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系統識別號 U0007-1704200714542195
論文名稱(中文) 去乙醯幾丁聚醣之非對稱性膜滲透膠囊之製備與特性解析
論文名稱(英文) Characterization of Osmotic Capsule with Asymmetric Membrane Using Chitosan
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) 王聖希
研究生(英文) Sheng Shi Wang
學號 m301091011
學位類別 博士
語文別 英文
口試日期
論文頁數 107頁
口試委員 指導教授-許明照教授
中文關鍵字 去乙醯幾丁聚醣  非對稱性膜  滲透膠囊 
英文關鍵字 chitosan  asymmertric membrane  osmotic capsule 
學科別分類
中文摘要 去乙醯幾丁聚醣之非對稱性膜滲透膠囊之製備與特性解析 中 文 摘 要 本研究主要目的是要以去乙醯幾丁聚醣(Chitosan)來當作非對稱性膠囊之材質,設計合適的滲透性控釋膠囊。非對稱性膜在膠囊化處理後可改善滲透性幫浦難溶性藥物釋放的情形。 膠囊殼乃是以交聯的方式膠化所產生,先將模具浸入含有聚合物的包覆溶液(coating solution),再浸入到淬鍊溶液(quenching solution),而在膜具上形成具有非對稱結構之膠囊殼。選用不同的膜衣材質,包覆溶液,浸漬溶液和浸漬時間來製作並評估非對稱結構之膠囊殼之特性。 滲透壓實驗中,薄膜釋藥孔之存在由包覆葉綠素的膠囊緩緩釋出葉綠素而得到證實。選用不同溶解度的藥物來評估對稱性膠囊的控釋效果。結果顯示藥物從非對稱性膜膠囊的釋放會因藥物的溶解度增加而增加,藥物的溶出速率與藥物溶解度成線性相關。在實用的觀點下考量製作難易度及通透效果後,選取以去乙醯幾丁聚醣與三磷酸鹽交聯三十分鐘這組膠囊為試驗膠囊。膠囊的通透率經計算而得 1.40*10-6 cm2/h-atm 於 攝氏37.8度,因為難溶性藥物felodipine 及 nifedipine不能提供足夠的滲透壓動力,於是在處方中添加助溶劑SLS 或添加助懸劑 HPMC 以增加藥物釋放。經計算而得之複回歸方程式: YF(drug max released %)= 32.48367-1.04456* F+0.14909 * H+ 0.23256 * S(mg) YN(drug max released %)= 30.99458-0.95958 * N+0.12802 * H+0.21321 * S(mg) 最後,我們成功地設計出以去乙醯幾丁聚醣與三磷酸鹽 (TPP)交聯之非對稱性滲透膠囊。
英文摘要 Characterization of Osmotic Capsule with Asymmetric Membrane Using Chitosan ABSTRACT The major purpose of the study was to devise a suitable osmotic capsule for drug release. In this study, chitosan was utilized as the matrix of asymmetric membrane capsules. Asymmetric membrane offering an improved osmotic pump effect was used to release poorly water-soluble drug in a control manner after encapsulation. The capsule wall was composed of membrane produced by gelation process, controlled by the ionic cross-linking reaction between protonated chitosan and ionized triphosphate (TPP). Asymmetric membrane was formed on stainless steel mold pins by dipping the mold pins into a coating solution containing a polymeric material followed by dipping into a quenching solution. The factors influenced the prosperities of the capsule membrane, such as the molecular weight of chitosan、the solvent、the dipping solution and the dipping time were investigated in view of the drug release. In situ formation of a delivery orifice in the thin membrane was proven by observation of a jet stream of chlorophyll being released from the capsule. Drugs with different solubility were selected as the model to demonstrate that the controlled release characteristics can be manipulated by the design of polymeric capsule coating an asymmetric membrane. The results showed that the release rate from asymmetric membrane capsule increased with the solubility for drugs. A correlation between drug solubility and the initial drug release rate calculated from the slope of the drug release profile was verified to be linear. From the practical viewpoint it is useful to estimate selectivity of the capsules towards the difficulty of production and permeability. The model capsule made of chitosan 500 cross-linked with triphosphate. Permeability across the selected asymmetric membrane of the C500/TPP30 capsule was determined to be 1.40*10-6 cm2/h-atm at 37.8OC for drugs with water solubilities in a moderate to high range. The poorly water-soluble drug, felodipine and nifedipine, were unable to create a sufficient osmotic effect on activating the release of drug. Solubilization either by the addition of the solubility enhancer, SLS, or by a solid dispersion with HPMC could increase the solubility of nifedipine to a sufficient extent to activate drug release. It was found that HPMC further interacted with SLS to synergistically increase the maximal percent of release amount and the release rate of felodipine and nifedipine. The multi regression formulations of felodipine and nifedipine were “YF( drug max released %) =32.48367-1.04456*F+0.14909*H+0.23256*S(mg)” and“YN(drug max released%) =30.99458-0.95958*N+0.12802*H+0.21321*S(mg)”, respectively. Consequently, we successfully designed the osmotic capsule with asymmetric membrane which was made of chitosan and cross-linked with TPP.
論文目次 English Abstract 13 Chinese Abstract 15 1. Introduction 17 1.1 The background of research 17 1.2 osmotic pump 18 1.2.1. Principles of osmosis 18 1.2.2. History of osmotic pump 20 1.2.2.1. The Rose-Nelson pump 20 1.2.2.2. Higuchi-Leeper pump 24 1.2.2.3. Higuchi-Theeuwes pump 25 1.2.2.4. Elementary osmotic pump (EOP) 26 1.2.3. Asymmetric membrane 32 1.3. Chitosan characteristic 32 1.3.1 Degree of deacetylation 33 1.3.2 Molecular weight 34 1.3.3. Application of chitosan in pharmaceutics 35 1.3.4. Classified of chitosan capsule 36 1.3.4.1. Chitosan hard capsule 36 1.3.4.2. Chitosan alginate capsule 37 1.4 Cross-linked membrane 38 1.5.The motive of the research 39 1.6 The profiles of the design 39 2. Experimental 40 2.1. Materials 40 2.2. Apparatus 41 2.3. Characteristic of chitosan 42 2.3.1 Molecular weight 42 2.3.2 Viscosity 42 2.3.3 Degree of deacetylation 42 2.4. Solvent 43 2.5. Quenching solution 44 2.6. Pure chitosan capsule 44 2.7. Chitosan/multivalent phosphates capsule 44 2.8. Solubility 46 2.9. Validation of assay model drugs 46 2.10. Release test 47 2.11. Osmotic pump capsule preparation 47 2.12. Theoretical considerations 50 3. Results and discussion 52 3.1. Characteristic of chitosan 52 3.1.1. Molecular weight 52 3.1.2 Viscosity 53 3.1.3. Degree of deacetylation 53 3.1.4. Solvent 54 3.2. Capsule preparation 56 3.2.1. Pure chitosan capsules 58 3.2.2. Chitosan/multivalent phosphates capsules 59 3.3. Physical characteristics of optimal chitosan capsules 3.4. Validation of assay method 64 3.5. In vitro drug release profiles 77 3.6. The permeability of chitosan/TPP and other chitosan/multi phosphates capsules 82 3.7. Release test of poor soluble drug 85 3.8. Validation of Dissolution Method 86 4. Conclusions 95 5. References 96 Table 1 Osmotic pressure for concentrated solutions of excipients 21 Table 2 Evolution of osmotic pump 28 Table 3 Elementary osmotic pump patents covering the use of various membranes 29 Table 4 Elementary osmotic pump patents covering design modifications 29 Table 5 Patent on some drugs formulated in the form of elementary osmotic pump 30 Table 6 Some commercially marketed products 31 Table.7 Chitin derivatives and their proposed uses 35 Table 8 Chitosan 100 coating solution formulations 43 Table 9 Quenching solution formulations 44 Table 10 Pure chitosan capsule formulations 45 Table 11 Chitosan/TPP capsule formulations 45 Table 12 Chitosan500/multivalent phosphates capsule formulations 46 Table 13 Design of chitosan osmotic capsules filled with Felodipine/HPMC/SLS 48 Table 14 Design of chitosan osmotic capsules filled with Nifedipine/HPMC/SLS 49 Table 15 Chitosan degree of deacetylation (DD) 54 Table 16 Chitosan morphology 57 Table 17 Characteristic profiles of chitosan capsule 63 Table 18 The solubility of drugs in water at 37.8℃ (n=3) 84 Table 19 Permeability of C500/multivalent phosphates capsules 85 Fig. 1. Profile of Pfeiffer’s osmosis experiment 19 Fig. 2. Rose-Nelson pump 21 Fig. 3. Pharmetrix pump 23 Fig. 4. Higuchi-Leeper pump 24 Fig. 5. Higuchi-Theeuwes pump 25 Fig. 6. Elementary osmotic pump 27 Fig. 7. The future of Alza’s OROS® system 28 Fig. 8. Structures of cellulose, chitin and chitosan. 33 Fig. 9. Chitosan capsules 37 Fig. 10. Membrane classification 38 Fig. 11. Chitosan molecular weights 52 Fig. 12. Chitosan viscosity 53 Fig. 13. Titration for chitosan degree of deacetylation 54 Fig. 14. Chitosan 100 dissolve in acetic/alcoholic solution (1:1) 55 Fig. 15. Chitosan 100 dissolve in acetic aqueous solution (3%w/w) 56 Fig. 16. Chitosan morphology (A) Chitosan 10 (B) Chitosan 100 (C) Chitosan 500 (D) Chitosan 1000 57 Fig. 17. Morphology of chitosan capsules 58 Fig. 18. Scanning electron micrographs of chitosan 500 membrane without quenching) formulation (A) dense region (outer layer) at 200 x magnification(B) cross-section at 1000 x magnification 59 Fig. 19. Morphology of chitosan/TPP capsules 60 Fig. 20. Morphology of chitosan/TPP capsules 60 Fig. 21. Scanning electron micrographs of chitosan membrane(quenching 15mins ) formulation cross-section at 200 x magnification(A)chitosan 10(B)chitosan100 (C)chitosan 500 (D)chitosan1000 61 Fig. 22. Scanning electron micrographs of Chitosan500 membrane formulation cross section at 200 X magnification (quenching 30 mins) 61 Fig. 23. Scanning electron micrographs of chitosan membrane formulation cross-section at 200 x magnification(A) C500/15Phos (B) C500/30Phos (C) C500/15Pyro (D) C500/30Pyro 62 Fig. 24. Photograph of asymmetric membrane C500/30TPP with chlorophyllin in water. (A)After 30 mins (B)After 60 mins(C)After 3hours(D)In NaCl 6%(w/w) solution(1 day) 64 Fig. 25. Intraday accuracy and precision of Chlorpheniramine 65 Fig. 26. Interday accuracy and precision of Chlorpheniramine 66 Fig. 27. Intraday accuracy and precision of Diltiazem 67 Fig. 28. Interday accuracy and precision of Diltiazem. 68 Fig. 29. Intraday accuracy and precision of Naproxen 69 Fig. 30. Interday accuracy and precision of Naproxen 70 Fig. 31. Intraday accuracy and precision of Pyridoxine. 71 Fig. 32. Interday accuracy and precision of Pyridoxine. 72 Fig. 33. Intraday accuracy and precision of Felodipine 73 Fig. 34. Interday accuracy and precision of Felodipine 74 Fig. 35. Interday accuracy and precision of Nifedipine 75 Fig. 36. Interday accuracy and precision of Nifedipine 76 Fig. 37. Chlorphenamine release profiles 78 Fig. 38. Diltiazem release profiles 78 Fig. 39. Naproxen release profiles 79 Fig. 40. Pyridoxine release profiles 79 Fig. 41. Felodipine release profiles 80 Fig. 42. The release profiles of chitosan capsules formulation C500,C500/TPP15 and C500/TPP30 in (A) Chlorpheniramine (B)Diltiazem (C)Naproxen (D)Pyridoxine (E)Felodipine 81 Fig. 43. Release profiles of formulation (A)C500/TPP15 (B) C500/TPP30 81 Fig. 44. Chitosan 500 capsules Linear relationship between the release rate and the square of solubility divided by molecular weight of the drug. (A)C500/TPP15 (B)C500/TPP30 83 Fig. 45. Release profiles of Felodipine in 1%Tween 80 solutions Felodipine (F)was made by HPMC(H) and physical mixed with SLS(S) 86 Fig. 46. Release profiles of Felodipine in 1%Tween 80 solutions Felodipine (F)was made by HPMC(H) and physical mixed with SLS(S) 87 Fig. 47. Release profiles of Nifedipine in 1%Tween 80 solutions Nifedipine (N)was made by HPMC(H) and physical mixed with SLS(S) 88 Fig. 48. Release profiles of Nifedipine in 1%Tween 80 solutions Nifedipine (N)was made by HPMC(H) and physical mixed with SLS(S) 89 Fig. 49. Release profiles of Nifedipine in 1%Tween 80 solutions Nifedipine(F) was made by HPMC(H) and physical mixed with SLS(S) 90 Fig. 50. Release profiles of Nifedipine in 1%Tween 80 solutions Nifedipine(F) was made by HPMC(H) and physical mixed with SLS(S) 91 Fig. 51. Release profiles of Nifedipine in 1%Tween 80 solutions Nifedipine(F) was made by HPMC(H) and physical mixed with SLS(S) 93 Fig. 52. The relationship among max released ratio/Felodipine/ HPMC 3D profiles (SLS amount was limited) 94 Fig. 53. The relationship among max released ratio/Nifedipine/ HPMC 3D profiles (SLS amount was limited) 95 Diagnostics Case Statistics A Felodipine 102 Diagnostics Case Statistics B Nifedipine 105
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