Novel Extended Release Povidone Iodine Ophthalmic Drop for Viral Conjunctivitis

摘要/概要 我们建议开发一种长效原位水凝胶聚维酮碘滴剂， 治疗由细菌、分枝杆菌、病毒引起的结膜和角膜的活动性感染， 真菌或变形虫引起的目前还没有广泛有效的治疗方法来治疗所有的原因， 病毒性结膜炎的治疗方法有哪些？这表示 眼科领域巨大的未满足需求。 急性结膜炎（“红眼病”）是最常见和最具传染性的眼部疾病之一。 在美国、日本和欧洲都有感染。大约50%的传染性 结膜炎病例有病毒病因，其中65%到90%是由腺病毒引起的。 病毒性结膜炎具有高度传染性和传播性，也会导致工作和上学时间的损失 因为不必要的抗生素处方增加了医疗费用和风险。有5.9 在美国，每年有100万例传染性结膜炎病例， 每年在欧盟的案件。 聚维酮碘（PVP-I）是一种市售碘伏，常规用于眼科 和普通外科。聚维酮碘溶液已被证明有效之前（5%溶液）和之后 眼部手术（1.25%），出生时（2.5%），活动性感染（1.25%）。PVP-I是唯一已知的 预防术后眼内炎PVP-I溶液对病毒（包括HIV）、真菌、 寄生虫和细菌，没有已知的耐药性发展。在文献中有很好的描述， PVP-I水溶液在较低浓度下表现出更大的防腐功效。而且这些 较低浓度对眼睛、耳朵和皮肤的刺激较小。我们建议开发一种原位凝胶 其中PVP-I的有效浓度通过以下之间的平衡来维持的制剂 溶液PVP-I和凝胶结合组分，产生持久的、毒性较小的药理学 效果该项目的目标是优化稳定的水凝胶PVP-I制剂， 凝胶强度、缓慢释放特性并且对眼睛无刺激。 我们设计了一个筛选模型，用于测量凝胶基质粘度与凝胶浓度的关系 基质在25 ℃，也在生理条件下，通过添加模拟泪液（34 ℃-STF）。该方法将用于选择具有最大粘度Δ值的凝胶基质， 凝胶强度的优化和原位凝胶PVP-I制剂的澄清度。我们已经发现 原位凝胶形成聚维酮碘组合物可以用一种或多种离子- 敏感的原位凝胶形成材料，如多糖，成功地克服了 PVP-I不能在普通缓释聚合物中形成原位凝胶。眼部停留时间 将通过测量角膜表面上的连续荧光来测定NZW兔中的药物 香豆素-6标记的药物溶液与对照研究。计划在NZW家兔中进行刺激性研究， 证实这种制剂对眼睛的刺激最小化。体外抗菌、抗真菌和抗病毒 计划进行研究以证明原位凝胶PVP-I制剂的广谱功效。后 原位凝胶PVP-I制剂优化及其体外确认的成功研究 疗效、进一步的体内局部毒性和疗效研究以及概念验证临床开发 优化的原位凝胶PVP-I制剂的第二阶段SBIR提案将继续进行。

Abstract/Summary We propose to develop a long-acting in-situ hydrogel povidone iodine drop for the treatment of active infections of the conjunctiva and cornea by bacteria, mycobacteria, virus, fungus, or amoebic causes. There is currently no broadly effective therapy that treats all causes of infection and nothing is approved for the treatment of viral conjunctivitis. This represents a massive unmet need in ophthalmology. Acute conjunctivitis (“pink eye”) is one of the most common and most contagious ocular infections seen in the United States, Japan and Europe. Approximately 50 percent of infectious conjunctivitis cases have a viral etiology, and 65 to 90 percent of these are caused by adenovirus. Viral conjunctivitis is highly infectious and transmissible, causing lost work and school days as well as increased healthcare costs and risks from unnecessary antibiotic prescriptions. There are 5.9 million cases of infectious conjunctivitis annually in the United States and approximately 5.4 million cases in the EU annually. Povidone-iodine (PVP-I) is a commercially available iodophor routinely used in ophthalmology and general surgery. Povidone-iodine solutions have been proven effective before (5% solution) and after ocular surgery (1.25%), at birth (2.5%), and for active infections (1.25%). PVP-I is the only agent known to prevent post-op endophthalmitis. Solutions of PVP-I are toxic to viruses (including HIV), fungi, parasites and bacteria with no known development of resistance. It is well described in the literature that aqueous PVP-I solutions exhibit greater antiseptic efficacy at lower concentrations. Furthermore, these lower concentrations are less irritating to the eyes, ears and skin. We propose to develop an in-situ gel formulation where the effective concentration of PVP-I is maintained by the equilibrium between solution PVP-I and the gel bound components resulting in a long lasting, less toxic pharmacological effect. The goal of the project is to optimize stable hydrogel PVP-I formulations that have acceptable gel strength, slow releasing properties and are non-irritating to the eye. We designed a screening model for measuring gel matrix Viscosity vs. Concentrations of gel matrix at 25 ℃, and also under physiological conditions by the addition of simulated tear fluid (34 ℃-STF). This method will be used to select the gel matrix with the largest viscosity Δ value for optimization of gel strength, and clarity of the in-situ gel PVP-I formulations. We have discovered the in-situ gel forming povidone iodine compositions can be formulated with one or more ion- sensitive in-situ gel forming materials such as polysaccharides, which successfully overcome PVP-I’s inability to form in-situ gel in common slow-release polymers. Ocular residence time of the drug will be determined in NZW rabbits by measuring continuous florescence on corneal surface with coumarin-6 labeled drug solution vs. control studies. Irritation studies in NZW rabbits are planned to confirm minimized irritation of such formulations to the eye. In-vitro antibacterial, fungi and anti-viral studies are planned to demonstrate in-situ gel PVP-I formulations’ broad-spectrum efficacy. Upon successful studies for Optimization of in-situ gel PVP-I formulations and confirmation of their in-vitro efficacies, further in-vivo topical toxicity and efficacy studies and proof-of-concept clinical development of the optimized in-situ gel PVP-I formulations will be pursued by a phase II SBIR proposal.