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.

项目概要 大约 70% 的眼部感染是由细菌引起的。每年仅在美国就有数百万 细菌性角膜炎和结膜炎病例。氟喹诺酮类药物对治疗和预防均有效 由于眼内生物利用度较高，莫西沙星通常是这些感染的首选药物 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作用 治疗耐药微生物（包括耐甲氧西林葡萄球菌）的优势 与隐形眼镜相关的角膜炎相关的假单胞菌属。不管怎样，抗生素滴眼液 规定每天至少使用三次，严重感染时每小时最多使用一次。作为 每天所需的剂量数量增加，患者的依从性降低，从而治疗效果降低。 依从性问题可能会导致威胁视力的并发症，并可能导致细菌感染 反抗。需要更有效且给药频率更低的抗生素滴眼剂配方 改善患者的治疗结果和生活质量，并减缓细菌耐药性的发展。滴眼药水的同时 主导眼科市场，通过滴眼剂实现有效的眼内药物输送是相当重要的 具有挑战性的。泪液产生、反射性眨眼和鼻泪管引流限制了停留时间，而 配方和药物特性可以进一步限制所需的眼内药物快速吸收的潜力。 我们开发了一种粘膜药物递送技术，可以增加药物的递送和吸收 粘膜屏障，称为粘液穿透颗粒（MPP）技术。在这里，我们描述了一个创新的 将水溶性氟喹诺酮抗生素盐配制为离子对药物核心的方法 纳米悬浮液。我们的初步数据表明，莫西沙星-双羟萘酸 MPP 纳米混悬剂 (MOX-PAM NS) 可改善细菌性角膜炎大鼠模型的预防和治疗。重要的是， 每日一次 MOX-PAM NS 给药与每日三次商业给药一样好或更好 配方，维加莫斯。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谱治疗选择。 在目标1中，我们将进一步改变滴眼剂的配方，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。在目标 2 中，我们将描述 治疗大鼠细菌性角膜炎的局部药物渗透和功效。在目标3中，我们将全面执行 兔子的药代动力学研究、治疗效果研究和局部安全性研究，这些研究对眼部有影响 尺寸和结构与人类更加相似。我们预计在减少给药频率的同时 保持对多种常见细菌病原体的功效将对患者产生积极影响 护理和生活质量。