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系統識別號 U0026-2108201415182600
論文名稱(中文) 口服與局部投與Terbinafine微乳劑型之開發研究
論文名稱(英文) Development and Evaluation of Terbinafine Microemulsion for Oral and Topical Administration
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 102
學期 2
出版年 103
研究生(中文) 蔡佳洵
研究生(英文) Chia-Hsun Tsai
學號 S66014047
學位類別 碩士
語文別 中文
論文頁數 94頁
口試委員 指導教授-蔡瑞真
口試委員-周辰熹
口試委員-駱雨利
中文關鍵字 微乳劑  terbinafine  口服投與  局部投與  處方 
英文關鍵字 topical delivery  oral delivery  microemulsion  terbinafine  formulation 
學科別分類
中文摘要 Terbinafine屬於allylamine類,具廣效抗黴菌作用 (有抑菌或殺菌能力),且在低濃度即有殺菌效果 (fungicidal)。目前市售產品以口服和外用製劑為主,口服terbinafine有明顯的首渡代謝效應,且藥品本身溶解度不佳,造成其口服生體可用率低 (40 %),另外長期使用可能會造成腸胃道不適、皮膚過敏反應、味覺異常和肝膽功能異常等不良反應。外用劑型舉凡溶液、乳膏、凝膠到噴霧劑型都有,考量藥物溶解度和穿透能力,添加助溶劑和穿皮促進劑,主要用於皮表淺層處的黴菌治療。
微乳劑是由水相、油相及界面活性劑所組成,具有澄清透明外觀,為熱力學穩定系統,微乳劑相較於傳統劑型其能增加藥物的溶解度、生體可用率、增加皮膚穿透量等優點,並可使用於不同的投與途徑。因此本研究透過微乳劑型之設計,評估體外皮膚穿透速率並篩選處方,進一步進行動物活體試驗比較口服與局部投與藥物的生體分佈情形。
本研究以oleic acid / tween 80:Transcutol® P (1:1) / water:PG (2:1)製備出6個不同組成比例的微乳劑型 (處方A~F),依界面活性劑和助溶劑的多寡各處方的粒徑大小不同 (介於90~800 nm),且在20~25 ℃和濕度50~70 %的條件下保持良好的安定性。體外穿皮試驗結果顯示,最高的穿透速率為微乳劑處方中油相較多者 (處方F,3.37 ± 1.04 μg/cm2/hr);最低的穿透速率為微乳劑處方中水相較多者 (處方B,0.45± 0.10 μg/cm2/hr)。相反的,藥物在表皮層和真皮層的組織濃度則是組成中水相較多者高於油相較多者。依體外穿皮試驗結果選擇微乳劑處方B、D、F進行體內試驗,研究結果顯示口服投與微乳劑型有效增加口服生體可用率,然而微乳劑處方間差異不大;局部投與微乳劑型在給藥處皮膚組織有極高的藥物濃度,血中濃度則與拭去處方後藥物在皮膚的蓄積量有關,並且提高生體可用率。比較不同給藥途徑發現皮膚投與微乳劑處方B,在非塗藥處的皮膚和脂肪組織的曲線下面積與口服投與的曲線下面積最為相近。
綜合研究結果,顯示微乳劑型有效增加terbinafine的溶解度和生體可用率,皮膚投與微乳劑處方B,可改善口服投與的缺點,除了在給藥處皮膚組織可達高的濃度外,並且在其他組織的藥物濃度亦與口服投與相似,因此微乳劑處方B為最佳處方,可以口服或是局部投與,而對於皮癬菌 (dermatophytes)的療效則可進一步探討。
英文摘要 Development and Evaluation of Terbinafine Microemulsion for Oral and Topical Administration
Author:Chia-Hsun Tsai
Advisor:Jui-Chen Tsai
Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine

SUMMARY

Terbinafine has poor solubility and has low bioavailability by oral and topical administration. Microemulsion is a stable system and easy to form. Microemulsions offer several advantages such as improving drug-loading, bioavailability and skin penetration, and can be administered via various routes. The objective of this study was to develop terbinafine microemulsion for both oral and topical administration. Solubility test of various excipients, ternary phase diagrams, characterization of each formulation, in vitro skin permeation properties and in vivo tissue distribution following oral and topical administration were studied and evaluated. We developed stable terbinafine microemulsions (oleic acid/tween80:Transcutol ®P (1:1)/water:PG (2:1)) for oral and skin delivery. Six terbinafine formulations representing water-rich (A, B), surfactant-rich (C, D), and oil-rich (E, F) formulations at concentration of 10 mg/ml. Their droplet sizes varied between 90 to 800 nm depending on the amounts of surfactant and cosurfactants. The solubility of terbinafine in microemulsions was improved at least 4 fold. In vitro studies, we found that oil-rich formulation had higher skin fluxes, with lower amount of terbinafine retained in skin. In vivo studies, microemulsions had higher terbinafine concentration in plasma and tissues following oral and topical administration. Formulation B is most promising one for both oral and topical administration for the treatment of dermatophytes.

Key words:topical delivery, oral delivery, microemulsion, terbinafine, formulation

INTRODUCTION

Terbinafine is an antifungal agent from the allylamine class that has potent fungistatic and fungicidal activity against fungi and yeast associated with skin and nail infection. There are a number of oral and topical preparations available commercially. Following oral administration, terbinafine is well absorbed and not affected by the presence of food. However, it undergoes first-pass metabolism, and has poor solubility and oral bioavailability. Nausea, abdominal pain, diarrhea, erythematous rash, taste disturbance and hepatic side effects may occur with long-term therapy. There are a number of topical terbinafine preparations including solution, cream, gel and spray. Considering the poor solubility and ability of skin penetration, coslovent and permeation enhancer are added to those topical formulations to treat topical fungal infections.

Microemulsion is a transparent, optically isotropic and thermodynamically stable dispersion of water, oil and amphiphilic compounds (surfactant and co-surfactant). Microemulsions offer several advantages such as improving drug-loading, bioavailability and skin penetration, and can be administered via various routes. The objective of this study was to develop terbinafine microemulsion for both oral and topical administration.

MATERIALS AND METHODS

Materials
Terbinafine was provided by Yungshin Pharm Ind. Co. Ltd., Taiwan. Capryol 90 was received from Gattefossé Co. Clotrimazole, tween 80, Transcutol® P, span 80 and PG were purchased from Sigma - Aldrich Co. Lamisil® 250 mg tablet and Lamisil® 1 % Dermgel were products of Novartis Pharmaceuticals UK Ltd. All other chemicals are HPLC or analytical grade.

HPLC method
The concentration of terbinafine was determined using a C18-reversed phase column eluted with mobile phase consisted of acentonitrile and distilled water (40:60) with ortho-phosphoric acid (0.02 M) and triethylamine (0.01 M) at a flow rate of 1 mL/min with UV detection at 224 nm. Clotrimazole was used as internal standard. The HPLC method was validated in different sample matrices.

Study design
Various biocompatible oils, surfactant/cosurfactants, and cosolvents were screened for maximal terbinafine solubility. Oleic acid, tween 80, Transcutol® P and propylene glycol as oil, surfactant and cosurfactants were selected to determine microemulsion regions based on ternary phase diagrams. Droplet size and in vitro skin permeation properties through nude mouse skin were characterized for six terbinafine formulations representing water-rich (A, B), surfactant-rich (C, D), and oil-rich (E, F) formulations at concentration of 10 mg/ml. In vivo tissue distribution following oral and topical administration were studied and evaluated.

RESULTS AND DISCUSSION

Based on ternary phase diagrams, oleic acid, tween 80, Transcutol® P and propylene glycol as oil, surfactant and cosurfactants were selected to prepare microemulsions. The droplet sizes of six formulations were varied between 90 to 800 nm depending on the amounts of surfactant and cosurfactants. Moreover, these microemulsions showed no apparent degradation and separation for up to 5 months under 20~25 ℃ and 50~70 % RH conditions. Skin flux of terbinafine was found to be highest with oil-rich formulation (formulation F, 3.37 ± 1.04 μg/cm-2/hr) and lowest in water-rich formulation (formulation B, 0.45 ± 0.10 μg/cm-2/hr). On the other hand, the amount of terbinafine retained in the epidermis and dermis of water-rich formulation was greater than oil-rich formulation. Based on skin flux results, formulations B, D and F were selected to be evaluated in vivo. Oral administration of microemulsions enhanced terbinafine bioavailability in comparison with the suspended-tablet control, but there was no difference among the microemulsion formulations. Following topical administration, drug concentrations in the treated skin tissues were higher in comparison with the gel control. Plasma concentrations were found to be related to the amount of drug retained in skin after removal of residual formulations and hence improved bioavailability. Area under the skin and adipose tissue concentration curves at the site without drug application was similar between oral and topical administration of formulation B.

CONCLUSION

Stable microemulsions of terbinafine were developed for oral and topical delivery. Terbinafine microemulsion improved terbinafine solubility by at least 4 folds, and enhanced bioavailability via both oral and topical routes. Topical administration formulation B enhanced local concentrations and achieved similar tissue distributions to oral administration. These results indicated that formulation B can be administered both orally and topically for the treatment of dermatophytes. Its therapeutic efficacy may require further investigation.

論文目次 中文摘要 I
Extended abstract III
誌謝 VI
目錄 VII
表目錄 X
圖目錄 XI
縮寫表 XIII
第壹章 緒論 1
第一節 研究背景 1
第二節 皮癬菌症 (dermatophytosis) 4
一、病原特性 4
二、臨床表徵 5
三、臨床治療與預防 8
第三節 Terbinafine簡介 10
一、物化特性 10
二、藥理作用 11
三、藥物動力學特性 14
四、市售劑型和建議治療療程 16
五、藥物毒性和不良反應 17
第四節 藥物傳輸系統 18
一、微乳劑結構 19
二、微乳劑特性 21
三、微乳劑應用 21
第貳章 研究目的 25
第參章 研究材料與方法 26
第一節 研究材料 26
一、實驗動物 26
二、藥品與試劑 26
三、儀器 29
四、耗材 30
五、繪圖及藥動分析軟體 30
第二節 研究方法 31
一、藥品配製與定量分析 31
二、Terbinafine微乳劑的製備 35
三、體外穿皮試驗(In vitro skin permeation study) 39
四、體內試驗 (In vivo studies) 42
第三節 統計分析 44
第肆章 研究結果 45
第一節 Terbinafine分析方法 45
一、Terbinafine分析圖譜 45
二、分析方法確效 49
第二節 Terbinafine 微乳劑製備 51
一、溶解度試驗 51
二、三相圖繪製 51
三、微乳劑處方配置 55
四、微乳劑處方特性 56
第三節 體外穿皮試驗 59
第四節 體內試驗 62
一、口服給藥 62
二、皮膚給藥 71
三、不同投與途徑之比較 75
第伍章 討論 81
第一節、微乳劑處方特性 81
一、微乳劑處方對terbinafine溶解性之影響 81
二、微乳劑處方對terbinafine粒徑大小之影響 82
第二節、體外穿皮試驗 83
一、微乳劑處方組成對穿皮速率之影響 83
二、粒徑大小對穿皮速率之影響 84
三、微乳劑處方組成對皮膚蓄積量之影響 85
四、處方組成與處方特性的綜合比較 86
第三節、體內試驗 87
一、口服給藥 87
二、經皮給藥 88
第陸章 結論 89
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