经皮给药压敏胶和水凝胶材料的制备与性能
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摘要
经皮给药具有诸多优点,是现代给药制剂一大发展方向,但目前我国经皮给药制剂所用辅料严重缺乏,极大限制了该剂型的发展,本论文对适于皮肤用的亲水性非离子聚氨酯压敏胶及两类聚乙烯醇(PVA)凝胶基质进行了研究,期望制得新型经皮给药制剂的适宜基质。
非离子聚氨酯压敏胶是由二异氰酸酯与多元醇的混合物进行反应,生成预聚体,再经扩链制得。论文考察了异氰酸酯的种类、反应温度、时间及原料配比等因素的影响,确定了工艺稳定、产品性能优良的亲水性聚氨酯压敏胶的配方及制备工艺。采用斜坡滚球停止法、180°剥离、持粘力测试等方法对一些影响压敏胶力学性能的因素进行了考察。采用Franz扩散池对载药压敏胶贴剂的经皮药物释放行为进行了体外考察。结果表明,该聚氨酯压敏胶贴剂具有良好的力学性能及药物控释能力,适用于经皮给药系统。
本论文分别采用硼砂和正硅酸乙酯为交联剂,制备出了Ⅰ型和Ⅱ型PVA凝胶。考察了两类凝胶的力学性能与溶胀性能和各影响因素;对两类凝胶进行了透皮释放实验,研究了它们与药物的相容性及经皮给药性能。结果表明,Ⅱ型PVA凝胶在力学性能(如强度、韧性等方面)和溶胀性能上优于Ⅰ型PVA凝胶,其药物释放速率略低于Ⅰ型PVA凝胶。
Transdermal drug delivery system (TDDs) has received much attention in drug release because of several advantages. The serious lack of polymer materials used in TDDs is a big bottle-neck problem embarrassing the development of TDDs. In this paper the skin compatible hydrophilic polyurethane pressure sensitive adhesives (PSAs) and two types of polyvinyl alcohol (PVA) hydrogel were studied in order to developed new materials for TDDs.
The hydrophilic polyurethane PSAs were synthesized by polyaddition of polymer glycol, diisocyanate and extender. The effects, such as the kinds of the diisocyanates, the temperature, the reaction time and the ratios of the materials on the productions, were studied carefully in this work. The methods of rolling boll at a slope, peeling at 180°angle and cohesion test were used to evaluate the mechanical properties of PSAs. The transdermal drug delivery properties of the prepared PSAs were evaluated invitro by Franze diffuse method. The study results indicated that the hydrophilic polyurethane PSAs prepared in this paper show good mechanical and drug delivery properties, which suit for the TDDs application.
Two types of PVA hydrogels, PVA-Ⅰand PVA-Ⅱ, were prepared by using borax and tetraethoxysilanes (TEOS) as crosslinkers. The mechanics and swelling behavior of the two gels, as well as their influence factors, were investigated. The transdermal release experiments were also performed in order to evaluate the drug compatibility and control drug release problem. The study results show that PVA-Ⅱhydrogel presents better performance in mechanics and swelling properties than PVA-Ⅰ, while PVA-Ⅰshows lightly higher drug release rate.
非离子聚氨酯压敏胶是由二异氰酸酯与多元醇的混合物进行反应,生成预聚体,再经扩链制得。论文考察了异氰酸酯的种类、反应温度、时间及原料配比等因素的影响,确定了工艺稳定、产品性能优良的亲水性聚氨酯压敏胶的配方及制备工艺。采用斜坡滚球停止法、180°剥离、持粘力测试等方法对一些影响压敏胶力学性能的因素进行了考察。采用Franz扩散池对载药压敏胶贴剂的经皮药物释放行为进行了体外考察。结果表明,该聚氨酯压敏胶贴剂具有良好的力学性能及药物控释能力,适用于经皮给药系统。
本论文分别采用硼砂和正硅酸乙酯为交联剂,制备出了Ⅰ型和Ⅱ型PVA凝胶。考察了两类凝胶的力学性能与溶胀性能和各影响因素;对两类凝胶进行了透皮释放实验,研究了它们与药物的相容性及经皮给药性能。结果表明,Ⅱ型PVA凝胶在力学性能(如强度、韧性等方面)和溶胀性能上优于Ⅰ型PVA凝胶,其药物释放速率略低于Ⅰ型PVA凝胶。
Transdermal drug delivery system (TDDs) has received much attention in drug release because of several advantages. The serious lack of polymer materials used in TDDs is a big bottle-neck problem embarrassing the development of TDDs. In this paper the skin compatible hydrophilic polyurethane pressure sensitive adhesives (PSAs) and two types of polyvinyl alcohol (PVA) hydrogel were studied in order to developed new materials for TDDs.
The hydrophilic polyurethane PSAs were synthesized by polyaddition of polymer glycol, diisocyanate and extender. The effects, such as the kinds of the diisocyanates, the temperature, the reaction time and the ratios of the materials on the productions, were studied carefully in this work. The methods of rolling boll at a slope, peeling at 180°angle and cohesion test were used to evaluate the mechanical properties of PSAs. The transdermal drug delivery properties of the prepared PSAs were evaluated invitro by Franze diffuse method. The study results indicated that the hydrophilic polyurethane PSAs prepared in this paper show good mechanical and drug delivery properties, which suit for the TDDs application.
Two types of PVA hydrogels, PVA-Ⅰand PVA-Ⅱ, were prepared by using borax and tetraethoxysilanes (TEOS) as crosslinkers. The mechanics and swelling behavior of the two gels, as well as their influence factors, were investigated. The transdermal release experiments were also performed in order to evaluate the drug compatibility and control drug release problem. The study results show that PVA-Ⅱhydrogel presents better performance in mechanics and swelling properties than PVA-Ⅰ, while PVA-Ⅰshows lightly higher drug release rate.
引文
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[6] 赵兴红,王翔,邓虹珠.心脉通贴剂中冰片的透皮吸收实验研究.Chinese Journal of Medical Research and Application,2004,2(2):36-37
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[19] Qinglin S, Qiang G, Shuqing Z, et al.Study on the composition design of the water emulsion acrylates pressure-sensitive adhesive, Chemical Engineering, 1996 24(2):65~67
[20] Trenor S R, Suggs A E, J, L. B., Influence of penetration enhancers on the thermomechanical properties and peel strength of a poly(isobutylene) pressure sensitive adhesive, Journal of Materials Science Letters, 2002, 12, (17), 1321-1323
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[28] Chiriac A P, The improvement of adhesive character of an acrylovinylic macromolecular compound, Polymer Testing, 2001, 20, 873-877
[29] Yamamoto M, Nakano F, Doi T.Synthesis and PSA performance study for novel acrylic and butyl acrylate block copolymers, International Journal of Adhesion & Adhesives, 2002, 22, 37-40
[30] M.M. Feldstein, G.A. Shandryuk, S.A. Kuptsov, N.A. Plate.Coherence of thermal transitions in poly(N-vinyl pyrrolidone)-poly(ethylene glycol) compatible blends 1. Interrelations among the temperatures of melting, maximum cold crystallization rate and glass transition, Polymer 2000, 41, 5327–5338
[31] Shult KA, DR, P., Water sorption and transport in blends of poly(vinyl pyrrolidone) and polysulfone, J Polym Sci Polym Phys, 1997, 35, (4), 655-674
[32] Jain G K, Sharma A K, S, A. S., Transdermal controlled administration of verapamil-enhancement of skin permeability, Inter J of Pharmaceutics, 1996, 130, (2), 169-177
[33] Tsunemine N, Tanaka Y, Banba A, Water-dispersion type pressure-sensitive adhesive composition, method of production thereof, and pressure-sensitive adhesive product employing the same, US 6121355, 2000-09-19
[34] Backer T E,Proc Int’1 Symp Control Release Bioact Mater, 1998, 25:571~572
[35] 吉井文男等, 有粘性的 PVA 水凝胶的制备方法, JP9263671,1997-10-07
[36] Mirzan T.Razzak, Irradiation of polyvinyl alcohol and polyvinyl pyrrolidone blended hydrogel for wound dressing, Radiation Physics and Chemistry, 2001, 62, 107~133
[37] Hans-Heribert B, Dietmar S, Gel pads and a process for their preparation, US4456642,1984-07-26
[38] Francis E G, Christian W J, George E S, Thermally reversible polyurethane hydrogels and cosmetic, biological and medical uses, US5000955,1991-03-19
[39] 梁晓丽.经皮给药制剂简述.首都医药,2005,12:38-40
[40] British.Pharmacopoeia.1993
[41] United States Pharmac0poeia.XXⅣ,1999,2346
[42] Xun C.Survey of studies on gel preparation.The Taiwan Medical News,2000,2723:3-5
[43] 方和桂.适用于中药外用的剂型——凝胶剂.药学专论,2002,11(8): 25-26
[44] 杨万兴. 中药缓控释制剂的研究进展.中华实用医学,2004,25(3): 94-95
[45] 王明坤,方晓玲.泊洛沙姆在药剂学中的应用.中国医药工业杂志,2002,33(12):621-625
[46] 林亚平,周静,朱新宇.聚乙烯醇凝胶及其中药透皮给药系统的初步研究.中国中药杂志,1997,22(2):93-96
[47] 秦东梅,王恒,李海瑛.羟丙甲基纤维素在药剂学中的应用.安徽医药,2004,8(3):173-175
[48] 王康,何志敏. 海藻酸钠与钙或锌离子凝胶动力学过程研究.离子交换与吸附, 2004,20(5): 424-429
[49] Finnin B.C.,Morgan T.M..Active ingredients in sunscreens act as topical penetration enhancers for the herbicide 2,4-dichlorophenoxyacetic acid.Toxicology and Applied Pharmacology,2004,195: 348–354
[50] 冯怡,谢树华,史志英,徐莲英.不同基质小儿哮喘直肠凝胶剂的释放度比.中成药,2000,22(7):461-464
[51] 姜洪芳,汪国华.单皮酚复乳型凝胶的制备.中成药,2001,23(3): 173-176
[52] L.Kanga,X.Y. Liub,P.D.Sawantb,et al.SMGA gels for the skin permeation of haloperidol.Journal of Controlled Release,2005,106:88-98
[53] 夏洪德.双黄冰凝胶剂的制备.中国医药学杂志,1999,19(12):755
[54] 韩颂军,杨荣杰.聚乙烯醇(PVA)水凝胶研究进展.材料导报,1997,11(2):43-45
[55] 杨眉,褚良银,曲剑波等.水凝胶在药物控释及pH感应型给药系统中的应用.中国新医药,2004,3(10):61-63
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[2] 元英进,刘明言,董岸杰.中药现代化生产关键技术,北京:化学工业出版社,2002,227-232
[3] B.W.Barry. Novel mechanisms and devices to enable successful transdermal drug delivery, European Journal of Pharmaceutical Sciences, 2001, 14:101–114
[4] 李凤龙,崔东浩,朱彩风等.Enhancing effects of lepaloine on percutaneous absorption on isoniazid and fluocinonine in rats. 北京:第三届世界传统药物大会, 1994, 9-13
[5] 赵洪武,林宁,谵章和等.氮酮增强如意金黄散黑膏药透皮吸收的实验研究.中草药,1998,23(10):525-527
[6] 赵兴红,王翔,邓虹珠.心脉通贴剂中冰片的透皮吸收实验研究.Chinese Journal of Medical Research and Application,2004,2(2):36-37
[7] R.J.Babu,J.K.Pandit.Effect of penetration enhancers on the release and skin permeation of bupranolol from reservoir-type transdermal delivery systems.International journal of pharmaceutics,2005,288:325-334
[8] 戚国荣,杨云松,杨士林等.氯硝柳胺透皮控释给药的研究.应用化学,1997,14(8):25-28
[9] 赵义军,穆玉荣.经皮给药系统类型及生物学概况.山东医药工业,1994,13(2):30-33
[10] Beverley J.Thomas,Barrie C.Finnin.The transdermal revolution.Drug Discovery Today,2004,9(16):697-703
[11] 张一甫,谭淑珍.溶剂型三元共聚丙烯酸酯压敏胶黏剂的合成研究.化学与粘合,2002,128,(3),115-116
[12] 杨性坤,栗印环.改性聚丙烯酸酯压敏胶的研制.化学与粘合, 2002, 59, (2), 63-64
[13] Arrowsmith DJ, Trans Inst Met Finsh, 1970, 48:88~97
[14] Packham DE, Adhesive aspects of polymeric coating, New York, Plenum Press, 1983
[15] 陈子达,李玲,邹翰.医用胶黏剂的研究进展,化学与粘合,2001,1:21～28
[16] 梁秉文.经皮给药制剂,北京:中国医药科技出版社.1992,223～226
[17] Temin S C, In:Skeist I.Handbook of Adhesives,New York, NY NSA: Marcel Dekker,1990:133～135
[18] Babiuk S, Cutaneous vaccination: the skin as an immunologically active tissue and challenge of antigen delivery, J Control Rel, 2000, 66, (2-3), 199
[19] Qinglin S, Qiang G, Shuqing Z, et al.Study on the composition design of the water emulsion acrylates pressure-sensitive adhesive, Chemical Engineering, 1996 24(2):65~67
[20] Trenor S R, Suggs A E, J, L. B., Influence of penetration enhancers on the thermomechanical properties and peel strength of a poly(isobutylene) pressure sensitive adhesive, Journal of Materials Science Letters, 2002, 12, (17), 1321-1323
[21] Christensen S F, H, M. G., Rheological modeling of the peeling of pressure-sensitive adhesives and other elastomers, International Journal of Adhesion & Adhesives, 1998, 18, 333-343
[22] Kinning D J, Bulk.Surface and interfacial characterization of silicone-polyurea segmented copolymers, Journal of Adhesion, 2001, 75, (1), 1-26
[23] Gordon G V, Schmidt R.G.PSA release force profiles from silicone liners: probing viscoelastic contributions from release system components, Journal of Adhesion, 2000, 72, (2), 133-156
[24] 黄月文, 有机硅胶黏剂, 化学与粘合, 2001, (1), 25-28
[25] Bunker S, C, S.Miniemulsion polymerization of acrylated methyl oleate for pressure sensitive adhesives, International Journal of Adhesion & Adhesives, 2003, 23, 29-38
[26] 张一甫,谭淑珍.溶剂型三元共聚丙烯酸酯压敏胶黏剂的合成研究, 化学与粘合, 2002, 128, (3), 115-116
[27] Ozawa T, Ishiwata S, Y, K..Acrylate copolymer/ultraviolet curable oligomer blends as pressure-sensitive adhesives, Journal of Adhesion, 2000, 72, (1), 1-16
[28] Chiriac A P, The improvement of adhesive character of an acrylovinylic macromolecular compound, Polymer Testing, 2001, 20, 873-877
[29] Yamamoto M, Nakano F, Doi T.Synthesis and PSA performance study for novel acrylic and butyl acrylate block copolymers, International Journal of Adhesion & Adhesives, 2002, 22, 37-40
[30] M.M. Feldstein, G.A. Shandryuk, S.A. Kuptsov, N.A. Plate.Coherence of thermal transitions in poly(N-vinyl pyrrolidone)-poly(ethylene glycol) compatible blends 1. Interrelations among the temperatures of melting, maximum cold crystallization rate and glass transition, Polymer 2000, 41, 5327–5338
[31] Shult KA, DR, P., Water sorption and transport in blends of poly(vinyl pyrrolidone) and polysulfone, J Polym Sci Polym Phys, 1997, 35, (4), 655-674
[32] Jain G K, Sharma A K, S, A. S., Transdermal controlled administration of verapamil-enhancement of skin permeability, Inter J of Pharmaceutics, 1996, 130, (2), 169-177
[33] Tsunemine N, Tanaka Y, Banba A, Water-dispersion type pressure-sensitive adhesive composition, method of production thereof, and pressure-sensitive adhesive product employing the same, US 6121355, 2000-09-19
[34] Backer T E,Proc Int’1 Symp Control Release Bioact Mater, 1998, 25:571~572
[35] 吉井文男等, 有粘性的 PVA 水凝胶的制备方法, JP9263671,1997-10-07
[36] Mirzan T.Razzak, Irradiation of polyvinyl alcohol and polyvinyl pyrrolidone blended hydrogel for wound dressing, Radiation Physics and Chemistry, 2001, 62, 107~133
[37] Hans-Heribert B, Dietmar S, Gel pads and a process for their preparation, US4456642,1984-07-26
[38] Francis E G, Christian W J, George E S, Thermally reversible polyurethane hydrogels and cosmetic, biological and medical uses, US5000955,1991-03-19
[39] 梁晓丽.经皮给药制剂简述.首都医药,2005,12:38-40
[40] British.Pharmacopoeia.1993
[41] United States Pharmac0poeia.XXⅣ,1999,2346
[42] Xun C.Survey of studies on gel preparation.The Taiwan Medical News,2000,2723:3-5
[43] 方和桂.适用于中药外用的剂型——凝胶剂.药学专论,2002,11(8): 25-26
[44] 杨万兴. 中药缓控释制剂的研究进展.中华实用医学,2004,25(3): 94-95
[45] 王明坤,方晓玲.泊洛沙姆在药剂学中的应用.中国医药工业杂志,2002,33(12):621-625
[46] 林亚平,周静,朱新宇.聚乙烯醇凝胶及其中药透皮给药系统的初步研究.中国中药杂志,1997,22(2):93-96
[47] 秦东梅,王恒,李海瑛.羟丙甲基纤维素在药剂学中的应用.安徽医药,2004,8(3):173-175
[48] 王康,何志敏. 海藻酸钠与钙或锌离子凝胶动力学过程研究.离子交换与吸附, 2004,20(5): 424-429
[49] Finnin B.C.,Morgan T.M..Active ingredients in sunscreens act as topical penetration enhancers for the herbicide 2,4-dichlorophenoxyacetic acid.Toxicology and Applied Pharmacology,2004,195: 348–354
[50] 冯怡,谢树华,史志英,徐莲英.不同基质小儿哮喘直肠凝胶剂的释放度比.中成药,2000,22(7):461-464
[51] 姜洪芳,汪国华.单皮酚复乳型凝胶的制备.中成药,2001,23(3): 173-176
[52] L.Kanga,X.Y. Liub,P.D.Sawantb,et al.SMGA gels for the skin permeation of haloperidol.Journal of Controlled Release,2005,106:88-98
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