Once Daily Pregabalin Eye Drops for Management of Glaucoma

Abstract

Elevated intraocular pressure (IOP) is the most significant risk factor contributing to visual field loss in glaucoma. Unfortunately, the deficiencies associated with current therapies have resulted in reduced efficacy, several daily dosings, and poor patient compliance. Previously, we identified the calcium voltage-gated channel auxiliary subunit alpha2delta 1 gene (Cacna2d1) as a modulator of IOP and demonstrated that pregabalin, a drug with high affinity and selectivity for CACNA2D1, lowered IOP in a dose-dependent manner. Unfortunately, IOP returned to baseline at 6 h after dosing. In the current study, we develop a once daily topical pregabalin-loaded multiple water-inoil-in-water microemulsion formulation to improve drug efficacy. We characterize our formulations using multiple in vitro and in vivo evaluations. Our lead formulation provides continuous release of pregabalin for up to 24 h. Because of its miniscule droplet size (<20 nm), our microemulsion has a transparent appearance and should not blur vision. It is also stable at one month of storage at temperatures ranging from 5 to 40 °C. Our formulation is nontoxic, as illustrated by a cell toxicity study and slit-lamp biomicroscopic exams. CACNA2D1 is highly expressed in both the ciliary body and the trabecular meshwork, where it functions to modulate IOP. A single drop of our lead pregabalin formulation reduces IOP by greater than 40%, which does not return to baseline until >30 h post-application. Although there were no significant differences in the amplitude of IOP reduction between the formulations we tested, a significant difference was clearly observed in their duration of action. Our multilayered microemulsion is a promising carrier that sustains the release and prolongs the duration of action of pregabalin, a proposed glaucoma therapeutic.

Enhanced Corneal Penetration of a Poorly Permeable Drug Using Bioadhesive Multiple Microemulsion Technology

“…The bioadhesive multiple W/O/W ME was prepared in 3 steps according to our recently published protocol [22]. Briefly, the ratios of the primary ME were selected from a previously constructed pseudo-ternary phase diagram.…”

“…The viscosity of ribavirin-loaded ME was measured using a cone and plate rotary viscometer (Brookfield DV-II+; Brookfield Engineering Laboratories, Middleboro, MA, USA) at 35 • C according to our previously published protocols [22,30,31]. Briefly, 0.5 mL of the formulation was placed between the cone and plate and allowed to equilibrate with the machine temperature for 5 min before measuring.…”

“…The control formulations were ribavirin solutions in water, sodium alginate or Carbopol 981 polymeric solutions at the same concentration used in the MEs. The dialyzers were shaken at 50 rpm in a thermostatically controlled shaker that maintained at 35 • C. The entire medium in the receiver chambers was removed and replaced by a fresh warm PBS (at 35 • C) at predetermined time intervals ranging between 0.25 and 24 h. All withdrawn samples were immediately assayed for their drug contents using the previously mentioned HPLC method [22,34]. The cumulative amount released was calculated as a percentage from the total drug content of the 100 mg of the same formulation batch.…”

“…Each formulation was evaluated in six replicates and the cumulative amount permeated was calculated as mean ± SEM. The steady state flux (J) and the permeability coefficient (P) were calculated from the following equations [22,35]:…”

“…We previously demonstrated the suitability of a multiple W/O/W microemulsion formulation for controlling the corneal permeability and sustaining the drug release of pregabalin, a model BCS class I drug. Although pregabalin has high water solubility and high permeability, we controlled its release for up to one day and its corneal penetration to adhere to a once daily dosing [22]. In the current study, we selected ribavirin, as a model BCS class III drug [23] that has high water solubility and low permeability.…”