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An investigation of the physicochemical mechanisms underlying enhanced oral bioavailability following administration of hydrophobic drugs via lipid-based delivery systems.

机译：通过基于脂质的递送系统施用疏水性药物后，口服化学利用度增强的理化机理的研究。

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摘要

The dissolution and solubilization process following oral administration of poorly water-soluble compounds is inherently slow, resulting in incomplete absorption and correspondingly low bioavailability. As a result, lipid-based dispersed systems have beer developed as a means of enhancing the transport rate of hydrophobic compounds. The current dissertation focuses on examining the physicochemical mechanism(s) by which mass transport of poorly water-soluble compounds from lipid-based aggregate systems is modulated. We have hypothesized that the mass flux of steroids across a silastic rubber membrane (model lipophilic membrane) does not correlate directly with thermodynamic activity of the solute in the bulk phase of micelle or microemulsion formulations as is commonly suggested in the literature, but instead mass flux rate correlates with diffusivity of the solute in the lipid-based formulations.; Using a model lipid-based drug delivery system and the poorly water-soluble compounds progesterone and estradiol, it was demonstrated that the Miglyol 812/Brij 97/H2O lipid-based formulations do in fact have the potential to significantly alter mass flux of the poorly water-soluble drugs progesterone and estradiol. Thermodynamic activities of the model drugs in lipid-based delivery systems employed in transport studies were directly measured using the Silicone Polymer Uptake Method, revealing that AT alone cannot fully explain transport of poorly water-soluble compounds from the Miglyol 812Brij 97/H2O model lipid-based system.; Diffusivities of progesterone and estradiol in a variety of microemulsion and micellar formulations were measured using the Pulsed Gradient Spin Echo Nuclear Magnetic Resonance technique. A clear correlation between overall diffusivity of drug in lipid-based formulations and transport rate was observed, suggesting that diffusivity seems to play a role in modulating transport from lipid-based formulations. Taken together, these results would seem to add support to the proposal that microemulsion aggregates enhance mass transport by carrying larger amounts of drug across the aqueous boundary layer adjacent to the membrane, enabling a fast replacement of drug that has permeated the membrane, thus diminishing the effect of the aqueous boundary layer on mass transport.
机译：口服给药水溶性差的化合物后的溶解和增溶过程本质上很慢，导致吸收不完全和相应的低生物利用度。结果，基于脂质的分散系统已开发出啤酒，以提高疏水性化合物的传输速率。本论文的重点是研究理化机理，通过该理化机理，可调节来自脂类聚集体系统的水溶性差的化合物的质量传输。我们已经假设，通过硅橡胶膜（亲脂膜模型）的类固醇的质量通量与胶束或微乳液制剂的本体相中的溶质的热力学活性不直接相关，而通常与质量通量相关。速率与基于脂质的制剂中的溶质的扩散率相关。使用基于脂质的模型药物递送系统和水溶性较差的化合物孕酮和雌二醇，事实证明，基于Miglyol 812 / Brij 97 / H2O脂质的制剂确实有可能显着改变较差药物的质量通量水溶性药物黄体酮和雌二醇。使用硅氧烷聚合物摄取方法直接测量了运输研究中使用的基于脂质的递送系统中模型药物的热力学活性，这表明仅AT不能完全解释Miglyol 812Brij 97 / H2O模型脂质-中水溶性差的化合物的运输。基于系统。使用脉冲梯度自旋回波核磁共振技术测量了各种微乳和胶束配方中孕酮和雌二醇的扩散性。观察到基于脂质的制剂中药物的总体扩散率与转运速率之间存在明显的相关性，这表明扩散性似乎在调节基于脂质的制剂的转运中发挥作用。综上所述，这些结果似乎为微乳液聚集体通过将大量药物跨过邻近膜的水边界层携带更多的药物来增强质量传输的提议提供了支持，从而能够快速更换渗透到膜上的药物，从而减少了水边界层对传质的影响。

著录项

  • 作者

    Land, Laura McCargar.;

  • 作者单位

    University of Kentucky.;

  • 授予单位 University of Kentucky.;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 237 p.
  • 总页数 237
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药剂学;
  • 关键词

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