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系統識別號 U0026-2308201400055100
論文名稱(中文) 口服與局部投與Acyclovir微乳劑型之開發研究
論文名稱(英文) Development and evaluation of acyclovir microemulsion as oral and topical drug delivery systems
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) 許齡方
研究生(英文) Ling-Fang Hsu
學號 S66011065
學位類別 碩士
語文別 中文
論文頁數 77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 acyclovir  微乳劑  口服  局部  處方 
英文關鍵字 acyclovir  microemulsion  oral  topical  formulation 
學科別分類
中文摘要 研究背景
疱疹為疱疹病毒引起之炎症性疾病,其特徵為集簇的水皰。Acyclovir (ACV)因價格便宜且治療效果較佳,為常用的抗疱疹病毒藥物,投與途徑包括注射、口服、乳膏劑及眼用軟膏。然而其水溶性不佳,腸胃道吸收緩慢、易變且不完全,須頻繁給藥進而影響病人服藥順從性。而在局部使用方面,ACV難以穿透角質層,造成藥品在表皮基底層的量不足,亦須一天使用多次來達到療效。
微乳劑是同質、透明、熱力學上的穩定態,組成包含水、油和界面活性劑,通常還會添加共界面活性劑(co-surfactant)。做為藥物傳輸送系統,微乳劑具有高穩定性、增加藥品溶解度而提高口服生體可用率、對皮膚的穿透性比傳統劑型佳等優點。
研究目的
本研究目的在製備ACV微乳劑並評估其特性,探討不同油、水、界面活性劑組成對皮膚穿透的影響,並比較口服與局部投與微乳劑在藥動、生體分佈與生體可用率之差異,期望能開發口服與局部投與ACV微乳劑型應用於疱疹之治療。
研究結果
以水: dimethylacetamide (1:1)、油酸與tween 20: transcutol P (2:1) 組成的微乳系統具有最大的微乳相面積,並且有助於增加ACV溶解度。本研究中選擇的四個微乳處方皆為奈米大小 (< 200 nm)、含藥量為0.1%,在室溫環境下貯存三個半月處方之油滴大小與藥物含量百分比皆保持安定。
體外穿皮試驗結果顯示所有微乳劑處方皆比市售品Zovirax具較高的皮膚滲透性,而處方A與其他三個處方相比具最高穿皮速率、八小時累積穿透量,以及八小時表皮層與真皮層滯留濃度,且皆有統計上顯著差異,組成中的水相為提升穿皮速率之主要因素。
口服投與試驗結果顯示所有微乳劑處方(10 mg/kg)皆比懸液劑對照組 (25 mg/kg)具較高的最高血中濃度、曲線下面積與大幅增加生體可用率,界面活性劑是增加ACV吸收的主要因素。在皮膚的分佈情形為表皮層高於真皮層,處方A的表皮層與真皮層藥物濃度略高於其他處方與懸液劑。皮膚投與試驗結果顯示四個微乳處方(100 μg/ 3.72cm2)皆比市售品對照組(5 mg/ 3.72cm2)具較高的最高血中濃度、曲線下面積,市售品在給藥處表皮層濃度明顯較高,在給藥處真皮層則與微乳劑差異不大,在未給藥處皮膚的藥物分佈情形則相似。
研究結論
本研究開發之ACV微乳處方不論是口服或經皮投與對於改善藥物吸收確實有其可行性。口服微乳劑於溶解度、體內吸收與生體可用率皆有增加,皮膚局部使用亦有增加穿皮速率與穿透量,因此ACV微乳劑對於未來臨床抗病毒具有相當潛力,亦可做為未來相關劑型研究之參考。
英文摘要 Summary
The purpose of the study was firstly to develop acyclovir (ACV) microemulsions (ME) for enhancing its oral and topical bioavailability and compare pharmacokinetics and biodistribution between two administration routes. Briefly, solubility of ACV in various excipients, construction of ternary phase diagrams, formulation characterization, in vitro skin permeation properties, and in vivo pharmacokinetics and tissue distribution following oral and topical administration were studied and evaluated. ACV MEs were prepared using combinations of oleic acid as the oil phase, tween 20/transcutol P (2:1) as the surfactant phase, and water/dimethyacetamide (1:1) as the aqueous phase with large ME region. All the four formulations had droplet size in the nanoscale and small polydispersity, indicating small variability in the droplet size. In vitro study demonstrated MEs enhanced skin permeability of ACV. Skin flux, cumulative amount of ACV penetrated in 8 hours, and amount retained in epidermis and dermis from formulation A were significantly higher than the other formulations. In addition, in in vivo studies, MEs led to improved oral bioavailability in comparison with the control suspension, and topical administration of MEs demonstrated higher plasma concentration and AUC than these of Zovirax. ACV distribution in the skin site without drug application was similar among the MEs and Zovirax, while at the site with drug application, significantly greater amount of drug in the epidermis was found from topical Zovirax, presumably due to difference in drug content (0.1% vs 5%). In conclusion, the present study developed stable ACV ME with improved drug absorption via both oral and topical administration.

INTRODUCTION
Herpes is an inflammatory disease caused by herpes virus. Its typical manifestation is clusters of inflamed vesicles. Acyclovir is one of the commonly used anti-herpes drug due to its good efficacy and low cost. Commercially available dosage forms include tablets, injectables, topical and ophthalmic semisolids. However, poor water solubility together with slow, variable and incomplete gastrointestinal absorption of the drug lead to low oral bioavailability (10~20 %) and poor compliance (orally five times per day). On the other hand, acyclovir hardly penetrates stratum corneum, As a result, topical delivery of acyclovir cream has low efficacy due to insufficient amount of acyclovir in basal epidermis, and must be applied several times per day for therapeutic effects.
Microemulsions (MEs) are clear, thermodynamically stable, isotropic liquid mixtures of oil, water and surfactant, frequently in combination with a cosurfactant. As a drug delivery system, ME has several advantages including high stability, improved oral bioavailability due to drug solubilization, and better skin permeability. The aim of this study was to develop acyclovir MEs for both oral and topical administration.

MATERIALS AND METHODS
Preformulation study
ACV solubility was screened in various excipients for good solublizing capacity. Phase diagrams were constructed by water titration method for examining the formation of MEs using different components: (1) oleic acid and I.P.M. as oil phase, (2) mixture of tween 80 or tween 20 and labrasol or transcutol P as surfactant and (3) mixture of water and dimethylacetamide or glycerol as aqueous phase. Formulations A to D in the ME region were selected with varied combination of aqueous, surfactant and oil phases, and final concentration of acyclovir in the MEs was 0.1%. Characterization of MEs was done for droplet size, polydispersity index and drug loading capacity. The stability of MEs was checked periodically with respect to transparency, phase separation, color change, droplet size and ACV content.

In vitro study
  Skin penetration studies were performed through nude mouse skin using Franz-type diffusion cells. The acceptor compartment was filled with phosphate buffer pH 6.5. 300 μl of the ME formulations or Zovirax were applied onto the skin fixed in the Franz-cells, which were thermostatted at 37°C, 700 rpm. Samples were drawn after 1, 2, 3, 4, 5, 6 and 8 h and analyzed for their drug content by HPLC
In vivo study
  In oral study, mice were divided into five groups and orally administered with ACV without fasting: MEs A to D groups (10 mg/kg) and suspension control group (25 mg/kg). In topical study, mice were also divided into five groups with formulations topically applied to back area: MEs A to D groups (100 μg/3.72 cm2) and Zovirax® control group (5 mg/3.72cm2).

RESULTS AND DISCUSSION
Based on ternary phase diagrams, oleic acid/tween 20: transcutol P (2:1)/water: dimethylacetamide (1:1) system was selected to prepare MEs. Four formulations (A-D) in the ME region with 0.1% of acyclovir were prepared and characterized. Their droplet sizes were in the nanoscale range (< 200 nm), and were decreased with increased proportion of aqueous phase in the ME. Moreover, these MEs showed no apparent degradation and aggregation over a 3-month period under 20~25℃ and 50~70 % RH conditions.
In vitro study demonstrated MEs enhanced skin permeability of acyclovir. Skin flux, cumulative amount penetrated in 8 hours, and amount retained in epidermis and dermis from formulation A were significantly higher than the other formulations. Aqueous phase was the main factor contributing to the enhanced flux. In comparison with Zovirax, MEs had higher flux and permeability but lower concentration retained in skin.
In in vivo studies, MEs led to improved oral bioavailability in comparison with the control suspension, and was attributed to the proportion of surfactant phase. Topical administration of MEs (100 μg/3.72cm2) demonstrated higher plasma concentration and AUC than Zovirax (5 mg/3.72cm2). Acyclovir distribution in the skin site without drug application was similar among the MEs and Zovirax, while at the site with drug application, significantly greater amount of drug in the epidermis was found from topical Zovirax, presumably due to difference in drug content (0.1% vs 5%) .

CONCLUSION
The present study developed stable acyclovir ME with improved drug absorption via both oral and topical administration. It may be potential therapeutics for the treatment of herpes, and can be a reference for future study with other ME systems.
論文目次 中文摘要 I
Extended Abstract III
誌謝 VI
目錄 VII
表目錄 XI
圖目錄 XII
縮寫表 XV
第壹章 文獻回顧 1
第一節 疱疹 (Herpes) 1
一、流行病學 1
二、疱疹病毒感染之病理機轉與症狀 2
三、疱疹病毒感染之預防與治療 3
第二節 Acyclovir 6
一、一般特性 6
二、藥理機轉 6
三、物化性質 7
四、藥物動力學 8
五、副作用 8
六、用法與劑量 8
七、臨床使用限制 9
第三節 Acyclovir藥物傳輸系統 9
一、前驅物 9
二、囊泡藥物傳遞系統 (Vesicular drug delivery systems) 11
三、微/奈米顆粒 13
四、其他傳遞系統 14
第四節 微乳劑藥物傳輸系統 16
一、微乳劑形成理論與組成 16
二、微乳劑特性評估 18
三、微乳劑優缺點 18
四、微乳劑應用 19
第貳章 研究目的 21
第参章 研究材料與方法 22
第一節 研究材料 22
一、實驗動物 22
二、試劑、藥品與耗材 22
三、實驗儀器 24
第二節 研究方法 25
一、ACV高效液相層析技術分析方法之確效 25
二、溶解度試驗 27
三、建立三相圖 27
四、特性評估與安定性試驗 28
五、體外穿皮試驗 29
六、口服投藥體內試驗 30
七、皮膚投藥體內試驗 32
第三節統計分析 33
第肆章 研究結果 34
第一節 Acyclovir之分析方法確效 34
一、標準液和皮膚萃取液 34
二、血漿萃取液 37
第二節Acyclovir於不同賦形劑之溶解度 39
第三節 不同賦形劑組成之三相圖 41
第四節 Acyclovir微乳劑組成、特性與安定性 45
第五節 Acyclovir微乳劑體外穿皮試驗 49
第六節 Acyclovir微乳劑口服與局部投與藥物動力學 52
一.口服投與 52
二.局部投與 57
第伍章討論 60
第一節 微乳劑組成對acyclovir溶解度之影響 60
第二節 組成對三相圖微乳相面積之影響 61
第三節 微乳劑組成對特性之影響 62
第四節 微乳劑組成對acyclovir皮膚穿透量之影響 62
第五節 微乳劑組成對藥動學參數之影響 64
第六節 口服與外用投與微乳劑在藥動學之差異 65
第七節 微乳劑油滴粒徑對穿皮速率與生體可用率之影響 68
第陸章結論 70
參考文獻 71
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