Nicardipine鹽酸鹽微乳劑型之經皮吸收研究

Study on Transdermal Delivery of Nicardipine Hydrochloride from Microemulsions

林怡慧(Yei-Huan Lin)

指導教授 ： 蔡義弘

高雄醫學大學/藥學院/藥學研究所/碩士(2005年)

摘要

Nicardipine鹽酸鹽為第二代的鈣離子通道阻斷劑，結構屬於dihydropyridine類，臨床上可用於治療高血壓、心絞痛，雖然口服後可被快速吸收，但由於nicardipine在人體內具有顯著的首度效應，因此生體可用率不高，且其生物半衰期亦極短，故擬以一經皮輸藥系統來投與藥物，不僅可避免首度效應，增加藥物的生體可用率，並且能提供持續輸出的藥物投與量。
本研究將nicardipine鹽酸鹽製成以Tween 80、Tween 20、Span 80、Span 20為界面活性劑，IPM、IPP為油相，二次水為水相，乙醇為輔助界面活性劑之微乳劑系統作為基劑的經皮製劑，由溶解度試驗結果，證實微乳劑的確有增加藥物溶解的能力，而微乳劑處方的粒徑大小均在150 nm以下，polydispersity index大約都在0.2，由導電度大小及稀釋法推斷大部分微乳劑處方均為水/油型微乳劑，而處方D5-3、D6-31、D7-31、D8-31、D9-31則是屬於油/水型微乳劑。
體外穿透實驗結果顯示，藥量的增加對穿透率大小的影響具有較為顯著的效應，而微乳劑處方對穿透結果的影響主要取決於處方本身的性質，尤其是處方的安定性及對藥物的溶解度，此外促進劑的使用並無顯著促進效果，在大部分的情況下，反而會造成藥物釋出降低的效應，推測可能與釋出競爭的機制有關。
體內實驗的結果顯示靜脈注射投與nicardipine在Wisatr大白鼠體內藥物動力學符合二室模式，且在經皮處方投與的部分，血中濃度在經皮投藥後約10小時已趨近一穩定數值，顯示在此經皮處方投藥情形下，具有持續輸出給藥的能力，可維持恆定之血中藥物濃度。此外由皮膚色差的測定的結果推測微乳劑處方對皮膚不具明顯刺激性。

關鍵字

微乳劑 ； 經皮輸藥系統 ； Nicardipine鹽酸鹽

並列摘要

Nicardipine hydrochloride, a calcium channel blocker with dihydropyridine structure, is widely used in the clinical treatment of hypertension and angina pectoris. Although it is rapidly absorbed after oral administration, it undergoes extensive first-pass elimination in the liver. Therefore, it is suitable for developing the transdermal delivery system.
In this study, we have developed a microemulsion system consisted of Tween 80, Tween 20, Span 80, and Span 20 as surfactant phase, isopropyl myristate as oil phase, doubled-distilled water as aqueous phase, and ethanol as co-surfactant phase for transdermal delivery of nicardipine. According to the result of solubility test, it proved that microemulsion system has the ability to elevate the drug solubility of formulation. The droplet size of microemulsion formulations was below 150 nm, and the polydispersity index was around 0.2. Most of these microemulsion formulations belonged to water-in-oil type, except for the formulation D5-3, D6-31, D7-31, D8-31 and D9-31.
The in vitro permeation data indicated that the main affecting factor on flux was the increase of drug content of the microemulsion formulation. And the effect of microemulsion formulation on permeation depended upon the properties of formulation itself, especially the stability of formulation and its solubility of drug. Besides, the use of enhancer did not show much effect on permeation. In most cases, it contrarily caused the decrease of drug release, which may be concerned with the competitive release mechanism.
The in vivo study result showed that the pharmacokinetic data conformed to the two-compartment model. Transderaml administration of these formulations could maintain a constant plasma concentration through a sustained drug release. In addition, the results measured by colorimeter exhibited that microemulsion formulations didn’t cause obvious skin irritation.

並列關鍵字

Microemulsion ； Transdermal drug delivery system ； Nicardipine

參考文獻

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