title: Design and in vitro assessment of L-lactic acid-based copolymers as prodrug and carrier for intravitreal sustained L-lactate release to reverse retinal arteriolar occlusions.
abstract: Ophthalmic conditions in which the retinal vasculature is obstructed generally lead to vision loss. Administration of the vasodilator L-lactate might offer a treatment strategy by restoring the blood flow, but unfortunately its effect after single intravitreal injection is short-lived. This study describes a concept in which the sustained release of L-lactic acid from a biodegradable copolymer system is investigated. The 50:50 (n/n) copolymer system, composed of L-lactic acid and L,D-2-hydroxyoctanoic acid, is a viscous injectable that will form an intravitreal drug depot. Hydrolysis of the copolymer will automatically lead to the release of L-lactic acid, which will convert to L-lactate at physiological pH, thereby providing a carrier and pro-drug in one. In vitro and ex vivo release studies demonstrate an L-lactic acid release over several weeks. Biocompatibility of the co-polymer and its degradation products is shown on a human retinal pigment epithelial cell line and on ex vivo retinal tissues. A low molecular weight copolymer (1200 g/mol) with low polydispersity has promising properties with a constant release profile, good biocompatibility and injectability.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211 Geneva, Switzerland.
authors.forename: Marieke
authors.initials: M
authors.lastname: Veurink
authors.forename: Lutz
authors.initials: L
authors.lastname: Asmus
authors.forename: Maren
authors.initials: M
authors.lastname: Hennig
authors.forename: Béatrice
authors.initials: B
authors.lastname: Kaufmann
authors.forename: Lena
authors.initials: L
authors.lastname: Bagnewski
authors.forename: Arnd
authors.initials: A
authors.lastname: Heiligenhaus
authors.forename: Efstratios
authors.initials: E
authors.lastname: Mendrinos
authors.forename: Constantin J
authors.initials: CJ
authors.lastname: Pournaras
authors.forename: Robert
authors.initials: R
authors.lastname: Gurny
authors.forename: Michael
authors.initials: M
authors.lastname: Möller
mesh_terms: D000818:Animals; D002460:Cell Line; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry*; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D058449:Intravitreal Injections; D019344:Lactic Acid / Q000008:administration & dosage / Q000737:chemistry*; D011091:Polyesters / Q000008:administration & dosage / Q000737:chemistry*; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry*; D015356:Retinal Artery Occlusion / Q000188:drug therapy; D013552:Swine
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D011091:Polyesters; D011108:Polymers; D011355:Prodrugs; C570618:poly(2-hydroxyoctanoic acid); D019344:Lactic Acid; C033616:poly(lactide)