Porous Silicon Particles for Oral Drug Delivery

描述(由申请人提供)： 口服给药仍然是给药的首选途径。然而，目前正在开发的治疗性大分子药物存在口服生物利用度低的问题。与传统的药物输送策略相比，微制造技术可能提供潜在的优势。这项技术与适当的表面化学相结合，可以实现药物和渗透促进剂的高度本地化输送。在这项提案中，我们研究了微制造策略，以创建包含储存库的微设备，以及可用于将粘附剂或细胞粘附剂结合到这些平台上的表面化学协议。这项建议的长期目标是开发一种生物医学微系统，通过创建一种强大的有机/无机混合给药系统，将药理活性大分子口服给药到全身循环中。预计拟议的药物输送系统将能够在腔-肠细胞界面实现定向释放，从而提高局部浓度。我们提出的研究的中心假设是，通过增加上皮停留时间和局部浓度，低渗透性药物的渗透潜力显著增强。我们提出了以下具体目标： 1.将生物黏附配体不对称偶联到微器件上 2.确定载药微系统的体外释药机制 3.将生物黏附微装置的渗透促进作用与既定的口服给药标准进行比较 4.在体内测试微型设备输送治疗相关剂量药物的能力。 我们希望发现，由于我们能够在主体材料、形状、大小和表面化学方面控制设备架构，微设备可以表现出更好的生物兼容性和生物粘附性。这可能允许以更可控和更有针对性的方式将多种治疗性大分子输送到胃肠道。

DESCRIPTION (provided by applicant): Oral delivery remains the preferred route for drug administration. However, therapeutic macromolecular drugs currently under development suffer from poor oral bioavailability. Microfabrication technology may offer potential advantages over conventional drug delivery stratagems. This technology, combined with appropriate surface chemistry, can permit highly localized delivery of drugs and permeation enhancers. In this proposal, we investigate microfabrication strategies to create reservoir-containing microdevices and a surface chemistry protocol that can be used to bind muco- or cytoadhesives to these platforms. The long-term objective of this proposal is to develop a biomedical microsystem for oral delivery of pharmacologically active macromolecules into the systemic circulation via the creation of a robust hybrid organic/inorganic delivery system. It is expected that the proposed drug delivery system will enable directional release at the lumen-enterocyte interface resulting in elevated local concentrations. The central hypothesis to our proposed research is that the penetration potential of poorly permeable drugs is significantly enhanced by increasing both the epithelial residence time and local concentration. We propose the following specific aims: 1. To asymmetrically conjugate bioadhesive ligands to microdevices 2. To determine the in vitro release mechanism of drug-loaded microsystems 3. To compare the permeation enhancement effects of bioadhesive microdevices against established oral drug delivery standards 4. Test microdevices in vivo for their ability to deliver therapeutically relevant amounts of drug. We expect to find that microdevices can exhibit enhanced biocompatibility and bioadhesion due to our ability to control device architecture in terms of bulk material, shape, size, and surface chemistry. This may allow for the delivery of multiple therapeutic macromolecules in a more controlled and targeted manner to the GI tract.