Abstract
Purpose :
Cream-based formulations applied to the eyelid offer a novel approach for the delivery of pharmaceutically active compounds for the treatment of ocular disorders. We performed studies to investigate the tolerability and toxicity of a pilocarpine ophthalmic topical cream applied to the eyelids of Hanford minipigs.
Methods :
Male Hanford minipigs (N=16; 3-5/group) were administered sterile Pilocarpine Ophthalmic Topical Cream (low, mid and high dose) or its vehicle (Pilocarpine Ophthalmic Topical Cream, 0%) to the upper eyelids of both eyes for 28 days with a 14-day recovery period. Parameters evaluated included viability, clinical signs, dermal and ocular irritation, ophthalmic examinations, intraocular pressure (IOP), pupillometry, body weight, food consumption, toxicokinetics, clinical pathology (hematology, coagulation and serum chemistry), organ weights, macroscopic and ocular and systemic microscopic observations.
Results :
There were no vehicle- or drug-related effects on mortality, clinical signs, eyelid dermal and ocular irritation scores, ophthalmic examinations, IOP, pupil size, body weights, clinical pathology, organ weights, or macroscopic observations. There were no vehicle- or drug-related microscopic findings in ocular tissues and extraocular tissues including eyelids and lacrimal glands. Toxicokinetic evaluation at a local dose 2.1 times higher than the highest planned clinical dose showed lower systemic exposures than those observed following a single dose of 10 mg pilocarpine hydrochloride tablets in human. Pilocarpine concentrations in target tissues, including main and accessory lacrimal glands and ciliary body, were at levels deemed likely to be effective.
Conclusions :
A novel sterile Pilocarpine Ophthalmic Topical Cream was well tolerated with low systemic exposures after application to the eyelids. Concentrations achieved in the target tissues support the eyelid route of administration. Therefore, local and systemic safety concerns of Pilocarpine Ophthalmic Topical Cream are low and support the evaluation of the efficacy and safety in the Phase 2 clinical trials for the indications of dry eye disease and presbyopia.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.