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

描述（由申请人提供）：眼部炎症治疗不当会导致严重不适和并发症，包括失明。目前治疗眼部炎症的手段不能在不损害患者安全性、舒适性或依从性的情况下维持长期功效。常规滴眼剂由于患者舒适和局部作用而优于其它眼用和全身剂型，其在几分钟内通过流泪、眨眼和引流从眼表面清除。即使是高效的抗炎皮质类固醇，也必须以补偿近90%损失率的剂量滴注至少4 W/天。这样的方案大大降低了患者的依从性并增加了不良反应的风险。纳米粒具有延长眼部滞留和增加局部药物生物利用度的潜力。然而，这种潜力无法完全实现，因为几乎所有的合成纳米颗粒都被眼睛中的外周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）和同事们开创了粘液穿透颗粒（MPP）技术，由Kala独家授权。MPP通过穿透快速清除的粘液层，已被证明可延长在粘膜表面的滞留时间，并促进直接持续释放至下层组织。兔子的初步数据表明，MPP在眼表面保留数小时，而传统滴眼液仅需数分钟。在SBIR I期，我们将根据这些发现开发醋酸泼尼松龙（PA）的缓释MPP制剂，醋酸泼尼松龙是最常用的眼用皮质类固醇。我们预计PA MPP通过实现延长的眼部驻留，将仅需要1- 2 W/天的剂量，而目前的PA滴眼液需要4 W/天。此外，PA MPP将随时间释放药物，消除滴眼剂固有的眼部药物水平的尖峰，从而减轻浓度相关不良反应的风险。在具体目标1中，我们将配制全GRAS（FDA公认安全）PA MPP，其中（i）载药量10%，（ii）体外持续释放PA 12小时，（iii）储存稳定性2周，（iv）粒度为50-500 nm（能够渗透粘液的粒度范围），以及（v）动物研究所需的足够量。在具体目标2中，我们将证明单次滴注PA MPP将使兔眼房水中的药物浓度维持12小时，高于6小时时PRED MILD（R）的药物浓度（基于PRED MILD（R），4 W/天）。这种改进的药代动力学将导致第二阶段提案，重点是开发一种可扩展的工艺来生产人体试验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PA MPP滴眼液，每日1- 2 W给药，用于改善眼部炎症的治疗。这项工作的成功完成也将为将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动力。 公众健康相关性：手术、过敏、感染等引起的眼部炎症影响着数百万美国人。虽然皮质类固醇滴眼液仍然是炎症治疗的主要药物，但由于其快速从眼睛中消除，因此需要频繁应用。Kala Pharmaceuticals旨在证明我们专有的粘液渗透颗粒可以减少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1次或2次，从而提高患者的依从性。

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.