Dispersion of Nanoparticles in Hydrogels for Ophthalmic Drug Delivery

纳米颗粒在水凝胶中的分散性眼科药物输送目前大约90%的眼科药物制剂被用作滴眼剂1。虽然眼药水很方便，也很容易被患者接受，但由于泪水排出，滴眼液中含有的大部分药物都会丢失。液滴与泪液混合，随后，大约95%的药物流经上小管和下小管。最终，大部分药物被鼻泪管吸收，并进入血流。这可能会导致严重的副作用。例如，用于治疗青光眼的β-阻滞剂替莫洛尔的吸收对心脏有有害影响。此外，局部眼部给药导致泪膜中的药物浓度相对较高，随后迅速下降。这会导致药物输送到角膜的速率急剧变化，从而降低眼科药物的疗效。智力价值：为了减少药物损失，消除全身副作用，提高药物疗效，我们建议开发一次性软性隐形眼镜作为眼科药物输送的新载体。其基本思想是将眼科药物配方封装在纳米颗粒中，并将这些携带药物的颗粒分散在镜片材料中。这项工作的重点是由聚甲基丙烯酸羟乙酯(HEMA)水凝胶制成的软透镜。HEMA镜片的水凝胶基质是在交联剂如乙二醇二甲基丙烯酸酯(EGDMA)5的存在下，通过HEMA单体的本体聚合或溶液聚合合成的。在聚合介质中加入载药粒子，可在水凝胶基质中形成粒子分散。如果将这种材料制成的隐形眼镜放在眼睛上，药物就会从微粒中扩散，并通过晶状体基质，进入角膜和晶状体之间的薄泪膜。这项研究的三个具体目标是：(I)将眼科药物包裹在纳米胶体颗粒中并研究这些颗粒的稳定性，(Ii)在聚合过程中将载药颗粒引入水凝胶基质中，并研究载药凝胶的微观结构和物理性质，以及(Iii)测量颗粒和水凝胶中的药物释放速率并建立模型，以确定控制机制，并最终通过操纵颗粒和/或凝胶的性质来控制水凝胶的释放速率。我们已经成功地制备了两种不同类型颗粒的透明凝胶：微乳滴剂和脂质体。我们还证实，由含有颗粒的凝胶制成的隐形眼镜可以在几天内以治疗率输送眼科药物。提出的未来工作重点是促进颗粒捕获、聚集、分离、药物传输的控制机制和人眼流体力学的基础知识。此外，我们希望增加载药量和改善药物释放曲线，以获得零级递送速率，并开发各种眼科药物的最佳系统。更广泛的影响：由于其巨大的社会影响，药物传递正迅速成为一个非常重要的研究领域。这一领域有可能显著提高生活质量，拯救大量生命，并为许多疾病提供更好的治疗。我们拟议的研究将有助于以有效和受控的方式提供眼科药物，这可能会减少药物浪费，提高依从性，将副作用降至最低，并使现有药物的疗效最大化。通过隐形眼镜给药对青光眼患者非常有用，因为使用β-受体阻滞剂治疗这种疾病对心脏有严重的副作用。此外，由于药物传递的重要性迅速增加，重要的是让学生在职业生涯早期就接触到这一领域的研究。为了实现这一目标，PI建议在传输和界面现象课程中包括凝胶制备和通过凝胶输送药物，并让本科生参与研究。

ABSTRACT - 0426327Dispersion of Nanoparticles in Hydrogels for Ophthalmic Drug Delivery Approximately 90% of all ophthalmic drug formulations are now applied as eye-drops1. While eye-drops are convenient and well accepted by patients, a majority of the drug contained in the drops is lost due to tear drainage. The drops mix with the tear fluid, and subsequently, about 95% of the drug flows through the upper and the lower canaliculi2. Eventually, a major portion of the drug is absorbed in the nasolacrymal duct, and enters the blood stream. This can lead to serious side effects. For instance, absorption of Timolol, a beta-blocker used to treat glaucoma, has harmful effects on the heart3. Furthermore, topical ophthalmic drug delivery results in a relatively high drug concentration in the tear film followed by a rapid decline. This causes sharp variations in the drug delivery rates to the cornea that reduces the efficacy of ophthalmic drugs4. Intellectual Merit: To reduce drug loss, eliminate systemic side effects, and improve drug efficacy, we propose to develop disposable soft contact lenses as a new vehicle for ophthalmic drug delivery. The essential idea is to encapsulate the ophthalmic drug formulations in nanoparticles, and to disperse these drug-laden particles in the lens material. This work focuses on soft lenses made of poly 2-hydroxyethyl methacrylate (HEMA) hydrogel. The hydrogel matrix of HEMA lenses is synthesized by bulk or solution polymerization of HEMA monomers in the presence of a cross linker such as ethylene glycol di-methacrylate (EGDMA)5. Addition of drug-laden particles in the polymerizing medium results in the formation of a particle-dispersion in the hydrogel matrix. If a contact lens made of this material is placed on an eye, the drug diffuses from the particles, and through the lens matrix, and enters the thin tear film trapped between the cornea and the lens. The three specific objectives of the study are, (i) encapsulate ophthalmic drugs in nanosized colloidal particles and study the stability of these particles, (ii) incorporate the drug-laden particles in the hydrogel matrix during the polymerization process, and study the microstructure and the physical properties of the particle-laden gel, and (iii) measure and model the drug release rates from the particles and the hydrogel to determine the controlling mechanism, and eventually control the release rates from the hydrogel by manipulating the particle and/or gel properties. We have successfully fabricated transparent gels loaded with two different types of particles: microemulsion drops and liposomes. We have also established that contact lenses fabricated from the particle laden gels can deliver ophthalmic drugs at therapeutic rates for a few days. The proposed future work focuses on advancing the fundamental knowledge of particle entrapment, aggregation, segregation, controlling mechanisms of drug transport, and fluid mechanics of the human eye. In addition we wish to increase drug loading and improve the drug release profiles to obtain zero order delivery rates, and also develop the optimal systems for various ophthalmic drugs. Broader Impact: Drug delivery is rapidly becoming a very important research area due to its enormous societal impact. This field has the potential to significantly improve the quality of life, save lots of lives, and offer improved treatment for a number of diseases. Our proposed research will help deliver ophthalmic drugs in an efficient and controlled manner that could potentially reduce drug wastage, improve compliance, minimize side effects and maximize the efficacy of currently available drugs. Drug delivery through contact lenses could be very useful for patients suffering from glaucoma because use of beta-blockers to treat this disease has serious side effects on heart. Furthermore due to the rapidly increasing importance of drug delivery, it is important to expose students to this area of research as early in their careers as possible. To achieve this objective, the PI proposes to include gel fabrication and drug delivery through gels in Transport and Interfacial Phenomena classes and involve undergraduate students in the research.