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The oral delivery of hydrophobic drugs - a role for amphiphilic polymers.

机译：疏水药物的口服给药-两亲聚合物的作用。

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摘要

Nine poly(ethylenimine) (PEI) and glycol chitosan based amphiphiles were synthesised with the aim of creating effective carriers for the oral delivery of poorly soluble drugs. The architecture of the amphiphilic molecules was controlled through varying hydrophobic substitution levels, varying molecular weight and using both branched and linear molecules. The molecular weights of the nine amphiphiles ranged from 1.3 kDa -- 22 kDa. Amphiphiles dispersed well in aqueous media and formed positively charged nanoparticles of 100 -- 300 nm in diameter above the critical aggregation concentration (CAC). Glycol chitosan based amphiphiles formed a polydisperse mixture of microparticles and nanoparticles. The CAC ranged from 0.01 mM to 0.4 mM, depending on the chemical structure of amphiphiles. It was observed that the CAC values and aggregate sizes decreased with an increase in the hydrophobicity and molecular weight of amphiphiles. Low molecular weight amphiphiles formed larger aggregates than their higher molecular weight derivatives. In addition, aggregates from linear polymers were also larger than these from the branched counterparts. The viscosity of the polymers increased with an increase in the intermolecular interactions caused by an increase in polymer concentration, number of hydrophobic pendants on the polymer backbones and polymer molecular weight.;Amphiphilic PEIs however demonstrated high levels of cytotoxicity and haemolysis on the epidermoid carcinoma cells and red blood cells, respectively. Meanwhile quaternary palmitoyl glycol chitosan (GCPQ) proved to be less toxic.;The polymers improved drug oral absorption by up to 550% in a rat model compared to drug alone. Drug absorption enhancement was favoured by increasing the polymer concentration (up to a point), hydrophobicity and molecular weight and by reducing polymer aggregate size.;The mechanism of oral absorption enhancement of polycationic amphiphiles was hypothesized to involve: a) an increase in the dissolution rate and/or aqueous solubility of the drug and b) adhesion to absorptive epithelium to promote drug residence time at the gastrointestinal absorption sites.;Amphiphilic polymers encapsulated cyclosporine A, (CsA) a lipophilic Class II drug in the Biopharmaceutical Classification System. The drug loading in polymer dispersions was favoured by an increase in polymer hydrophobicity, molecular weight and concentration and liquid formulations were stable for 6 months. The polymers increased the dissolution rate from CsA tablet formulations after 2 hours.
机译：合成了九种基于聚乙烯基亚胺（PEI）和乙二醇壳聚糖的两亲物，目的是为口服难溶性药物提供有效的载体。通过改变疏水取代水平，改变分子量以及使用支链和直链分子来控制两亲分子的结构。九种两亲物的分子量范围为1.3 kDa至22 kDa。两亲物在水性介质中分散良好，并在临界聚集浓度（CAC）以上形成直径为100-300 nm的带正电的纳米颗粒。基于乙二醇壳聚糖的两亲物形成了微粒和纳米颗粒的多分散混合物。根据两亲物的化学结构，CAC的范围为0.01 mM至0.4 mM。观察到，随着两亲物的疏水性和分子量的增加，CAC值和聚集体尺寸减小。低分子量两亲物比其较高分子量衍生物形成更大的聚集体。另外，来自线性聚合物的聚集体也大于来自分支对应物的聚集体。聚合物的粘度随着聚合物浓度，聚合物主链上疏水性侧基的数量和聚合物分子量的增加而引起的分子间相互作用的增加而增加。然而，两亲性PEI在表皮样癌细胞上表现出高水平的细胞毒性和溶血作用和红细胞。同时，季棕榈酰乙二醇壳聚糖（GCPQ）的毒性更小。与单独使用药物相比，该聚合物在大鼠模型中将药物的口服吸收提高了550％。通过增加聚合物的浓度（达到一个点），疏水性和分子量以及减小聚合物的聚集体大小，有利于提高药物的吸收。假设聚阳离子两亲物的口服吸收增强机制涉及：a）溶出度增加速率和/或药物的水溶性和b）粘附至吸收性上皮以促进药物在胃肠道吸收位点的停留时间;两亲性聚合物将环孢菌素A（CsA）包裹在生物制药分类系统中的亲脂性II类药物上。聚合物疏水性，分子量和浓度的增加有利于聚合物分散体中的药物负载，并且液体制剂可稳定使用6个月。 2小时后，聚合物增加了CsA片剂配方的溶出度。

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  • 作者

    Le, Hang Thi Bich.;

  • 作者单位

    University of London, University College London (United Kingdom).;

  • 授予单位 University of London, University College London (United Kingdom).;
  • 学科 Pharmaceutical sciences.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 271 p.
  • 总页数 271
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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