混合膜衣材料之吸水力與機械特性評估以開發製備發泡型多單元漂浮劑型

Evaluation of water uptake and mechanical properties of blending polymer films for preparing gas-generated multiple-unit floating doasage form

沙震(Chen Sha)

指導教授 ： 林本元

共同指導教授 ： 許明照

臺北醫學大學/藥學院/藥學研究所/碩士(2010年)

摘要

控釋劑型(Controlled release dosage form)的發展改善了藥效持續時間，進而減少了病人的服藥次數，故在病人順服性的提升和不良反應的下降都有更顯著的效果，但對於有特別性質的藥物，如：吸收侷限於腸胃道中特定小區段 (narrow absorption window)或代謝物比原型藥活性更佳之藥物，仍然效果不彰，此時就發展出了胃滯留藥物傳遞系統(Gastroretentive drug delivery systems, GRDDS)。
以膜衣包覆方式製備發泡型多單元漂浮劑型 (Gas-generated, multiple-unit gastroretentive dosage form)為近期內胃滯留藥物傳遞系統中常為討論之方法，但使用單一材料及能成為此類劑型之理想膜衣卻是少之又少，故本研究主要目的就是希望利用腸胃道可溶性材料 (GIT soluble polymer)來改善腸胃道不可溶性膜衣 (GIT insoluble polymer)之吸水力及機械強度，並觀察膜衣吸水力與機械強度和漂浮能力之間的關連性。
首先，利用吸水力與拉張力試驗了解Eudragit® RS、Eudragit® NE、Surelease®、Ethylcellulose®和Kollicoat® SR等腸胃道不溶性膜衣搭配不同腸胃道可溶性膜衣HPMC 6cps、PEG600、PEG6000和Kollicoat® IR之吸水能力以及於乾燥及濕潤情況下的膜衣強度及延展性等機械特性。根據上述實驗結果篩選出處方SRT(5)P600(10)、NIR(10)、ST(30)IR(10)和RSD(15)IR(10)進行劑型製備，並以漂浮能力試驗與溶離試驗測試其漂浮與藥物釋放情形，以期建立出膜衣技術用於製備發泡型多單元胃滯留劑型之非特異性藥物劑型的技術平台。
研究結果大致可依吸水力高低分為兩組，吸水力較高的為SRT(5)P600(10)和ST(30)IR(10)，呈現了能快速漂浮但漂浮持續與緩釋能力不足的結果；相對地吸水力較低的組別NIR(10)與RSD(15)IR(10)則有著不易漂浮但緩釋能力明顯的結果。於是針對上述之結果進行改良，並再嘗試SRT(5)P600(5)、NIR(20)、ST(30)IR(5)和RSD(15)IR(20)等處方，結果發現不論在各處方皆提升了漂浮的能力，尤其是SRT(5)P600(5)呈現了15分鐘以內全數漂浮，且漂浮持續能力在12小時內維持60%以上的圓粒仍在漂浮，另外也確實地降低了藥物的釋放速率。
由上述結果可彙整出三項結論，第一、在膜衣混合使用的部分，利用腸胃道中可溶性材料大幅增加膜衣整體吸水力的方法確實使得原本不適用於製作發泡型漂浮劑型的膜衣擁有了漂浮的能力；第二、膜衣之吸水力和拉張力試驗的結果能夠反映出實際包覆後的狀況，當中以吸水力與漂浮所需時間 (floating lag time)和藥物釋放較為相關，而膜衣機械強度則與漂浮持續時間 (floating time)較為相關，於是透過此兩項試驗的前篩選可降低開發此劑型所需的成本與時間；第三、發現膜衣處方為Kollicoat® SR合併5%的PEG 600時擁有良好的漂浮與藥物緩釋能力。

關鍵字

漂浮 ； 多單元 ； 混合膜衣 ； 吸水力 ； 機械特性

並列摘要

Controlled-release drug delivery systems (CRDDS) appear to improve many drawbacks of the conventional dosage form such as duration. Such improvements not only significantly elevate patient’s compliance but also reduce the opportunity of adverse reactions. However, drugs having narrow absorption window or more active metabolites are unsuitable to design as CRDDS. Therefore gastroretentive drug delivery system (GRDDS) is invented to solve this problem.
Using polymer coating technique to prepare gas-generated multiple-unit GRDF is commonly discussed recently. Since using single polymer is unable to fulfill all the conditions of becoming an ideal GRDF material, GIT soluble polymer and GIT insoluble polymer are mixed together to achieve certain goal of water uptake and mechanical property in this study.
At first, the water uptake and mechanical properties of blending GIT insoluble polymer (Eudragit® RS, Eudragit® NE, Surelease®, EC and Kollicoat® SR) with GIT soluble polymer (HPMC, PEG600, PEG6000 and Kollicoat® IR) is studied in the dry and wet state. According to the results from the experiments mentioned above, several blending polymers such as SRT(5)P600(10), NIR(10), ST(30)IR(10) and RSD(15)IR(10) are picked for further studies. After considering the outcome of dissolution tests and floating ability tests, this study expects to build a non-drug-specific platform of applying polymer in gas-generated multiple-unit GRDF.
Base on the water uptake data, we can simply divide the formulations into two groups. The formulations with higher water uptake ability, SRT(5)P600(10) and ST(30)IR(10), which have very short floating lag time but floating time and sustained release properties could not be achieved. On the other hand, formulations with lower water uptake abilities, NIR(10) and RSD(15)IR(10) are difficult to float but having good sustained release properties. As the result, we further try SRT(5)P600(5), NIR(20), ST(30)IR(5) and RSD(15)IR(20), then find out that all these formulations have better floating abilities and sustain release properties. From which SRT(5)P600(5) can even float within 15 minutes and remain floating for about 12 hours.
According to the results of this research, the adding of GIT-soluble polymers indeed makes GIT-insoluble polymers have the ability to become a suitable polymer for gas-generated floating dosage form. Although it’s still hard to have both excellent floating ability and sustain release properties, water uptake and mechanical properties tests should be preliminary screening tools to identify film properties for application as floating system.

並列關鍵字

Floating ； Multiple-unit ； Blending polymer ； Water uptake ； Mechanicla properties

參考文獻

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