Abstract
PurposeTo determine if a Microemulsion Drug Ocular Penetration System (MiDROPS) formulation of cyclosporine A (CsA) delivers more drug and is more efficacious for treatment of dry eye disease (DED) than the current clinical formulation.MethodsTissue distribution of CsA was quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS). To assess tolerability, CsA-MiDROPS (0.1%) was applied to the eyes of rabbits twice per day for 14 days and assessed using ophthalmoscopic examinations. Mice were exposed to desiccating stress for 10 days and received daily topical instillation of the vehicle or test agent. Cornea staining was done to quantify corneal permeability. Histologic quantification of goblet cell (GC) density and CD4+ T-cell infiltration in the conjunctiva was performed.ResultsOphthalmic distribution studies indicate significantly increased drug concentration with CsA-MiDROPS compared with Restasis. CsA-MiDROPS is well tolerated with little toxicity in a 2-week tolerability study. In the DED model, both 0.05% and 0.1% CsA-MiDROPS conferred a significant effect and were more effective than Restasis for treating experimental DED when dosed twice per day. As compared with Restasis dosed twice per day, 0.1% CsA-MiDROPS dosed once per day demonstrated superiority.ConclusionsCsA-MiDROPS showed superior drug delivery and efficacy compared with other clinical formulations. As this product is simple to produce and needs to be only applied once daily, the clinical development of CsA-MiDROPS will help to reduce societal and patient burdens by lowering drug costs and accelerating/improving the activity of CsA.Translational RelevanceMiDROPS has broad application concerning the ophthalmic development of lipophilic small molecule therapeutics.
Highlights
Dry eye disease (DED) is a multifactorial syndrome that affects the daily lives of millions of people and is the result of dysfunctional tear production.[1]
Translational Relevance: Microemulsion Drug Ocular Penetration System (MiDROPS) has broad application concerning the ophthalmic development of lipophilic small molecule therapeutics
While CsA has been difficult to formulate into efficacious and stable eye drops, we identified a number of parental formulations in the MiDROPS library suitable for clinical development
Summary
Dry eye disease (DED) is a multifactorial syndrome that affects the daily lives of millions of people and is the result of dysfunctional tear production.[1] In the United States alone, it is reported that up to 30% of the population over age 50 suffers from DED.[2] Patients that suffer from DED have symptoms that often include eye irritation, redness, ocular discharge, decrease in tear volume, and can cause a significant decrease in the quality of life.[1,3,4] Ocular surface pathology often includes superficial punctate lesions and epithelial defects. The initial induction of inflammation varies and can include systemic autoimmune diseases, such as Sjogren’s syndrome, which cause destruction of the lacrimal gland, leading to aqueous deficient dry eye, or meibomian gland dysfunction, reducing the lipid component of the tear film, leading to evaporative dry eye.[1,6] regardless of the initiating cause, the result is a loss of integrity of the tear film, leading to ocular surface inflammation.[7]
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