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

用于增强水溶性抗生素渗透以治疗感染的滴眼剂配方

• 批准号: 10696222
• 负责人: Laura Ensign
• 金额: $ 47.14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696222
• 关键词: Acids; Adherence; Adhesions; Antibiotics; Bacteria; Bacterial Infections; Bacterial Model; Biological Availability; Blinking; Clinical; Complex; Conjunctivitis; Contact Lenses; Data; Development; Dose; Drainage procedure; Drug Delivery Systems; Drug Kinetics; Effectiveness; Eye; Eye Infections; Eyedrops; Female; Film; Fluoroquinolones; Formulation; Frequencies; Gastrointestinal tract structure; Genus staphylococcus; Goals; Hour; Human; In Vitro; Infection; Infection prevention; Ions; Keratitis; Marketing; Methicillin Resistance; Minimum Inhibitory Concentration measurement; Modeling; Moxifloxacin; Mucins; Mucous Membrane; Mucous body substance; Organism; Oryctolagus cuniculus; Particle Size; Patient Care; Patient-Focused Outcomes; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Prevention; Production; Property; Proteins; Pseudomonas; Pseudomonas aeruginosa; Quality of life; Rattus; Resistance; Safety; Salts; Staphylococcus aureus; Staphylococcus aureus infection; Structure; Surface; Surface Properties; Suspensions; Technology; Testing; Time; Treatment Efficacy; Vision; Water; absorption; antimicrobial; bacterial resistance; biomaterial compatibility; compliance behavior; design; efficacy study; efficacy testing; improved; innovation; nano; nanoparticle; particle; pathogen; pathogenic bacteria; reproductive tract; residence; safety study; surface coating

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.

项目摘要 大约70％的眼部感染是由细菌引起的。仅在美国，每年就有数百万美元 细菌性角膜炎和结膜炎的病例。氟喹诺酮对治疗和预防均有效 在这些感染中，由于眼内生物利用度较高，通常是选择的药物 与其他氟喹诺酮相比。最新的氟喹诺酮贝贝沙星也已证明有一些 治疗抗性生物的优势，包括耐甲氧西林的葡萄球菌物种和 与隐形眼镜相关角膜炎相关的假单胞菌物种。无论如何，抗生素眼滴是 规定每天至少使用三次，每小时最多可用于严重感染。作为 每天需要增加剂量的数量，患者依从性以及治疗效率降低。 依从性问题可能导致视力危险并发症，并可能导致细菌 反抗。需要更有效的抗生素眼滴配方，需要较少的剂量才能 改善患者的结果和生活质量，并减缓细菌抗性的发展。而眼睛掉落 在眼科市场中占主导地位，通过眼部滴剂实现有效的眼内药物 具有挑战性的。泪水产生，反身闪烁和鼻缸排水限制停留时间，而 制剂和药物特性可以进一步限制所需的快速眼内药物吸收的潜力。 我们已经开发了一种粘膜药物输送技术，可以增加药物的输送和吸收 粘膜屏障称为粘液渗透颗粒（MPP）技术。在这里，我们描述了一种创新的 将水溶性氟喹诺酮抗生素盐制成离子对药核的方法 纳米肌。我们的初步数据表明，莫西法沙星 - 帕莫酸MPP纳米震荡 （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， 一旦每天用Mox-Pam NS给药，或者每天都要与商业用来三次。 配方，vigamox。目的是开发莫西法沙星和贝贝沙星的眼滴配方 为革兰氏阳性，革兰氏阴性和抗性细菌感染提供广泛的治疗选择。 在AIM 1中，我们将进一步改变眼部滴剂，以增加眼内药物的吸收和 筛选针对商业和临床细菌分离株的抗菌活性。在AIM 2中，我们将描述 局部药物渗透和在治疗大鼠细菌性角膜炎方面的功效。在AIM 3中，我们将表现出色 药代动力学研究，治疗功效研究和具有眼的局部安全研究 大小和结构与人类更相似。我们预计剂量频率会降低 维持对广泛的常见细菌病原体的疗效将对患者产生积极影响 照顾和生活质量。