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方法不能在不影响患者安全、舒适或依从性的情况下维持长期疗效。由于患者舒适和局部作用，传统滴眼液比其他眼科和全身剂型更受欢迎，可在几分钟内通过泪液、眨眼和引流从眼表清除。即使是非常有效的抗炎皮质类固醇，也必须每天注入至少4W，以补偿近90%的损失率。这样的治疗方案大大降低了患者的依从性，增加了不良反应的风险。纳米颗粒具有延长眼潴留和增加局部药物生物利用度的潜力。然而，这种潜力并不能完全实现，因为几乎所有的合成纳米颗粒都被眼睛周围快速清除的粘液广泛捕获，因此也被迅速清除。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）和同事们率先开发了粘液穿透颗粒（MPP）技术，该技术由Kala独家授权。MPP通过穿透快速清除的黏液层，已被证明可以延长在粘膜表面的滞留时间，并促进直接持续释放到下层组织。家兔实验的初步数据表明，MPP在眼表滞留数小时，而传统滴眼液仅几分钟。在SBIR一期研究中，我们将以这些发现为基础，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，通过延长眼部停留时间，PA MPP只需要1-2W/天的剂量，而目前PA滴眼液的剂量为4W/天。此外，PA MPP会随着时间的推移释放药物，消除眼药水固有的眼部药物水平的尖峰，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公认安全的）PA MPP，其中(i)载药量为10%，（ii） PA在体外持续释放12小时，（iii）储存稳定性为2周，（iv）粒径为50-500 nm（能够穿透黏液的尺寸范围），以及(v)动物研究所需的足够量。在特异性目标2中，我们将证明单次注射PA MPP将使兔房水中的药物浓度维持12小时，高于6小时的PRED MILD(R)（基于PRED MILD(R)在4W/天）。这种改善的药代动力学将导致第二阶段的建议，重点是开发一个可扩展的过程来生产用于人体试验的用品，并完成临床前疗效和毒理学研究。我们的最终目标是开发每日1-2W剂量的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有力地推动MPP技术应用于目前需要频繁给药的其他眼科药物。

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.