- 學位論文
Minoxidil局部給藥系統之開發研究
Development of Topical Delivery System for Minoxidil
摘要
Minoxidil是一種降血壓藥，同時會誘導臉部及身體的毛髮增生，在多年前已用於治療雄性禿。Minoxidil局部給藥系統之開發研究著重於將毛髮增生作用限制於局部，且防止過量的Minoxidil進入血液循環產生副作用。TPGS（Tocopheryl polyethylene glycol succinate），是一種自然來源維他命E的水溶性衍生物，也是一種界面活性劑。在本實驗中探討它在混合溶媒系統中（Water、Alcohol與PEG 400），對Minoxidil溶解度及體外穿皮試驗的影響，以及降低Minoxidil 局部給藥吸收後進入全身循環系統之效能。結果顯示Minoxidil溶解度主要由處方溶媒決定，加入TPGS對Minoxidil溶解度的影響不大。添加低濃度TPGS（低於2%）時，對多數處方有提高溶解度的效果，但超過某程度的TPGS添加量反而會降低高於25 mg/ml Minoxidil處方的溶解度。 在體外穿皮試驗中，以裸鼠皮為主要的障礙層模式，利用Franz滲透裝置探討含不同濃度的TPGS溶媒組合對Minoxidil穿皮吸收之影響以及對Minoxidil局部吸收之影響。給藥室中加入含有2% Minoxidil (w/v)的不同處方，將Minoxidil穿皮滲透累積量對時間作圖，取其直線部分的斜率計算通透量。並分析72小時末給藥室的Minoxidil殘留量以計算出裸鼠皮中Minoxidil殘留量。結果顯示TPGS對穿皮吸收有明顯的影響，尤其是處方三（100% PEG 400）、六（W：A：P=0：50：50）、九（W：A：P=17：17：66）與十（W：A：P=34：33：33）。但濃度較高的TPGS (15~ 20%) 處方，因為有較高黏度的關係，多數會降低Minoxidil的穿皮吸收與裸鼠皮中的殘留量。由溶解度因子來看，當Minoxidil與溶媒的溶解度因子越接近時，Minoxidil的溶解度越高，但Minoxidil的通透量與皮膚中殘留量則是隨溶媒的溶解度因子增加而增加。 最後，進行Minoxidil在含不同TPGS的不同溶媒組合中促進黑毛小鼠（C57BL/6J）之毛髮生長的動物實驗。結果發現多數處方的毛髮增生速率與落建（2% Regaine®）相近，且實驗處方的小鼠血中濃度皆較落建（2% Regaine®）為低。若以節省成本為考量，加入低濃度TPGS（約0.5%）的處方五（W：A：P= 50：0：50）或許是Minoxidil新處方不錯的選擇。所以，TPGS在發展能提高毛髮增生能力及降低低血壓效力的Minoxidil經皮劑型上扮演重要的角色。
並列摘要
Minoxidil is a potent vasodilator that also induces hypertrichosis of facial and body hair. It has been used for androgenic alopecia for several years. Percutaneous delivery of minoxidil would focus on providing a mean to limit the efficacy of hypertrichosis on local site and to avoid the excess of minoxidil entering the blood circulation to proceed with side effects. The effect of tocopheryl polyethylene glycol succinate (TPGS), a water-soluble derivative of nature-source vitamin E similar to a surface-active agent, was examined on the solubility in different ratio of cosolvent systems (Water, alcohol and PEG 400), in vitro percutaneous penetration of minoxidil and potential to reduce the amount penetrated into general circulation. Results show that the solubility of minoxidil was determined by the solvent composition of the formulations and it was influenced in an insignificant extent by TPGS in the solvent system. The addition of low concentration TPGS (＜2%) could improve the solubility of minoxidil. The addition of excess TPGS would reduce the solubility of minoxidil in the formulations that their solubility is large than 25 mg/ml. The nude mouse skin was employed as the principal barrier and Franz diffusion cells were used as a device to assess the percutaneous penetration of the formulations that contain various concentration of TPGS. At a fixed concentration of 2% (w/v) minoxidil, different ratios of solvent compositions were added to donor compartment. The cumulative amount of minoxidil permeated was plotted against time and the slop of linear portion of the graph was estimated as the flux. The residue of minoxidil in the donor compartment at 72 hrs was collected to calculate the retention amount of minoxidil in the nude mouse skin. TPGS has a significant effect on percutaneous penetration of minoxidil from various solvent compositions, especially for formulation No. 3 (100% PEG 400), 6 (W:A:P=0:50:50), 9 (W:A:P=17:17:66), 10 (W:A:P=34:33:33). The higher concentration of TPGS (15~ 20%) added in the formulations that have higher viscosity would reduce the flux and the retention amount of minoxidil in the skin. Results also demonstrate that solubility reach its maximun when solubility parameter of solvent system is close to that of minoxidil. But the flux and the retention of minoxidil are linearly increased with increasing solubility parameter of solvent system. Finally, we proceed with in vivo study of examining the influence of various solvent compositions on the enhancement of hair growth on C57BL/6J mouse at various added amount of TPGS. The results confirms that abilities of those containing 2% minoxidil solvent systems examined to enhance the hair growth are nearly equivalent compared to 2% Regaine®, but the plasma concentration of minoxidil after topical application of those formulation examined is lower than that for 2% Regaine®. In terms of saving the cost, formulation No.5 that contains a low concentration of TPGS (about 0.5%) is the best choice. In conclusion, TPGS plays an important role in percutaneous delivery of minoxdil with the ability to induce hair growth and decrease hypotensive activity of Minoxidil.