Strategies to achieve sustained medication delivery in glaucoma treatment

 描述(申请人提供)：可以预防青光眼导致的视力丧失和失明。降低眼压(IOP)的药物可防止青光眼的发病和青光眼进展为一种虚弱的、威胁视力的疾病。然而，降低眼压的有效性受到局部副作用和毒性、患者依从性差、生物利用度差和全身副作用的阻碍。只有40%的患者开出了第一张处方。即使在理想的条件下，滴眼液的监测依从性也不到75%[1]。鉴于这些局限性，青光眼患者的视力状况持续恶化到不可接受的程度也就不足为奇了。通过更好的药物输送，青光眼的治疗可以得到极大的改善，特别是通过在医生就诊时将药剂放在眼睛上来将患者从等式中移除的方法。我计划进行为期多年的临床科学家培训，重点是改善青光眼治疗的药物输送系统。这次培训将由一个由经验丰富的科学家组成的导师小组进行，每个人都带来了我培训的关键领域的专业知识。同意指导我的高级调查人员小组已经在NEI-NIH赞助的多项研究拨款上进行了富有成效的合作。哈里·奎格利博士是Wilmer K12项目的首席研究员，在动物青光眼模型方面拥有40年的经验。我的第二位主要导师将是贾斯汀·哈内斯博士，他是威尔默/霍普金斯大学纳米医学中心的负责人，已经生产出使用可生物降解的聚合物微粒治疗青光眼的眼部给药系统[2]。使用这些缓释制剂，一次剂量的降眼压药物或神经保护剂可以产生持续几个月的效果，同时克服副作用、毒性、粘连失败和生物利用度不足。在我目前在Wilmer的青光眼临床研究员年期间，我已经开始与Harry Quigley博士和Justin Hanes博士一起进行试点研究培训。此外，我将受益于其他3名调查人员，他们同意在我的项目的重要方面提供具体的指导培训。亨利·埃德尔豪泽博士(埃默里大学)是眼部药物输送方面的世界级专家。他已同意就药物渗透方法提供专家指导。傅杰博士是威尔默/霍普金斯大学纳米医学中心的成员，他是受控药物配方方面的专家。她将提供她的配方技巧和培训，让我开发这些配方。Dana Ferraris博士是一名药物化学家，她同意在这个项目中为我提供建议。虽然我们打算开发多种降眼压药物用于缓释，但我们选择了多唑胺的缓释作为我的培训的初始研究领域，因为它说明了研究问题的几个重要方面，并具有很高的实际应用概率。多唑胺作为一种局部碳酸酐酶抑制剂可以降低眼压，但在滴剂形式下，由于需要每天服用两到三次，其疗效受到毒性和便秘患者依从性的限制。我们假设，这些限制可以通过配制多唑胺注射到结膜下或眼内，在缓释系统中被克服。在目标1中，我们将生产和表征可生物降解的聚合物微粒，用于多唑胺在眼睛中的持续释放。一旦优化了多唑胺的缓释条件，就会有更多的降眼压药物用于控制释放。在活体实验之前，将使用兔和人的巩膜进行体外试验，以评估这些制剂经巩膜给药的效果。在目标2中，我们将评估多唑胺微粒制剂在兔和啮齿动物眼睛中的药代动力学、降低眼压和保护视网膜神经节细胞(RGC)。我们还将测试在注射我们的新控制释放配方与现有的由Hanes与Quigley和Zack(2)合作开发的现有控制释放神经保护配方后的RGC保护效果。我计划作为一名大学临床科学家的职业生涯，在治疗青光眼的新疗法方面为患者提供主要的临床和实验室研究。培养开展竞争性研究所需的技能和知识。我提出了这个多年的研究计划，由在创造控释制剂、靶向给药和青光眼动物模型方面拥有专业知识的教师参与。

 DESCRIPTION (provided by applicant): Vision loss and blindness from glaucoma can be prevented. Medications that lower intraocular pressure (IOP) prevent the onset of glaucoma and glaucoma's progression to a debilitating, vision threatening disease. The effectiveness of IOP lowering drops, however, is hindered by topical side effects and toxicity, poor patient adherence, poor bioavailability, and systemic side effects. Only 40% of patients fill the first prescription tey are given. Monitored adherence with eyedrops is less than 75% even under ideal conditions [1]. Given these limitations, it is not surprising that continued worsening of vision status among glaucoma patients continues to an unacceptable degree. Glaucoma treatment could be greatly improved by better drug delivery, specifically an approach that removes the patient from the equation by placing the agent on the eye at the time of doctor visits. I plan a multi-year period of clinical-scientist training focused on improved drug delivery systems for glaucoma therapy. This training will be carried out with a mentor group of experienced scientists, each bringing expertise in vital areas of my training. The group of senior investigators who have agreed to mentor me already works productively together on multiple NEI---NIH sponsored research grants. Dr. Harry Quigley is principal investigator for the Wilmer K12 program and has 40 years of experience in glaucoma models in animals. My second principal mentor will be Dr. Justin Hanes, who heads the Center for Nanomedicine at Wilmer/Hopkins and has already produced ocular drug delivery systems using biodegradable polymer microparticles for treatment of glaucoma [2]. Using these sustained release formulations, a single dosage of an IOP lowering medication or neuroprotective agent could have an effect that lasts for several months, while overcoming side---effects, toxicity, adherence failure, and inadequate bioavailability. During my present clinical fellowship year at Wilmer in Glaucoma, I have begun pilot research training with Drs. Harry Quigley with Dr. Justin Hanes. In addition, I will benefit from inclusion of 3 other investigators who have agreed to provide specific mentored training in important aspects of my program. Henry Edelhauser, PhD., (Emory University) is a world---expert in drug delivery to the eye. He has agreed to provide expert guidance on drug penetration methodologies. Jie Fu, PhD., is a member of the Center for Nanomedicine at Wilmer/Hopkins, who is expert in controlled drug formulation. She will provide both her formulation skills and training for me to develop these formulations. Dana Ferraris, PhD is a medicinal chemist, who has agreed to advise me in this program. Although we intend to formulate multiple IOP lowering medications for sustained release, we have chosen the sustained release of dorzolamide as an initial research area for my training, as it illustrates several important aspects of the research problem and has a high probability of practical application. Dorzolamide lowers IOP through action as a topical carbonic anhydrase inhibitor but, in drop form, its efficacy is limited by toxicity and poo patient adherence due to the need for dosing two or three times daily. We hypothesize that these limitations can be overcome by formulating dorzolamide for injection under the conjunctiva or into the eye, in a sustained release delivery system. In Aim 1, we will generate and characterize biodegradable, polymer microparticles for sustained release of dorzolamide to the eye. Once conditions are optimized for sustained release of dorzolamide, additional IOP lowering medications will be formulated for controlled release. Prior to in vivo experiments ex vivo assays using rabbit and human sclera will be performed to evaluate trans---scleral delivery of medication by these formulations. In Aim 2, we will evaluate pharmacokinetics, IOP lowering, and retinal ganglion cell (RGC) protection by dorzolamide microparticle formulations in rabbit and rodent eyes. We will also test efficacy in RGC protection upon injection of a combination of our new controlled release formulation with an existing controlled release neuroprotection formulation recently developed by Hanes in collaboration with Quigley and Zack (2). I plan a career as a university-based clinician scientist, providing patient care with a major effort in clinical and laboratory research in novel therapeutic approaches to treating glaucoma. To develop the necessary skills and knowledge to conduct competitive research. I propose this multi-year research program with faculty who has expertise in creating controlled release formulations, targeted drug delivery, and animal models of glaucoma.