盐酸尼卡地平渗透泵控释片的研究
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摘要
本文主要研究了难溶性药物盐酸尼卡地平双层渗透泵控释片的处方工艺、生物利用度及其体内外相关性，并对该药的单室单层渗透泵控释片的处方及工艺进行了初步考察。
在对盐酸尼卡地平双层渗透泵控释片处方工艺研究时，先以12小时累积释放百分量和释放线性相关系数r为考察指标，对各因素(片芯和衣膜处方、相关工艺以及体外释药条件)进行单因素考察，选出显著影响因素，然后以3、8和12小时的累积释放百分量F_3，F_8和F_(12)为考察指标，经多元逐步回归后，用L_9(3~4)表对处方进行正交设计，筛选最优处方。研究结果表明：盐酸尼卡地平双层渗透泵控释片体外12小时内累积释放百分量大于80％，16小时内释药完全(＞90％)，12小时内零级释放特征明显(r=0.9994)；盐酸尼卡地平单室单层渗透泵控释片体外12小时内累积释放百分量达77.6％，12小时内零级释放特征明显(r=0.9900)，但16小时内的最终释放百分量小于90％(释放不完全)。
在进行盐酸尼卡地平双层渗透泵控释片体内药代动力学研究时，选用市售普通片为参比制剂，以6只健康家犬为试验对象，一次口服相同剂量进行生物利用度和体内外相关性考察。采用HPLC法对血药浓度进行测定，控释片和普通片的T_(max)分别为7.0±1.6h和1.2±0.4h；C_(max)分别为49.3±7.2ng／ml和139.6±10.5ng／ml；t_(1/2)分别8.6±1.3h和2.3±0.4h；k_e分别为0.08±0.01h~(-1)和0.3±0.1 h~(-1)；AUC_(0→∞)分别为1016.3±66.9 ng·h／ml和921.3±16.0ng·h／ml。控释片的相对生物利用度为110.3％；体内外相关性良好(r为0.9900)。
本文的研究结果表明：以聚氧乙烯为主要辅料，用醋酸纤维素包衣制成的盐酸尼卡地平双层渗透泵控释片具有明显的控释作用。
This paper is mainly researching on the recipe, technique, bioavailability and in vitro-in vivo correlation of insoluble nicardipine hydrochloride' s bi-layer osmotic pump tablets; a preliminary research on the recipe of the said drug' s mono-layer osmotic pump tablets has also been involved.
While researching on the recipe and technique of the bi-layer osmotic pump tablets, first , we used the cumulative release amount within 12 hours and the linear release to measure the influence of the factors (core of the tablets, membrane compositions, relative techniques and in vitro-in vivo release conditions) by single-factor analysis method, and selected the dominatingly influence factors. Second, we used 3 hours, 8 hours, 12 hours cumulative release amount F3, F8, F12 as the index to screen the best recipe with multivariable linear stepwise regressing analysis. Finally , we picked out optimized prescription by 34 factors-analysis orthogonal design. We found that the bi-layer osmotic tablets cumulatively released the drug more than 80% in 12 hours, and completely released the drug within 16 hours (>90%), owning obvious zero-order release characters(r=0. 9994) within 12 hours. While the mono-layer osmotic tablets cumulative released
only 77. 6% in 12 hours and the utmost release amount was below 90%( not completely release), with obvious zero-order release characters.
While researching on the drug' s in-vivo pharmacokinetics of the bi-layer osmotic pump tablets, we selected normal tablets as contrast preparation containing the same drug, 6 healthy dogs as test objects, to administrate in the same dose once and measured the bioavailability in vitro-in vivo correlation in plasma with HPLC. The results showed: Tmax of bi-layer osmotic tablet and normal tablet was 7.0±1.6h and 1.2±0.4h respectively; Cmax was 43. 3 ± 7. 2ng/ml and 139. 36 + 10. 5ng/ml; Tl/2 was 8.6=1.3 and 2.3 ±0.4h; Ke was 0.08 ± 0. 01h-1 and 0.3±0. 1h-1; AUC0- was 1016. 3 ± 66. 9ng. h/ml and 921. 3 ± 16. 0ng. h/ml respectively; the relative bioavailability was 110.3% with better in vitro-in vivo correlation (r=0. 9900).
Conclusion: nicardipine hydrochloride bi-layer osmotic pump tablets had obvious in vitro-in vivo controlled release effect.
在对盐酸尼卡地平双层渗透泵控释片处方工艺研究时，先以12小时累积释放百分量和释放线性相关系数r为考察指标，对各因素(片芯和衣膜处方、相关工艺以及体外释药条件)进行单因素考察，选出显著影响因素，然后以3、8和12小时的累积释放百分量F_3，F_8和F_(12)为考察指标，经多元逐步回归后，用L_9(3~4)表对处方进行正交设计，筛选最优处方。研究结果表明：盐酸尼卡地平双层渗透泵控释片体外12小时内累积释放百分量大于80％，16小时内释药完全(＞90％)，12小时内零级释放特征明显(r=0.9994)；盐酸尼卡地平单室单层渗透泵控释片体外12小时内累积释放百分量达77.6％，12小时内零级释放特征明显(r=0.9900)，但16小时内的最终释放百分量小于90％(释放不完全)。
在进行盐酸尼卡地平双层渗透泵控释片体内药代动力学研究时，选用市售普通片为参比制剂，以6只健康家犬为试验对象，一次口服相同剂量进行生物利用度和体内外相关性考察。采用HPLC法对血药浓度进行测定，控释片和普通片的T_(max)分别为7.0±1.6h和1.2±0.4h；C_(max)分别为49.3±7.2ng／ml和139.6±10.5ng／ml；t_(1/2)分别8.6±1.3h和2.3±0.4h；k_e分别为0.08±0.01h~(-1)和0.3±0.1 h~(-1)；AUC_(0→∞)分别为1016.3±66.9 ng·h／ml和921.3±16.0ng·h／ml。控释片的相对生物利用度为110.3％；体内外相关性良好(r为0.9900)。
本文的研究结果表明：以聚氧乙烯为主要辅料，用醋酸纤维素包衣制成的盐酸尼卡地平双层渗透泵控释片具有明显的控释作用。
This paper is mainly researching on the recipe, technique, bioavailability and in vitro-in vivo correlation of insoluble nicardipine hydrochloride' s bi-layer osmotic pump tablets; a preliminary research on the recipe of the said drug' s mono-layer osmotic pump tablets has also been involved.
While researching on the recipe and technique of the bi-layer osmotic pump tablets, first , we used the cumulative release amount within 12 hours and the linear release to measure the influence of the factors (core of the tablets, membrane compositions, relative techniques and in vitro-in vivo release conditions) by single-factor analysis method, and selected the dominatingly influence factors. Second, we used 3 hours, 8 hours, 12 hours cumulative release amount F3, F8, F12 as the index to screen the best recipe with multivariable linear stepwise regressing analysis. Finally , we picked out optimized prescription by 34 factors-analysis orthogonal design. We found that the bi-layer osmotic tablets cumulatively released the drug more than 80% in 12 hours, and completely released the drug within 16 hours (>90%), owning obvious zero-order release characters(r=0. 9994) within 12 hours. While the mono-layer osmotic tablets cumulative released
only 77. 6% in 12 hours and the utmost release amount was below 90%( not completely release), with obvious zero-order release characters.
While researching on the drug' s in-vivo pharmacokinetics of the bi-layer osmotic pump tablets, we selected normal tablets as contrast preparation containing the same drug, 6 healthy dogs as test objects, to administrate in the same dose once and measured the bioavailability in vitro-in vivo correlation in plasma with HPLC. The results showed: Tmax of bi-layer osmotic tablet and normal tablet was 7.0±1.6h and 1.2±0.4h respectively; Cmax was 43. 3 ± 7. 2ng/ml and 139. 36 + 10. 5ng/ml; Tl/2 was 8.6=1.3 and 2.3 ±0.4h; Ke was 0.08 ± 0. 01h-1 and 0.3±0. 1h-1; AUC0- was 1016. 3 ± 66. 9ng. h/ml and 921. 3 ± 16. 0ng. h/ml respectively; the relative bioavailability was 110.3% with better in vitro-in vivo correlation (r=0. 9900).
Conclusion: nicardipine hydrochloride bi-layer osmotic pump tablets had obvious in vitro-in vivo controlled release effect.
引文
[1] Sastry SV, DeGennaro MD, Reddy IK, etal. Atenolol gastrointestinal therapeutic system. Ⅰ. Screening of formulation variables. Drug Dev. Ind Pharm, 1997,23(2):152-165
[2] S.V. Sastry, M.A. Khan. Aqueous based polymeric dispersion: Plackett-Burman design for screening of formulation variables of atenolol gastrointestinal therapeutic system. Pharm Acta helv, 1998,73:105-112
[3] Sastry SV, Reddy IK, Khan MA. Atenolol gastrointestinal therapeutic system: optimization of formulation variables using response surface methodology.J Control Release, 1997,45:121-130
[4] Swanson DR, Barclay BL, Wong PSL, et al. Nifedipine gastrointestinal therapeutic system. Am J Med, 1987,83 (Suppl. 6B):3-9
[5] 毕殿洲．药剂学．第四版．人民卫生出版社，1999：13
[6] LongXiao Liu, Gilson Khang, et al. Monolithic osmotic tablet system for nifedipine delivery. Journal Controlled Release, 2000, 67:309-322
[7] Sastry SV, Reddy IK, Jhan MA, et al. Effect of vehicle amphiphilicity on the Dissolution and bioavailability of a poorly water-soluble drug from solid dispersions [J].J Controlled Release, 1997, 45 (2): 121
[8] Sastry SV DeGennarro MD, Reddy IK, et al. Controlled release of water soluble medicine by using solid dispersion[J], drug Der Ind Pharm, 1997,23(2):157
[9] Liu L, Lu J, Khang G, et al. Nifedipine controlled delivery by sandwiched osmotic tablet system [J].J Controlled Release, 2000, 68 (2):145-156
[10] Ozdemir N, Sahin J. Design of a controlled release osmotic pump system of ibuprofen [J]. Int J Pharm, 1997, 158(1):91-97
[11] Cardinal JR, Herbig SM, Korsmeyer RM, et al. Use of asymmetric membranes in delivery devices [P]. US Patent :5612059, 1992-03-18
[12] 陆彬主编．药物新剂型与新技术．人民卫生出版社，1998，265
[13] 上海医药工业研究院药物制剂研究室编著．药用辅料应用技术．中国医药科技出版社，1993，129
[14] L. Liu, G. Khang, J. M. Rhee, H. B. Lee. Osmotic-suspending delivery of monolithic tablet of hiredipine. Biomater. Res. 1999, 3:47-53
[15] 严瑞瑄主编．水深性高分子．化学工业出版社，2001，269
[16] Mcclelland GA, Sutton SC, Engle K , et al. The controlled porosity osmotic pump. Pharm. Res, 1991, 8:88
[17] Modi NB, Lindemulder B, Gupta SK. Singls- andmultiple-dose pharmacokineticsof an oral once-a-day osmotic controlled-release OROS (methylphenidate HCl)formulation[J]. J Clin Pharmacol, 2000, 48 (1): 71-78
[18] Zentner GM, McClelland GA, Sutton SC. Controlled porosity- and resin-modulated osmotic drug delivery system for release of diltiazem hydroehloride [J]. J Controlled Release, 1991, 16 (1) :237
[19] 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
[20] Vahid Zia, Roger A. Rajewski, EstebanR., Bornancini ER, et al. Effect of alkyl chain length and degree of substitution on the complexation of sulfoalkyl ether-β-cyclodextrin with steroids [J]. J Pharm Sci, 1997, 86 (2): 220-224
[21] Okimoto K, Rajewski RA, Stella VJ, et al. Release of testosterone from an osmotic pump tablet utilizing (sero) 7m-β-CD as both a solubilizing and an osmotic pump agent [J]. J Controlled Release, 1999, 58 (1): 9-38
[22] A.D. Koparkar, S.B. Shah, Oral osmotic system for slightly soluble acitve agents.US patent No. 5284662, Feb. 8,1944.
[23] W.J. Curatolo. Dispensing devices powered by lyotropic liquid crystals, Uspatent No. 5108756, April 28,1992
[24] Chen CM, Lee DY, Xie J. Conrolled release formulation Tot water insoluble drugs in which a passageway is formed in situ[P].US Patent:5736159,1998-04-07
[25] Longxiao Liu, Jeong Ku, Gilson Khang, Bong Lee, John M. Rhee, Hai Bang Lee. Nifedipine controlled delivery by sandwiched osmotic tablet system. Journal of Controlled Release 2000, 68: 145-156.
[26] F. Theeuwes Osmotic dispenser with gas generating means. US patent4036228, July 19,1977.
[27] Herbig SM, Cardinal JR, Korsmeyer RW, et al. Asymmetric-membrane tablet coatings for osmotic drug delivery [J]. J Controlled Release, 1995, 35 (1): 127-136
[28] F. Theeuwes, U.S. Patent4,111,201(1978)
[29] Takeda, Mitsuo, Matsuda, et al. Fine zinc oxide particles, process for producing the same, and use thereof [P]. US: 6200680,2001-03-13
[30] 陆彬主编．药物新剂型与新技术．人民卫生出版社，1998：309
[31] 陆彬主编．药物新剂型与新技术．人民卫生出版社，1998：7
[32] 卢恩先，江志强，难溶性药物口服渗透泵片工艺的研究进展．药学学报，2001，36 (3)：235
[33] 罗明生，高天惠主编．药剂辅料大全．四川科学技术出版社．1995，218
[34] 陈汇等，国产盐酸尼卡地平缓释胶囊人体药代动力学及生物利用度．中国药理学通报，2000，16(1)：107-110
[35] S. Higuchi and Y. Shiobara, Biomed. Mass Spectrom, 1980, 7:339
[36] ANNE T. Wux, IAN J. MASSEY, et al, A High-Performance Liquid Chromatographic Method for The Simultaneous Determination of Nicardipine and Its PyridineMetabolite Ⅱin Plasma J
pharmaceutical Sciences,1984,73(10):1444-1447
[37] 魏树礼主编．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．1997，89
[2] S.V. Sastry, M.A. Khan. Aqueous based polymeric dispersion: Plackett-Burman design for screening of formulation variables of atenolol gastrointestinal therapeutic system. Pharm Acta helv, 1998,73:105-112
[3] Sastry SV, Reddy IK, Khan MA. Atenolol gastrointestinal therapeutic system: optimization of formulation variables using response surface methodology.J Control Release, 1997,45:121-130
[4] Swanson DR, Barclay BL, Wong PSL, et al. Nifedipine gastrointestinal therapeutic system. Am J Med, 1987,83 (Suppl. 6B):3-9
[5] 毕殿洲．药剂学．第四版．人民卫生出版社，1999：13
[6] LongXiao Liu, Gilson Khang, et al. Monolithic osmotic tablet system for nifedipine delivery. Journal Controlled Release, 2000, 67:309-322
[7] Sastry SV, Reddy IK, Jhan MA, et al. Effect of vehicle amphiphilicity on the Dissolution and bioavailability of a poorly water-soluble drug from solid dispersions [J].J Controlled Release, 1997, 45 (2): 121
[8] Sastry SV DeGennarro MD, Reddy IK, et al. Controlled release of water soluble medicine by using solid dispersion[J], drug Der Ind Pharm, 1997,23(2):157
[9] Liu L, Lu J, Khang G, et al. Nifedipine controlled delivery by sandwiched osmotic tablet system [J].J Controlled Release, 2000, 68 (2):145-156
[10] Ozdemir N, Sahin J. Design of a controlled release osmotic pump system of ibuprofen [J]. Int J Pharm, 1997, 158(1):91-97
[11] Cardinal JR, Herbig SM, Korsmeyer RM, et al. Use of asymmetric membranes in delivery devices [P]. US Patent :5612059, 1992-03-18
[12] 陆彬主编．药物新剂型与新技术．人民卫生出版社，1998，265
[13] 上海医药工业研究院药物制剂研究室编著．药用辅料应用技术．中国医药科技出版社，1993，129
[14] L. Liu, G. Khang, J. M. Rhee, H. B. Lee. Osmotic-suspending delivery of monolithic tablet of hiredipine. Biomater. Res. 1999, 3:47-53
[15] 严瑞瑄主编．水深性高分子．化学工业出版社，2001，269
[16] Mcclelland GA, Sutton SC, Engle K , et al. The controlled porosity osmotic pump. Pharm. Res, 1991, 8:88
[17] Modi NB, Lindemulder B, Gupta SK. Singls- andmultiple-dose pharmacokineticsof an oral once-a-day osmotic controlled-release OROS (methylphenidate HCl)formulation[J]. J Clin Pharmacol, 2000, 48 (1): 71-78
[18] Zentner GM, McClelland GA, Sutton SC. Controlled porosity- and resin-modulated osmotic drug delivery system for release of diltiazem hydroehloride [J]. J Controlled Release, 1991, 16 (1) :237
[19] 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
[20] Vahid Zia, Roger A. Rajewski, EstebanR., Bornancini ER, et al. Effect of alkyl chain length and degree of substitution on the complexation of sulfoalkyl ether-β-cyclodextrin with steroids [J]. J Pharm Sci, 1997, 86 (2): 220-224
[21] Okimoto K, Rajewski RA, Stella VJ, et al. Release of testosterone from an osmotic pump tablet utilizing (sero) 7m-β-CD as both a solubilizing and an osmotic pump agent [J]. J Controlled Release, 1999, 58 (1): 9-38
[22] A.D. Koparkar, S.B. Shah, Oral osmotic system for slightly soluble acitve agents.US patent No. 5284662, Feb. 8,1944.
[23] W.J. Curatolo. Dispensing devices powered by lyotropic liquid crystals, Uspatent No. 5108756, April 28,1992
[24] Chen CM, Lee DY, Xie J. Conrolled release formulation Tot water insoluble drugs in which a passageway is formed in situ[P].US Patent:5736159,1998-04-07
[25] Longxiao Liu, Jeong Ku, Gilson Khang, Bong Lee, John M. Rhee, Hai Bang Lee. Nifedipine controlled delivery by sandwiched osmotic tablet system. Journal of Controlled Release 2000, 68: 145-156.
[26] F. Theeuwes Osmotic dispenser with gas generating means. US patent4036228, July 19,1977.
[27] Herbig SM, Cardinal JR, Korsmeyer RW, et al. Asymmetric-membrane tablet coatings for osmotic drug delivery [J]. J Controlled Release, 1995, 35 (1): 127-136
[28] F. Theeuwes, U.S. Patent4,111,201(1978)
[29] Takeda, Mitsuo, Matsuda, et al. Fine zinc oxide particles, process for producing the same, and use thereof [P]. US: 6200680,2001-03-13
[30] 陆彬主编．药物新剂型与新技术．人民卫生出版社，1998：309
[31] 陆彬主编．药物新剂型与新技术．人民卫生出版社，1998：7
[32] 卢恩先，江志强，难溶性药物口服渗透泵片工艺的研究进展．药学学报，2001，36 (3)：235
[33] 罗明生，高天惠主编．药剂辅料大全．四川科学技术出版社．1995，218
[34] 陈汇等，国产盐酸尼卡地平缓释胶囊人体药代动力学及生物利用度．中国药理学通报，2000，16(1)：107-110
[35] S. Higuchi and Y. Shiobara, Biomed. Mass Spectrom, 1980, 7:339
[36] ANNE T. Wux, IAN J. MASSEY, et al, A High-Performance Liquid Chromatographic Method for The Simultaneous Determination of Nicardipine and Its PyridineMetabolite Ⅱin Plasma J
pharmaceutical Sciences,1984,73(10):1444-1447
[37] 魏树礼主编．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．1997，89
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