title: Subconjunctival Delivery of Dorzolamide-Loaded Poly(ether-anhydride) Microparticles Produces Sustained Lowering of Intraocular Pressure in Rabbits.
abstract: Topical medications that inhibit the enzyme carbonic anhydrase (CAI) are widely used to lower intraocular pressure in glaucoma; however, their clinical efficacy is limited by the requirement for multiple-daily dosing, as well as side effects such as blurred vision and discomfort on drop instillation. We developed a biodegradable polymer microparticle formulation of the CAI dorzolamide that produces sustained lowering of intraocular pressure after subconjunctival injection. Dorzolamide was ion paired with sodium dodecyl sulfate (SDS) and sodium oleate (SO) with 0.8% and 1.5% drug loading in poly(lactic-co-glycolic acid) (PLGA), respectively. Encapsulating dorzolamide into poly(ethylene glycol)-co-poly(sebacic acid) (PEG3-PSA) microparticles in the presence of triethylamine (TEA) resulted in 14.9% drug loading and drug release that occurred over 12 days in vitro. Subconjunctival injection of dorzolamide-PEG3-PSA microparticles (DPP) in Dutch belted rabbits reduced IOP as much as 4.0 ± 1.5 mmHg compared to untreated fellow eyes for 35 days. IOP reduction after injection of DPP microparticles was significant when compared to baseline untreated IOPs (P < 0.001); however, injection of blank microparticles (PEG3-PSA) did not affect IOP (P = 0.9). Microparticle injection was associated with transient clinical vascularity and inflammatory cell infiltration in conjunctiva on histological examination. Fluorescently labeled PEG3-PSA microparticles were detected for at least 42 days after injection, indicating that in vivo particle degradation is several-fold longer than in vitro degradation. Subconjunctival DPP microparticle delivery is a promising new platform for sustained intraocular pressure lowering in glaucoma.
authors.affiliation: Department of Ophthalmology, ‡Center for Nanomedicine, and ∥Glaucoma Center of Excellence, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Ophthalmology, ‡Center for Nanomedicine, and ∥Glaucoma Center of Excellence, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Fengying
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, ‡Center for Nanomedicine, and ∥Glaucoma Center of Excellence, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, ‡Center for Nanomedicine, and ∥Glaucoma Center of Excellence, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, ‡Center for Nanomedicine, and ∥Glaucoma Center of Excellence, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Manasee
authors.initials: M
authors.lastname: Gedam
authors.affiliation: Department of Ophthalmology, ‡Center for Nanomedicine, and ∥Glaucoma Center of Excellence, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Ophthalmology, ‡Center for Nanomedicine, and ∥Glaucoma Center of Excellence, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Colleen
authors.initials: C
authors.lastname: Fridley
authors.affiliation: Department of Ophthalmology, ‡Center for Nanomedicine, and ∥Glaucoma Center of Excellence, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Harry A
authors.initials: HA
authors.lastname: Quigley
authors.affiliation: Department of Ophthalmology, ‡Center for Nanomedicine, and ∥Glaucoma Center of Excellence, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
authors.affiliation: Department of Ophthalmology, ‡Center for Nanomedicine, and ∥Glaucoma Center of Excellence, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Ian
authors.initials: I
authors.lastname: Pitha
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D005021:Ethylamines / Q000737:chemistry; D005260:Female; D005901:Glaucoma / Q000188:drug therapy; D007429:Intraocular Pressure / Q000187:drug effects*; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D019301:Oleic Acid / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D011817:Rabbits; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013449:Sulfonamides / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D013876:Thiophenes / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D002257:Carbonic Anhydrase Inhibitors; D005021:Ethylamines; D011108:Polymers; D013449:Sulfonamides; D013876:Thiophenes; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019301:Oleic Acid; D019344:Lactic Acid; D012967:Sodium Dodecyl Sulfate; C013173:osteum; D011092:Polyethylene Glycols; C062765:dorzolamide; C016162:triethylamine
keywords: carbonic anhydrase inhibitor; controlled delivery; glaucoma; polymer