Eye drop formulations for enhanced penetration of water soluble antibiotics to treat infections

项目总结 大约70%的眼部感染是由细菌引起的。仅在美国，每年就有数百万 细菌性角膜炎、结膜炎3例。氟喹诺酮类药物对治疗和预防都有效。 在这些感染中，莫西沙星往往是首选药物，因为它具有较高的眼内生物利用度 与其他氟喹诺酮类药物相比。最新的氟喹诺酮类药物贝西沙星也显示出一些 在治疗耐药生物方面的优势，包括耐甲氧西林葡萄球菌和 与隐形眼镜相关角膜炎相关的假单胞菌种类。不管怎样，抗生素眼药水是 规定每天至少使用三次，严重感染时最多每小时使用一次。作为 每天所需剂量增加，患者依从性降低，从而降低治疗效果。 坚持使用的问题可能会导致威胁视力的并发症，并可能导致细菌 抵抗。更有效的抗生素滴眼液配方需要更少的剂量 改善患者的预后和生活质量，减缓细菌耐药性的发展。而眼药水 主宰眼科市场，通过滴眼液实现有效的眼内给药 很有挑战性。泪水产生、反射性眨眼和鼻泪液引流限制了停留时间，而 配方和药物性质会进一步限制所需的眼内药物快速吸收的潜力。 我们已经开发了一种粘膜给药技术，可以增加药物在整个体内的传递和吸收 粘膜屏障，称为粘液穿透颗粒(MPP)技术。在这里，我们描述了一种创新的 将水溶性氟喹诺酮类抗生素盐制成离子配对药物核心的方法 纳米悬浮液。我们的初步数据显示，莫西沙星-帕米酸MPP纳米悬浮剂 (MOX-PAM NS)在细菌性角膜炎大鼠模型中提供了改进的预防和治疗。重要的是 每日一次使用MOX-PAM NS的效果与使用商业广告的每日三次一样好或更好 配方，维格莫司。目标是开发莫西沙星和贝西沙星的滴眼剂配方，以 为革兰氏阳性、革兰氏阴性和耐药细菌感染提供广泛的治疗选择。 在目标1中，我们将进一步修改滴眼剂的配方，以增加眼内药物的吸收和 对商业和临床分离的细菌进行抗菌活性筛选。在目标2中，我们将描述 外用药物对大鼠细菌性角膜炎的透过性和疗效。在《目标3》中，我们将全面演绎 在兔身上的药代动力学研究、治疗效果研究和局部安全性研究 体型和结构更接近人类。我们预计，剂量频率的减少将在 保持对多种常见细菌的疗效将对患者产生积极影响 关爱和生活质量。

PROJECT SUMMARY About 70% of all ocular infections are caused by bacteria. Each year in the US alone, there are millions of cases of bacterial keratitis and conjunctivitis. Fluoroquinolones are effective for both treatment and prevention of these infections, and moxifloxacin is often the drug of choice due to higher intraocular bioavailability compared to other fluoroquinolones. The newest fluoroquinolone, besifloxacin, has also shown to have some advantages in treating resistant organisms, including methicillin-resistant Staphyloccocus species and Pseudomonas species associated with contact lens-related keratitis. Regardless, antibiotic eye drops are prescribed to be used at least three times per day, and up to once every hour for severe infections. As the required number of doses per day increases, patient compliance, and thus, treatment efficacy, decreases. Issues with adherence can lead to sight-threatening complications and potentially contribute to bacterial resistance. Antibiotic eye drop formulations that are more effective with less frequent dosing are needed to improve patient outcomes and quality of life and slow the development of bacterial resistance. While eye drops dominate the ophthalmic market, achieving effective intraocular drug delivery via eye drops is quite challenging. Tear production, reflexive blinking, and nasolacrimal drainage limit residence time, while formulation and drug properties can further limit the potential for the rapid intraocular drug absorption needed. We have developed a mucosal drug delivery technology that increases drug delivery and absorption across mucosal barriers, termed the mucus-penetrating particle (MPP) technology. Here, we describe an innovative approach for formulating water-soluble fluoroquinolone antibiotic salts into ion-paired drug-core nanosuspensions. Our preliminary data demonstrates that a moxifloxacin-pamoic acid MPP nanosuspension (MOX-PAM NS) provides improved prevention and treatment in a rat model of bacterial keratitis. Importantly, once daily dosing with MOX-PAM NS was as good or better than three times daily dosing with the commercial formulation, Vigamox. The goal is to develop eye drop formulations of both moxifloxacin and besifloxacin to provide broad spectrum treatment options for gram-positive, gram-negative, and resistant bacterial infections. In Aim 1, we will make further formulation changes in the eye drops to increase intraocular drug absorption and screen for antimicrobial activity against commercial and clinical bacterial isolates. In Aim 2, we will characterize the topical drug penetration and efficacy in treating bacterial keratitis in rats. In Aim 3, we will perform full pharmacokinetic studies, treatment efficacy studies, and topical safety studies in rabbits, which have ocular size and structure more similar to humans. We anticipate that a reduction in dosing frequency while maintaining efficacy against a wide range of common bacterial pathogens will have a positive impact on patient care and quality of life.