(3.236.122.9) 您好!臺灣時間:2021/05/12 20:35
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

我願授權國圖
: 
twitterline
研究生:劉建辰
研究生(外文):Jian-Chen Liu
論文名稱:Captopril凝膠軟膏劑型安定性、刺激性與經皮穿透性之研究
論文名稱(外文):The Stability, Skin Irritation and Transdermal of Captopril in Gel
指導教授:蔡 義 弘
指導教授(外文):Yi-Hung Tsai
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:95
中文關鍵詞:安定性刺激性經皮穿透性
相關次數:
  • 被引用被引用:0
  • 點閱點閱:328
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
Captopril屬於血管張力素轉換抑制劑類的藥物(Inhibitor of angiotensin converting enzyme,ACE inhibitor),為目前的ACE inhibitor中分子量最小的藥物,其分子量只有217。根據過去文獻指出captopril的經皮輸藥系統處方中,其5% captopril凝膠處方只需投與約10平方公分(平均500mg/cm2的captopril),即可達到最低有效治療濃度;然而由於captopril易氧化,文獻指出其在水溶液中則相對不穩定,於4 ℃下之架貯期約為14天,22 ℃下之架貯期約為7天。此外,亦有文獻指出captopril會使皮膚引起類似過敏反應 (Histamine-mediated inflammatory) 之紅腫現象。因此本實驗的主要目的是改善captopril在製劑中的安定性以及抑制captopril製劑對皮膚之刺激性,並能維持其一定之皮膚穿透量。
在安定性研究方面:除了添加常用的抗氧化劑,來評估是否可增加captopril製劑的架貯期外,還探討溶媒、賦型劑、經皮吸收促進劑以及環糊精 (cyclodextrin) 等對captopril安定性的影響。其結果顯示:EDTA trisodium和1% acetic acid 對增加captopril安定性具有最顯著的效果。在含有EDTA trisodium和1% acetic acid的captopril凝膠劑型,其架貯期約為420天左右(30℃,70% RH)。
在刺激性研究方面:藉由皮膚表皮水分蒸發儀和色差儀來評估製劑對皮膚刺激性的影響,在實驗中除了評估具抑制刺激性作用的藥物之抑制皮膚刺激效果外,還評估其給藥時間長短、劑量及整體性處方等因素對引起皮膚刺激之影響。其結果顯示: 含有5% captopril的凝膠劑型之皮膚刺激性為未塗藥部位的6-7倍;然而captopril在含有diphenhydramine與clobetsol的凝膠劑型則有顯著抑制皮膚刺激性的作用。
在經皮穿透方面:根據安定性與刺激性實驗的結果,篩選適當的處方,進一步探討其經皮穿透量。其結果顯示:captopril在含有diphenhydramine、clobetsol、EDTA trisodium和1% acetic acid的凝膠劑型,其通透率可高達600μg/cm2hr,明顯高於文獻所指出達到最低有效治療濃度所需之通透率(460μg/cm2hr)。

Captopril, an ACE inhibitor, has been used to develop transdermal delivery system in recent years. In previous studies, captopril gel had good transdermal absorption effects and only required 10 cm2-area administrations to attain minimum effective concentration. However, topical use of captopril gel might induce delayed-type hypersensitivity to skin rash and captopril could easily decompose in semisolid or in water. Therefore, the aims of this study were to reduce the skin irritation of captopril and to improve the stability of captopril.
In the stability study, captopril in different formulations of solution, gel and absorption cream were evaluated. The study also tried to add some common stabilizers, such as Vit. E, TPGS(Alpha-tocopheryl polyethylene glycol succinate, water soluble Vit. E), ascorbic acid, sodium ascorbate, sodium sulfite, sodium bisulfite, EDTA trisodium to increase the stability of captopril. The shelf life of gel containing 1% acetic acid and EDTA trisodium was up to 420 days.
In the skin irritation study, captopril gel with or without irritative inhibitors, such as clobetasol, betamethasone, diphenhydramine, promethazine, cyprohetadine, Gluconolactone, Glucono-δ-lactone, amiloride, ethacrynic acid and nifedipine were applied on abdominal skin of rabbits. Tewameter and colorimeter were used to measure the transepidermal water loss (TEWL) and the change of the skin color, respectively, to determine the irritation of skin. The irritation of skin that caused by captopril gel was about 6-7 folds than that without any captopril gel. However, The irritation that caused by captopril gel containing diphenhydramine and clobetsol caused less irritation(about 2-3 folds than that without any captopril gel).
Formulations with better performance were chosen according to the results of the stability and skin irritation study for further experiment. In the transdermal study, the flux of captopril gel containing diphenhydramine and clobetsol was up to 600 μg/cm2hr and higher than 460μg/cm2hr which reported to be necessary to reach the minimal therapeutic concentration.

壹、 中文摘要 ----------------------------------------------------------- 1
英文摘要 ----------------------------------------------------------- 2
貳、 緒論 ----------------------------------------------------------------- 3
參、 材料與方法
一、 藥品與試劑----------------------------------------------------- 13
二、 儀器 設備------------------------------------------------------ 13
三、 Captopril 分析方法------------------------------------------- 14
四、 Captopril處方及安定性實驗------------------------------ 14
五、 親水性凝膠製劑與吸收性軟膏萃取方法---------------- 19
六、 Captopril/Cyclodextrin複合物之製備方法--------------- 19
七、Captopril/Cyclodextrin複合物性質之評估----------------- 20
八、皮膚刺激性評估------------------------------------------------- 21
九、體外穿透實驗---------------------------------------------------- 27
十、藥物穿透皮膚之相關數據的資料分析---------------------- 27
肆、 結果與討論
一、 Captopril 分析方法-------------------------------------------- 31
二、 Captopril安定性之評估-------------------------------------- 31
三、 Captopril與cyclodextrin交互作用------------------------- 56
四、 皮膚刺激性評估------------------------------------------------ 71
五、 經皮穿透性評估------------------------------------------------ 84
伍、 結論 ----------------------------------------------------------------- 89
陸、 參考文獻------------------------------------------------------------- 91

Agner T. Serup J. Time course of occlusive effects on skin evaluated by measurement of transepidermal water loss (TEWL). Including patch tests with sodium lauryl sulphate and water. Contact Dermatitis. 28(1): 6-9, 1993 Jan.
Allen AE. Das Gupta V. Stability of hydrocortisone in polyethylene glycol ointment base. Journal of Pharmaceutical Sciences. 63(1): 107-9, 1974 Jan.
Allen LV Jr. Erickson MA 3rd. Stability of baclofen, captopril, diltiazem hydrochloride, dipyridamole, and flecainide acetate in extemporaneously compounded oral liquids. American Journal of Health-System Pharmacy. 53(18): 2179-84, 1996 Sep 15.
Andreoli SP. Captopril scavenges hydrogen peroxide and reduces, but does not eliminate, oxidant-induced cell injury. American Journal of Physiology. 264(1 Pt 2): F120-7, 1993 Jan.
Bartosz M. Kedziora J. Bartosz G. Antioxidant and prooxidant properties of captopril and enalapril. Free Radical Biology & Medicine. 23(5): 729-35, 1997.
Bauduceau B. Mayaudon H. Dupuy O. Rilmenidine in the hypertensive type-2 diabetic: a controlled pilot study versus captopril. Journal of Cardiovascular Risk. 7(1): 57-61, 2000 Feb.
Bhuyan KC. Bhuyan DK. Santos O. Podos SM. Antioxidant and anticataractogenic effects of topical captopril in diquat-induced cataract in rabbits. Free Radical Biology & Medicine. 12(4): 251-61, 1992.
Cavanagh EM. Fraga CG. Ferder L. Inserra F. Enalapril and captopril enhance antioxidant defenses in mouse tissues. American Journal of Physiology. 272(2 Pt 2): R514-8, 1997 Feb.
Cavanagh EM. Inserra F. Ferder L. Fraga CG. Enalapril and captopril enhance glutathione-dependent antioxidant defenses in mouse tissues. American Journal of Physiology - Regulatory Integrative & Comparative Physiology. 278(3): R572-7, 2000 Mar.
Colucci RD. Auty R. Scavone J. Glassner-Cohen L. The chemical stability of captopril capsules. International Journal of Clinical Pharmacology, Therapy, & Toxicology. 27(12): 599-601, 1989 Dec.
Das Gupta V. Effect of ethanol, glycerol, and propylene glycol on the stability of phenobarbital sodium. Journal of Pharmaceutical Sciences. 73(11): 1661-2, 1984 Nov.
Dobrucki R. Radomska A. Zgola W. The antioxidant properties of captopril. Pharmazie. 51(12): 992, 1996 Dec.
Echezarreta-Lopez M. Torres-Labandeira JJ. Castineiras-Seijo L. Santana-Penin L. Vila-Jato JL. Complexation of the interferon inducer, bropirimine, with hydroxypropyl-beta-cyclodextrin. European Journal of Pharmaceutical Sciences. 9(4): 381-6, 2000 Feb.
Gurer H. Neal R. Yang P. Oztezcan S. Ercal N. Captopril as an antioxidant in lead-exposed Fischer 344 rats. Human & Experimental Toxicology. 18(1): 27-32, 1999 Jan.
Held E. Agner T. Comparison between 2 test models in evaluating the effect of a moisturizer on irritated human skin. Contact Dermatitis. 40(5):261-8, 1999 May.
Ikeda Y. Kimura K. Hirayama F. Arima H. Uekama K. Controlled release of a water-soluble drug, captopril, by a combination of hydrophilic and hydrophobic cyclodextrin derivatives. Journal of Controlled Release. 66(2-3): 271-80, 2000 May 15.
Katoh M. Ohmachi Y. Kurosawa Y. Yoneda H. Tanaka N. Narita H. Effects of imidapril and captopril on streptozotocin-induced diabetic nephropathy in mice. European Journal of Pharmacology. 398(3): 381-7, 2000 Jun 23.
Kaukonen AM. Lennernas H. Mannermaa JP. Water-soluble beta-cyclodextrins in paediatric oral solutions of spironolactone: preclinical evaluation of spironolactone bioavailability from solutions of beta-cyclodextrin derivatives in rats. Journal of Pharmacy & Pharmacology. 50(6): 611-9, 1998 Jun.
Kofuji K. Shibata K. Murata Y. Miyamoto E. Kawashima S. Preparation and drug retention of biodegradable chitosan gel beads. Chemical & Pharmaceutical Bulletin. 47(10): 1494-6, 1999 Oct.
Lapenna D. De Gioia S. Ciofani G. Daniele F. Cuccurullo F. Captopril has no significant scavenging antioxidant activity in human plasma in vitro or in vivo [see comments]. British Journal of Clinical Pharmacology. 42(4): 451-6, 1996 Oct.
Lee TY. Notari RE. Kinetics and mechanism of captopril oxidation in aqueous solution under controlled oxygen partial pressure. Pharmaceutical Research. 4(2): 98-103, 1987 Apr.
Liu J. Chan SY. Ho PC. Effects of sucrose, citric buffer and glucose oxidase on the stability of captopril in liquid formulations. Journal of Clinical Pharmacy & Therapeutics. 24(2): 145-50, 1999 Apr.
Lye MY. Yow KL. Lim LY. Chan SY. Chan E. Ho PC. Effects of ingredients on stability of captopril in extemporaneously prepared oral liquids. American Journal of Health-System Pharmacy. 54(21): 2483-7, 1997 Nov 1.
Nahata MC. Morosco RS. Hipple TF. Stability of captopril in liquid containing ascorbic acid or sodium ascorbate [letter]. American Journal of Hospital Pharmacy. 51(13): 1707-8, 1994 Jul 1.
Ozkan Y. Atay T. Dikmen N. Isimer A. Aboul-Enein HY. Improvement of water solubility and in vitro dissolution rate of gliclazide by complexation with beta-cyclodextrin. Pharmaceutica Acta Helvetiae. 74(4): 365-70, 2000 Apr.
Pereira CM. Tam YK. Stability of captopril in tap water. American Journal of Hospital Pharmacy. 49(3): 612-5, 1992 Mar.
Pramar Y. Das Gupta V. Bethea C. Stability of captopril in some aqueous systems. Journal of Clinical Pharmacy & Therapeutics. 17(3): 185-9, 1992 Jun.
Repka MA. McGinity JW. Influence of vitamin E TPGS on the properties of hydrophilic films produced by hot-melt extrusion. International Journal of Pharmaceutics. 202(1-2): 63-70, 2000 Jul 20.
Sam WJ. Ho PC. Stability of captopril in invert sugar solution. Journal of Clinical Pharmacy & Therapeutics. 23(6): 451-6, 1998 Dec.
Seidenari S. Pepe P. Di Nardo A. Sodium hydroxide-induced irritant dermatitis as assessed by computerized elaboration of 20 MHz B-scan images and by TEWL measurement: a method for investigating skin barrier function. Acta Dermato-Venereologica. 75(2): 97-101, 1995 Mar.
Seitz JC. Whitmore CG. Measurement of erythema and tanning responses in human skin using a tri-stimulus colorimeter. Dermatologica. 177(2): 70-5, 1988.
Sharma K. Eltayeb BO. McGowan TA. Dunn SR. Alzahabi B. Rohde R. Ziyadeh FN. Lewis EJ. Captopril-induced reduction of serum levels of transforming growth factor-beta1 correlates with long-term renoprotection in insulin-dependent diabetic patients [see comments] [published erratum appears in Am J Kidney Dis 2000 Mar; 35(3):572]. American Journal of Kidney Diseases. 34(5): 818-23, 1999 Nov.
Suda H. Okamoto M. Fukumoto M. Delayed-type skin allergic reaction in guinea pigs induced by anti-rheumatic compounds with sulfhydryl groups. Immunopharmacology & Immunotoxicology. 15(4): 387-96, 1993 Aug.
Suphajettra P. Strohl JH. Lim JK. Nitroglycerin stability in polyethylene glycol 400 and povidone solutions. Journal of Pharmaceutical Sciences. 67(10): 1394-6, 1978 Oct.
Taketomo CK. Chu SA. Cheng MH. Corpuz RP. Stability of captopril in powder papers under three storage conditions. American Journal of Hospital Pharmacy. 47(8): 1799-801, 1990 Aug.
Trujillo O. Vanezis P. Cermignani M. Photometric assessment of skin colour and lightness using a tristimulus colorimeter: reliability of inter and intra-investigator observations in healthy adult volunteers. Forensic Science International. 81(1): 1-10, 1996 Jul 31.
Tsai CJ. Hsu LR. Fang JY. Lin HH. Chitosan hydrogel as a base for transdermal delivery of berberine and its evaluation in rat skin. Biological & Pharmaceutical Bulletin. 22(4): 397-401, 1999 Apr.
Veiga MD. Ahsan F. Influence of surfactants (present in the dissolution media) on the release behaviour of tolbutamide from its inclusion complex with beta-cyclodextrin. European Journal of Pharmaceutical Sciences. 9(3): 291-9, 2000 Jan.
Welzel J. Metker C. Wolff HH. Wilhelm KP. SLS-irritated human skin shows no correlation between degree of proliferation and TEWL increase
Welzel J. Metker C. Wolff HH. Wilhelm KP. SLS-irritated human skin shows no correlation between degree of proliferation and TEWL increase. Archives of Dermatological Research. 290(11): 615-20, 1998 Nov.
Wu P-C. Huang Y-B. Fang J-Y. Tsai Y-H. Percutaneous absorption of captopril from hydrophilic cellulose derivatives through excised rabbit skin and human skin. Drug Development & Industrial Pharmacy. Vol 24(2) (pp 179-182), 1998.
Wu P-C. Huang Y-B. Lin H-H. Tsai Y-H. In vitro percutaneous absorption of captopril through excised rabbit skin. International Journal of Pharmaceutics. Vol 143(1) (pp 119-123), 1996.
Wulff M. Alden M. Solid state studies of drug-cyclodextrin inclusion complexes in PEG 6000 prepared by a new method. European Journal of Pharmaceutical Sciences. 8(4): 269-81, 1999 Aug.
Yusuff NT. York P. Chrystyn H. Bramley PN. Swallow RD. Tuladhar BR. Losowsky MS. Improved bioavailability from a spironolactone beta-cyclodextrin complex. European Journal of Clinical Pharmacology. 40(5): 507-11, 1991.
Zhou XH. Li Wan Po A. Stability and in vitro absorption of captopril, enalapril and lisinopril across the rat intestine. Biochemical Pharmacology. 47(7): 1121-6, 1994 Mar 29.

QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關論文
 
系統版面圖檔 系統版面圖檔