Once-Daily Cyclosporine-A-MiDROPS for Treatment of Dry Eye Disease

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.

<p>A Review of Topical Cyclosporine A Formulations—A Disease-Modifying Agent for Keratoconjunctivitis Sicca</p>

“…37 Other novel carriers under development include Microemulsion Drug Ocular Penetration System (MiDR-OPS) of CsA (Table 1). 20 Droplets in this system are <10 nm in diameter and are thermodynamically stable with longer shelf life. 20 Unlike conventional emulsions, MiDROPS are in a single phase and can be easily manufactured at a lower cost.…”

“…20 Droplets in this system are <10 nm in diameter and are thermodynamically stable with longer shelf life. 20 Unlike conventional emulsions, MiDROPS are in a single phase and can be easily manufactured at a lower cost. This microemulsion was developed to safely deliver higher amounts of CsA to ocular tissue than existing formulations.…”

“…19 High hydrophobicity and poor aqueous solubility of CsA make it extremely difficult to formulate as conventional topical eye drops. 19,20 The release and subsequent intraocular penetration of CsA from a lipophilic carrier, such as an emulsion, are generally low. 16 Although emulsions have the advantage of rapid ocular spreading upon application, lower bioavailability of lipophilic drugs from emulsions limits the amount of CsA available in an already challenging aqueous ocular environment.…”

“…This microemulsion was developed to safely deliver higher amounts of CsA to ocular tissue than existing formulations. 20 A preclinical study in Dutch-belted rabbits that compared MiDROPS and conventional CsA 0.05% emulsion showed MiDROPS delivered amounts of CsA into ocular tissue 2 to 3 times greater than CsA 0.05% emulsion. 20 Both twice daily 0.05% and once-daily 0.1% CsA-MiDROPS in mice significantly reduced corneal permeability, T cell infiltration, and conjunctival goblet cell loss compared with CsA 0.05% emulsion.…”

“…20 A preclinical study in Dutch-belted rabbits that compared MiDROPS and conventional CsA 0.05% emulsion showed MiDROPS delivered amounts of CsA into ocular tissue 2 to 3 times greater than CsA 0.05% emulsion. 20 Both twice daily 0.05% and once-daily 0.1% CsA-MiDROPS in mice significantly reduced corneal permeability, T cell infiltration, and conjunctival goblet cell loss compared with CsA 0.05% emulsion. 20 Another novel formulation under development loads lyophilized CsA into polymeric micelles (Table 1).…”