【作者】 谷福根；

【导师】 崔福德； 高永良；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2005， 博士

【摘要】 本文以水溶性小、化学稳定性差的前列腺素E₁（Prostaglandin E₁，PGE₁）为模型药物，研究了PGE₁的溶解度、溶液稳定性及其二者的影响因素，并以羟丙-β-环糊精（HP-β-CD）为包合材料，制备了PGE₁的包合物，最后研制了PGE₁-HP-β-CD包合物的两种新剂型——鼻粉剂与舌下片，并对它们的体外质量以及体内药效学进行了较为深入的研究和探讨。 在PGE₁溶解度的研究中，研究了溶液pH值、HP-β-CD以及二者综合对药物溶解度的影响。结果表明，提高溶液pH值或加入HP-β-CD，均可明显增加PGE₁的溶解度。 在PGE₁溶液稳定性的研究中，分别研究了pH值、HP-β-CD、离子强度以及乙醇对药物溶液稳定性的影响。结果表明，PGE₁溶液的最稳定pH值在3.0～4.0之间，而在强酸或强碱pH值下，很不稳定；在强酸或强碱pH值下，HP-β-CD可增加PGE₁溶液的稳定性，但在中性条件下，却降低PGE₁溶液的稳定性；离子强度对PGE₁溶液的稳定性没有影响；乙醇可明显增加PGE₁溶液的稳定性。 在PGE₁与HP-β-CD在溶液中包合作用的研究中，分别采用了UV法、相溶解度图法、圆二色谱法、NMR法以及等摩尔系列法等对主、客分子间的包合作用、包合比、包合物空间构型、热力学参数变化进行了研究。结果表明，PGE₁与HP-β-CD在溶液中可形成1：1摩尔比可溶性包合物，相溶解度图呈A₁-型；包合物的表观稳定常数Ka值随pH的增大而减小。PGE₁分子的五元碳环部分已嵌入了HP-β-CD分子的疏水性空穴中。包合过程中的Gibbs自由能变化（ΔG）、焓变（ΔH）及熵变（ΔS）均为负值，提示包合过程在常温常压下可自发进行，同时为放热反应和熵减过程。 在PGE₁-HP-β-CD固体包合物的研究中，选定了冷冻干燥法来制备药物的包合物。以包合物的化学稳定性为指标，研究投料比、超声处理、环糊精的种类对PGE₁包合物稳定性的影响，同时结合包合物溶液的物理稳定性，来确定最佳包合材料、包合比及包合工艺。结果表明，以摩尔取代度为5.0的HP-β-CD为包合材料，主、客分子投料摩尔比为10：1，所制备PGE₁包合物的化学稳定性最佳。经IR、X-光衍射法研究证实，PGE₁与HP-β-CD已形成包合物；溶出实验结果表明，PGE₁形成包合物后，其溶出速率显著提高。 在PGE₁-HP-β-CD包合物鼻粉剂处方筛选与制备工艺研究中，对鼻粉剂辅料的吸湿性、流动性及喷流性进行了考察并比较了不同处方组成包合物鼻粉剂的化学稳定性。结更多还原

【Abstract】 Prostaglandin E₁ （PGE₁） with poor aqueous solubility and chemical stability was used as a model drug in this paper. Firstly, the solubility, chemical stability of PGE₁ and their respective affecting factors were investigated and a solid PGE₁ complex with hydroxypropyl-β-cyclodextrin （HP-β-CD） having greater aqueous solubility and better safetythan natural cyclodextrins was prepared. Then, two new dosage forms--PGE₁-HP-β-CDcomplex nasal powders and sublingual tablets were developed and their in vitro qualities and in vivo pharmacodynamics were intensively studied.In the study of PGE₁ aqueous solubility, the effect of media pH, HP-β-CD alone and both on the solubility of the drug was investigated. The results showed that the solubility of PGE₁ was significantly improved by increasing the media pH or addition of HP-β-CD. Furthermore, a synergistic solubilizing effect was produced when increasing media pH combined with the addition of HP-β-CD.In the study of the stability of PGE₁ aqueous solution, effect of pH, HP-β-CD, ionic strength, and ethanol on the stability of PGE₁ solution was investigated, respectively. The results demonstrated that PGE₁ solution was most stable at pH 3.0-4.0 and very unstable under strongly acidic or basic pH conditions. HP-β-CD could obviously increase the stability of PGE₁ solution under strongly acidic or alkaline conditions, but slightly promote the drug degradation at neutral pHs. In addition, the stability of PGE₁ solution was not affected by solution ionic strength, but significantly improved by ethanol.In the study of the complexation of PGE₁ with HP-β-CD in solution, the host-guest molecular interactions, complexing molar ratio, complex steric conformation, change of thermodynamic parameters were studied by lots of methods such as UV absorption spectroscopy, phase solubility method, circular dichroism spectroscopy, nuclear magnetic resonance and equimolar series method. The results indicated that a 1:1 molar ratio soluble PGE₁ complex with HP-β-CD could form in aqueous solution and the phase solubility diagram exhibited A₁-type. The conformation of PGE₁-HP-β-CD complex is that the p-hydroxyketo moiety-containing five-membered ring of PGE₁ molecules was probably included within the hydrophobic cavity of HP-β-CD molecules. Additionally, the changes of thermodynamic parameters determined such as Gibbs free energy change （△G）, enthalpy change（△H）, and更多还原