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.
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