依托泊苷磷脂复合物自乳化制剂的研究
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摘要
依托泊苷(Etoposide,VP-16)是鬼臼毒素的半合成产物,是从小檗科鬼臼属植物的根中提取的一种具有抗肿瘤活性的天然有效成分,主要作用机制是抑制哺乳类动物DNA拓扑异构酶Ⅱ的活性和/或直接诱导DNA,被广泛用于治疗小细胞肺癌,睾丸肿瘤,卡波西氏肉瘤,淋巴瘤和白血病。由于VP-16几乎不溶于水,其脂溶性也较差,药物口服吸收不规则,所以,现有的片剂、软胶囊等口服制剂均不同程度地存在生物利用度低的缺点,这已经成为制约该类药物发挥药效的主要因素。磷脂复合物载药系统和自乳化释药系统(SEDDS)由于其独特的作用机制,可作为难溶性、口服吸收差、生物利用度低的药物载体,成为提高难溶性药物口服生物利用度的新工具。本文将依托泊苷制备成磷脂复合物(Etoposide-Phospholipid Complex, EPC)后,进一步制备成SEDDS,以期两者有协同作用,从而提高依托泊苷的生物利用度。
第一部分研究依托泊苷磷脂复合物的制备方法并对其理化性质进行分析。通过单因素考察后,采用正交设计优化复合物制备工艺,对新生成的物质进行紫外光谱、红外光谱、差示扫描量热分析鉴别,并研究其溶解性能和油水分配系数。结果表明,VP-16磷脂复合物的优化制备条件为:四氢呋喃作溶剂,药物与大豆磷脂(Soy Phospholipids, SP)的摩尔比为1:1.2,25℃搅拌0.5 h;新生成物质的光谱分析不同于反应物单体及VP-16和SP的物理混合物;在0.1N HCl、水和pH6.8磷酸缓冲盐溶液(PBS)三种不同介质中,VP-16的溶解度和油水表观分配系数均有明显提高。
第二部分研究依托泊苷磷脂复合物自乳化制剂的制备方法并对其基本特征进行分析。通过考察依托泊苷磷脂复合物在油和(助)表活性剂中的溶解度、伪三元相图和粒径分析在,确定了自乳化制剂处方和制备方法;对依托泊苷磷脂复合物自乳化制剂(EPC-SEDDS)进行体外质量评价。结果表明,托泊苷磷脂复合物在油和(助)表活性剂中的溶解度有明显的提高,并筛选出最佳处方为:磷脂复合物100mg,辛癸酸甘油单酯(ODO)200mg,聚氧乙烯(35)氢化蓖麻油(Cremopher EL)480mg,聚乙二醇(400)(PEG-400)320mg。体外质量评价表明,EPC-SEDDS在水相介质中乳化速度较快,形成粒径约为200nm稳定的球形乳滴;在阴凉、避光和密闭条件下有良好的稳定性。体外溶出试验表明,EPC-SEDDS在15min约有93%的药物溶出到介质中,而EPC和VP-16在90min的累积溶出率才分别达到71%和42%,和EPC、VP-16相比较,EPC-SEDDS有较好的溶出度。
第三部分主要研究了EPC-SEDDS与其它制剂在大鼠体内的生物利用度的比较,并探讨了其吸收机制。这部分实验建立了依托泊苷的动物体内分析方法,经方法学考察,符合体内药物分析要求。选择了四种参比制剂,并对生物利用度进行相互比较。从实验结果可以得知,EPC-SEDDS、E-SEDDS(依托泊苷自乳化制剂)和EPCS(EPC混悬液)的AUC 0→24是ES(依托泊苷混悬液)的60.21、44.9和8.44倍,EPC-SEDDS的AUC 0→24是E-SEDDS、EPCS和市售制剂(威克)的2.34、7.13和2.55倍。结果说明磷脂复合物自乳化制剂提高药物的生物利用度和磷脂复合物及自乳化制剂相比有显著性不同,自乳化制剂生物利用度的提高比磷脂复合物明显,说明磷脂复合物和自乳化制剂两者有协同作用。与市售制剂的比较结果,再次验证了磷脂复合物自乳化制剂可以较大提高药物的生物利用度。
Etoposide (VP-16), a semisyntheticderivative product of podophyllotoxin, is naturally effective compound extracted from the roots and rhizomes of Podophyllum peltatum and P.emodi. The mechanism of anti-tumour involve inhibiting the activity of topoisomerase II enzyme and/or breaking DNA directly. Etoposide is widely used for curing patients with small cell lung cancer, testicular tumors, Kaposi’s sarcoma, lymphomas, and leukemia. For its poor solution in water and oil and high variability in absorption, etoposide oral formulations, like the tablet or soft capsule, have a shortcoming of low bioavailability in some way, which plays a major role on limiting the efficacy of these drugs. The unique mechanism of phospholipid complex and self-emulsifying drug delivery system (SEDDS) make them be a convenient carrier for insoluble, poor oral absorption and low bioavailability drugs, and a new tool to improve oral bioavailability of insoluble drugs. In this study, the etoposide- phospholipid complex (EPC) was prepared first for the following SEDDS. We supposed that there were synergistic effect between phospholipid complex and SEDDS to enhance the drug bioavailability.
In the first part, preparation of etoposide-phospholipid complex and its physicochemical properties were studied. Before the preparation conditions for etoposide-phospholipid complex were optimized by means of orthogonal design, single-factor study was performed. The physicochemical properties of new complex were analyzed by using the ultraviolet spectrum, infrared spectrum and differential scanning calorimetry. The changes of solubility and oil/water apparent partition coefficient of new complex in some solvents were manipulated. The results showed that optimized preparation conditions for etoposide-phospholipid complex as follows: solvent was tetrahydrofuran, the ratio of etoposide to phospholipids was 1 to 1.2(m/m), reactants were stirred for 0.5 h at 25℃. This new complex was different from reactant monomer and physical mixture of VP-16 and Soy Phospholipids with spectral analysis. The solubility and oil/water apparent partition coefficient of etoposide were enhanced rESCectively in 0.1N HCl, water and PBS.
In the second part, preparation of SEDDS and their basic characteristics were studied. The formulation and preparation of EPC-ESDDS were obtained by solubility study in oils and (co-) surfactants, pseudo-ternary phase diagram construction and droplet size analysis. Furthermore, EPC-SEDDS quality system was evaluated. Results showed, EPC solubility increased significantly in oils and (co-) surfactants, the optimum formulation: EPC 100mg, ODO (mixed decanoyl actanoyl glycerides) 200mg, Cremopher EL 480mg, PEG-400 320mg. Quality system evaluation showed, EPC-SEDDS in aqueous medium quickly formed a stable spherical emulsion which the particle size is about 200nm. Benign stability was present when EPC-SEDDS was stored at cool, dark, sealed condition. In vitro release study also showed that, about 93% EPC-SEDDS was released into media at 15min while the cumulative dissolution of EPC and VP-16 were only 71%和42%,rESCectably,which it showed EPC-SEDDS dissolution was better than EPC and VP-16.
In the third part,in vivo bioavailability of EPC-SEDDS compared with other preparations and probable absorption mechanism was discussed. The etoposide in vivo analysis was set up and accorded to the analysis requirements by analysis validation. Four reference preparations were selected and their bioavailability was compared with each other. Results showed, the EPC-SEDDS, E-SEDDS (etoposide-SEDDS) and EPCS (EPC suspension) of AUC 0→24 were 60.21, 44.9 and 8.44 fold compared with ES (etoposide suspension). The EPC-SEDDS AUC 0→24 was 2.34, 7.13 and 2.55 fold compared with E-SEDDS, EPCS and commercial preparation (Wick). Results indicated that the bioavailability of EPC-SEDDS was significantly different from E-SEDDS and EPC. It is concluded that bioavailability of etoposide was enhanced by phospholipid complex and could be further enhanced by SEDDS. There was synergistic effect between phospholipid complex and SEDDS. Compared with commercial preparations, the results showed EPC-SEDDS would obviously improve the bioavailability of these drugs.
第一部分研究依托泊苷磷脂复合物的制备方法并对其理化性质进行分析。通过单因素考察后,采用正交设计优化复合物制备工艺,对新生成的物质进行紫外光谱、红外光谱、差示扫描量热分析鉴别,并研究其溶解性能和油水分配系数。结果表明,VP-16磷脂复合物的优化制备条件为:四氢呋喃作溶剂,药物与大豆磷脂(Soy Phospholipids, SP)的摩尔比为1:1.2,25℃搅拌0.5 h;新生成物质的光谱分析不同于反应物单体及VP-16和SP的物理混合物;在0.1N HCl、水和pH6.8磷酸缓冲盐溶液(PBS)三种不同介质中,VP-16的溶解度和油水表观分配系数均有明显提高。
第二部分研究依托泊苷磷脂复合物自乳化制剂的制备方法并对其基本特征进行分析。通过考察依托泊苷磷脂复合物在油和(助)表活性剂中的溶解度、伪三元相图和粒径分析在,确定了自乳化制剂处方和制备方法;对依托泊苷磷脂复合物自乳化制剂(EPC-SEDDS)进行体外质量评价。结果表明,托泊苷磷脂复合物在油和(助)表活性剂中的溶解度有明显的提高,并筛选出最佳处方为:磷脂复合物100mg,辛癸酸甘油单酯(ODO)200mg,聚氧乙烯(35)氢化蓖麻油(Cremopher EL)480mg,聚乙二醇(400)(PEG-400)320mg。体外质量评价表明,EPC-SEDDS在水相介质中乳化速度较快,形成粒径约为200nm稳定的球形乳滴;在阴凉、避光和密闭条件下有良好的稳定性。体外溶出试验表明,EPC-SEDDS在15min约有93%的药物溶出到介质中,而EPC和VP-16在90min的累积溶出率才分别达到71%和42%,和EPC、VP-16相比较,EPC-SEDDS有较好的溶出度。
第三部分主要研究了EPC-SEDDS与其它制剂在大鼠体内的生物利用度的比较,并探讨了其吸收机制。这部分实验建立了依托泊苷的动物体内分析方法,经方法学考察,符合体内药物分析要求。选择了四种参比制剂,并对生物利用度进行相互比较。从实验结果可以得知,EPC-SEDDS、E-SEDDS(依托泊苷自乳化制剂)和EPCS(EPC混悬液)的AUC 0→24是ES(依托泊苷混悬液)的60.21、44.9和8.44倍,EPC-SEDDS的AUC 0→24是E-SEDDS、EPCS和市售制剂(威克)的2.34、7.13和2.55倍。结果说明磷脂复合物自乳化制剂提高药物的生物利用度和磷脂复合物及自乳化制剂相比有显著性不同,自乳化制剂生物利用度的提高比磷脂复合物明显,说明磷脂复合物和自乳化制剂两者有协同作用。与市售制剂的比较结果,再次验证了磷脂复合物自乳化制剂可以较大提高药物的生物利用度。
Etoposide (VP-16), a semisyntheticderivative product of podophyllotoxin, is naturally effective compound extracted from the roots and rhizomes of Podophyllum peltatum and P.emodi. The mechanism of anti-tumour involve inhibiting the activity of topoisomerase II enzyme and/or breaking DNA directly. Etoposide is widely used for curing patients with small cell lung cancer, testicular tumors, Kaposi’s sarcoma, lymphomas, and leukemia. For its poor solution in water and oil and high variability in absorption, etoposide oral formulations, like the tablet or soft capsule, have a shortcoming of low bioavailability in some way, which plays a major role on limiting the efficacy of these drugs. The unique mechanism of phospholipid complex and self-emulsifying drug delivery system (SEDDS) make them be a convenient carrier for insoluble, poor oral absorption and low bioavailability drugs, and a new tool to improve oral bioavailability of insoluble drugs. In this study, the etoposide- phospholipid complex (EPC) was prepared first for the following SEDDS. We supposed that there were synergistic effect between phospholipid complex and SEDDS to enhance the drug bioavailability.
In the first part, preparation of etoposide-phospholipid complex and its physicochemical properties were studied. Before the preparation conditions for etoposide-phospholipid complex were optimized by means of orthogonal design, single-factor study was performed. The physicochemical properties of new complex were analyzed by using the ultraviolet spectrum, infrared spectrum and differential scanning calorimetry. The changes of solubility and oil/water apparent partition coefficient of new complex in some solvents were manipulated. The results showed that optimized preparation conditions for etoposide-phospholipid complex as follows: solvent was tetrahydrofuran, the ratio of etoposide to phospholipids was 1 to 1.2(m/m), reactants were stirred for 0.5 h at 25℃. This new complex was different from reactant monomer and physical mixture of VP-16 and Soy Phospholipids with spectral analysis. The solubility and oil/water apparent partition coefficient of etoposide were enhanced rESCectively in 0.1N HCl, water and PBS.
In the second part, preparation of SEDDS and their basic characteristics were studied. The formulation and preparation of EPC-ESDDS were obtained by solubility study in oils and (co-) surfactants, pseudo-ternary phase diagram construction and droplet size analysis. Furthermore, EPC-SEDDS quality system was evaluated. Results showed, EPC solubility increased significantly in oils and (co-) surfactants, the optimum formulation: EPC 100mg, ODO (mixed decanoyl actanoyl glycerides) 200mg, Cremopher EL 480mg, PEG-400 320mg. Quality system evaluation showed, EPC-SEDDS in aqueous medium quickly formed a stable spherical emulsion which the particle size is about 200nm. Benign stability was present when EPC-SEDDS was stored at cool, dark, sealed condition. In vitro release study also showed that, about 93% EPC-SEDDS was released into media at 15min while the cumulative dissolution of EPC and VP-16 were only 71%和42%,rESCectably,which it showed EPC-SEDDS dissolution was better than EPC and VP-16.
In the third part,in vivo bioavailability of EPC-SEDDS compared with other preparations and probable absorption mechanism was discussed. The etoposide in vivo analysis was set up and accorded to the analysis requirements by analysis validation. Four reference preparations were selected and their bioavailability was compared with each other. Results showed, the EPC-SEDDS, E-SEDDS (etoposide-SEDDS) and EPCS (EPC suspension) of AUC 0→24 were 60.21, 44.9 and 8.44 fold compared with ES (etoposide suspension). The EPC-SEDDS AUC 0→24 was 2.34, 7.13 and 2.55 fold compared with E-SEDDS, EPCS and commercial preparation (Wick). Results indicated that the bioavailability of EPC-SEDDS was significantly different from E-SEDDS and EPC. It is concluded that bioavailability of etoposide was enhanced by phospholipid complex and could be further enhanced by SEDDS. There was synergistic effect between phospholipid complex and SEDDS. Compared with commercial preparations, the results showed EPC-SEDDS would obviously improve the bioavailability of these drugs.
引文
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[1] Shah N.H., Carvajal M.T., Patel C.I., et al. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs [J]. Int J Pharm., 1994,106 (1): 15-23
[2] Pouton CW. Formulation of self-emulsifying drug delivery systems [J]. Adv.Drug De1.Rev., 1997, 25, 474-458.
[3] Shinoda K,Araki M,Sadaghiani A,et a1.Lecithin based microemulsions:phase behaviour and microstructure[J].J. Phys. Chem., 1991, 95, 989-993
[4] Swenson ES., Milisen WB., Curatolo W.. Intestinal permeability enhancement:efficacy acute local toxicity and reversibility [J]. Pharm. Res., 1994, l1 (8): l132-1142
[5] Craig DQM., Barker SA., Banning D., et a1.An investigation into the mechanisms of self-em ulsification using particle sege anal~is and low frequency dielectric spectroscopy [J]. Int. J. Pharm., 1995,114 (1):103-113
[6] Ping, Zh., Ying L., Nianping F., et al. Preparation and evaluation of self-emulsifying drug delivery system of oridonin [J]. Int J Pharm., 2008,355: 269-276.
[7]陆彬药物新剂型与新技术(第2版)人民卫生出版社P89
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[10] Gershanik T,Benzeno S,Beniton S.Interaction of Self-emulsifying lipid drug delivery system with the evened rat intestinal macosa as a function of droplet size and surface charge [J].Pharm. Res., l998,l5 (6): 863-869
[11]刘晓阳,曹丰亮,刘锡联等.氟比洛芬自乳化给药系统的制备及体外溶出度考察[J].中国医院药学杂志,2007,27 (4): 463-466
[12]蔡勤,梁隆,黄艳萍等.川芎油自乳化释药系统体外评价[J].中国中药杂志, 2007,32 (19): 2003-2007
[13] Mads Kreilgaard. Dermal pharmacokinetics of microemulsion formulations determined by in vivo microdialysis [J]. Pharmaceutical Research, 2001,18 (3): 367-373
[14] NS Santos Magalhaes, G Cave, M Seiller, et al. The stability and in vitro release kinetics of a clofibride emulsion [J]. International journal of pharmaceutics, 1991, 76 (3): 225-237
[15]刘华,李三鸣,袁悦等.酮洛芬自乳化制剂处方及化学稳定性研究[J].沈阳药科大学学报, 2005,22 (1):5-7
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[19]周庆辉,平其能.自乳化药物传递系统的应用与前景[J].药学进展, 2001, 25 (3): 134-138
[20]涂秋榕,陈洁,朱家壁.自乳化药物传递系统[J].国外医药一合成药、生化药、制剂分册, 2002, 23 (3): 170-173
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[22] Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs [J]. Eur J Pharm Bio, 2000, 50,179-188
[23] Mueller E A, Kovarikl M, Van B, et a1 . Improved dose linearity of cyclosporin pharmacokinetics from a microemulsion formulation [J]. Pharm Res., 1994, 11 (2): 301-304
[24] Malmsten M.Surfactants and polymers in drug delivery [B]. Drugs and Pharmaceutical Sciences, V122M. New York: Marcel Dekker,2002, 5-159
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[28] Wei L,Sun P,Nie S.Preparation and evaluation of SEDDS and SMEDDS containingearvedilol[J]. Drug Dev Ind Pharm,. 2005, 31 (8): 785-794
[29] O Driseoll C M.Lipid-based formulations for intestinal lymphatic delivery [J]. Eur. J. Pharm. Sic., 2002, 15 (5): 405-415
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[1] Shah N.H., Carvajal M.T., Patel C.I., et al. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs [J]. Int J Pharm., 1994,106 (1): 15-23
[2] Pouton CW. Formulation of self-emulsifying drug delivery systems [J]. Adv.Drug De1.Rev., 1997, 25, 474-458.
[3] Shinoda K,Araki M,Sadaghiani A,et a1.Lecithin based microemulsions:phase behaviour and microstructure[J].J. Phys. Chem., 1991, 95, 989-993
[4] Swenson ES., Milisen WB., Curatolo W.. Intestinal permeability enhancement:efficacy acute local toxicity and reversibility [J]. Pharm. Res., 1994, l1 (8): l132-1142
[5] Craig DQM., Barker SA., Banning D., et a1.An investigation into the mechanisms of self-em ulsification using particle sege anal~is and low frequency dielectric spectroscopy [J]. Int. J. Pharm., 1995,114 (1):103-113
[6] Ping, Zh., Ying L., Nianping F., et al. Preparation and evaluation of self-emulsifying drug delivery system of oridonin [J]. Int J Pharm., 2008,355: 269-276.
[7]陆彬药物新剂型与新技术(第2版)人民卫生出版社P89
[8]徐琛,张钧寿.自我乳化药物传递系统[J].药学进展, 2001, 25 (1): 21-24
[9] CW Pouton. Self-emulsifying drug delivery systems: assessment of the efficiency of emulsification. [J]. Int. J. Pharm., 1985, 27, 335–348
[10] Gershanik T,Benzeno S,Beniton S.Interaction of Self-emulsifying lipid drug delivery system with the evened rat intestinal macosa as a function of droplet size and surface charge [J].Pharm. Res., l998,l5 (6): 863-869
[11]刘晓阳,曹丰亮,刘锡联等.氟比洛芬自乳化给药系统的制备及体外溶出度考察[J].中国医院药学杂志,2007,27 (4): 463-466
[12]蔡勤,梁隆,黄艳萍等.川芎油自乳化释药系统体外评价[J].中国中药杂志, 2007,32 (19): 2003-2007
[13] Mads Kreilgaard. Dermal pharmacokinetics of microemulsion formulations determined by in vivo microdialysis [J]. Pharmaceutical Research, 2001,18 (3): 367-373
[14] NS Santos Magalhaes, G Cave, M Seiller, et al. The stability and in vitro release kinetics of a clofibride emulsion [J]. International journal of pharmaceutics, 1991, 76 (3): 225-237
[15]刘华,李三鸣,袁悦等.酮洛芬自乳化制剂处方及化学稳定性研究[J].沈阳药科大学学报, 2005,22 (1):5-7
[16] Kawakami K, Yoshikawa T, Hayashi T, et a1.Microemulsion formulaion for enhanced absorption of poorly soluble drugs II In vivo study [J]. J. Controlled Release, 2002,81 (1-2): 75-82
[17]沈熊,吴伟.自乳化和自微乳化释药系统[J].复旦学报(医学版), 2003, 30(2): 180-183
[18] Neslihan, Gursoy R., Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs [J]. Biomed Pharmacother, 2004, 58 (3): 173-182
[19]周庆辉,平其能.自乳化药物传递系统的应用与前景[J].药学进展, 2001, 25 (3): 134-138
[20]涂秋榕,陈洁,朱家壁.自乳化药物传递系统[J].国外医药一合成药、生化药、制剂分册, 2002, 23 (3): 170-173
[21] Ghosh A, Wagner RF, et a1. Effect of combined use of nonionic surfaetant on form ation of oil-in water microemulsions [J]. Int. J. Pharm., 2005,288 (1): 27-34
[22] Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs [J]. Eur J Pharm Bio, 2000, 50,179-188
[23] Mueller E A, Kovarikl M, Van B, et a1 . Improved dose linearity of cyclosporin pharmacokinetics from a microemulsion formulation [J]. Pharm Res., 1994, 11 (2): 301-304
[24] Malmsten M.Surfactants and polymers in drug delivery [B]. Drugs and Pharmaceutical Sciences, V122M. New York: Marcel Dekker,2002, 5-159
[25] CW Pouton. Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system [J].European Journal of Pharmaceutical Sciences, 2006, 29, 278–287
[26] Gao P, Rush BD, Pfund W P, et a1. Development of a supersaturable SEDDS (S-SEDDS) formulation of paelitaxel with improved oral bioavailability [J].Journal of Pharmaceutical Sciences, 2003, 92 (2):2386-2398
[27] Gao P, Guyton ME, Huang T, et a1. Enhanced oral bioavailability of a poody water soluble drug PNU-91325 by supersaturatable formulations[J]. Drug Dev Ind Pharm., 2004,30 (2):22l-229
[28] Wei L,Sun P,Nie S.Preparation and evaluation of SEDDS and SMEDDS containingearvedilol[J]. Drug Dev Ind Pharm,. 2005, 31 (8): 785-794
[29] O Driseoll C M.Lipid-based formulations for intestinal lymphatic delivery [J]. Eur. J. Pharm. Sic., 2002, 15 (5): 405-415