共溶媒與卵磷脂改善PLGA微球體物性之技術性探討

Technical improvement of PLGA microspheres formation by using cosolvent and lecithin

顏君如(Chun-Ju Yan)

指導教授 ： 何秀娥

臺北醫學大學/藥學院/藥學系(碩博士班)/碩士(2013年)

摘要

本研究以具生物可降解性及生體相容性之聚乳酸–甘胺酸共聚物 (Poly(D,L-lactide-co-glycolide), PLGA) 為材料，利用溶劑揮發法 (solvent evaporation process) 製備微球體 (microspheres)，以治療酒精成癮性之 naltrexone 為模式藥物，瞭解 PLGA 微球體製備及藥物釋放情況，並探討共溶媒 (cosolvent) 與大豆卵磷脂 (lecithin) 對微球體劑型的影響性。
　　實驗中探討各製程及處方因素對微球體粒徑、形態、模式藥物包覆率及藥物釋放之影響，分別為：(1) 連續相對分散相比例 (CP/DP ratio)，(2) 連續相中聚乙烯醇 (polyvinyl alcohol, PVA) 濃度，(3) 製程中攪拌速度，(4) 調整 PLGA 濃度及黏度，(5) 不同比例二氯甲烷 (dichloromethane, DCM) 和甲醇或丙酮之共溶媒為分散相，(6) 添加不同比例的 lecithin 於分散相與 (7) 不同濃度及黏度的 PLGA 合併添加 lecithin 於分散相之作用。
　　實驗結果顯示，在單純使用 DCM 為分散相的條件下，能夠製備出粒徑分布集中之微球體，但其 naltrexone 包覆率相當低 (16.5%)，藉由調整 PLGA 濃度及黏度亦無法有效改善此缺點；當利用 DCM 與丙酮 (1:2) 形成之共溶媒系統為分散相時，則能大幅提升 naltrexone 之包覆率 (73.9%)，但卻導致微球體粒徑分布過廣。當添加不同比例的 lecithin 於分散相時，隨著添加量的增加，微球體粒徑及包覆率僅些微改變，但最重要的是，明顯地改善以共溶媒系統為分散相時，粒徑分布過廣的問題。
　　無論在體外藥物釋放及大鼠體內藥物動力學研究，都觀察到 lecithin 的添加有助於改善微球體之粒徑分布，且不降低 naltrexone 包覆率，但因其親水特質，會促進微包體於體外的藥物釋放，並造成微球體於大鼠體內藥物釋放速率較快、藥效作用時間較短。

關鍵字

共溶媒 ； 微球體 ； 卵磷脂

並列摘要

Poly(lactide-co-glycolide) (PLGA), a biocompatible and biodegradable polymer, has been tremendously researched in the drug delivery system. Naltrexone treatment of alcohol dependence was chosen as the model drug and loaded in PLGA microspheres.
　In order to develop the platform of PLGA microspheres, various process parameters were evaluated such as (1) continue phase/disperse phase ratio (CP/DP), (2) polyvinyl alcohol (PVA) concentration in continuous phase, (3) agitation rate, (4) different concentration and viscosity of PLGA, (5) different cosolvent as disperse phase and (6) the addition of soy bean lecithin in disperse phase.
　As the results, the dichloromethane (DCM) only as disperse phase, the encapsulation efficiency (E.E.) was too low (16.5%). It was useless to enhance the E.E. obviously by adjusting the concentration and grades of PLGA. But the cosolvent system containing DCM and acetone (1:2) could have higher E.E. about 73.9%. However, the particle size distribution became broader with the lower ratio of dichloromethane in disperse phase. By the addition of 0.1% lecithin, the particle size distribution could be narrow down.
　In vitro drug release and animal studies were to investigate the effect of formulations, particle size, and inherent viscosity of PLGA. The inherent viscosity of PLGA was the key factor of drug release. Furthermore, hydrophilic lecithin could enhance naltrexone release from the PLGA microspheres.

並列關鍵字

cosolvent ； microspheres ； lecithin

參考文獻

1. Wischke C, et. al. Principles of encapsulating hydrophobic drugs in PLA/PLGA microparticles. International Journal of Pharmaceutics (2008) 364(2):298-327.

2. Vroman I, et. al. Biodegradable polymers. Materials (2009) 2(2):307-344.

3. Wu XS, et. al. Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid polymers. Part ii: Biodegradation. Journal of Biomaterials Science, Polymer Edition (2001) 12(1):21-34.

4. Ikada Y, et. al. Biodegradable polyesters for medical and ecological applications. Macromolecular Rapid Communications (2000) 21(3):117-132.

5. 陳嘉文. 生物相容性共聚物之製備及其在皮質固醇. 國立成功大學 化學工程研究所, (2002, 六月).