曲安奈德环糊精超分子包合物的制备及其鼻喷雾剂的研究

发布时间：2018-05-20 09:10

本文选题：曲安奈德 + 羟丙基-β-环糊精　；参考：《辽宁大学》2017年硕士论文

【摘要】：过敏性鼻炎(Allergic Rhinitis AR)是一种由多种致敏源引起的免疫球蛋白IgE介导的机体炎症反应,主要临床表现为鼻塞、鼻痒、流鼻涕、打喷嚏等,严重影响患者的正常生活。使用鼻喷雾剂是治疗过敏性鼻炎,缓解症状的主要方法。环糊精是超分子化学的重要组成部分,可以与疏水性药物通过非共价键形成超分子包合物。超分子药物具有溶解度好,生物利用度高,毒性低等优点。曲安奈德是一种强效糖皮质激素,是治疗过敏性鼻炎的首选药物,具有很好的治疗效果和较弱的不良反应。由于曲安奈德的溶解性较差,故目前国内外上市的曲安奈德鼻喷雾剂均为混悬剂。药物振摇后混合不均匀,药物均一度较差,而且没有从根本上解决曲安奈德溶解性差的问题。故本课题选用环糊精作为包合材料,使之与曲安奈德形成超分子包合物,增加曲安奈德的溶解度。溶液型曲安奈德鼻喷雾剂在鼻腔内具有更好的铺展性,可以促进曲安奈德在鼻腔内的吸收,从而提高药物的生物利用度。本文研究了曲安奈德的理化性质,选用羟丙基-β-环糊精和磺丁基-β-环糊精两种β-环糊精衍生物作为包合材料,形成曲安奈德环糊精超分子包合物,以包合率为指标,确定主客分子投料比以及最佳制备工艺;采用冷冻干燥法制备曲安奈德环糊精超分子包合物固体,并通过表征和光谱研究验证曲安奈德与环糊精形成超分子包合物。在曲安奈德环糊精超分子包合物水溶液制备的基础上,参考赛诺菲的产品(Nasacort AQ),确定辅料的种类,根据粘度和毫摩尔渗透压为指标,确定了生物粘附剂HPMC和渗透压调节剂无水葡萄糖的用量,筛选得到曲安奈德环糊精超分子包合物鼻喷雾剂的处方;通过特征性对比研究,确定曲安奈德环糊精超分子包合物鼻喷雾剂优于触变性曲安奈德鼻喷雾剂。通过二甲苯致小鼠耳廓肿胀模型和角叉菜胶致大鼠足爪肿胀模型试验考察曲安奈德环糊精超分子包合物鼻喷雾剂对肿胀模型的影响,实验结果表明,曲安奈德环糊精超分子包合物鼻喷雾剂对急性炎症有治疗作用;通过建立豚鼠过敏性鼻炎模型,来考察曲安奈德环糊精超分子包合物鼻喷雾剂对过敏性鼻炎的影响,实验结果表明,曲安奈德环糊精超分子包合物鼻喷雾剂对过敏性鼻炎药效明显,中剂量组和高剂量组药效优于阳性对照药。
[Abstract]:Allergic rhinitis Allergic Rhinitis ARA is an immunoglobulin IgE mediated inflammatory response caused by various allergens. Its main clinical manifestations are nasal congestion, itching, runny nose, sneezing and so on, which seriously affect the normal life of patients. Nasal spray is the main way to treat allergic rhinitis and relieve symptoms. Cyclodextrin is an important component of supramolecular chemistry and can form supramolecular inclusion complexes with hydrophobic drugs through non-covalent bonds. Supramolecular drugs have the advantages of good solubility, high bioavailability and low toxicity. Triamcinolone acetonide is a powerful glucocorticoid and is the first choice in the treatment of allergic rhinitis. Because of the poor solubility of triamcinolone acetonide, triamcinolone acetonide nasal spray is a suspension. After shaking, the mixture was uneven, the drug was once poor, and the problem of poor solubility of triamcinolone acetonide was not fundamentally solved. Therefore, cyclodextrin was chosen as inclusion material to form supramolecular inclusion compound with triamcinolone acetonide, and the solubility of triamcinolone acetonide was increased. The solution type triamcinolone acetonide nasal spray has better spread in the nasal cavity, can promote the triamcinolone acetonide absorption in the nasal cavity, thus enhances the bioavailability of the drug. The physical and chemical properties of triamcinolone acetonide were studied. Two 尾 -cyclodextrin derivatives, hydroxypropyl- 尾 -cyclodextrin and Ding Ji-尾 -cyclodextrin, were used as inclusion materials to form triamcinolone acetonide cyclodextrin supramolecular inclusion complex. The supermolecular inclusion complex of triamcinolone acetonide cyclodextrin was prepared by freeze-drying method, and the supramolecular inclusion complex between triamcinolone acetonide and cyclodextrin was confirmed by characterization and spectroscopic study. Based on the preparation of triamcinolone acetonide cyclodextrin supramolecular inclusion complex aqueous solution and referring to the product of Sanofir, Nasacort AQA, the types of excipients were determined, and the viscosity and molar osmotic pressure were used as indexes. The dosage of bioadhesive HPMC and osmotic pressure regulator anhydrous glucose was determined and the formulation of triamcinolone acetonide cyclodextrin inclusion compound nasal spray was obtained. It was determined that triamcinolone acetonide cyclodextrin inclusion compound nasal spray was superior to thixotropic triamcinolone acetonide nasal spray. The effects of triamcinolone acetonide cyclodextrin inclusion compound nasal spray on the swelling model of mouse auricle and rat paw induced by carrageenin were studied. The nasal spray of triamcinolone acetonide cyclodextrin inclusion compound has a therapeutic effect on acute inflammation and the effect of triamcinolone acetonide cyclodextrin inclusion compound nasal spray on allergic rhinitis was investigated by establishing a guinea pig allergic rhinitis model. The results showed that triamcinolone acetonide cyclodextrin supramolecular inclusion compound nasal spray had obvious effect on allergic rhinitis.
【学位授予单位】：辽宁大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

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