title: Development of a novel injectable drug delivery system for subconjunctival glaucoma treatment.
abstract: In this study we present the development of an injectable polymeric drug delivery system for subconjunctival treatment of primary open angle glaucoma. The system consists of hyaluronic acid sodium salt (HA), which is commonly used in ophthalmology in anterior segment surgery, and an isocyanate-functionalized 1,2-ethylene glycol bis(dilactic acid) (ELA-NCO). The polymer mixtures with different ratios of HA to ELA-NCO (1/1, 1/4, and 1/10 (v/v)) were investigated for biocompatibility, degradation behavior and applicability as a sustained release system. For the latter, the lipophilic latanoprost ester pro-drug (LA) was incorporated into the HA/ELA-NCO system. In vitro, a sustained LA release over a period of about 60days was achieved. In cell culture experiments, the HA/ELA-NCO (1/1, (v/v)) system was proven to be biocompatible for human and rabbit Tenon's fibroblasts. Examination of in vitro degradation behavior revealed a total mass loss of more than 60% during the observation period of 26weeks. In vivo, LA was continuously released for 152days into rabbit aqueous humor and serum. Histological investigations revealed a marked leuko-lymphocytic infiltration soon after subconjunctival injection. Thereafter, the initial tissue reaction declined concomitantly with a continuous degradation of the polymer, which was completed after 10months. Our study demonstrates the suitability of the polymer resulting from the reaction of HA with ELA-NCO as an injectable local drug delivery system for glaucoma therapy, combining biocompatibility and biodegradability with prolonged drug release.
authors.affiliation: Institute for Biomedical Engineering, Rostock University Medical Center, Friederich-Barnewitz-Strasse 4, D-18119 Rostock, Germany. Electronic address: vosskarsten@gmx.de.
authors.forename: Karsten
authors.initials: K
authors.lastname: Voss
authors.affiliation: Department of Ophthalmology, Rostock University Medical Center, Doberaner Strasse 140, D-18057 Rostock, Germany. Electronic address: karen.falke@gmx.de.
authors.forename: Karen
authors.initials: K
authors.lastname: Falke
authors.affiliation: Institute for Biomedical Engineering, Rostock University Medical Center, Friederich-Barnewitz-Strasse 4, D-18119 Rostock, Germany. Electronic address: arne.bernsdorf@uni-rostock.de.
authors.forename: Arne
authors.initials: A
authors.lastname: Bernsdorf
authors.affiliation: Institute for Biomedical Engineering, Rostock University Medical Center, Friederich-Barnewitz-Strasse 4, D-18119 Rostock, Germany. Electronic address: niels.grabow@uni-rostock.de.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabow
authors.affiliation: Institute for Biomedical Engineering, Rostock University Medical Center, Friederich-Barnewitz-Strasse 4, D-18119 Rostock, Germany. Electronic address: christian_kastner@gmx.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Kastner
authors.affiliation: Institute for Biomedical Engineering, Rostock University Medical Center, Friederich-Barnewitz-Strasse 4, D-18119 Rostock, Germany. Electronic address: katrin.sternberg@yahoo.de.
authors.forename: Katrin
authors.initials: K
authors.lastname: Sternberg
authors.affiliation: Institute for Biomedical Engineering, Rostock University Medical Center, Friederich-Barnewitz-Strasse 4, D-18119 Rostock, Germany. Electronic address: ingo.minrath@uni-rostock.de.
authors.forename: Ingo
authors.initials: I
authors.lastname: Minrath
authors.affiliation: Institute for Biomedical Engineering, Rostock University Medical Center, Friederich-Barnewitz-Strasse 4, D-18119 Rostock, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eickner
authors.affiliation: Department of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9a, D-18057 Rostock, Germany. Electronic address: andreas.wree@med.uni-rostock.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wree
authors.affiliation: Institute for Biomedical Engineering, Rostock University Medical Center, Friederich-Barnewitz-Strasse 4, D-18119 Rostock, Germany. Electronic address: klaus-peter.schmitz@uni-rostock.de.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Schmitz
authors.affiliation: Institute for Biomedical Engineering, Rostock University Medical Center, Friederich-Barnewitz-Strasse 4, D-18119 Rostock, Germany. Electronic address: rudolf.guthoff@uni-rostock.de.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Guthoff
authors.affiliation: Department of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9a, D-18057 Rostock, Germany. Electronic address: martin.witt@med.uni-rostock.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Witt
authors.affiliation: Institute for Biomedical Engineering, Rostock University Medical Center, Friederich-Barnewitz-Strasse 4, D-18119 Rostock, Germany. Electronic address: marina.hovakimyan@med.uni-rostock.de.
authors.forename: Marina
authors.initials: M
authors.lastname: Hovakimyan
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D001672:Biocompatible Materials; D002478:Cells, Cultured; D003228:Conjunctiva; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005123:Eye / Q000473:pathology; D005902:Glaucoma, Open-Angle / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000627:therapeutic use; D007267:Injections; D000077338:Latanoprost; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use; D011108:Polymers; D011355:Prodrugs / Q000008:administration & dosage; D011461:Prostaglandins F, Synthetic / Q000008:administration & dosage / Q000627:therapeutic use; D011817:Rabbits
chemical_list: D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D018696:Neuroprotective Agents; D011108:Polymers; D011355:Prodrugs; D011461:Prostaglandins F, Synthetic; D000077338:Latanoprost; D006820:Hyaluronic Acid
keywords: 1,2-Ethylene glycol bis(dilactic acid); DMEM: Dulbecco's Modified Eagle's Medium (PubChem SID: 56312938); Dimethylsulfoxide (PubChem CID: 679); Egg white lysozyme (19–36) [Gallus gallus] (PubChem CID: 71581463); Ethylene glycol (PubChem CID: 174); Glaucoma; Hexamethylene diisocyanate (PubChem CID: 13192); Hyaluronic acid; Hyaluronic acid sodium salt (PubChem CID: 53398704); Injectable polymer; Lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) (PubChem CID: 7272); Latanoprost (PubChem CID: 5311221); Local drug delivery; Penicillin/streptomycin Pen-Strep (PubChem SID: 162248774); Phosphoric acid (PubChem CID: 1004); Poly(l-lactide) (d-lactic acid?) (PubChem CID: 61503); Sodium chloride (PubChem CID: 5234); Sodium chloride: isotonic (PubChem CID: 103770557); l-glutamine (PubChem CID: 5961); with d(+)-glucose (PubChem CID: 5793); with penicillin/streptomycin Pen-Strep (PubChem CID: 71311919); with sodium chloride (PubChem CID: 5234)