- 學位論文
Sildenafil之舌下滴丸及自組型卵磷脂共聚微胞傳輸系統發展研究
Development of Sublingual Dropping Pill and Self-assembly Lecithin-based Polymeric Mixed Micelles Delivery System for Sildenafil
摘要
口服威而鋼® (Viagra®)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，及口服生體可用率較低的缺點。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的舌下滴丸劑及自組型共聚微胞劑型。 本研究所製備舌下滴丸劑為發泡型滴丸，分為兩處方，組成分別為sildenafil citrate/citric acid/NaHCO3/PEG6000/PEG400 (18.8:4.8:6.4:42:28%, w/w)及sildenafil base/citric acid/NaHCO3/PEG6000/PEG400 (10.8:4.0:5.2:48:32%, w/w)，冷凝液皆為二甲基矽油，滴注條件為藥液、油浴溫度72 °C、滴盤溫度77 °C、管口溫度30 °C、制冷溫度10 °C、滴距7公分、滴頭內徑1.5公厘、冷卻柱長100公分、直徑15公分。平均丸重及90 %溶離率測量結果分別為31.8和32.4毫克、及3和5分鐘。舌下投予動物試驗結果顯示，含藥sldenafil citrate 6.20毫克的發泡滴丸，藥物血漿中濃度低於偵測極限；含藥sldenafil base 3.56毫克的發泡滴丸，藥效開始作用時間為1.68 ± 0.22分鐘，有效濃度時間持續0.88 ± 0.68分鐘，然而因有效濃度時間短暫且生體可用率50.62 ± 7.88 %，不符臨床使用，體內崩解的效果不如體外溶離試驗結果表現佳，故改發展自組型卵磷脂共聚微胞劑型。 Sildenafil自組型卵磷脂共聚微胞劑是以薄膜水合法製備，處方比為sildenafil base /卵磷脂/Cremophor® ELP (1:1:20, w/w)。sildenafil base、卵磷脂和Cremophor® ELP依序溶解在乙酸乙酯與二氯甲烷之體積比為4：16的溶媒，以薄膜水合法的製備方式將該溶液減壓濃縮形成均勻薄膜，待溶媒完全揮發後，加入二次過濾水水合並以60 °C加熱使自體組織形成微胞。Sildenafil自組型微胞平均粒徑大小為15.2 ± 3.49 納米 (P.I. 0.781 ± 0.211)，包覆率為98.22 ± 11.85 %，藥物負載率為5.5 ± 0.32 %。動物舌下投予結果顯示，相對於口服威而鋼®錠劑，有較高的藥效開始作用時間1.01 ± 1.45分鐘及較高的生體可用率96.89 ± 15.25 %，能有效改善目前市售口服威而鋼®錠劑作用時間太慢、生體可用率不佳的缺點，以及能減低給予劑量，減少不必要的副作用產生。 本研究成功地以簡單的方式製備出sildenafil base舌下微胞劑，在吸收速率、使用安全性及生體可用率方面，皆優於市售口服劑型，具備有製程簡單、可大量製備、粒子大小再現性高，安定性高、吸收速率快、生體可用率高、使用劑量低的優點，提供臨床上治療成年男性勃起功能障礙的新劑型選擇。
並列摘要
Oral Viagra® (sildenafil) tablet is the most popular drug to treat erectile dysfunction. However, it should be taken 1 hour before sexual intercourse and has lower oral 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 dropping pill and self-assembling lecithin-based polymeric micelles. In this study, sildenafil dropping pill was developed as effervescent dropping pill which was formulated in two different composition : the first composition was sildenafil citrate/citric acid/NaHCO3/PEG6000/PEG400 (18.8:4.8:6.4:42:28%, w/w). The second composition was sildenafil base/citric acid/NaHCO3/PEG6000/PEG400 (10.8:4.0:5.2:48:32%, w/w). Both of the coolant were dimethyl silicone oil. The temperature of drug solution, oil bath, dripper, upper column, and coolant were 72, 72, 77, 30, and 10 °C. The dropping distance was 7 cm, the caliber size of dripper was 1.5 mm, and the length of cooling column was 100 cm with 15 cm in diameter. The average pill weight and the time of 90% accumulative dissolution rate of these two formulations were 31.8 and 32.4 mg, 3 and 5 minutes, respectively. Sildenafil effervescent dropping pill was administered sublingually to rabbits and in vivo sublingual absorption of effervescent dropping pill contained 3.56 mg sildenafil base was found to be fairly rapid with the mean onset of action (Tonset) of 1.68 ± 0.22 minutes. However, the duration was too short for clinical treament, 0.88 ± 0.68 minutes ,and the bioavailability was 50.62 ± 7.88 %. Self-assembly lecithin-based polymeric micelles for sildenafil were prepared by using thin film hydration method. Sildenafil base, lecithin, and Cremophor® ELP (1:1:20, w/w) were sequentially co-dissolved in the mixed solvent of ethyl acetate and dichloromethane (4:16, v/v), and then the solution was evaporated in rotary evaporator to form homogenous thin film. Until the solvent was evaporated completely, thin film was rehydrated in double distilled water with vibration and was heated at 60 °C to self-assemble into sildenafil base/Lec-ELP micelles. The mean particle size of sildenafil base/Lec-ELP micelles was 15.2 ± 3.49 (P.I. 0.781 ± 0.211) nm, with an encapsulation efficiency of 98.22 ± 11.85 %, and drug loading of 5.5 ± 0.32 %. In vivo studies showed that the Tonset of sublingual absorption of self-assembly sildenafil base/Lec-ELP micelles in rabbits was fast at 5 ± 3.30 min and the bioavailability was 96.89 ± 15.25 %, which reduced the disadvantage of slow onset, low bioavailability of oral sildenafil. In the study, the sildenafil base/Lec-ELP micelles which were relatively easier to manufacture on a large scale were succefully prepared. Sildenafil base/Lec-ELP micelles were developed spontaneously aqueous media with well-defined reproducible particle size and high stability. With the advantages of faster onset, higher bioavailability and lower dose then commercial products, the new formulation of sildenafil micelles provided another choice to treat erectile dysfunction.