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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-in-oil-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 (&amp;lt;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 \u00b0C. 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 &amp;gt;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.<\/jats:p>","DOI":"10.1021\/acsnano.9b07214","type":"journal-article","created":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T11:51:51Z","timestamp":1573559511000},"page":"13728-13744","source":"Crossref","is-referenced-by-count":45,"title":["Once Daily Pregabalin\nEye Drops for Management of\nGlaucoma"],"prefix":"10.1021","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7691-6128","authenticated-orcid":true,"given":"Mohamed\nMoustafa","family":"Ibrahim","sequence":"first","affiliation":[{"name":"University of Tennessee Health Science Center , , , ,","place":["Memphis, Tennessee, United States, 38163"]},{"name":"Mansoura University , , ,","place":["Mansoura, Egypt, 35516"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doaa Nabih","family":"Maria","sequence":"additional","affiliation":[{"name":"University of Tennessee Health Science Center , , , ,","place":["Memphis, Tennessee, United States, 38163"]},{"name":"Mansoura University , , ,","place":["Mansoura, Egypt, 35516"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay R.","family":"Mishra","sequence":"additional","affiliation":[{"name":"The University of Memphis , , , ,","place":["Memphis, Tennessee, United States, 38152"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa","family":"Guragain","sequence":"additional","affiliation":[{"name":"The University of Memphis , , , ,","place":["Memphis, Tennessee, United States, 38152"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"XiangDi","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Tennessee Health Science Center , , , ,","place":["Memphis, Tennessee, United States, 38163"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4021-3559","authenticated-orcid":true,"given":"Monica M.","family":"Jablonski","sequence":"additional","affiliation":[{"name":"University of Tennessee Health Science Center , , , ,","place":["Memphis, Tennessee, United States, 38163"]},{"name":"University of Tennessee Health Science Center , , , ,","place":["Memphis, Tennessee, United States, 38163"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2019,11,12]]},"reference":[{"key":"2026081718222659600_cit1","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1136\/bjo.80.5.389","article-title":"Number\nof People with Glaucoma Worldwide","volume":"80","author":"Quigley","year":"1996","journal-title":"Br. 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