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Devices and mechanisms for ophthalmic drug delivery.

机译：眼科药物输送的装置和机构。

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摘要

Currently millions of people in the United States suffer from eye ailments such as glaucoma, infections, cataract, macular degeneration, dry eyes etc. and the number is likely to increase due to the continuous increase in the mean age in the country. Most current ophthalmic drugs are delivered through eye drops, which are relatively inefficient due to rapid clearance from the ocular surface. Improvements in ophthalmic drug delivery require a thorough understanding of various transport mechanisms in the eyes so that optimal delivery vehicles and devices could be developed. This thesis focuses on understanding and modeling various transport processes in the eyes to predict the effectiveness of various drug delivery approaches. The thesis also focuses on development of novel devices for drug delivery, and modeling release from the devices in vitro and predicting the release behavior in vivo.;Ophthalmic drugs that are instilled via eye drops get cleared through tear drainage from eyes to the nose, and through transport across various ocular epithelia. We focused on understanding each of these pathways individually, and then combining these into a comprehensive model that can be used to predict the bioavailability of drugs delivered through eye drops or through any other device. While permeability values are reported in literature for transport of drugs across cornea and conjunctiva, these are based on assumptions of pseudo-steady state which are likely not accurate. To understand the detailed transport mechanisms in the eyes, we exposed an excised rabbit cornea to fluorescent drug analogs and measured the time and position dependent fluorescence through a confocal microscope. The profiles were than fitted to mechanistic multiscale diffusion-binding models to obtain various transport parameters. These studies were conducted for a hydrophobic molecule Rhodamine B and a hydrophilic molecule fluorescein. In future, similar studies will be conducted to obtain the detailed models for various ophthalmic drugs. Based on our models and previous existing tear drainage models, we demonstrate that the bioavailability increases when drugs are delivered through extended release devices rather than through eye drops. We thus also focused on developing some extended release devices for ocular applications particularly for treatment of dry eyes. We developed conjunctival inserts and puncta plugs that can deliver dry eye drug cyclosporine A for about 3 months at therapeutic doses. These devices will likely increase bioavailability and also improve patient compliance. These devices were prepared by thermal polymerization in presence of drug at high loadings to create inserts and plugs containing particles of drug dispersed in the matrix. The drug release rates were measured to explore the effect of length, drug loading, crosslinking, and mixing in the release medium. Mathematical models were developed and simulated to understand the mechanism of transport of drug molecules inside these polymeric devices. A model combining tear drainage and tear balance is used to predict that our plugs can deliver similar amount of drug as RestasisRTM eye drops, the only approved medication for dry eyes.;The results from this thesis will hopefully lead to a better understanding of various transport mechanisms in eyes, and to development of better drug delivery vehicles. While the main focus of this work is in ophthalmology, the mechanisms for transport across epithelia and also from drug delivery devices may find applications in other areas of biomedical engineering.
机译：目前，在美国有数以百万计的人患有诸如青光眼，感染，白内障，黄斑变性，干眼等眼疾，并且由于该国平均年龄的持续增长，这一数字很可能会增加。当前大多数眼科药物是通过滴眼剂递送的，由于从眼表快速清除，滴眼剂的效率相对较低。眼科药物输送的改进要求透彻理解眼睛中的各种输送机制，以便可以开发出最佳的输送工具和装置。本文着眼于理解和建模眼中的各种转运过程，以预测各种药物输送方法的有效性。本文的重点还在于开发新型药物输送装置，并模拟体外装置的释放并预测体内的释放行为。通过滴眼液滴入的眼科药物通过从眼部到鼻子的泪液引流得以清除，以及通过各种眼上皮运输。我们专注于分别理解这些途径中的每一个，然后将它们组合成一个综合模型，该模型可用于预测通过滴眼剂或任何其他设备递送的药物的生物利用度。尽管文献中报道了渗透率值用于药物穿过角膜和结膜的运输，但这些渗透率值是基于假稳态的假设，这些假设可能不准确。为了了解眼睛中详细的转运机制，我们将切下的兔角膜暴露于荧光药物类似物，并通过共聚焦显微镜测量了时间和位置依赖性荧光。然后将轮廓拟合到机械多尺度扩散-结合模型以获得各种运输参数。对疏水分子若丹明B和亲水分子荧光素进行了这些研究。将来，将进行类似的研究以获得各种眼科药物的详细模型。根据我们的模型和以前的现有泪液引流模型，我们证明了通过延长释放装置而不是通过眼药水输送药物时，生物利用度增加。因此，我们还专注于开发一些眼用的缓释装置，特别是用于治疗干眼症。我们开发了结膜插入物和泪点塞，可以在治疗剂量下将干眼药环孢菌素A递送约3个月。这些设备将可能提高生物利用度，并改善患者依从性。这些装置是通过在药物高负荷存在下进行热聚合而制备的，以产生包含分散在基质中的药物颗粒的插入物和塞子。测量药物释放速率以探索长度，药物载量，交联和在释放介质中混合的影响。开发并模拟了数学模型，以了解药物分子在这些聚合物装置内的传输机理。结合泪液引流和泪液平衡的模型可以预测我们的栓塞可以提供与RestasisRTM滴眼液相似的药物量，RestasisRTM滴眼液是唯一一种被批准用于干眼的药物。该论文的结果有望使人们更好地理解各种转运机制，以及开发更好的药物输送工具。尽管这项工作的主要重点是眼科，但跨上皮以及从药物输送装置转运的机制可能会在生物医学工程的其他领域中找到应用。

著录项

  • 作者

    Gupta, Chhavi.;

  • 作者单位

    University of Florida.;

  • 授予单位 University of Florida.;
  • 学科 Health Sciences Pharmacology.;Engineering Chemical.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 147 p.
  • 总页数 147
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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