Novel Extended Release Povidone Iodine Ophthalmic Drop for Viral Conjunctivitis

新型缓释聚维酮碘滴眼液治疗病毒性结膜炎

• 批准号: 9519433
• 负责人: Bo Liang
• 金额: $ 2.5万
• 依托单位: IVIEW THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9519433
• 关键词: Acidity; Acute; Acute Conjunctivitis; Adenoviruses; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Antiviral Agents; Area; Bacteria; Birth; Candida; Characteristics; Clinical; Clinical Trials; Complex; Conjunctivitis; Controlled Study; Cornea; Coumarins; Development; Disinfectants; Drainage procedure; Drops; Drug Delivery Systems; Ear; Endophthalmitis; Equilibrium; Etiology; Europe; European Union; Exhibits; Eye; Eye Infections; Formulation; Gel; Genus Mycobacterium; Goals; HIV; Health Care Costs; Hour; Human; Hydrogels; In Situ; In Vitro; Infection; Ions; Japan; Label; Licensing; Liquid substance; Literature; Local Anesthetics; Local Anti-Infective Agents; Measures; Methods; Modeling; Molds; New Zealand; Operative Surgical Procedures; Ophthalmology; Oryctolagus cuniculus; Parasites; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase II Clinical Trials; Phase Transition; Physicians; Physiological; Polymers; Polysaccharides; Povidone-Iodine; Property; Pseudomonas aeruginosa; Reproduction spores; Resistance development; Risk; Schools; Skin; Small Business Innovation Research Grant; Surface; System; Technology; Therapeutic; Time; Toxic effect; United States; Viral; Viral Conjunctivitis; Virus; Viscosity; Work; active method; anti-viral efficacy; aqueous; clinical development; commercialization; comparative efficacy; conjunctiva; design; economic implication; effective therapy; efficacy study; fungus; in vivo; irritation; killings; methicillin resistant Staphylococcus aureus; novel; prevent; residence; screening; treatment duration

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.

摘要/总结 我们建议开发一种长效原位水凝胶聚维酮碘滴剂，用于 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， 真菌或阿米巴原因。目前还没有一种广泛有效的疗法可以治疗所有原因 感染，并且没有任何药物被批准用于治疗病毒性结膜炎。这代表了一个 眼科领域存在大量未满足的需求。 急性结膜炎（“红眼病”）是最常见、最具传染性的眼病之一 美国、日本和欧洲都出现了感染。大约50%的感染者 结膜炎病例有病毒病因，其中 65% 至 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，还会导致工作和学业损失 由于医疗保健成本增加以及不必要的抗生素处方带来的风险。有5.9个 美国每年有 100 万例传染性结膜炎病例，其中约 540 万例 每年在欧盟发生的案件。 聚维酮碘 (PVP-I) 是一种市售碘伏，常用于眼科 和普通外科。聚维酮碘溶液在使用前（5% 溶液）和使用后已被证明是有效的 眼科手术（1.25%）、出生时（2.5%）和活动性感染（1.25%）。 PVP-I 是唯一已知的药剂 以预防术后眼内炎。 PVP-I 溶液对病毒（包括 HIV）、真菌、 没有已知的抗药性发展的寄生虫和细菌。文献中有很好的描述 PVP-I 水溶液在较低浓度下表现出更高的防腐功效。此外，这些 较低的浓度对眼睛、耳朵和皮肤的刺激较小。我们建议开发一种原位凝胶 配方中 PVP-I 的有效浓度通过以下平衡维持： 溶液 PVP-I 和凝胶结合成分产生持久、毒性较小的药理作用 影响。该项目的目标是优化稳定的水凝胶 PVP-I 配方，使其具有可接受的性能 凝胶强度、缓释特性并且对眼睛无刺激。 我们设计了一个用于测量凝胶基质粘度与凝胶浓度的筛选模型 25℃下的基质，以及在生理条件下添加模拟泪液（34 ℃-STF）。该方法将用于选择具有最大粘度Δ值的凝胶基质 优化原位凝胶 PVP-I 配方的凝胶强度和透明度。我们发现 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，成功克服了 PVP-I 无法在常见的缓释聚合物中形成原位凝胶。眼内停留时间 通过测量角膜表面的连续荧光来确定 NZW 兔的药物含量 使用香豆素 6 标记的​​药物溶液与对照研究。计划对 NZW 兔子进行刺激研究 确认此类制剂对眼睛的刺激最小化。体外抗菌、真菌和抗病毒 计划进行研究来证明原位凝胶 PVP-I 制剂的广谱功效。之上 原位凝胶 PVP-I 配方优化及其体外验证的成功研究 功效、进一步的体内局部毒性和功效研究以及概念验证临床开发 II 期 SBIR 提案将追求优化的原位凝胶 PVP-I 配方。