丁丙诺啡经皮给药制剂的研究
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摘要
盐酸丁丙诺啡(buprenorphine.HCl,简称丁丙诺啡)是半合成的奥列巴文类衍生物,兼具有阿片受体激动和拮抗性。长期以来都被用于临床上治疗中度或中强度的疼痛;近些年来,许多国家,例如美国、澳大利亚、瑞士和法国等已将其逐渐用于戒毒药物。目前丁丙诺啡市售剂型有片剂、注射剂和胶囊剂等,未见国内外丁丙诺啡贴剂上市。
丁丙诺啡具有药理作用强,分子量小(504.11),而且具有适宜的水溶性及较高的亲脂性的特点,适于制成透皮贴剂。
本论文对丁丙诺啡的部分理化性质进行了测定;对丁丙诺啡经豚鼠背部皮肤的渗透性进行了研究;并考察了3种促渗剂对丁丙诺啡经皮渗透的作用,其结果表明,使用促渗剂能显著的提高药物的透皮量。
本文对丁丙诺啡透皮贴剂处方进行了设计。处方设计采用正交设计实验对系统中的促渗剂、压敏胶和药量等进行选择。实验结果表明,丁丙诺啡经皮给药制剂的最佳处方为:即主药含量10%;促渗剂1、促渗剂2和促渗剂3,含量分别为x%、y%和z%;压敏胶含量为70%;背衬层材料为共聚物微孔膜,防粘层材料为聚酯膜。
分析方法学研究表明紫外分光光度法和HPLC分析法具有很好的重现性和准确性。建立了丁丙诺啡的鉴别方法——紫外分光光度法和贴剂含量的HPLC分析法。
质量标准研究和制剂性能研究等表明,丁丙诺啡贴剂具有较好初粘力和持粘力,体外透皮速率符合零级方程。对丁丙诺啡贴剂质量标准包括制剂的性状、体外透皮和粘附性等进行了研究。
另外,本文还对丁丙诺啡离子导入过程中的影响因素,包括电流密度,占空比,离子导入频率选择和给药池药物浓度大小等,进行了考察。结果表明,在电流密度、药物浓度和占空比分别为0.3 mA/cm~2,0.3m/mL和1∶2时,药物的离子导入效果最好。并对常规的贴剂与离子导入两种剂型的导入效果做了比较,发现离子导入给药的导入效果远好于普通经皮给药。
实验结果表明,丁丙诺啡透皮贴剂具有良好的性能,能维持3天的恒定药物释放,对皮肤无强烈刺激,是一种安全、有效的新剂型。
Buprenorphine is a partial agonist atμ-opioid receptors but has also antagonistic or agonistic properties atκ-andδ-opioid receptors. It has long been in clinical use for treatment of moderate-to-severe pain. More recently, evidence has accumulated in support of its efficacy for maintenance treatment of heroin dependence, and the drug has been approved for this indication in numerous countries, including the United States, Australia, Sweden, and France. The dosage forms of buprenorphine available on the market are tablet, injection and capsule. However, at present, marketed transdermal therapeutic patches was not found.
Buprenorphine has a strong pharmaco dynamic effect and a low molecular weight (504.11) and a suitable octanol/water partition coefficient, which causes it adaptable to be made as transdermal therapeutic systems (TTS).
In this thesis, some physicochemical properties and the transdermal delivery across Guinea pig skin in vitro of buprenorphine with 3 kinds of penetration enhancers used alone were studied. For the successful development, a series of systematic studies were conducted. The prescription of buprenorphine TTS were designed. Pharmaceutical analysis methodology, quality standard and the properties of preparations were studied.
In order to obtain the optimal drug delivery, the main ingredients, pressure sensitive adhesives (PSA) and permeation enhancers were chosen through orthogonal tests. The results show crylic acid PSA and single permeation enhancer 1 can make a remarked synergistic enhancement of buprenorphine permeating through Guinea pig skin. Finally, based on the extensive development studies, a prototype of buprenorphine TTS is prepared with 10% buprenorphine, x% enhancer 1, y% enhancer 2, z% enhancer 3, 70% crylic acid PSA, and Polyester films.
In this study, the effects of current density of alternating current, drug concentration, the enhancing effect of propylene glycol and on/off ratio on the in vitro skin permeability of buprenorphine have also been investigated. The result indicated that iontophoresis could modify the skin morphology and consequently, increase the passive transport of BUP at a certain current density, drug concentration, on/off ratio, which are 0.3 mA/cm~2, 0.3mg/mL and 1:2 respectively. Besides, when buprenorphine was transported iontophoretically, passive skin pretreatment with 1% propylene glycol, produced higher flux values than iontophoretic skin pretreatment.
The method of UV was used as distinguished. The method of HPLC has been developed to determine the content and relative substances of buprenorphine TTS.
Quality measures included sample size and shape, homogeneity, detection of relative substances, release rates, penatration rates and adhesiveness.
The results above indicate that buprenorphine -TTS is capable of 1 days continuous delivery of buprenorphine with a stable permeation rate and has not any skin irritation. So it is a safe and effective transdermal therapeutic system.
丁丙诺啡具有药理作用强,分子量小(504.11),而且具有适宜的水溶性及较高的亲脂性的特点,适于制成透皮贴剂。
本论文对丁丙诺啡的部分理化性质进行了测定;对丁丙诺啡经豚鼠背部皮肤的渗透性进行了研究;并考察了3种促渗剂对丁丙诺啡经皮渗透的作用,其结果表明,使用促渗剂能显著的提高药物的透皮量。
本文对丁丙诺啡透皮贴剂处方进行了设计。处方设计采用正交设计实验对系统中的促渗剂、压敏胶和药量等进行选择。实验结果表明,丁丙诺啡经皮给药制剂的最佳处方为:即主药含量10%;促渗剂1、促渗剂2和促渗剂3,含量分别为x%、y%和z%;压敏胶含量为70%;背衬层材料为共聚物微孔膜,防粘层材料为聚酯膜。
分析方法学研究表明紫外分光光度法和HPLC分析法具有很好的重现性和准确性。建立了丁丙诺啡的鉴别方法——紫外分光光度法和贴剂含量的HPLC分析法。
质量标准研究和制剂性能研究等表明,丁丙诺啡贴剂具有较好初粘力和持粘力,体外透皮速率符合零级方程。对丁丙诺啡贴剂质量标准包括制剂的性状、体外透皮和粘附性等进行了研究。
另外,本文还对丁丙诺啡离子导入过程中的影响因素,包括电流密度,占空比,离子导入频率选择和给药池药物浓度大小等,进行了考察。结果表明,在电流密度、药物浓度和占空比分别为0.3 mA/cm~2,0.3m/mL和1∶2时,药物的离子导入效果最好。并对常规的贴剂与离子导入两种剂型的导入效果做了比较,发现离子导入给药的导入效果远好于普通经皮给药。
实验结果表明,丁丙诺啡透皮贴剂具有良好的性能,能维持3天的恒定药物释放,对皮肤无强烈刺激,是一种安全、有效的新剂型。
Buprenorphine is a partial agonist atμ-opioid receptors but has also antagonistic or agonistic properties atκ-andδ-opioid receptors. It has long been in clinical use for treatment of moderate-to-severe pain. More recently, evidence has accumulated in support of its efficacy for maintenance treatment of heroin dependence, and the drug has been approved for this indication in numerous countries, including the United States, Australia, Sweden, and France. The dosage forms of buprenorphine available on the market are tablet, injection and capsule. However, at present, marketed transdermal therapeutic patches was not found.
Buprenorphine has a strong pharmaco dynamic effect and a low molecular weight (504.11) and a suitable octanol/water partition coefficient, which causes it adaptable to be made as transdermal therapeutic systems (TTS).
In this thesis, some physicochemical properties and the transdermal delivery across Guinea pig skin in vitro of buprenorphine with 3 kinds of penetration enhancers used alone were studied. For the successful development, a series of systematic studies were conducted. The prescription of buprenorphine TTS were designed. Pharmaceutical analysis methodology, quality standard and the properties of preparations were studied.
In order to obtain the optimal drug delivery, the main ingredients, pressure sensitive adhesives (PSA) and permeation enhancers were chosen through orthogonal tests. The results show crylic acid PSA and single permeation enhancer 1 can make a remarked synergistic enhancement of buprenorphine permeating through Guinea pig skin. Finally, based on the extensive development studies, a prototype of buprenorphine TTS is prepared with 10% buprenorphine, x% enhancer 1, y% enhancer 2, z% enhancer 3, 70% crylic acid PSA, and Polyester films.
In this study, the effects of current density of alternating current, drug concentration, the enhancing effect of propylene glycol and on/off ratio on the in vitro skin permeability of buprenorphine have also been investigated. The result indicated that iontophoresis could modify the skin morphology and consequently, increase the passive transport of BUP at a certain current density, drug concentration, on/off ratio, which are 0.3 mA/cm~2, 0.3mg/mL and 1:2 respectively. Besides, when buprenorphine was transported iontophoretically, passive skin pretreatment with 1% propylene glycol, produced higher flux values than iontophoretic skin pretreatment.
The method of UV was used as distinguished. The method of HPLC has been developed to determine the content and relative substances of buprenorphine TTS.
Quality measures included sample size and shape, homogeneity, detection of relative substances, release rates, penatration rates and adhesiveness.
The results above indicate that buprenorphine -TTS is capable of 1 days continuous delivery of buprenorphine with a stable permeation rate and has not any skin irritation. So it is a safe and effective transdermal therapeutic system.
引文
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