Strategies to achieve sustained medication delivery in glaucoma treatment

青光眼治疗中实现持续药物输送的策略

• 批准号: 8973554
• 负责人: Ian Franz Pitha
• 金额: $ 15.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8973554
• 关键词: Acetic Acids; Acids; Adherence; Adverse effects; Animal Model; Animals; Appearance; Area; Biological Assay; Biological Availability; Blindness; Carbonic Anhydrase Inhibitors; Chemicals; Clinical; Clinical Research; Collaborations; Complex; Cosmetics; Cytoprotection; Development; Disease; Disease Progression; Doctor of Philosophy; Dorzolamide; Dose; Drops; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Effectiveness; Equation; Eye; Eyedrops; Faculty; Failure; Fatty Acids; Fellowship; Formulation; Glaucoma; Head; Health; Histology; Human; Hydrophobicity; In Vitro; Injection of therapeutic agent; Ions; Kinetics; Knowledge; Laboratories; Laboratory Research; Lasers; Measures; Memory; Mentored Clinical Scientist Development Program; Mentors; Methodology; Methods; Modeling; Monitor; Neuroprotective Agents; Oryctolagus cuniculus; Pain; Patient Care; Patients; Penetration; Performance; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Physiological; Polymers; Principal Investigator; Probability; Protocols documentation; Rattus; Research; Research Personnel; Research Project Grants; Research Training; Retinal Ganglion Cells; Rodent; Safety; Scientist; Sclera; Site; System; Testing; Time; Tissues; Topical application; Toxic effect; Training; United States National Institutes of Health; Universities; Vision; Visit; Work; base; biodegradable polymer; career; compliance behavior; conjunctiva; controlled release; dosage; efficacy testing; experience; glaucoma surgery; hydrophilicity; improved; in vivo; member; nanomedicine; neuroprotection; novel therapeutic intervention; particle; practical application; prevent; programs; research study; safety study; skills; skills training; stoichiometry; success; tool

 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.

 描述（由申请人提供）：可以预防青光眼引起的视力丧失和失明。降低眼内压（IOP）的药物可以预防青光眼的发作和青光眼发展为一种使人衰弱的、威胁视力的疾病。然而，降IOP滴剂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%的病人会按他们开的第一个处方配药。即使在理想条件下，滴眼液的粘附性也低于75%[1]。考虑到这些局限性，青光眼患者视力状况持续恶化到不可接受的程度并不奇怪。青光眼治疗可以通过更好的药物输送来大大改善，特别是通过在医生就诊时将药物放置在眼睛上来将患者从等式中移除的方法。 我计划对临床科学家进行为期多年的培训，重点是改进青光眼治疗的药物输送系统。这项培训将由经验丰富的科学家组成的导师小组进行，每个人都为我的培训的重要领域带来了专业知识。同意指导我的一群高级研究人员已经在多个NEI-NIH赞助的研究赠款上富有成效地合作。Harry Quigley博士是威尔默K12项目的首席研究员，在动物青光眼模型方面有40年的经验。我的第二位主要导师将是Justin Hanes博士，他是威尔默/霍普金斯纳米医学中心的负责人，并且已经使用可生物降解的聚合物微粒生产了用于治疗青光眼的眼部药物递送系统[2]。使用这些持续释放制剂，单剂量的IOP降低药物或神经保护剂可以具有持续数月的效果，同时克服副作用、毒性、粘附失败和生物利用度不足。在我目前在威尔默青光眼临床研究期间，我已经开始与Harry Quigley博士和Justin Hanes博士进行试点研究培训。此外，我将受益于其他3名研究人员，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）是一个世界-专家在药物输送到眼睛。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/霍普金斯纳米医学中心的成员，他是受控药物制剂方面的专家。她将提供她的制定技能和培训，为我开发这些配方。Dana Ferraris博士是一位药物化学家，他同意在这个项目中为我提供建议。 尽管我们打算配制多种缓释降眼压药物，但我们选择多佐胺的缓释作为我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，并且具有很高的实际应用可能性。多佐胺通过作为局部碳酸酐酶抑制剂降低IOP，但在滴剂形式下，由于需要每日给药2次或3次，其疗效受到毒性和粪便患者依从性的限制。我们假设，这些局限性可以通过将多佐胺配制成用于结膜下或眼内注射的缓释给药系统来克服。在目标1中，我们将生成并表征可生物降解的聚合物微粒，用于将多佐胺缓释至眼睛。一旦多佐胺缓释条件优化，将配制其他降IOP药物用于控释。在体内实验之前，将使用兔和人巩膜进行离体测定以评价这些制剂的药物经巩膜递送。在目标2中，我们将在兔和啮齿动物眼中评价多佐胺微粒制剂的药代动力学、IOP降低和视网膜神经节细胞（RGC）保护作用。我们还将测试我们的新控释制剂与Hanes最近与Quigley和Zack合作开发的现有控释神经保护制剂的组合注射后RGC保护的功效（2）。 我计划作为一名大学临床科学家的职业生涯，在治疗青光眼的新治疗方法的临床和实验室研究方面做出重大努力，为患者提供护理。培养进行竞争性研究所需的技能和知识。我提出这个多年的研究计划与教师谁拥有专业知识，创造控制释放配方，靶向药物输送，和青光眼的动物模型。