长春西汀原位凝胶及原位微球的制备与评价
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摘要
以可生物降解的高分子材料为载体，通过制剂新技术将药物制成微球、微囊、纳米粒、凝胶等剂型，用作缓控释注射剂的研究，是近年来药剂学研究的热点之一。长春西汀是一种有效的抗心脑血管病药物，极难溶，口服生物利用度约为7％左右。本文以其为模型药物，尝试了制备长春西汀原位凝胶及原位微球注射剂，以期达到延长药物的作用时间、减少用药次数和提高生物利用度的目的。
本研究首先采用高效液相色谱法(HPLC法)建立了长春西汀原位凝胶和原位微球中药物的含量和释放度的测定。通过单因素考察试验，以药物含量和体外释放为依据筛选出长春西汀原位凝胶注射剂的较优处方。由于长春西汀原位微球变量较多，利用球面设计优化方法优化并得到长春西汀原位微球最优处方。
释药机理的研究结果表明长春西汀原位凝胶和原位微球的释药过程符合药物扩散机制或药物扩散和骨架溶蚀协同作用的机制。稳定性的影响因素试验结果表明，长春西汀原位凝胶及原位微球对高温、高湿和光照均比较稳定；加速试验结果表明长春西汀原位凝胶及原位微球经过包装后稳定性良好。
对自制长春西汀原位凝胶、原位微球和长春西汀苯甲酸卞酯溶液注射剂进行了家兔体内药动学研究，其体内分析方法采用HPLC法。结果表明：长春西汀原位凝胶、原位微球和苯甲酸卞酯溶液的T_(max)依次为2、4和1h；C_(max)依次为(410．5±76．8)、(2121．6±121．3)和(2757．1±172．9)ng·ml~(-1)；AUC_(0-∞)依次为(665．1±59．3)、(842．6±71．1)和(560．4±47．4)ng·d·ml~(-1)。以长春西汀溶液为参比制剂，原位凝胶和原位微球的相对生物利用度分别为17．6％和24．8％。采用Loo-Riegelman法计算，长春西汀原位凝胶的体内外相关性显著(df=23，0．597Using new technologies and biodegradable polymers to develop microshperes, nanoparticles and gel is one of the most promising area in pharmacy. Vinpocetine is a kind of effective drug for cerebrovascular disease. However, it is almost aqueous insoluble, which significantly restricts its bioavailability to 7%. In this paper, vinpocetine was used as the model drug to prepare in situ forming gel and microparticles, with the aim to prolong its action time, reduce the times of administration and enhance the bioavailability.
In this paper, the HPLC method, which was suitable to detect vinpocetine in formulations, was firstly established. By single factor tests, the optimal formula of in situ forming gel was obtained. Because there were quite a few factors influencing the in situ forming microparticles, the spherical symmetric design-response surface methodology was utilized to optimize the formulation.
The study on the drug release mechanism showed that the the releasing process was fitted to diffusion, or the synergism of diffusion and bulk erosion. The stability test indicated that both the in situ forming gel and microparticles were stable when exposed to high temperature, high humidity and light. The accelerated test showed that both the formulations were rather stable after package.
The pharmacokinetics study on the prepared vinpocetine in situ forming gel, microparticles and BB solution was carried out with rabbits. The analytical procedure was based on HPLC method. The results revealed that the T_(max),C_(max) and AUC_(0-t) of in situ gel, in situ microparticles and BB solution were 2h, 410.5±76.8 ng·ml~(-1), 618.4±96.5 ng·d·ml~(-1); 3h, 2121.6±121.3 ng·ml~(-1), 813.6±71.6 ng·d·ml~(-1); 1h, 2757.1±172.9 ng·ml~(-1), 486.5±47.5 ng·d·ml~(-1) respectively. Using vinpocetine BB solution as the reference, the bioavailability of the vinpocetine in situ forming gel and microparticles were 17.6% and 24.8%, respectively. Calculated with Loo-Riegelman method, the in vitro-in vivo correlation of vinpocetine in situ forming gel was significant(df=23, 0.597
本研究首先采用高效液相色谱法(HPLC法)建立了长春西汀原位凝胶和原位微球中药物的含量和释放度的测定。通过单因素考察试验，以药物含量和体外释放为依据筛选出长春西汀原位凝胶注射剂的较优处方。由于长春西汀原位微球变量较多，利用球面设计优化方法优化并得到长春西汀原位微球最优处方。
释药机理的研究结果表明长春西汀原位凝胶和原位微球的释药过程符合药物扩散机制或药物扩散和骨架溶蚀协同作用的机制。稳定性的影响因素试验结果表明，长春西汀原位凝胶及原位微球对高温、高湿和光照均比较稳定；加速试验结果表明长春西汀原位凝胶及原位微球经过包装后稳定性良好。
对自制长春西汀原位凝胶、原位微球和长春西汀苯甲酸卞酯溶液注射剂进行了家兔体内药动学研究，其体内分析方法采用HPLC法。结果表明：长春西汀原位凝胶、原位微球和苯甲酸卞酯溶液的T_(max)依次为2、4和1h；C_(max)依次为(410．5±76．8)、(2121．6±121．3)和(2757．1±172．9)ng·ml~(-1)；AUC_(0-∞)依次为(665．1±59．3)、(842．6±71．1)和(560．4±47．4)ng·d·ml~(-1)。以长春西汀溶液为参比制剂，原位凝胶和原位微球的相对生物利用度分别为17．6％和24．8％。采用Loo-Riegelman法计算，长春西汀原位凝胶的体内外相关性显著(df=23，0．597
In this paper, the HPLC method, which was suitable to detect vinpocetine in formulations, was firstly established. By single factor tests, the optimal formula of in situ forming gel was obtained. Because there were quite a few factors influencing the in situ forming microparticles, the spherical symmetric design-response surface methodology was utilized to optimize the formulation.
The study on the drug release mechanism showed that the the releasing process was fitted to diffusion, or the synergism of diffusion and bulk erosion. The stability test indicated that both the in situ forming gel and microparticles were stable when exposed to high temperature, high humidity and light. The accelerated test showed that both the formulations were rather stable after package.
The pharmacokinetics study on the prepared vinpocetine in situ forming gel, microparticles and BB solution was carried out with rabbits. The analytical procedure was based on HPLC method. The results revealed that the T_(max),C_(max) and AUC_(0-t) of in situ gel, in situ microparticles and BB solution were 2h, 410.5±76.8 ng·ml~(-1), 618.4±96.5 ng·d·ml~(-1); 3h, 2121.6±121.3 ng·ml~(-1), 813.6±71.6 ng·d·ml~(-1); 1h, 2757.1±172.9 ng·ml~(-1), 486.5±47.5 ng·d·ml~(-1) respectively. Using vinpocetine BB solution as the reference, the bioavailability of the vinpocetine in situ forming gel and microparticles were 17.6% and 24.8%, respectively. Calculated with Loo-Riegelman method, the in vitro-in vivo correlation of vinpocetine in situ forming gel was significant(df=23, 0.597
引文
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[50]Kiwada H, Morito K, Hayashi M, S. Awazu, M. Hanano, A new numerical calculation method for deconvolution in linear compartment analysis of pharmacokinetics[J]. Chem Pharm Bull, 1977, 25: 1312-1318.
[2] 俞媛，高申，钟延强，等．布比卡因聚乳酸缓释微球在家兔体内药动学研究[J]．中国药学杂志，2002,37(11)：849-852．
[3] 李凤前，陆彬，陈文彬，等．肺靶向汉防己甲素缓释微囊的小鼠体内分布[J]．中国医院药学杂志，2001,21(5)：259-261．
[4] 陈军，易以木，杨希雄，等．胰岛素聚乳酸纳米粒的初步研究[J]．华西药学杂志，2002,17(4)：272-273．
[5] 尹宗宁，陆彬．注射用胰岛素缓释纳米囊的研究[J]．中国医药工业杂志，2000,31(8)：349-352．
[6] 张蜀，谭载友，陈济民．可生物降解盐酸多西环素缓释凝胶的含量测定[J]．中国新药杂志，2001,10(6)：439-441．
[7] 赵锋，高永良．乳化分散法制备聚乳酸微球的研究进展[J]．中国新药杂志，2002,11(2)：123-126．
[8] Bostman OM. Current concept review absorbable impiants for the fixation of fracture [J]. J Bone Joint Surg, 1991,73(1):148.
[9] S.M. Herbig ,J.R. Cardinal, R.W. Korsmeyer .Asymmetric-membrane tablet coatings forosmotic drug delivery. J Control Release, 1995, (35) 127-136.
[10] Yong Gan,Weisan Pan,Mingchun Wei. Cyclodextrin complex osmotic pump tablet forglipizide delivery . Drug Dev Ind Pharm, 2002, 28(8):1015-1021.
[11] K. Okimoto, R.A. Rajewski, V.J. Stella .Release of testosterone from an osmotic pump tabletutilizing (SBE)7m-β-CD as both a solubilizer and osmotic agent . J Control Release, 1999,(58):29-38.
[12] K. Okimoto, M. Miyake, N. Ohnishi, R.A, et al Design and Evalulation of an osmotic pumptablets for chlorpromazing using (SBE)7m-β-CD. Pharm Res, 1999,16:1562-1568.
[13] K. Okimoto, R.A. Rajewski, V.J. Stella. Factors affecting membrane-controlled drug release for an osmotic pump tablets(OPT) utilizing (SBE)7m-β-CD as both a both a solubilizer and osmotic agent. J Control Release, 1999, 60:311-319.
[14] Ouyang D, Nie S, Li W, Guo H, Liu H, Pan W Design and evaluation of compound metformin/glipizide elementary osmotic pump tablets. J Pharm Pharmacol. 2005,57(7):817-820.
[15] Casnda E, Harcoss P, Bacsy Z, Berghammer R.Ten years of experience with Cavinton. Drug Dev Res, 1988,14:185-187.
[16] 张杰文，刘忠祥．长春西汀治疗急性脑梗死50例．医药导报，2003，22(2)：92．
[17] 花放 李绍英．国产长春西汀治疗脑梗塞恢复期75例．中国新药杂志,1994，3：40-41．
[18] Tohgi H, Sasaki K, Chiba K, Nozaki Y. Effect of vinpocetine on oxygen release of hemoglobinand erythrocyte organic polyphosphate concentrations in patients with vascular dementia of theBinswanger type. Arzneim Forsch, 1990,40(6): 640-643.
[19] Hayakawa M. Comparative efficacy of vinpocetine, pentoxifylline and nicergoline on redblood cell deformability. Arzneimittelforschung, 1992,42(2): 108-110.
[20] Hayakawa, M. Effect of vinpocetine on red blood cell deformability in stroke patients.Arzneimittelforschung, 1992,42(4), 425-427.
[21] Bereczki D, Fekete I. A systematic review of vinpocetine therapy in acute ischaemicstroke.Eur J Clin Pharmacol. 1999,55(5): 349-352.
[22] 陈鹰，李高，王瑞华，汤韧．长春西汀固体分散体的制备及体外溶出特性．中国医院药学杂志，2006，5：559-562.
[23] Chilko D, Howard S. On the analysis of dissolution rate. Drug Dev Ind Pharm,1986,12 (7) :969-992.
[24] Shah VP, Tsong Y, Sathe P, et al. In vitro dissolution profile comparison-statistics and analysisof the similarity factor f_2. Pharm Res, 1998,15(6) : 889-896.
[25] Gohel MC, Panchal MK. Novel use of similarity factors f_2 and Sd for the development ofdiltiazem HCL modified-release tablets using a 32 factorail design . Drug Dev Ind Pharm, 2002,28(1): 77-87.
[26] Gabrielsson J, Nystrom A, Lundstedt T. Application of Multivariate analysis in pharmaceuticaldevelopment work . Drug Dev Ind Pharm, 2000, 26(3): 275-296.
[27] 程刚主编．FDA生物药剂学指南．沈阳：沈阳药科大学，2001年3月
[28] Center for Drug Evaluation and Research, FDA. Guidance for industry bioavailability and bioequivalences studies for orally administered drug products: General considerations, 1999: 10-14.
[29] 聂淑芳，潘卫三，李伟．长春西汀的大鼠在体肠吸收研究．中国医药工业杂志.2005，36(10)：625-628
[30] Rajan K. Verma, Divi Murali Krishna, Sanjay Garg. Formulation aspects in the developmentof osmotically controlled oral drug delivery systems. J. Control. Release, 2002, 79: 7-27.
[31]Shively, M.L., Bennett, A.T., Coonts, B.A., Renner, W.D., Southard, J.L., Physico-chemicalcharacterization of polymer injectable implant delivery system. J. Control Release 33, 237-243(1995).
[32] Ritger R.L.Peppas, NA. Asimple equation for description of solute release I Fickian andnon-Fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs[J].J Control. Release. 1987,
[33] Iskandarani B, Clair JH, Patel P,et al. Simultane-ous optimization of capsule and tabletformulationusing response surface methodology[J].Drug Dev Ind Pharm, 1993,19(16):2089-2101.
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