Sustained Drug Release for Antifibrosis

描述（由申请人提供）：青光眼是美国不可逆视力丧失的第二大原因。眼内压（IOP）升高是发生青光眼性视神经病变和视野丧失的重要风险因素;1-5降低风险患者的IOP可以保护视功能。6 -10青光眼滤过手术的目标是创建和维持通畅的瘘管，以降低IOP并最终保护视功能。青光眼滤过性手术失败的主要原因是由于积极的伤口愈合导致的结膜泡的外部瘢痕形成。11 -12使用抗纤维化药物旨在限制眼睛手术瘘部位的成纤维细胞增殖，这被认为在手术过程中和手术后都有较高的失败风险，13 -34 5-氟尿嘧啶和丝裂霉素是最常用的药物，然而，前者受到其作用持续时间短的限制，需要重复给药，而后者具有非常窄的过度暴露范围。将药物偶联到具有持续释放能力的生物可吸收载体上提供了在术后伤口愈合早期期间有限的局部递送到靶组织的机会。本项目的目标是开发一种生物相容性和可生物降解的原位可凝胶水凝胶系统作为抗纤维化剂的载体，以更好地解决滤过手术的瘢痕形成问题。最初将优化水凝胶制剂的性能特征;在兔青光眼滤过手术模型中进行体内有效性评价后，将结束该项目。该I期SBIR项目将为开发未来的抗纤维化治疗奠定基础。公共卫生相关性：青光眼是美国第二大导致不可逆视力丧失的原因，影响全球超过7000万人。35如果早期发现，青光眼是可控的。36青光眼治疗的目标是降低眼内压，可以进行滤过手术，以创建一个通畅的通道，使压力降低，从而保护视觉功能。青光眼滤过手术失败的主要原因是由于积极的伤口愈合造成的结膜滤过泡的外部瘢痕形成。11 -12在手术过程中和手术后都使用了旨在限制瘢痕组织形成的抗纤维化药物，以大大提高该手术的成功率。13 -34然而，这些试剂的性能受到短的作用持续时间或非常窄的过度暴露范围的限制。将药物偶联到具有持续释放能力的生物可吸收载体上提供了在术后伤口愈合早期向靶组织进行有限、局部递送的机会。该项目的目的是开发一种抗纤维化系统，无需重复给药和过度暴露风险，以更好地解决当前滤过手术的障碍。

DESCRIPTION (provided by applicant): Glaucoma is the second leading cause of irreversible vision losss in the United States. Elevated intraocular pressure (IOP) is a significant risk factor for the development of glaucomatous optic neuropathy and visual field loss;1-5 that reduction of the IOP in patients at risk can preserve visual function.6-10 The goal of filtering surgery for glaucoma is the creation and maintenance of a patent fistula to lower IOP and eventually preserving visual function. The major cause of glaucoma filtering surgery failure is external scarring of the conjunctival bleb due to aggressive wound healing.11-12 The use of antifibrosis agents with the intent of limiting fibroblast proliferation at the site of the surgical fistula in eyes, that are presumed to be at a higher risk for failure both during and after the operative procedure, has greatly increased the success of this procedure.13-34 5-fluorouracil and mitomycin are the most commonly utilized agents, however, the former is limited by its short duration of action, which requires repeated administration, whilst the latter has a very narrow margin for over-exposure. Coupling drugs to a bioresorbable vehicle with sustained release capability offers the opportunity for limited, localized delivery to the target tissue during the early post- operative wound healing. The goal of this project is to develop a biocompatible and biodegradable in situ gelable hydrogel system as a carrier of an antifibrosis agent, for more optimally addressing the scar formation issue of filtering surgery. The performance characteristics of the hydrogel formulations will initially be optimized; and the project will be concluded after performing in vivo efficacy evaluations in rabbit glaucoma filtering surgery models. This Phase I SBIR project will set the stage for developing future treatment for antifibrosis. PUBLIC HEALTH RELEVANCE: Glaucoma is the second leading cause of irreversible vision loss in the United States and affects over 70 million people worldwide.35 Glaucoma is controllable if detected early.36 The goal of glaucoma treatment is to reduce intraocular pressure and filtering surgery can be performed to create a patent channel to enable pressure reduction, thereby preserve visual function. The major cause of glaucoma filtration surgery failure is external scarring of the created conjunctival bleb due to aggressive wound healing.11-12 Antifibrosis agents with the intent of limiting scar tissue formation have been utilized both during and after the operative procedure to greatly increase the success of this procedure.13-34 However, the performance of these agents are limited by either a short duration of action or a very narrow margin for over-exposure. Coupling drugs to a bioresorbable vehicle with sustained release capability offers the opportunity for limited, localized delivery to the target tissue during the early post-operative wound healing. The objective of this project is to develop a system for antifibrosis without the need of repeated administration and risk of over-exposure to more optimally address the current obstacle of filtering surgery.