓释片的基本处方和制备工艺。释放度是影响缓释片内在质量的重要因素，初步建立了TP缓释片释放度测定的方法，考察了影响TP缓释片释放的各种因素，在单因素考察的基础上采用正交实验优化了缓释处方，优化处方释放度验证实验表明，在既定的释放度测定方法条件下，TP缓释片中TP在2h、6h、10h的累计释放度分别为15～35％、40～60％和75％以上。f2相似因子分析表明，优化后的TP缓释片释放重现性好，工艺稳定。
在TP缓释片的质量评价研究中，建立了TP缓释片的鉴别方法；通过比较紫外分光光度法和HPLC法，确定了缓释片中TP的HPLC的含量测定方法，并据此建立了TP缓释片的释放度测定方法；建立了TP缓释片有关物质的检查方法。对TP缓释片的质量评价研究并按研究项目进行考察，结果表明，TP缓释片质量评价方法科学合理，TP缓释片质量可控。研究了TP缓释片的释放规律，结果用Ritgcr-Pcppas方程较好的描述了其规律，释放参数n=0.7439，0.45＜n＜0.89，说明药物的释放机制是扩散和骨架溶蚀的协同作用。
TP缓释片的研制及体内外相关胜钾价
对TP缓释片进行初步稳定性研究，稳定性影响因素实验结果表明，
高热和光照对TP缓释片稳定性影响不显著，而高湿对其有影响。提示本
产品应采用防潮包装，置干燥处保存。
进行了家犬体内TP缓释片药物动力学和生物利用度的研究。建立了
TP在家犬血浆中的RP一HPLC测定方法，方法学研究及药物动力学试验
结果表明，该方法较好的满足了试验研究的需要。采用自身对照交叉试
验设计方法，以TP普通片为参比制剂进行了单剂量和多剂量试验，试验
结果表明，单剂量或多剂量给予家犬即缓释片后，仰在家犬体内的药
动学模型符合一室模型。对TP的药动学参数分别计算，结果表明，单剂
量给予家犬供试品T和参比制剂R后，AUC。一t分别是:1463.1士223.9
ng·h·d一1与1443.3土262.2ng·h·nil一，;腼分别为:4.5士0.3h与1.5士0.3
h;Cmax分别是:1 5 1 .3士20.5 ng·nil一，与335.5士69.3 ng·nil一，。以TP普通
片为参比制剂。多剂量给予家犬供试品T和参比制剂R后，AuCO一:分别
是:1557.2士92.3 ng·h·ml一，与1554.2士8一8飞·h·ml一‘;tmax分别为:4.4
士0.2h与1 .7士o.3h;Cmax分别是:205.9士6.7 ng·ml一1与430.5士26.0
ngol一，。多剂量给药TP缓释片和普通片的cav分别为129.8士7.7与259.0
士13.6;DF分别是121.1%士 163%与144.4%土13.5%;平均稳态血药
谷浓度Cssm、。分别是5 1 .7士1 5.01 ng·而一，与亏6.5士15.3 ng·ml一，。TP缓释
片家犬单剂量给药的相对生物利用度为]02.0%士6.2%;多剂量给药的
相对生物利用度为100.2%士5.4%。生物等效性评价结果表明，AUC生
物等效，cmax和tmax生物不等效，cmax和DF较普通片小，tmax延长，
TP缓释片有明显的缓释特征，初步达到了课题设计的目的。
采用wanger一Nelson法和逆卷积分法对TP缓释片的体内外相关性进
行评价，结果皆证明了TP缓释片体内外相关性显著，释放度测定方法科
学合理，并可对TP缓释片内在质量的可控性提供保证。
TP缓释片的研制国内外均未见报道，关于光学活性体TP可供参考
冲级释片的翩阅时娜洲冲珍泪钾价
的资料少，工作具有一定的探索性。研究结果为TP多种剂型的综合开发
奠定了良好的基础.
本课题探讨了以光学活性体为模型药物的缓释制剂开发研制的一般
途径，为手性药物在生物药剂学和药物动力学理论指导下进行缓释制剂
处方工艺筛选和质量控制提供方法和思路。
The paper discussed the thinking and the pathway of the manufacture of sustained-release form based on a optical activity-TP as model drug by using the principles of biophamaceutics and pharmacokinetics. The thesis adopted HPMC as the basic matrix material, pregelatinized starch as compression aids, magnesium stearate as lubricant.The TP sustained-release tablet was prepared which could release twelve hours continuously in vitro.The basic prescription and preparation technology was initially defined by the study about formulation screening and technology optimizing ,based on the pharmacy rule as indicator and the stability maintaining of optical activity as premiss.Dissolution rate is an important factor of influencing internal quality of tablet. The determination method was initially set up for the dissolution rate of the TP sustained-release tablet. And the various factors were studied,which influence the TP release of TP sustained-release tablet.Orthogonal project was employed to screen the prescriptions
which based on the study of mono-factor experiment. Verification experiments about the dissolution rate of optimized prescription were done . The results showed that the dissolution rate of TP among the TP sustained-release tablets at 2h,6h,10h was 15~35%,40~60%,>75% respectively.The f2 similar factor analysis explained that the recur capability of TP sustained-release
tablets releasing was good and the craft was stable.
The quality study of the TP sustained-release tablet was done.The main components included that the identification methods were set up,the HPLC method was established for the content determination of the TP in the TP sustained-release tablet by the comparison of UV method and HPLC method, and the TP sustained-release tablet examining method of the correlated material was founded. The studing results according to items of the quality evaluating showed that evaluating method was reasonable and the quality of the TP sustained-release tablet was under the control. The release law of the TP sustained-release tablet was studied, the Ritger-Peppas equation describes the law,and the n,the releasing parameter,equaling to 0.7439(0.45 The initial stability study showed that high temperature and light have not obvious effects on the TP sustained-release tablet but the humidity was of influence. The result gave a clue that the TP sustained-release tablet should be packed in moistureproof material and preserved under dry enviroment.
The pharmacokinetics and bioavailability study of the TP sustained-release tablet in dogs was made.The HPLC method which determinates the TP concentration in the dog plasma was established.The results of the method evaluaion and pharmacokinetics experiment showed that the method could satisfy the needs of experiment and study. As the TP ordinary tablet being the reference preparation,experiments of single and multiple dosage regimens were done by self-comparison crossing trial design.The result indicated that the TP fits the one-compartment. After administering single dosage of the sample and the reference preparation to dogs respectively, AUC0-t is 1463.1 223.9 ng-h-ml-1 and 1443.3 262.2 ng h ml-1 respectively; tmax is 4.5 0.3 h and 1.5 0.3 h respectively, Cmax
is 151.3 20.5 ng-rnl-1 and 338.5 69.3 ng-ml-1 respectively. After
administering multiple dosage to dogs, AUC0- is 1557.2 92.3 ng h ml-1 and 1554.2 81.8 ng h ml-1 respectively; tmax is 4.4 0.2 h and 1.7 0.3h respectively; Cmax is 208.9 6.7 ng ml-1 and 430.5 26.0 ng ml-1 respectively;Cav is 129.8 7.7 and 259.0 13.6 respectively;DF is 121.1% 16.3% and 144.4% 13.5% respectively;Cssmin is 51.7 15.01 ng-ml-1 and 56.5 18.3 ng ml-1 respectively; relative bioavailability of single and multiple dosage regimens is 102.0 % 6.2 % and 100.2 % 5.4 % respectively.The evaluation result of bioequivalence showed that AUC is bioequivalent but Cmax and tmax are beyond the confine . The Cmax and the DF
在TP缓释片的质量评价研究中，建立了TP缓释片的鉴别方法；通过比较紫外分光光度法和HPLC法，确定了缓释片中TP的HPLC的含量测定方法，并据此建立了TP缓释片的释放度测定方法；建立了TP缓释片有关物质的检查方法。对TP缓释片的质量评价研究并按研究项目进行考察，结果表明，TP缓释片质量评价方法科学合理，TP缓释片质量可控。研究了TP缓释片的释放规律，结果用Ritgcr-Pcppas方程较好的描述了其规律，释放参数n=0.7439，0.45＜n＜0.89，说明药物的释放机制是扩散和骨架溶蚀的协同作用。
TP缓释片的研制及体内外相关胜钾价
对TP缓释片进行初步稳定性研究，稳定性影响因素实验结果表明，
高热和光照对TP缓释片稳定性影响不显著，而高湿对其有影响。提示本
产品应采用防潮包装，置干燥处保存。
进行了家犬体内TP缓释片药物动力学和生物利用度的研究。建立了
TP在家犬血浆中的RP一HPLC测定方法，方法学研究及药物动力学试验
结果表明，该方法较好的满足了试验研究的需要。采用自身对照交叉试
验设计方法，以TP普通片为参比制剂进行了单剂量和多剂量试验，试验
结果表明，单剂量或多剂量给予家犬即缓释片后，仰在家犬体内的药
动学模型符合一室模型。对TP的药动学参数分别计算，结果表明，单剂
量给予家犬供试品T和参比制剂R后，AUC。一t分别是:1463.1士223.9
ng·h·d一1与1443.3土262.2ng·h·nil一，;腼分别为:4.5士0.3h与1.5士0.3
h;Cmax分别是:1 5 1 .3士20.5 ng·nil一，与335.5士69.3 ng·nil一，。以TP普通
片为参比制剂。多剂量给予家犬供试品T和参比制剂R后，AuCO一:分别
是:1557.2士92.3 ng·h·ml一，与1554.2士8一8飞·h·ml一‘;tmax分别为:4.4
士0.2h与1 .7士o.3h;Cmax分别是:205.9士6.7 ng·ml一1与430.5士26.0
ngol一，。多剂量给药TP缓释片和普通片的cav分别为129.8士7.7与259.0
士13.6;DF分别是121.1%士 163%与144.4%土13.5%;平均稳态血药
谷浓度Cssm、。分别是5 1 .7士1 5.01 ng·而一，与亏6.5士15.3 ng·ml一，。TP缓释
片家犬单剂量给药的相对生物利用度为]02.0%士6.2%;多剂量给药的
相对生物利用度为100.2%士5.4%。生物等效性评价结果表明，AUC生
物等效，cmax和tmax生物不等效，cmax和DF较普通片小，tmax延长，
TP缓释片有明显的缓释特征，初步达到了课题设计的目的。
采用wanger一Nelson法和逆卷积分法对TP缓释片的体内外相关性进
行评价，结果皆证明了TP缓释片体内外相关性显著，释放度测定方法科
学合理，并可对TP缓释片内在质量的可控性提供保证。
TP缓释片的研制国内外均未见报道，关于光学活性体TP可供参考
冲级释片的翩阅时娜洲冲珍泪钾价
的资料少，工作具有一定的探索性。研究结果为TP多种剂型的综合开发
奠定了良好的基础.
本课题探讨了以光学活性体为模型药物的缓释制剂开发研制的一般
途径，为手性药物在生物药剂学和药物动力学理论指导下进行缓释制剂
处方工艺筛选和质量控制提供方法和思路。
The paper discussed the thinking and the pathway of the manufacture of sustained-release form based on a optical activity-TP as model drug by using the principles of biophamaceutics and pharmacokinetics. The thesis adopted HPMC as the basic matrix material, pregelatinized starch as compression aids, magnesium stearate as lubricant.The TP sustained-release tablet was prepared which could release twelve hours continuously in vitro.The basic prescription and preparation technology was initially defined by the study about formulation screening and technology optimizing ,based on the pharmacy rule as indicator and the stability maintaining of optical activity as premiss.Dissolution rate is an important factor of influencing internal quality of tablet. The determination method was initially set up for the dissolution rate of the TP sustained-release tablet. And the various factors were studied,which influence the TP release of TP sustained-release tablet.Orthogonal project was employed to screen the prescriptions
which based on the study of mono-factor experiment. Verification experiments about the dissolution rate of optimized prescription were done . The results showed that the dissolution rate of TP among the TP sustained-release tablets at 2h,6h,10h was 15~35%,40~60%,>75% respectively.The f2 similar factor analysis explained that the recur capability of TP sustained-release
tablets releasing was good and the craft was stable.
The quality study of the TP sustained-release tablet was done.The main components included that the identification methods were set up,the HPLC method was established for the content determination of the TP in the TP sustained-release tablet by the comparison of UV method and HPLC method, and the TP sustained-release tablet examining method of the correlated material was founded. The studing results according to items of the quality evaluating showed that evaluating method was reasonable and the quality of the TP sustained-release tablet was under the control. The release law of the TP sustained-release tablet was studied, the Ritger-Peppas equation describes the law,and the n,the releasing parameter,equaling to 0.7439(0.45
The pharmacokinetics and bioavailability study of the TP sustained-release tablet in dogs was made.The HPLC method which determinates the TP concentration in the dog plasma was established.The results of the method evaluaion and pharmacokinetics experiment showed that the method could satisfy the needs of experiment and study. As the TP ordinary tablet being the reference preparation,experiments of single and multiple dosage regimens were done by self-comparison crossing trial design.The result indicated that the TP fits the one-compartment. After administering single dosage of the sample and the reference preparation to dogs respectively, AUC0-t is 1463.1 223.9 ng-h-ml-1 and 1443.3 262.2 ng h ml-1 respectively; tmax is 4.5 0.3 h and 1.5 0.3 h respectively, Cmax
is 151.3 20.5 ng-rnl-1 and 338.5 69.3 ng-ml-1 respectively. After
administering multiple dosage to dogs, AUC0- is 1557.2 92.3 ng h ml-1 and 1554.2 81.8 ng h ml-1 respectively; tmax is 4.4 0.2 h and 1.7 0.3h respectively; Cmax is 208.9 6.7 ng ml-1 and 430.5 26.0 ng ml-1 respectively;Cav is 129.8 7.7 and 259.0 13.6 respectively;DF is 121.1% 16.3% and 144.4% 13.5% respectively;Cssmin is 51.7 15.01 ng-ml-1 and 56.5 18.3 ng ml-1 respectively; relative bioavailability of single and multiple dosage regimens is 102.0 % 6.2 % and 100.2 % 5.4 % respectively.The evaluation result of bioequivalence showed that AUC is bioequivalent but Cmax and tmax are beyond the confine . The Cmax and the DF
引文
1 中国药典2000版。
2 梁文权，生物药剂学与药物动力学，第一版，北京，人民卫生出版社，2000。
3 刘昌孝，孙瑞元，药物评价实验设计与统计学基础，第一版，北京，军事医学科学出版社，1999。
4 蔡正千，热分析，1993，第一版。
5 李发美，医药高效液相色谱技术，第一版，北京，人民卫生出版社，1999。
6 高声传等，双氯芬酸赖氨酸盐缓释片的制备及初步稳定性研究，中国药房，2001，12(6)：340。
7 魏霞等，盐酸安非他酮缓释片的研制，中国药科大学学报，2002，33(1)：13。
8 张正等，普罗布考包合物胶囊在家犬体内的药代动力学与相对生物利用度，药学学报，2002，37(3)：210。
9 张波等，盐酸曲普利啶的人体药代动力学及相对生物利用度，中国临床药理学杂志，2002，15(2)：116。
10 崔一民等，国产格列吡嗪片剂生物等效性研究，2001，10(3)：194。
11 郁继诚等，国产罗红霉素胶囊剂的药代动力学及相对生物利用度测定，中国新药杂志，2001，10(9)：685。
12 Han GY, Chow SC. Dissolution profile comparison versus bioequivalence. Drug Clinical Development and application of statistics, 1997(session 4):49.
13 刘昌孝等，缓释制剂的药物动力学原理及其评价，天津药学，1999，11(1)：1。
14 Humbert H et al, In vivo-in vitro correlation of a modified-release oral form of ketotifen:in vetro dissolution rate specification, J Pharm Sci,1994,83(2):131.
15 丁劲松等，萘哌地尔缓释胶囊的体外释放与体内吸收相关性研究，中国药房 2001，12(7)：395。
16 Wang Y, Nedelman J. Bias in the Wagner-Nelson estimate of the
fraction of drug absorbed. Pharm Res. 2002 Apr; 19(4):470.
17 Szakacs T, Veres Z, Vereczkey L. In vitro-in vivo correlation of the pharmacokinetics of vinpocetine.Pol J Pharmacol. 2001 Nov-Dec;53(6):623.
18 Tojo K, Isowaki A. Pharmacokinetic model for in vivo/in vitro correlation of intravitreal drag delivery. Adv Drag Deliv Rev. 2001 Oct 31;52(1):17.
19 董志超，羟丙基甲基纤维素在凝胶骨架片中的应用，国外医药，1993，14(1)：41。
20 董志超，羟丙基甲基纤维素在凝胶骨架片中的含量与水溶性药物释放机制的关系，药学学报，1996，31(1)：43。
21 夏之宁，正交设计与均匀设计的初步比较，重庆大学学报，1999，22(50)：112。
22 袁才英，运用正交试验优选氢溴酸高乌甲素制片工艺，广东药学 2001，11(2)：19。
23 高英，均匀设计与正交设计在金莲花提取工艺筛选研究中的比较应用，中国实验方剂学杂志，2002，8(1)：1。
24 Orienti I, Trere R. Hydrogels Formed by Crosslinked Poly as Sustained Drug Delivery Systems. Arch Pharm (Weinheim). 2002;335(2):89.
25 胡一桥，胰岛素聚乳酸微球处方筛选，中国药学杂志，1999，34(12)：822。
26 邓蓉玲等，洛伐他丁缓释片的制备和体外释药的研究，华西药学杂志，2001，16(4)：265。
27 肖秋生，羟丙甲基纤维素控释、缓释骨架片研究进展，西北药学杂志，2000，15(3)：133。
28 苏杰，亲水凝胶在药物制剂中的应用，药学进展，1999，23(3)：143。
29 董皎，压力作用对羟丙基甲基纤维素和聚羧乙烯结构及其相互作用的影响，第二军医大学学报，1999，20(1)：63。
30 柳晨，阿司匹林HPMC骨架片药物释放因素研究，中国药学杂志，1999，34(10)：674。
2 梁文权，生物药剂学与药物动力学，第一版，北京，人民卫生出版社，2000。
3 刘昌孝，孙瑞元，药物评价实验设计与统计学基础，第一版，北京，军事医学科学出版社，1999。
4 蔡正千，热分析，1993，第一版。
5 李发美，医药高效液相色谱技术，第一版，北京，人民卫生出版社，1999。
6 高声传等，双氯芬酸赖氨酸盐缓释片的制备及初步稳定性研究，中国药房，2001，12(6)：340。
7 魏霞等，盐酸安非他酮缓释片的研制，中国药科大学学报，2002，33(1)：13。
8 张正等，普罗布考包合物胶囊在家犬体内的药代动力学与相对生物利用度，药学学报，2002，37(3)：210。
9 张波等，盐酸曲普利啶的人体药代动力学及相对生物利用度，中国临床药理学杂志，2002，15(2)：116。
10 崔一民等，国产格列吡嗪片剂生物等效性研究，2001，10(3)：194。
11 郁继诚等，国产罗红霉素胶囊剂的药代动力学及相对生物利用度测定，中国新药杂志，2001，10(9)：685。
12 Han GY, Chow SC. Dissolution profile comparison versus bioequivalence. Drug Clinical Development and application of statistics, 1997(session 4):49.
13 刘昌孝等，缓释制剂的药物动力学原理及其评价，天津药学，1999，11(1)：1。
14 Humbert H et al, In vivo-in vitro correlation of a modified-release oral form of ketotifen:in vetro dissolution rate specification, J Pharm Sci,1994,83(2):131.
15 丁劲松等，萘哌地尔缓释胶囊的体外释放与体内吸收相关性研究，中国药房 2001，12(7)：395。
16 Wang Y, Nedelman J. Bias in the Wagner-Nelson estimate of the
fraction of drug absorbed. Pharm Res. 2002 Apr; 19(4):470.
17 Szakacs T, Veres Z, Vereczkey L. In vitro-in vivo correlation of the pharmacokinetics of vinpocetine.Pol J Pharmacol. 2001 Nov-Dec;53(6):623.
18 Tojo K, Isowaki A. Pharmacokinetic model for in vivo/in vitro correlation of intravitreal drag delivery. Adv Drag Deliv Rev. 2001 Oct 31;52(1):17.
19 董志超，羟丙基甲基纤维素在凝胶骨架片中的应用，国外医药，1993，14(1)：41。
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