利用羥乙基纖維素和幾丁聚醣開發Alendronate sodium之胃滯留藥物傳遞系統

Development of Gastroretentive Drug Delivery System for Alendronate sodium Based on Hydroxyethylcellulose and Chitosan

邱喬琪(Chiao-Chi Chiu)

指導教授 ： 許明照

臺北醫學大學/藥學院/藥學研究所/碩士(2011年)

摘要

骨質疏鬆症為目前常見的疾病之一，目前市面上許多治療方法當中最常使用的即是雙磷酸類(bisphosphonates)藥物，如 alendronate 、risedronate等。然而雙磷酸鹽類藥物最大的缺點即為口服吸收率極低以及造成上消化道黏膜的局部刺激，因此本實驗目的主要是以具有膨脹特性的幾丁聚醣溶於不同酸中形成不同的鹽類型式和聚合物羥乙基纖維素以不同比例混合來開發新穎的胃滯留藥物傳遞系統進而藉由延長胃部停留時間使模式藥物alendronate sodium經過其吸收部位時間增加導致其口服吸收率上升。此外，利用alendronate sodium和幾丁聚醣之間的結合，進而減少藥物對於消化道黏膜的局部刺激。
以不同分子量的幾丁聚醣和羥乙基纖維素以不同比例分別溶在醋酸、琥珀酸、檸檬酸、乳酸、蘋果酸，固定一噸的壓力打成錠，進而觀察其膨脹的狀態及錠劑結構，經綜合比較，發現以酸類處理後，醋酸鹽、琥珀酸鹽、檸檬酸鹽擁有較佳的膨脹效果以及錠劑結構；低中高分子量的幾丁聚醣的比較發現高分子量幾丁聚醣由於分子量及黏度過高進而導致錠劑過度黏稠緊密，無法有效導水進入而達到良好之膨脹效果；隨著羥乙基纖維素的增加，膨脹的效果下降，但錠劑結構相對提升。
進而以低分子量及中分子量的幾丁聚醣和羥乙基纖維素以不同比例分別溶在醋酸、琥珀酸、檸檬酸，進一步評估不同的打錠壓力(0.5噸/ 1噸/ 1.5噸)所造成的影響。實驗結果發現低分子量琥珀酸鹽及低分子量檸檬酸鹽在0.5噸的打錠壓力下均可快速的達到懸浮之效果；而1.5噸的打錠壓力在某些處方則有有較佳之膨脹效果。
經綜合比較之，挑選具有最佳膨脹及懸浮效果並具有良好胃滯留效果之處方添加模式藥物：alendronate sodium。結果顯示藥物皆能有效的緩慢釋出，沒有快速釋出的現象，而釋放機轉主要可由藥物擴散與膠體膨脹緩解效用所管控。
因此可以預期利用本研究所開發的胃滯留劑型於體內之緩釋效果不但可以提高模式藥物 alendronate的生體可用率，其與幾丁聚醣之間的正負電結合也可降低模式藥物對於腸胃道之副作用。

關鍵字

胃滯留藥物傳遞系統 ； 膨脹 ； 幾丁聚醣

並列摘要

Osteoporosis is one of the common diseases, and currentlythe most used drug is biphosphonates. However, the adverse reactions in bisphosphonates are local stimulation on upper digestive mucous and low bioavailability. Hence, the aim of the study was to develop a novel gastrorentive drug delivery system (GRDDS) with different molecular weight of swellable chitosan and hydroxyethyl cellulose. GRDDs can prolong alendronate sodium in the upper part of absorption region by increasing the gastric retention time. Also, the positive and negative charge interaction between alendronate sodium and chitosan can decrease the irritation of upper digestive mucous.
Chitosans with various molecular weights formed CS-salt in acetic acid, succinic acid, citric acid, lactic acid and malic acid. And then various ratios of hydroxyethyl cellulose were added to form swellable tablets. After comparison with swell ability and formula structure, Chitosan of acetate, succinate and citrate salt forms possessed a better physical charasteristics for gastroretentive ability; Comparison among chitosans with various molecular weight concluded that high molecular weight chitosan has a worse swelling ability due to the retardation of water inward progression by its high viscosity and higher molecular weight; With increasing ratio of hydroxyethyl cellulose, the swelling ability of chitosan tablet deteriorated but improving characteristics of resulting gel structure.
Furthermore, chitosan with low and medium molecular weight were converted to CS-salt in acetic acid, succinic acid and citric acid. And swellable tablets were formulated with various ratio of hydroxyethyl cellulose. After comparison with different tableting pressure(0.5 ton/ 1 ton/ 1.5 ton), LMCS-succinate and LMCS-citrate in 0.5 ton tableting pressure have the less floating leg time and some formulae have great performance on swelling ability in 1.5 ton tableting pressure.
Based on the result of Part I, formulae with the best gastroretentive effect were selected to evaluate the properties of model drug: alendronate sodium. As a result, drugs release slowly rather than fast. And the release model was controlled by drug diffusion and gel swelling relaxation.
Consequently, we developed GRDDs which can increase the bioavailability of model drug, alendronate sodium, and the interaction between model drug and chitosan can also decrease the irritation of upper digestive mucous.

並列關鍵字

gastroretentive ； swellimg ； chitosan

參考文獻

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