经皮给药压敏胶及聚合物纳米粒经皮药物传递的研究
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摘要
经皮给药制剂是一较有前景的给药方式,其中作为药物储库兼具压敏粘附作用的压敏胶对经皮给药制剂的作用效果有很大影响。本文针对经皮给药系统新型压敏胶及新型经皮给药技术需求,研制了三类亲水性压敏胶及两种药物纳米载体材料,并对其性能进行了研究。
采用两步法制备了亲水性非离子聚氨酯压敏胶,即由二异氰酸酯与多元醇的混合物进行反应,生成预聚体,再经扩链制备出聚氨酯压敏胶。通过在聚氨酯主链上引入亲水的聚乙二醇嵌段来赋予压敏胶亲水性。通过物理共混的方法制备了PVP/PVA、PVP/聚乳酸两类共混体系亲水性压敏胶。粘附力学性能研究结果表明三类压敏胶均具有良好的粘附性、透气性及抗水性,适于经皮给药系统应用。
采用TGA、DSC及DMA等方法详细分析了亲水性物质组成的共混压敏胶中水的存在状态,结果表明水与压敏胶中其它组分均能发生较强的氢键作用,体系中25%~35%的水可以增强压敏胶氢键网络的强度并保证体系良好的流动变形性,使共混体系表现出压敏胶的性能。以PVP/PDLLA共混体系压敏胶为例,研究了其组分间相互作用及结构特征。紫外光谱、红外光谱、拉伸实验及示差扫描量热法分析表明PVP与低相对分子质量的聚乳酸发生较强的氢键作用且相容性良好。
以疏水性药物布洛芬和亲水性药物水杨酸作为药物模型,进行了大鼠皮体外渗透实验和大鼠活体实验,研究了压敏胶作为药物储库及胶粘层的经皮药物渗透性。大鼠体外及活体实验结果表明亲水性共混体系压敏胶本身具有自促透作用,利于药物的经皮扩散,较传统橡胶膏在药物渗透量上有很大的提高。
本文还合成了聚D,L-乳酸-b-聚乙二醇共聚物(PEDLLA),聚氰基丙烯酸酯-g-聚乙二醇单甲醚共聚物(PEGECA)两种纳米载体材料,分别采用固相熔融分散法制备了负载紫杉醇的PEDLLA纳米粒子(PMT),纳米沉淀法制备出负载延胡索乙素的PEGECA纳米粒子(PEGECAT)。以纳米粒作为供试体系进行了体外经皮扩散渗透研究。利用HPLC,扫描电镜,红外光谱及核磁共振对接受液进行了分析,采用荧光电镜对经皮扩散后皮肤组织结构进行了观察,结果表明两种纳米粒均可以以完整的粒子形态负载药物扩散穿过皮肤,纳米粒的经皮渗透可能是通过了皮肤附属器路径和表皮路经而实现的。这一研究结果为难以经皮渗透的药物的经皮给药提供了新的手段。
Transdermal drug delivery system (TDDS) is a promising therapy instrument and pressure sensitive adhesives (PSA), which act as reservoir and adhesives in this system, may observably influence the curative effect of formulation. In this study, three kinds of hydrophilic pressure sensitive adhesives and two kinds of nanocarrier materials were prepared for technology requirement of TDDS and their properties were investigated.
The two-step method was adopted to prepare non-ionic polyurethane pressure sensitive adhesive (PU PSA). It was synthesized by the condensation copolymerization of polymer glycol, diisocyanate and extender. Polyethylene glycol (PEG), which was introduced on the polyurethane chain, can offer good hydrophilicity to the PSA. By physical mixing methods, two types of hybrid hydrophilic PSA, respectively polyvinyl pyrrolidone/polyvinyl alcohol (PVP/PVA) blend system, PVP/ poly (D,L-lactic acid) (PVP/PDLLA) blend system, were prepared. Mechanical testing results show these kinds of adhesives can provide excellent adhesive strength to skin, good humidity permeation behavior and proper water resistance, which are suit for application in TDDS.
TGA, DSC and DMA were utilized to analyze the states of water in hybrid hydrophilic PSA , and results reveal that a suitable amount of water (20~35wt%) in hybrid PSA system can enhance strength of hydrogen bonding net work and ensure its flowing deformability for its application as pressure sensitive adhesives. Interaction between components and structure character of hybrid PSA were investigated by choosing PVP/PDLLA system as a sample. UV spectrum, FT-IR spectrum, tensile testing and DSC analysis results indicate that strong hydrogen bonding interaction exists between PVP and PDLLA, and these two polymers can form good miscible blends.
The transdermal permeation behaviour of drug from all kinds of PSA matrix was evaluated by using hydrophobic ibuprofen and hydrophilic salicylic acid as model drug. In vitro and in vivo experiment results show that hybrid hydrophilic PSAs facilitate the drug permeating across the rat skin due to their self-enhancing penetration ability, which is more efficient than tradition rubber PSA considering drug permeation amount.
Paclitaxel-loaded methoxy poly(ethylene glycol)-b-poly(D,L-lactic acid) diblock copolymer nanoparticles (PMT) were prepared by solid dispersion technique and D,L-tetrahydropalmatine (THP)-loaded poly{[α-maleic anhydride-ω-methoxy- poly(ethylene glycol)]-co-(ethy cyanoacrylate)} (PEGECA) amphiphilic graft copolymer nanoparticles (PEGECAT NPs) were prepared by the nanoprecipitation technique. The transdermal permeation experiments in vitro were carried out in Franz diffusion cells using drug-loaded nanoparticles as donor system. HPLC, TEM, FT-IR and 1HNMR were used to assay the receptor fluid. The results showed that these two kinds of amphiphilic copolymer nanoparticles with the entrapped drug were able to penetrate the rat skin. Fluorescent microscopy measurements indicate that the nanoparticles can penetrate the skin not only via appendage routes but also via epidermal routes. This nanotechnology may provide transdermal feasibility for the drug which is hard to permeate across skin.
采用两步法制备了亲水性非离子聚氨酯压敏胶,即由二异氰酸酯与多元醇的混合物进行反应,生成预聚体,再经扩链制备出聚氨酯压敏胶。通过在聚氨酯主链上引入亲水的聚乙二醇嵌段来赋予压敏胶亲水性。通过物理共混的方法制备了PVP/PVA、PVP/聚乳酸两类共混体系亲水性压敏胶。粘附力学性能研究结果表明三类压敏胶均具有良好的粘附性、透气性及抗水性,适于经皮给药系统应用。
采用TGA、DSC及DMA等方法详细分析了亲水性物质组成的共混压敏胶中水的存在状态,结果表明水与压敏胶中其它组分均能发生较强的氢键作用,体系中25%~35%的水可以增强压敏胶氢键网络的强度并保证体系良好的流动变形性,使共混体系表现出压敏胶的性能。以PVP/PDLLA共混体系压敏胶为例,研究了其组分间相互作用及结构特征。紫外光谱、红外光谱、拉伸实验及示差扫描量热法分析表明PVP与低相对分子质量的聚乳酸发生较强的氢键作用且相容性良好。
以疏水性药物布洛芬和亲水性药物水杨酸作为药物模型,进行了大鼠皮体外渗透实验和大鼠活体实验,研究了压敏胶作为药物储库及胶粘层的经皮药物渗透性。大鼠体外及活体实验结果表明亲水性共混体系压敏胶本身具有自促透作用,利于药物的经皮扩散,较传统橡胶膏在药物渗透量上有很大的提高。
本文还合成了聚D,L-乳酸-b-聚乙二醇共聚物(PEDLLA),聚氰基丙烯酸酯-g-聚乙二醇单甲醚共聚物(PEGECA)两种纳米载体材料,分别采用固相熔融分散法制备了负载紫杉醇的PEDLLA纳米粒子(PMT),纳米沉淀法制备出负载延胡索乙素的PEGECA纳米粒子(PEGECAT)。以纳米粒作为供试体系进行了体外经皮扩散渗透研究。利用HPLC,扫描电镜,红外光谱及核磁共振对接受液进行了分析,采用荧光电镜对经皮扩散后皮肤组织结构进行了观察,结果表明两种纳米粒均可以以完整的粒子形态负载药物扩散穿过皮肤,纳米粒的经皮渗透可能是通过了皮肤附属器路径和表皮路经而实现的。这一研究结果为难以经皮渗透的药物的经皮给药提供了新的手段。
Transdermal drug delivery system (TDDS) is a promising therapy instrument and pressure sensitive adhesives (PSA), which act as reservoir and adhesives in this system, may observably influence the curative effect of formulation. In this study, three kinds of hydrophilic pressure sensitive adhesives and two kinds of nanocarrier materials were prepared for technology requirement of TDDS and their properties were investigated.
The two-step method was adopted to prepare non-ionic polyurethane pressure sensitive adhesive (PU PSA). It was synthesized by the condensation copolymerization of polymer glycol, diisocyanate and extender. Polyethylene glycol (PEG), which was introduced on the polyurethane chain, can offer good hydrophilicity to the PSA. By physical mixing methods, two types of hybrid hydrophilic PSA, respectively polyvinyl pyrrolidone/polyvinyl alcohol (PVP/PVA) blend system, PVP/ poly (D,L-lactic acid) (PVP/PDLLA) blend system, were prepared. Mechanical testing results show these kinds of adhesives can provide excellent adhesive strength to skin, good humidity permeation behavior and proper water resistance, which are suit for application in TDDS.
TGA, DSC and DMA were utilized to analyze the states of water in hybrid hydrophilic PSA , and results reveal that a suitable amount of water (20~35wt%) in hybrid PSA system can enhance strength of hydrogen bonding net work and ensure its flowing deformability for its application as pressure sensitive adhesives. Interaction between components and structure character of hybrid PSA were investigated by choosing PVP/PDLLA system as a sample. UV spectrum, FT-IR spectrum, tensile testing and DSC analysis results indicate that strong hydrogen bonding interaction exists between PVP and PDLLA, and these two polymers can form good miscible blends.
The transdermal permeation behaviour of drug from all kinds of PSA matrix was evaluated by using hydrophobic ibuprofen and hydrophilic salicylic acid as model drug. In vitro and in vivo experiment results show that hybrid hydrophilic PSAs facilitate the drug permeating across the rat skin due to their self-enhancing penetration ability, which is more efficient than tradition rubber PSA considering drug permeation amount.
Paclitaxel-loaded methoxy poly(ethylene glycol)-b-poly(D,L-lactic acid) diblock copolymer nanoparticles (PMT) were prepared by solid dispersion technique and D,L-tetrahydropalmatine (THP)-loaded poly{[α-maleic anhydride-ω-methoxy- poly(ethylene glycol)]-co-(ethy cyanoacrylate)} (PEGECA) amphiphilic graft copolymer nanoparticles (PEGECAT NPs) were prepared by the nanoprecipitation technique. The transdermal permeation experiments in vitro were carried out in Franz diffusion cells using drug-loaded nanoparticles as donor system. HPLC, TEM, FT-IR and 1HNMR were used to assay the receptor fluid. The results showed that these two kinds of amphiphilic copolymer nanoparticles with the entrapped drug were able to penetrate the rat skin. Fluorescent microscopy measurements indicate that the nanoparticles can penetrate the skin not only via appendage routes but also via epidermal routes. This nanotechnology may provide transdermal feasibility for the drug which is hard to permeate across skin.
引文
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