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。眼压升高是青光眼视神经病变和视野丧失的重要危险因素；1-5降低危险患者的IOP可以保持视觉功能。6-10青光眼滤过手术的目的是建立和维持未闭瘘管以降低IOP并最终保持视觉功能。青光眼滤过手术失败的主要原因是由于伤口愈合的侵略性导致结膜泡的外部瘢痕。11-12使用抗纤维化药物，目的是限制眼内手术瘘管部位的成纤维细胞增殖，这被认为是手术期间和手术后失败的高风险，这大大增加了手术的成功率。13-34 5-氟尿嘧啶和丝裂霉素是最常用的药物，然而，前者受其作用时间短的限制，需要反复给药，而后者则有非常窄的过度暴露余地。将药物偶联到具有持续释放能力的生物可吸收载体中，为术后早期伤口愈合提供了有限、局部递送到目标组织的机会。该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，以更优化地解决过滤手术中疤痕形成的问题。将初步优化水凝胶配方的性能特征；对兔青光眼滤过手术模型进行体内疗效评价后结案。该一期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：青光眼是美国造成不可逆视力丧失的第二大原因，影响着全球超过7000万人如果发现得早，青光眼是可以控制的青光眼治疗的目标是降低眼内压，通过滤过手术可以建立一个专利通道来降低眼压，从而保持视觉功能。青光眼滤过手术失败的主要原因是由于伤口愈合的侵略性造成结膜泡的外部瘢痕。为了限制瘢痕组织的形成，在手术期间和手术后都使用了抗纤维化药物，以大大提高手术的成功率。13-34然而，这些药剂的作用受到限制，要么是作用时间短，要么是过度接触的余地很小。将药物偶联到具有持续释放能力的生物可吸收载体上，为术后早期伤口愈合期间有限、局部地递送到目标组织提供了机会。该项目的目标是开发一种不需要重复给药和过度暴露风险的抗纤维化系统，以更优化地解决目前过滤手术的障碍。

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.