生物降解性材料用于药物缓释系统中的研究
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摘要
尼莫地平是1,4-双氢吡啶类钙通道拮抗剂,其药理特性是能有效地调节细胞内钙水平,使之保持正常的生理功能。对脑血管的作用尤为突出,能有效预防和治疗蛛网膜下腔出血所引起的脑血管痉挛造成的脑组织缺血性损害,对离体或体内的脑动脉,正常或缺血脑动脉均有扩张作用。因其水溶性差、口服生物利用度低,导致临床给药次数频繁,患者服药不便,且易因血药浓度积累引起毒副作用。
本课题研究的目标是应用现代药物制剂新技术,制备尼莫地平微球,从而达到缓释作用,减少服用剂量及毒副刺激作用,同时,建立相应的检测方法。
本研究中采用溶剂提取法制备了尼莫地平聚乳酸微球,通过正交实验,考察了各因素对微球性质的影响。实验结果表明:聚乳酸浓度、乳化剂浓度、投药比及油水两相体积比等均可成为微球的粒径大小、包封率、载药量及产率的影响因素。优选后的制备工艺为:聚乳酸的浓度为7.5%,乳化剂明胶的浓度为1.5%,尼莫地平:聚乳酸为2:3,油水相体积比为5:40。通过对最佳制备工艺的验证实验表明了以上工艺的重现性和稳定性是可靠的。
稳定性实验表明:37℃密闭保存,微球会产生粘连破坏。4℃及25℃下密闭保存,微球的形态、载药量及包封率均较稳定。这现象与聚乳酸的玻璃化温度(40-55℃)有关。因此,微球贮存条件应为不高于25℃密闭保存。
体外释药研究表明,释药过程可用零级方程拟合。微球的载药量及制备过程中的因素会对其释药性产生影响。
以聚乳酸为载体材料制备的尼莫地平微球具有明显的缓释作用,能够达到延长药效作用时间及减少给药次数的目的。
Nimodipine is a dihydropyridine calcium channel blocker, which regulatesintracellular calcium level effectively to maintain normal physiological functions. Itdemonstrates a marked specificity for cerebral vessels. Major interests have focusedon its use in the prevention and treatment of the cerebral ischemic lesions thatfrequently occur in patients with subarachnoid haemorrhages as a result of sustainedcerebral vasospasm and the inhibition of transmembrane calcium influx. However,there are several unfavorable characteristics for this drug. Because of its lower watersolubility, oral bioavailability is lower and variable.
In this work, the main goal is to prepare Nimodipine PLA microspheres , whichcan not only prolong acting time, decrease the dose but also minimize side effect, then,a series of novel study method are developed for the microspheres.
A solvent extraction method was employed to prepare the Nimodipine PLAmicrospheres. The influences in the process of preparing PLA microspheres werestudied according to an orthogonal-design of experiments. The polymeric theconcentration of internal phase, the concentration of dispersing agent, the ratio ofnimodipine: PLA, volume ratio of oil phase to water phase could affect microspheressize, drug encapsulating efficiency and drug content. The optimum preparationmethod is: the PLA concentration is 7.5%, the gelatin concentration is 1.5%, the ratioof nimodipine: PLA is 2:3, the volume ratio of oil phase to water phase is 5:40. Therepeated tests of optimum preparing method proved that its stability is good.
The study on stability indicates that when stored at 37℃, the microspheres fusedand aggregated;while stored at 4℃ or room temperature under sealed condition forsix months, surface morphology, drug content and in vitro release of microsphereswere not altered. It possibly related to the glasstransition temperature for PLA.
Studies on the release in vitro showed that the release kinetics of nimodipinefrom PLA microspheres could be described by zero-order equation. The release ratewas related to drug content and some factors for preparation.
In conclusion, a new Nimodipine-PLA microspheres that can prolonged actingtime and decrease side effects was developed.
本课题研究的目标是应用现代药物制剂新技术,制备尼莫地平微球,从而达到缓释作用,减少服用剂量及毒副刺激作用,同时,建立相应的检测方法。
本研究中采用溶剂提取法制备了尼莫地平聚乳酸微球,通过正交实验,考察了各因素对微球性质的影响。实验结果表明:聚乳酸浓度、乳化剂浓度、投药比及油水两相体积比等均可成为微球的粒径大小、包封率、载药量及产率的影响因素。优选后的制备工艺为:聚乳酸的浓度为7.5%,乳化剂明胶的浓度为1.5%,尼莫地平:聚乳酸为2:3,油水相体积比为5:40。通过对最佳制备工艺的验证实验表明了以上工艺的重现性和稳定性是可靠的。
稳定性实验表明:37℃密闭保存,微球会产生粘连破坏。4℃及25℃下密闭保存,微球的形态、载药量及包封率均较稳定。这现象与聚乳酸的玻璃化温度(40-55℃)有关。因此,微球贮存条件应为不高于25℃密闭保存。
体外释药研究表明,释药过程可用零级方程拟合。微球的载药量及制备过程中的因素会对其释药性产生影响。
以聚乳酸为载体材料制备的尼莫地平微球具有明显的缓释作用,能够达到延长药效作用时间及减少给药次数的目的。
Nimodipine is a dihydropyridine calcium channel blocker, which regulatesintracellular calcium level effectively to maintain normal physiological functions. Itdemonstrates a marked specificity for cerebral vessels. Major interests have focusedon its use in the prevention and treatment of the cerebral ischemic lesions thatfrequently occur in patients with subarachnoid haemorrhages as a result of sustainedcerebral vasospasm and the inhibition of transmembrane calcium influx. However,there are several unfavorable characteristics for this drug. Because of its lower watersolubility, oral bioavailability is lower and variable.
In this work, the main goal is to prepare Nimodipine PLA microspheres , whichcan not only prolong acting time, decrease the dose but also minimize side effect, then,a series of novel study method are developed for the microspheres.
A solvent extraction method was employed to prepare the Nimodipine PLAmicrospheres. The influences in the process of preparing PLA microspheres werestudied according to an orthogonal-design of experiments. The polymeric theconcentration of internal phase, the concentration of dispersing agent, the ratio ofnimodipine: PLA, volume ratio of oil phase to water phase could affect microspheressize, drug encapsulating efficiency and drug content. The optimum preparationmethod is: the PLA concentration is 7.5%, the gelatin concentration is 1.5%, the ratioof nimodipine: PLA is 2:3, the volume ratio of oil phase to water phase is 5:40. Therepeated tests of optimum preparing method proved that its stability is good.
The study on stability indicates that when stored at 37℃, the microspheres fusedand aggregated;while stored at 4℃ or room temperature under sealed condition forsix months, surface morphology, drug content and in vitro release of microsphereswere not altered. It possibly related to the glasstransition temperature for PLA.
Studies on the release in vitro showed that the release kinetics of nimodipinefrom PLA microspheres could be described by zero-order equation. The release ratewas related to drug content and some factors for preparation.
In conclusion, a new Nimodipine-PLA microspheres that can prolonged actingtime and decrease side effects was developed.
引文
[1] Anderson JM, Shive MS, Biodegradation and biocompatibility of PLA and PLGA microspheres, Adv. Drug Del. Rev.,1997, 28: 5-9
[2] Sampath P, Brem H, Implantable slow-release chemotherapeutic polymer for the treatment of malignant brain tumors, Cancer Control, 1998, 5(2): 130-137
[3] D. H. Lewis, Biodegradable polymers as drug delivery system, J. Controlled Release, 1991, 17, 23: 144-149
[4] 朱家蕙,沈正荣,王芳等,含睾丸酮的乳酸聚乳酸共聚物微球的制备即体外释放,中国药学杂志,1997,32(10):595
[5] Li WI, Anderson KW, Mehta RC, et al, Prediction of solvent removal profile and effect on properties for peptide-loaded PLGA microspheres prepared by solvent-extraction evaporation method, J. Controlled release, 1995, 37:199
[6] Li JK, Wang N, Wu XS, A novel biodegradable system based on gelatin nanoparticles and poly(Lactic-co-glycolic acid) microspheres for protein and peptide drug delivery, J. Pharm. Sci.,1997,88:891-898
[7] Ruiz JM, Tissier B, Benoit JP, Microencapsulation of peptide: a study of the phase separation of poly(D,L-Lactic acid) copolymers 50/50 by silicone oil, Int. J. Pharm.,1989,49(1): 69-77
[8] McGee JP, Davis SS, O'Hagan DT, Zero order release of protein from poly(D,L-lactide-co-glycolide) microparticles prepared using a modified phase separation technique, J. Controlled Release, 1995,34(2): 77-86
[9] Wang N, Wu XS, A novel approach to stabilization of protein drugs in poly(lactide-co-glycolic acid) microspheres using agarose hydrogel, Int. J. Pharm.,1998,166(1):1-14
[10] Park TG, Lee HY, Nam YS, A new preparation method for protein loaded poly(D,L-lactic-co-glycolic acid) microspheres and protein release mechanism study, J. Controlled Release, 1998, 55(23): 181-191
[11] Hayashi Y, Yoshioka S, Aso Y, entrapment of protein in poly(L-lactide) microspheres using reversed micelle solvent evaporation, Pharm. Res.,1994,11(2): 337-340
[12] 于开涛,封兴华,介入栓塞用微球制剂的应用和研究进展,介入放射学杂志,2002,11(2):132-133
[13] Bartkowski R, Kohler H, et al, Chemo-embolisation of experimental liver metastes Part Ⅰ: distribution of biodegradable microspheres of different sizes in an animal model for the locoregional therapy, Eur. J Pharm. Biopharm., 1998, 46(3):243-253
[14] Shi ZY, Jian ZG, Zhang MZ, The follow up of quality life after interventional therapy of post-peritoneum metastatic tumors, Zhongguo Linchuang Kangfu(Chin J Clin Rehabil), 2002,6(10): 1539-1541
[15] 张玉,王凯平, 谭红艾,肝靶向药物的研究进展,医药导报,2002,21(4):230-231
[16] Burger JJ, Tomlinson E, Mulder EMA. Albumin microspheres for intra-arterial tumor targeting, Int. J. Pharm, 1985, 23: 333-344
[17] 魏树礼,注射用硫酸链霉素白蛋白微球的研究,药学学报,1990,25(4):284-285
[18] 王永兴,应延风,慢性阻塞性肺疾病稳定期患者生存质量与肺功能的关系,中国临床康复,2002,6(19):2851-2852
[19] 何成奇,丁明甫,类风湿性关节炎的康复用药,中国临床康复,2002,6(7):926-927
[20] 章建华,裘秀菊,张淮,硒酸酯的糖联合类风湿关节炎的疼痛症状,中国临床康复,2002,6(12):1806-1807
[21] Walenkamp GH, Gentamicin PMMA beads and other local antibiotic carriers in two-stage revision of total knee infection, J. Chemother, 2001, 1(1): 66-72
[22] Ratcliffe JH, Hunneyball LM, Wilson CG, et al, Albumin microspheres for intra-articular drug delivery: investigation of their retention in normal and arthritic knee joints of rabbits, J. Pharm. Pharmacol, 1987, 39(4):290-295
[23] Giunchedi P, Gavini E, Bonacucina G, Tabletted polylactide microspheres prepared by a W/O emulsion-spray drying method, J. Microcapsul, 2000, 17(6): 711-720
[24] Farraj NF, Critchley H Nassl, administration of gentamicin using a novel microspheres delivery system, Int. J. Pharm., 1988,46: 261-265
[25] NF Farraj, SS Davis, et al, Investigation of the nasal absorption of biosynthetic human growth bonus in sheep-use of a bioadhesive microsphere delivery system, Int. J Pharm., 1990, 63: 207-211
[26] Seki T, Kawaguchi T, Endoh H, et al, Controlled release of 3',5'-diester prodrugs of 5-fluoro-2'-deoxyuridine from poly-L-Lactic acid microspheres, J. Pharm. Sci., 1990, 79(11): 985-987
[27] Blanco MD, Bernardo MV, Bupicacine-loaded comatrix formed by albumin microspheres included in a poly (lactide-co -glycolide) film in vitro biocompatibility and drug release studies, Biomaterials, 1999,20(20): 1919-1924
[28] Le Corro P, Chevanne F, et al, Spinal controlled delivery of bupivancane from DL-lactic acid oligomer microspheres, J. Pharm. Sci., 1995, 84: 75-78
[29] Le Corre P, Rytting JH, Gajan V, et al, In vitro controlled release kinetics of local anesthetics for poly(DL-Lactide) and poly(Lactide-co-glycolide) microspheres, J. Microencapsul, 1997, 14: 243-247
[30] 汪琴,脊髓损伤后的疼痛与处置,中国临床康复,2002,6(12):1716-1718
[31] 刘卫,李玲,中枢性疼痛,中国临床康复,2002,6(12):1707-1708
[32] 王泽民,当代结构药物全集,北京科学技术出版社,1332-1332
[33] 安国升,汪国芬,王宏图,尼莫地平的药动学研究,临床药学,1993,2:15-17
[34] 马霖,李静,尼莫地平分散片的人体相对利用度,山东医药工业,1999,18(2):3-5
[35] 周建平,王立新,张忠明,尼莫地平缓释胶囊的研究,中国药科大学学报,1999,30(5):346-349
[36] 徐榕青,王长连,邓思珊,尼莫地平漂浮缓释片的人体动力学及相对生物利用度,中国临床药学杂志,1999,8(6):347-350
[37] 蔡长春,李景苏,杨尊湘,尼莫地平软胶囊人体相对生物利用度研究,药学实践杂志,1997,15(5):288-290
[38] 薛秀珍,屈静,尼莫地平缓释胶囊质量控制方法的研究,山西医科大学学报,2002,33(3):233-234
[39] Yolles S, Leafe TD, Woodand JH, et al, Long acting delivery systems for narcotic antagonistsⅡ: release rates of natrexone from poly(lactic acid) composites, J. Pharm. Sci, 1975, 64(2):348
[40] 陶忠华,聚乳酸类生物降解聚合物在控释制剂中的应用,药学进展,1996,20(4):197-203
[41] 熊素彬,陆彬,氟尿嘧啶微球的体外释药模式研究,中国药师,2003,6(5):261-263
[42] 国家药典委员会编,中华人民共和国药典,2000 班,二部,北京:化学工业出版社,2000,附录 74
[43] 朱芳海,奚念珠,优选最佳数学模型用于固体制剂体外溶出实验数据处理程序的设计,药学学报,1994,29(6):459-461
[44] Higuchi T, Rate of release of medicaments from ointment base containing drug in suspension, J. Pharm. Sci., 1961,50:874-878
[45] Carstensen JT, Stability for solids and solid dosage form, J. Pharm. Sci., 1974, 3:1-5
[2] Sampath P, Brem H, Implantable slow-release chemotherapeutic polymer for the treatment of malignant brain tumors, Cancer Control, 1998, 5(2): 130-137
[3] D. H. Lewis, Biodegradable polymers as drug delivery system, J. Controlled Release, 1991, 17, 23: 144-149
[4] 朱家蕙,沈正荣,王芳等,含睾丸酮的乳酸聚乳酸共聚物微球的制备即体外释放,中国药学杂志,1997,32(10):595
[5] Li WI, Anderson KW, Mehta RC, et al, Prediction of solvent removal profile and effect on properties for peptide-loaded PLGA microspheres prepared by solvent-extraction evaporation method, J. Controlled release, 1995, 37:199
[6] Li JK, Wang N, Wu XS, A novel biodegradable system based on gelatin nanoparticles and poly(Lactic-co-glycolic acid) microspheres for protein and peptide drug delivery, J. Pharm. Sci.,1997,88:891-898
[7] Ruiz JM, Tissier B, Benoit JP, Microencapsulation of peptide: a study of the phase separation of poly(D,L-Lactic acid) copolymers 50/50 by silicone oil, Int. J. Pharm.,1989,49(1): 69-77
[8] McGee JP, Davis SS, O'Hagan DT, Zero order release of protein from poly(D,L-lactide-co-glycolide) microparticles prepared using a modified phase separation technique, J. Controlled Release, 1995,34(2): 77-86
[9] Wang N, Wu XS, A novel approach to stabilization of protein drugs in poly(lactide-co-glycolic acid) microspheres using agarose hydrogel, Int. J. Pharm.,1998,166(1):1-14
[10] Park TG, Lee HY, Nam YS, A new preparation method for protein loaded poly(D,L-lactic-co-glycolic acid) microspheres and protein release mechanism study, J. Controlled Release, 1998, 55(23): 181-191
[11] Hayashi Y, Yoshioka S, Aso Y, entrapment of protein in poly(L-lactide) microspheres using reversed micelle solvent evaporation, Pharm. Res.,1994,11(2): 337-340
[12] 于开涛,封兴华,介入栓塞用微球制剂的应用和研究进展,介入放射学杂志,2002,11(2):132-133
[13] Bartkowski R, Kohler H, et al, Chemo-embolisation of experimental liver metastes Part Ⅰ: distribution of biodegradable microspheres of different sizes in an animal model for the locoregional therapy, Eur. J Pharm. Biopharm., 1998, 46(3):243-253
[14] Shi ZY, Jian ZG, Zhang MZ, The follow up of quality life after interventional therapy of post-peritoneum metastatic tumors, Zhongguo Linchuang Kangfu(Chin J Clin Rehabil), 2002,6(10): 1539-1541
[15] 张玉,王凯平, 谭红艾,肝靶向药物的研究进展,医药导报,2002,21(4):230-231
[16] Burger JJ, Tomlinson E, Mulder EMA. Albumin microspheres for intra-arterial tumor targeting, Int. J. Pharm, 1985, 23: 333-344
[17] 魏树礼,注射用硫酸链霉素白蛋白微球的研究,药学学报,1990,25(4):284-285
[18] 王永兴,应延风,慢性阻塞性肺疾病稳定期患者生存质量与肺功能的关系,中国临床康复,2002,6(19):2851-2852
[19] 何成奇,丁明甫,类风湿性关节炎的康复用药,中国临床康复,2002,6(7):926-927
[20] 章建华,裘秀菊,张淮,硒酸酯的糖联合类风湿关节炎的疼痛症状,中国临床康复,2002,6(12):1806-1807
[21] Walenkamp GH, Gentamicin PMMA beads and other local antibiotic carriers in two-stage revision of total knee infection, J. Chemother, 2001, 1(1): 66-72
[22] Ratcliffe JH, Hunneyball LM, Wilson CG, et al, Albumin microspheres for intra-articular drug delivery: investigation of their retention in normal and arthritic knee joints of rabbits, J. Pharm. Pharmacol, 1987, 39(4):290-295
[23] Giunchedi P, Gavini E, Bonacucina G, Tabletted polylactide microspheres prepared by a W/O emulsion-spray drying method, J. Microcapsul, 2000, 17(6): 711-720
[24] Farraj NF, Critchley H Nassl, administration of gentamicin using a novel microspheres delivery system, Int. J. Pharm., 1988,46: 261-265
[25] NF Farraj, SS Davis, et al, Investigation of the nasal absorption of biosynthetic human growth bonus in sheep-use of a bioadhesive microsphere delivery system, Int. J Pharm., 1990, 63: 207-211
[26] Seki T, Kawaguchi T, Endoh H, et al, Controlled release of 3',5'-diester prodrugs of 5-fluoro-2'-deoxyuridine from poly-L-Lactic acid microspheres, J. Pharm. Sci., 1990, 79(11): 985-987
[27] Blanco MD, Bernardo MV, Bupicacine-loaded comatrix formed by albumin microspheres included in a poly (lactide-co -glycolide) film in vitro biocompatibility and drug release studies, Biomaterials, 1999,20(20): 1919-1924
[28] Le Corro P, Chevanne F, et al, Spinal controlled delivery of bupivancane from DL-lactic acid oligomer microspheres, J. Pharm. Sci., 1995, 84: 75-78
[29] Le Corre P, Rytting JH, Gajan V, et al, In vitro controlled release kinetics of local anesthetics for poly(DL-Lactide) and poly(Lactide-co-glycolide) microspheres, J. Microencapsul, 1997, 14: 243-247
[30] 汪琴,脊髓损伤后的疼痛与处置,中国临床康复,2002,6(12):1716-1718
[31] 刘卫,李玲,中枢性疼痛,中国临床康复,2002,6(12):1707-1708
[32] 王泽民,当代结构药物全集,北京科学技术出版社,1332-1332
[33] 安国升,汪国芬,王宏图,尼莫地平的药动学研究,临床药学,1993,2:15-17
[34] 马霖,李静,尼莫地平分散片的人体相对利用度,山东医药工业,1999,18(2):3-5
[35] 周建平,王立新,张忠明,尼莫地平缓释胶囊的研究,中国药科大学学报,1999,30(5):346-349
[36] 徐榕青,王长连,邓思珊,尼莫地平漂浮缓释片的人体动力学及相对生物利用度,中国临床药学杂志,1999,8(6):347-350
[37] 蔡长春,李景苏,杨尊湘,尼莫地平软胶囊人体相对生物利用度研究,药学实践杂志,1997,15(5):288-290
[38] 薛秀珍,屈静,尼莫地平缓释胶囊质量控制方法的研究,山西医科大学学报,2002,33(3):233-234
[39] Yolles S, Leafe TD, Woodand JH, et al, Long acting delivery systems for narcotic antagonistsⅡ: release rates of natrexone from poly(lactic acid) composites, J. Pharm. Sci, 1975, 64(2):348
[40] 陶忠华,聚乳酸类生物降解聚合物在控释制剂中的应用,药学进展,1996,20(4):197-203
[41] 熊素彬,陆彬,氟尿嘧啶微球的体外释药模式研究,中国药师,2003,6(5):261-263
[42] 国家药典委员会编,中华人民共和国药典,2000 班,二部,北京:化学工业出版社,2000,附录 74
[43] 朱芳海,奚念珠,优选最佳数学模型用于固体制剂体外溶出实验数据处理程序的设计,药学学报,1994,29(6):459-461
[44] Higuchi T, Rate of release of medicaments from ointment base containing drug in suspension, J. Pharm. Sci., 1961,50:874-878
[45] Carstensen JT, Stability for solids and solid dosage form, J. Pharm. Sci., 1974, 3:1-5