速效性Sildenafil之舌下藥物傳輸系統發展研究

Development of Sildenafil for Rapid-Onset Sublingual Drug Delivery System

周柏宇(Po-Yu Chou)

指導教授 ： 何秀娥

臺北醫學大學/藥學院/藥學研究所/碩士(2010年)

摘要

口服威而剛錠劑是在勃起功能障礙治療上，最為廣泛使用的藥物；然而，其仍存在著必須於需求前一小時服用，以及其較低的生體可用率的缺點。舌下路徑給藥方法提供快速吸收、高生體可用率及快速的藥效作用，因此本研究將藉由這些優點，發展sildenafil的舌下噴劑及舌下錠劑劑型。
本研究所用的Sildenafil舌下噴劑，其溶媒載體系統分別為油酸、丙烯乙二醇及微乳劑 (微乳劑由油相-油酸、界面活性劑¬-聚山梨醇酯80、輔助界面活性劑-聚乙二醇600或丙烯乙二醇組成)。 將所製備的舌下噴劑投與動物進行體內研究。實驗結果顯示，以0.53毫克劑量的sildenafil於丙烯乙二醇的舌下噴劑作用最為迅速，開始作用時間為1.33±0.57分鐘且藥效時間能達1.5小時。
Sildenafil 舌下錠劑的製備是先將上述sildenafil的舌下噴劑溶媒載體系統吸附於不同吸附劑 (FLORITE® R、Neusilin®US2、AEROSIL®200、SYLOID®244 FP及 AEROPERL® 300/30) 而成固態顆粒，再與結合劑 (EMDEX® 或Cyclocel® ) 及崩散劑 (Ac-Di-Sol ® 或 Kollidon®CL) 所搭配而成。先進行測量各種吸附劑吸附溶媒系統後的粉末流動性，再對錠劑溶離率、硬度及崩散時間進行評估；最後，將不同處方組成的舌下錠劑，投予動物進行體內動力學研究。其體內研究得知，sildenafil於丙烯乙二醇中，與吸附劑FLORITE® R進行1:1重量比例吸附，再與結合劑- Cyclocel®及崩散劑- Ac-Di-Sol ®所製備出的舌下錠劑，於0.52毫克劑量下，開始作用時間最快為1.94±0.41分鐘並藥效時間能達1小時。

關鍵字

舌下吸收 ； 速效性 ； 威爾剛

並列摘要

Oral sildenafil (Viagra®) is the most popular drug to treat erectile dysfunction. However, it should be taken 1 hour before sexual intercourse and lower bioavailability. It is well known that sublingual delivery of drugs offers rapid absorption and high bioavailability, with subsequent almost immediate onset of pharmacological effect. Due to these superiorities, we developed sildenafil sublingual spray and tablet.
Sildenafil in oleic acid, propylene glycol and microemulsion prepared by water phase (H2O), oil phase (oleic acid), surfactant (Tween 80) and cosurfactant (PEG600 or propylene glycol) were developed for rapid-onset sublingual spray of sildenafil. Sildenafil sublingual spray was administered sublingually to rabbits and in vivo sublingual absorption of sildenafil from different solvent systems was investigated. Sublingual absorption of sildenafil from propylene glycol was found to be fairly rapid. At 0.53 mg dose, the mean onset of action was 1.33±0.57 min and lasted for an average of 1.5 hour.
The sildenafil sublingual tablets containing the composition of various granulated sublingual spray adsorbed onto different silicate adsorbants (FLORITE® R, Neusilin®US2, AEROSIL®200, SYLOID®244FP and AEROPERL®300/30), binder (EMDEX® or Cyclocel® ) and disintegrant (Ac-Di-Sol ® or Kollidon® CL) were prepared. The powder rheometry and characteristics (dissolution, hardness and distegration) of sublingual tablets were characterized and in vivo sublingual absorption of sildenafil from different sublingual tablets was investigated in rabbits. In vivo studies showed that sildenafil in propylene glycol formulation adsorbed on FLORITE® R by 1:1 weight ratio mixed with Cyclocel® and Ac-Di-Sol ® , the onset of action was fast at 1.94±0.41 min and lasted for 1 hour at 0.52 mg.

並列關鍵字

Sublingual absorption ； Rapid-onset ； Sildeanfil

參考文獻

1.Agarwal V, Siddiqui A, Ali H, et al. 2009. Dissolution and powder flow characterization of solid self-emulsified drug delivery system (SEDDS). Int J Pharm 366(1-2):44-52.

2.Altokka G, Atkosar Z, Sener E, et al. 2001. FIA of sildenafil citrate using UV-detection. J Pharm Biomed Anal 25(2):339-342.

3.Andrade JR, Traboulsi A, Hussain A, et al. 2000. In vitro effects of sildenafil and phentolamine, drugs used for erectile dysfunction, on human sperm motility. Am J Obstet Gynecol 182(5):1093-1095.

4.Aungst BJ, Rogers NJ 1989. Comparison of the effects of various transmucosal absorption promoters on buccal insulin delivery. Int J Pharm 53(3):227-235.

6.Bigatello LM, Hess D, Dennehy KC, et al. 2000. Sildenafil can increase the response to inhaled nitric oxide. Anesthesiology 92(6):1827-1829.