Redesigning the Viscosupplement to Enhance the Mechanical and Biological Actions of Hyaluronic Acid

摘要 膝关节骨关节炎（OA）是一种严重影响生活质量的慢性疾病。关节内 通常施用粘性的高分子量透明质酸（HA）溶液的注射以恢复 本发明提供了一种用于治疗关节炎的药物组合物，其具有滑液的粘弹性，并减少OA相关的关节疼痛。除了它的机械效应， 与HA结合的细胞受体已经显示出减少炎症信号、软骨降解酶 活性，并刺激HA的内源性产生。尽管HA在治疗OA方面具有巨大的潜力， 基于其在关节功能中的关键作用，在滑液中维持高浓度的外源性HA 具有挑战性，因此其临床疗效有限。传统的粘性补充剂依赖于相同的 形成HA的粘性溶液，然后引入交联以稳定和保留HA的配制方法 注射后这种方法和对材料粘度和可接受的注射力的考虑限制了 HA剂量小于100 mg，半衰期小于1周。为了增加剂量， 在HA治疗的持续时间内，Prohibix LLC将HA粘性补充剂重新设计为致密水凝胶 在一些实施方案中，本发明的组合物包含随时间缓慢释放高分子量HA到滑液中的微粒。我们的承诺 初步结果证明了在单次注射中递送超过200 mg HA的能力， 超过4周。这种创新的HYALEASE水凝胶微粒技术具有巨大的潜力， 提高HA在治疗OA中的治疗效果，并且还具有作为包封的平台的巨大潜力。 并维持其他有希望但难以配制的治疗剂的释放。本SBIR第I阶段的目标 建议继续发展HYALEASE微粒技术，包括（i）证明 释放的HA的生物活性，（ii）定量大鼠中的滑膜半衰期，和（iii）将治疗功效与 使用工业上采用的大鼠OA模型的传统粘性补充剂。这些目标的实现将进一步 促进OA大型动物模型（II期研究）中的产品开发，以进行首次人体研究。

Abstract Knee osteoarthritis (OA) is an immobilizing chronic disease that drastically decreases quality of life. Intra-articular injections of viscous, high molecular weight hyaluronic acid (HA) solutions are commonly administered to restore viscoelastic properties of synovial fluid and reduce OA related joint pain. In addition to its mechanical effects, cellular receptor binding to HA has been shown to reduce inflammatory signaling, cartilage degrading enzyme activity, and stimulate endogenous production of HA. Despite the tremendous potential of HA in treating OA based on its critical roles in joint function, sustaining high concentrations of exogenous HA in the synovial fluid has been challenging and therefore its clinical efficacy limited. Traditional viscosupplements rely on the same formulation approach of creating a viscous solution of HA, then introducing crosslinks to stabilize and retain HA after injection. This approach and considerations of material viscosity and acceptable injection forces has limited HA doses to less than 100 mg and half-lives to less than one week. In order to increase the dose and enhance duration of HA treatment, Prohibix LLC has redesigned the HA viscosupplement into dense hydrogel microparticles that slowly release high molecular weight HA into the synovial fluid over time. Our promising preliminary results demonstrate the ability to deliver over 200 mg of HA in a single injection that releases HA for over 4 weeks. This innovative HYALEASE hydrogel microparticle technology has tremendous potential to improve the therapeutic efficacy of HA in treating OA, and also has great potential as a platform to encapsulate and sustain the release of other promising but hard to formulate therapeutics. The objective of this Phase I SBIR proposal is to continue the development of the HYALEASE microparticle technology including (i) demonstrate biological activity of released HA, (ii) quantify synovial half-life in rats, and (iii) compare therapeutic efficacy to a traditional viscosupplement using an industry adopted rat OA model. Completion of these Aims will further motivate product development in a large animal model of OA (Phase II studies) towards first-in-man studies.