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，每年就有数百万人 例细菌性角膜炎和结膜炎。氟喹诺酮类药物对治疗和预防都有效 这些感染中，由于眼内生物利用度较高， 与其他氟喹诺酮类药物相比。最新的氟喹诺酮，贝西沙星，也显示出一些 在治疗耐药性生物体，包括耐甲氧西林葡萄球菌属物种和 与接触镜相关角膜炎相关的假单胞菌属。无论如何，抗生素眼药水 规定每天至少使用三次，对于严重感染，每小时最多使用一次。为 每天所需的给药次数增加，患者依从性降低，因此治疗功效降低。 依从性问题可能导致危及视力的并发症，并可能导致细菌感染。 阻力需要更有效且给药频率更低的抗生素滴眼液制剂， 改善患者的预后和生活质量，减缓细菌耐药性的发展。虽然眼药水 眼内给药是眼药水市场的主流，通过眼药水实现有效的眼内给药是相当困难的。 挑战性泪液分泌、反射性眨眼和鼻泪管引流限制了停留时间， 制剂和药物性质可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给药技术，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，我们描述了一种创新的 将水溶性氟喹诺酮类抗生素盐配制成离子配对药核的方法 纳米悬浮液我们的初步数据表明，阿托伐他汀-扑酸MPP纳米混悬液 （MOX-PAM NS）在细菌性角膜炎的大鼠模型中提供改善的预防和治疗。重要的是， MOX-PAM NS每日一次给药与市售商品NS每日三次给药一样好或更好 配方，Vigamox。目标是开发阿托沙星和贝西沙星的滴眼液制剂， 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液的配方，以增加眼内药物吸收， 筛选对商业和临床细菌分离株的抗微生物活性。在目标2中，我们将描述 局部药物渗透性和治疗大鼠细菌性角膜炎的疗效。在目标3中，我们将全面执行 在兔中进行的药代动力学研究、治疗功效研究和局部安全性研究， 体型和结构更接近人类。我们预计，减少给药频率， 保持对广泛的常见细菌病原体的有效性将对患者产生积极影响， 护理和生活质量。