Long-Acting Mucus-Penetrating Steroid Particles for Treatment of Eye Inflammation

长效粘液穿透类固醇颗粒治疗眼部炎症

• 批准号: 8124737
• 负责人: Hongming Chen
• 金额: $ 25.56万
• 依托单位: KALA PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124737
• 关键词: Acetates; Adhesions; Adrenal Cortex Hormones; Adverse effects; Affect; Allergens; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Aqueous Humor; Behavior; Biological Availability; Blindness; Blinking; Caliber; Clinical; Data; Development; Diffuse; Dosage Forms; Dose; Drainage procedure; Drug Carriers; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Excipients; Eye; Eyedrops; Fiber; Film; Frequencies; Gel; Glycocalyx; Glycolates; Goals; Head; Hour; Human; Hypersensitivity; In Vitro; Infection; Inflammation; Investigational Drugs; Laboratories; Lead; Legal patent; Licensing; Liquid substance; Manufactured Supplies; Methods; Monitor; Mucins; Mucous body substance; New Zealand; Ointments; Operative Surgical Procedures; Oryctolagus cuniculus; Particle Size; Patients; Penetration; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Process; Refrigeration; Regimen; Risk; Role; Small Business Innovation Research Grant; Solutions; Steroids; Surface; Suspension substance; Suspensions; Technology; Therapeutic Effect; Time; Tissues; Toxicology; Universities; Work; base; chemical release; chemical stability; comparative efficacy; compliance behavior; improved; manufacturing process; nanoparticle; ocular surface; ophthalmic drug; particle; patient safety; preclinical efficacy; prednisolone; prevent; professor; residence; scale up

DESCRIPTION (provided by applicant): Inadequate treatment of ocular inflammation causes severe discomfort and complications, including blindness. Current means of treating ocular inflammation cannot sustain long-term efficacy without compromising patient safety, comfort or compliance. Conventional eye drops, which are preferred over other ophthalmic and systemic dosage forms due to patient comfort and localized action, are cleared from the ocular surface within minutes by lachrymation, blinking and drainage. Even highly potent anti-inflammatory corticosteroids must be instilled at least 4W/day at doses that compensate for the nearly 90% loss rate. Such a regimen greatly reduces patient compliance and increases the risk of adverse effects. Nanoparticles have the potential to prolong ocular retention and increase local drug bioavailability. However, this potential could not be fully realized since virtually all synthetic nanoparticles are extensively trapped by peripheral rapidly-cleared mucus in the eye and, hence, are also rapidly cleared. To overcome this limitation, Kala co-founder Professor Hanes (Johns Hopkins University) and coworkers have pioneered the mucus-penetrating particle (MPP) technology, exclusively licensed by Kala. MPP, by penetrating across rapidly-cleared mucus layers, have been shown to prolong retention at mucosal surfaces and facilitate sustained release directly to underlying tissues. Preliminary data in rabbits indicate retention of MPP at the eye surface for several hours, compared to a few minutes for conventional eye drops. In SBIR Phase I, we will build upon these findings to develop a sustained release MPP formulation of prednisolone acetate (PA), the most prescribed ophthalmic corticosteroid. We expect that PA MPP, by achieving prolonged ocular residence, will only require 1-2W/day dosing vs. 4W/day for current PA eye drops. In addition, PA MPP will release drugs over time and eliminate the sharp peaks in ocular drug levels inherent for eye drops, thus alleviating the risk of concentration-related adverse effects. In Specific Aim 1, we will formulate all-GRAS (Generally Recognized As Safe by FDA) PA MPP with (i) drug loading 10%, (ii) sustained release of PA for 12 h in vitro, (iii) storage stability for 2 weeks, (iv) particle sizes of 50-500 nm (the size range enabling mucus-penetration), and (v) sufficient quantities needed for animal studies. In Specific Aim 2, we will demonstrate that a single instillation of PA MPP will maintain drug concentration in rabbit aqueous humor for 12 h above that of PRED MILD(R) at 6 h (based on PRED MILD(R) at 4W/day). Such improved pharmacokinetics will lead to a Phase II proposal focused on developing a scalable process to manufacture supplies for human trials and completing preclinical efficacy and toxicology studies. Our ultimate goal is to develop PA MPP eye drops with 1-2W daily dosing for improved treatment of ocular inflammation. Successful completion of this work will also provide a strong impetus to apply the MPP technology to other ophthalmic drugs that currently require frequent dosing. PUBLIC HEALTH RELEVANCE: Eye inflammation resulting from surgery, allergy, infection, etc. affects millions of Americans. Though corticosteroid eye drops remain the mainstay for inflammation therapy, they require frequent application due to rapid elimination from the eyes. Kala Pharmaceuticals seeks to prove that our proprietary mucus-penetrating particles can reduce the dosing frequency of the most commonly prescribed corticosteroid eye drops, prednisolone acetate, from 4+ times daily to once- or twice-daily, leading to improved patient compliance.

描述（由申请人提供）：眼部炎症治疗不充分会导致严重不适和并发症，包括失明。目前治疗眼部炎症的方法无法在不影响患者安全、舒适或依从性的情况下维持长期疗效。由于患者舒适度和局部作用，传统滴眼剂优于其他眼科和全身剂型，可在几分钟内通过流泪、眨眼和引流从眼表面清除。即使是强效抗炎皮质类固醇也必须至少滴注 4W/天，剂量足以补偿近 90% 的损失率。这种治疗方案大大降低了患者的依从性并增加了不良反应的风险。纳米颗粒具有延长眼内滞留时间并提高局部药物生物利用度的潜力。然而，这种潜力无法完全实现，因为几乎所有合成纳米颗粒都被眼睛周围快速清除的粘液广泛捕获，因此也被快速清除。为了克服这一限制，Kala 联合创始人 Hanes 教授（约翰·霍普金斯大学）和同事开创了粘液穿透颗粒 (MPP) 技术，并由 Kala 独家授权。 MPP 通过渗透快速清除的粘液层，已被证明可以延长在粘膜表面的保留时间，并促进直接持续释放到下面的组织。兔子的初步数据表明，MPP 在眼睛表面保留数小时，而传统滴眼液只能保留几分钟。在 SBIR 第一阶段，我们将根据这些发现开发一种醋酸泼尼松龙 (PA) 的缓释 MPP 制剂，这是最常用的眼科皮质类固醇。我们预计，通过延长眼内停留时间，PA MPP 将仅需要 1-2W/天的剂量，而目前的 PA 滴眼剂则需要 4W/天。此外，PA MPP会随着时间的推移释放药物，并消除滴眼剂固有的眼部药物水平尖峰，从而减轻与浓度相关的不良反应的风险。在具体目标1中，我们将制定全GRAS（FDA普遍认为安全）PA MPP，其中（i）载药量为10％，（ii）PA在体外缓释12小时，（iii）储存稳定性为2周，（iv）粒径为50-500 nm（能够穿透粘液的粒径范围），以及（v）动物研究所需的足够数量。在具体目标 2 中，我们将证明单次滴注 PA MPP 可使家兔房水中的药物浓度维持 12 小时，高于 PRED MILD(R) 6 小时的浓度（基于 PRED MILD(R) 4 周/天）。这种改进的药代动力学将导致第二阶段提案的重点是开发可扩展的工艺来制造用于人体试验的用品并完成临床前功效和毒理学研究。我们的最终目标是开发每日剂量 1-2W 的 PA MPP 滴眼液，以改善眼部炎症的治疗。这项工作的成功完成也将为MPP技术应用于目前需要频繁给药的其他眼科药物提供强大的推动力。 公共卫生相关性：手术、过敏、感染等引起的眼部炎症影响着数百万美国人。尽管皮质类固醇滴眼剂仍然是炎症治疗的主要手段，但由于它们会快速从眼睛中消除，因此需要频繁使用。 Kala Pharmaceuticals 试图证明我们专有的粘液穿透颗粒可以将最常用的皮质类固醇滴眼液醋酸泼尼松龙的给药频率从每天 4 次以上减少到每天一次或两次，从而提高患者的依从性。