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系統識別號 U0007-1704200714542065
論文名稱(中文) 以TPGS作為微乳基劑之相圖研究與藥學應用
論文名稱(英文) Studies on the Phase Diagrams of TPGS Based Microemulsion Systems and Their Pharmaceutical Applications
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 93
學期 2
出版年 94
研究生(中文) 柯文庭
研究生(英文) Wen-Ting Ke
學號 D87010038
學位類別 博士
語文別 英文
口試日期
論文頁數 123頁
口試委員 指導教授-許明照
中文關鍵字 微乳劑  相圖  自發性微乳化 
英文關鍵字 Microemulsion  Phase diagram  Self-microemulsification  Fenofibrate 
學科別分類
中文摘要 本論文包含兩部分的研究:第一部分為以TPGS作為微乳基劑之相圖研究,第二部分為Fenofibrate自發性微乳化藥物傳輸系統之物性解析。 在第一部分的研究中,利用中鏈型三酸甘油酯(Medium Chain Triglyceride)(商品名為Captex 300)作為油相、去離子水作為水相以及D-?-Tocopheryl polyethylene glycol 1000 succinate(TPGS)作為界面活性劑所形成的微乳基劑可以作為蛋白質藥物或水難溶性藥物的載體。藉由擬三相圖(Pseudo-ternary Phase Diagrams)的建立來瞭解中鏈型三酸甘油酯、去離子水及TPGS為主要界面活性劑配合聚醇山梨酯(Polysorbates)(如Tween 20、Tween 40、Tween 60及Tween 80)為輔助界面活性劑或聚乙二醇(Polyethylene Glycol)(如PEG 400及PEG 600)及多醇類(Polyols)(如乙二醇、1,2-丙二醇、1,3-丙二醇、1,3-丁二醇、1,4-丁二醇及甘油)作為共界面活性劑所形成的微乳基劑之相變化。TPGS與聚醇山梨酯、聚乙二醇或多醇類以4/1、2/1、1/1、1/2及1/4之重量比例混合。當TPGS為唯一之界面活性劑組成時,水-Captex 300-TPGS微乳基劑系統之相圖顯示系統無法形成較大範圍的單一相均質系統。當TPGS與聚醇山梨酯依不同比例混合為界面活性劑組成時,水-Captex 300-TPGS-聚醇山梨酯微乳基劑系統之相圖顯示系統可以形成較大範圍的單一相均質系統;此單一相均質系統包括微乳相系或凝膠相系且其各相系的範圍受到界面活性劑組成及比例所影響。利用多醇類作為共界面活性劑所形成的微乳基劑系統之相圖顯示多醇類對於單一相均質系統的影響程度小。但是,多醇類的含量組成會影響到此單一相均質系統的範圍大小;亦即多醇類含量愈高,單一相均質系統的範圍就愈小,且減小的趨勢是往相圖的界面活性劑-水的軸線趨近,顯示系統中若多醇類的含量增加將會減少油相的乳化總量。凝膠相的範圍亦會隨著系統中的多醇類含量增加而減少。如多醇類未與TPGS共同混合使用,將無法有效的將Captex 300乳化形成單一相均質系統。 第二部分的研究屬於第一部分的應用,其目的在於建立及解析自發性微乳化藥物傳輸系統作為難溶性藥物的傳輸載體。選用的難溶性藥物為Fenofibrate(為一有效的降血脂藥物)作為模式藥,利用中鏈型三酸甘油脂及非離子型界面活性劑製備成自發性微乳化藥物傳輸系統;此一系統若接觸到水溶液或腸胃道液體會自發性乳化形成微乳化透明澄清之液體。所選用的油相為Myritol 318,非離子型界面活性劑為 TPGS 及Polysorbates (Tween 20或Tween 80)。當使用TPGS/Tween 20之重量比例為1/4時,可以得到具適當溶離速率的處方組成。經由體外溶離試驗結果顯示:Fenofibrate自發性微乳化藥物傳輸系統無論在0.025M的月桂酸鈉水溶液或水中均可以在30分鐘內完全釋出。但是對照處方Tricor? tablets及微粉化藥物分散系統於水中的溶離則受到限制。由本研究的結果顯示自發性微乳化藥物傳輸系統可以有效的作為難溶性藥物的載體 (fenofibrate 為例),增進其溶離速率與溶離量,因此可以相對有效的提高其生體可用率。
英文摘要 This dissertation is composed of two parts of studies; the title of part I is “Studies on the Phase Diagrams of D-?-Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS) Based Microemulsion Systems” and that of part II is “Physical Characterization of Self-Microemulsifying Drug Delivery System for Fenofibrate”. Attempts in part I of the dissertation were to develop microemulsion systems using medium chain triglyceride (MCT), Captex 300, deionized water (H2O), and TPGS as surfactant for the oral delivery of protein drugs or poorly water soluble drugs. Pseudo-ternary phase diagrams were constructed to elucidate the phase behavior of systems composed of medium-chain triglyceride and water with TPGS as main surfactant, polysorbates (Tween 20, Tween 40, Tween 60 and Tween 80) as adjuvant surfactants, and polyethylene glycols (PEG 400 and PEG 600) and polyols (ethanediol, 1,2-propanediol, 1,3-propanediol, 1,3-butanediol, 1,4-butanediol and glycerin) as cosurfactants. The weight ratios of TPGS to Tweens, PEGs or polyols (Km) were set at 4/1, 2/1, 1/1, 1/2, and 1/4. The phase diagram for H2O/Captex 300/TPGS system reveals that when TPGS was used as a sole surfactant, it is not capable of producing isotropic solutions of water and Captex 300 over a wide range of the compositions. H2O/Captex 300/TPGS/Tweens systems with various Km, regardless of the adjuvant surfactant used were capable of producing an isotropic phase. The extension of microemulsion phase and the presence and extension of the gel phase were found to be dependent on the surfactant mixture. The phase diagrams of H2O/Captex 300/TPGS systems using polyols as cosurfactants demonstrate that the types of polyols have a slight effect on the region of existence of the microemulsions. Comparison between the isotropic regions for the polyols system reveals that as the relative concentration of polyols increase, the isotropic region decrease in size. This decrease is towards the surfactant mixture (Smix)-water axis indicating that as the relative concentration of polyols increases the maximum amount of oil solubilized decreases. The gel region decreased in size with the increase of polyols weight ratio. All polyols do not solubilized Captex 300 without using TPGS as surfactant. The part II of this dissertation is the application of the studies of part I. Attempts in part II of the dissertation were to develop and characterize the self-microemulsifying drug delivery systems (SMEDDSs) for poorly water soluble drugs. Fenofibrate (an effective agent for the treatment of various types of dyslipidemia) was selected as a model drug that was formulated in a Myritol 318 and nonionic surfactant mixtures of TPGS and polysorbates (Tween 20 or Tween 80), which exhibited self-microemulsifying characteristics under conditions of gentle agitation in an aqueous medium. Using TPGS/Tween 20 as the mixture of surfactant (Smix) at a Km value of 1/4 was found to yield the desired SMEDDSs for fenofibrate. In vitro dissolution studies illustrated that the release of fenofibrate from SMEDDSs was complete within 30 minutes either in 0.025 M SLS solution or water medium. But the release of fenofibrate from Tricor? tablets or micronized fenofibrate dispersion systems (MDSs) was limited in water medium. The present study also revealed that the self-microemulsified drug delivery system of poorly-water soluble drugs exemplified by fenofibrate increased their dissolution rate leading to enhance their bioavailability correspondingly.
論文目次 Page English Abstract 1 Chinese Abstract 4 Part I Studies on the Phase Diagrams of Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS) Based Microemulsion Systems 7 English Abstract 8 Chinese Abstract 10 1. Introduction 12 2. Aim of the Study 16 3. Experimental 17 3.1. Materials 17 3.2. Construction of Pseudoternary Phase Diagrams 17 4. Results and Discussion 20 5. Conclusions 35 6. References 37 Table 1. Empirical formula, molecular weight, HLB and viscosity of selected polysorbates. 41 Figure 1. Theoretical phase diagram of hydrophile, lipophile, surfactant, and cosurfactant. 42 Figure 2. Phase diagram of H2O (X)/Captex 300 (Y)/Smix (Z) system; the solid lines represent the aqueous dilution lines. 43 Figure 3. Phase diagram of H2O (X)/Captex 300 (Y)/Smix (Z) system. G: transparent gel; ME: microemulsion. 44 Figure 4. Phase diagram of H2O/Captex 300/TPGS/Tween 20 systems. X: H2O; Y: Captex 300; Z: TPGS/Tween 20 = (a) 4/1, (b) 2/1, (c) 1/1, (d) 1/2, (e) 1/4, and (f) 0/1. G: transparent gel; ME: microemulsion. 45 Figure 5. Phase diagram of H2O/Captex 300/TPGS/Tween 40 systems. X: H2O; Y: Captex 300; Z: TPGS/Tween 40 = (a) 4/1, (b) 2/1, (c) 1/1, (d) 1/2, (e) 1/4, and (f) 0/1. G: transparent gel; ME: microemulsion. 46 Figure 6. Phase diagram of H2O/Captex 300/TPGS/Tween 60 systems. X: H2O; Y: Captex 300; Z: TPGS/Tween 60 = (a) 4/1, (b) 2/1, (c) 1/1, (d) 1/2, (e) 1/4, and (f) 0/1. G: transparent gel; ME: microemulsion. 47 Figure 7. Phase diagram of H2O/Captex 300/TPGS/Tween 80 systems. X: H2O; Y: Captex 300; Z: TPGS/Tween 80 = (a) 4/1, (b) 2/1, (c) 1/1, (d) 1/2, (e) 1/4, and (f) 0/1. G: transparent gel; ME: microemulsion. 48 Figure 8. Phase diagram of H2O/Captex 300/TPGS/PEG 400 systems. X: H2O; Y: Captex 300; Z: TPGS/PEG 400 = (a) 4/1, (b) 2/1, (c) 1/1, (d) 1/2, (e) 1/4, and (f) 0/1. G: transparent gel; ME: microemulsion. 49 Figure 9. Phase diagram of H2O/Captex 300/TPGS/PEG 600 systems. X: H2O; Y: Captex 300; Z: TPGS/PEG 600 = (a) 4/1, (b) 2/1, (c) 1/1, (d) 1/2, (e) 1/4, and (f) 0/1. G: transparent gel; ME: microemulsion. 50 Figure 10. Phase diagram of H2O/Captex 300/TPGS/ethanediol systems. X: H2O; Y: Captex 300; Z: TPGS/ethanediol = (a) 4/1, (b) 2/1, (c) 1/1, (d) 1/2, (e) 1/4, and (f) 0/1. G: transparent gel; ME: microemulsion. 51 Figure 11. Phase diagram of H2O/Captex 300/TPGS/1,2-propanediol systems. X: H2O; Y: Captex 300; Z: TPGS/1,2-propanediol = (a) 4/1, (b) 2/1, (c) 1/1, (d) 1/2, (e) 1/4, and (f) 0/1. G: transparent gel; ME: microemulsion. 52 Figure 12. Phase diagram of H2O/Captex 300/TPGS/1,3-propanediol systems. X: H2O; Y: Captex 300; Z: TPGS/1,3-propanediol = (a) 4/1, (b) 2/1, (c) 1/1, (d) 1/2, (e) 1/4, and (f) 0/1. G: transparent gel; ME: microemulsion. 53 Figure 13. Phase diagram of H2O/Captex 300/TPGS/1,3-butanediol systems. X: H2O; Y: Captex 300; Z: TPGS/1,3-butanediol = (a) 4/1, (b) 2/1, (c) 1/1, (d) 1/2, (e) 1/4, and (f) 0/1. G: transparent gel; ME: microemulsion. 54 Figure 14. Phase diagram of H2O/Captex 300/TPGS/1,4-butanediol systems. X: H2O; Y: Captex 300; Z: TPGS/1,4-butanediol = (a) 4/1, (b) 2/1, (c) 1/1, (d) 1/2, (e) 1/4, and (f) 0/1. G: transparent gel; ME: microemulsion. 55 Figure 15. Phase diagram of H2O/Captex 300/TPGS/glycerin systems. X: H2O; Y: Captex 300; Z: TPGS/glycerin = (a) 4/1, (b) 2/1, (c) 1/1, (d) 1/2, (e) 1/4, and (f) 0/1. G: transparent gel; ME: microemulsion. 56 Part II Physical Characterization of Self-Microemulsifying Drug Delivery System for Fenofibrate 57 English Abstract 58 Chinese Abstract 60 1. Introduction 61 1.1. Basic Properties of Fenofibrate 61 1.2. The Rationale for the Study 64 1.3. Development of Fenofibrate Microemulsion Delivery System 66 2. Aim of the Study 69 3. Experimental 70 3.1. Materials 70 3.2. Solubility Test 71 3.3. Preparation of SMEDDS Formulations 72 3.4. Dissolution Studies 73 3.5. Measurement of Viscosity 74 3.6. Construction of Pseudoternary Phase Diagrams 74 4. Results and Discussion 75 4.1. Solubility Studies 75 4.2. Dissolution Studies 76 4.2.1. Dissolution Studies of SMEDDS Formulations A1-A10 76 4.2.2. Dissolution Studies of SMEDDS Formulations B1-B6 79 4.2.3. Dissolution Studies of SMEDDS Formulations C1-C9 80 4.2.4. Dissolution Studies of Tricor? Tablets 81 4.2.5. Dissolution Studies of Formulations D1-D6 Micronized Fenofibrate Dispersion Systems 83 4.2.6. Dissolution Studies of SMEDDS Formulations E1-E9 87 4.3. Pseudo-ternary Phase Diagram Studies 93 5. Conclusions 95 6. References 96 Table 1. Physical properties of medium chain triglycerides of Captex 300 and Myritol 318. 101 Table 2. Solubility of fenofibrate in formulation components. 102 Table 3. Formulations (A1-A10) of fenofibrate SMEDDS. 103 Table 4. HLB values of surfactant mixtures. 104 Table 5. Formulations (B1-B6) of fenofibrate SMEDDS. 105 Table 6. Formulations (C1-C9) of fenofibrate SMEDDS containing different amount of PVP. 106 Table 7. Formulations (D1-D6) of fenofibrate micronized dispersion systems. 107 Table 8. Formulations (E1-E9) of fenofibrate SMEDDS. 108 Figure 1. Dissolution profiles of fenofibrate from SMEDDS formulations A1-A10. 109 Figure 2. Dissolution profiles of fenofibrate from SMEDDS formulations B1-B6. 110 Figure 3. Dissolution profiles of fenofibrate from SMEDDS formulations C1-C9. 111 Figure 4. Dissolution profiles of fenofibrate from Tricor? tablets (54mg and 160mg labeled amount) in different dissolution media. 112 Figure 5. Dissolution profiles of fenofibrate from micronized dispersion formulations D1-D6 in (a) water, and (b) 0.025M SLS dissolution media. 113 Figure 6. Dissolution profiles of fenofibrate from SMEDDS formulations E1-E9 in 0.025M SLS dissolution medium; (a) E1-E3, (b) E4-E6, and (c) E7-E9. 114 Figure 7. Dissolution profiles of fenofibrate from SMEDDS formulations E1-E9 in 0.025M SLS dissolution medium; (a) E1, E4, E7, (b) E2, E5, E8, and (c) E3, E6, E9. 115 Figure 8. Dissolution profiles of fenofibrate from SMEDDS formulations E1-E9 in water dissolution medium; (a) E1-E3, (b) E4-E6, and (c) E7-E9. 116 Figure 9. Dissolution profiles of fenofibrate from SMEDDS formulations E1-E9 in water dissolution medium; (a) E1, E4, E7, (b) E2, E5, E8, and (c) E3, E6, E9. 117 Figure 10. Dissolution profiles of fenofibrate from SMEDDS formulations in 0.025M SLS, and water dissolution media; (a) E1-E3, (b) E4-E6, and, (c) E7-E9. 118 Figure 11. Viscosity of fenofibrate SMEDDS formulations E2-E9. 119 Figure 12. Dissolution profiles of fenofibrate from micronized dispersion formulations D1-D3, and SMEDDS formulations E4-E6 in (a) water, and (b) 0.025M SLS dissolution media. 120 Figure 13. Dissolution profiles of fenofibrate from dispersion formulations D4-D6, and SMEDDS formulations E7-E9 in (a) water, and (b) 0.025M SLS dissolution media. 121 Figure 14. Phase diagrams of TPGS/Tween 20/Fenofibrate/Myritol 318 systems/Water. X: TPGS/Tween 20; Y: Fenofibrate; Z: Myritol 318; (a) 0%, (b) 5%, and (c) 10% water content. 122 Writings 123
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