title: Novel biodegradable polyesteramide microspheres for controlled drug delivery in Ophthalmology.
abstract: Most of the posterior segment diseases are chronic and multifactorial and require long-term intraocular medication. Conventional treatments of these pathologies consist of successive intraocular injections, which are associated with adverse effects. Successful therapy requires the development of new drug delivery systems able to release the active substance for a long term with a single administration. The present work involves the description of a new generation of microspheres based on poly(ester amide)s (PEA), which are novel polymers with improved biodegradability, processability and good thermal and mechanical properties. We report on the preparation of the PEA polymer, PEA microspheres (PEA Ms) and their characterization. PEA Ms (~15μm) were loaded with a lipophilic drug (dexamethasone) (181.0±2.4μg DX/mg Ms). The in vitro release profile of the drug showed a constant delivery for at least 90days. Based on the data from a performed in vitro release study, a kinetic ocular model to predict in vivo drug concentrations in a rabbit vitreous was built. According to the pharmacokinetic simulations, intravitreal injection of dexamethasone loaded PEA microspheres would provide release of the drug in rabbit eyes up to 3months. Cytotoxicity studies in macrophages and retinal pigment epithelial cells revealed a good in vitro tolerance of the microsystems. After sterilization, PEA Ms were administered in vivo by subtenon and intravitreal injections in male Sprague-Dawley rats and the location of the microspheres in rat eyes was monitored. We conclude that PEA Ms provide an alternative delivery system for controlling the delivery of drugs to the eye, allowing a novel generation of microsphere design.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University of Madrid, Spain; Pharmaceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC) and the Ocular Pathology National Net (OFTARED) of the Institute of Health Carlos III, Madrid, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Andrés-Guerrero
authors.affiliation: DSM, 6167 AC Geleen, The Netherlands.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Zong
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Finland; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Eva
authors.initials: E
authors.lastname: Ramsay
authors.affiliation: Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Complutense University of Madrid, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Rojas
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Finland.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sarkhel
authors.affiliation: Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Complutense University of Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Gallego
authors.affiliation: Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Complutense University of Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: de Hoz
authors.affiliation: Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Complutense University of Madrid, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Ramírez
authors.affiliation: Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Complutense University of Madrid, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Salazar
authors.affiliation: Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Complutense University of Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Triviño
authors.affiliation: Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Complutense University of Madrid, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Ramírez
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Finland; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Del Amo
authors.affiliation: Department of Materials Engineering, Monash University, School of Engineering, University of Warwick, Clayton, Australia.
authors.forename: Neil
authors.initials: N
authors.lastname: Cameron
authors.affiliation: Pharmaceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC) and the Ocular Pathology National Net (OFTARED) of the Institute of Health Carlos III, Madrid, Spain; Department of Pharmacology, Faculty of Pharmacy, Complutense University of Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: de-Las-Heras
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Finland; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Arto
authors.initials: A
authors.lastname: Urtti
authors.affiliation: DSM, 6167 AC Geleen, The Netherlands.
authors.forename: George
authors.initials: G
authors.lastname: Mihov
authors.affiliation: DSM, 6167 AC Geleen, The Netherlands.
authors.forename: Aylvin
authors.initials: A
authors.lastname: Dias
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University of Madrid, Spain; Pharmaceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC) and the Ocular Pathology National Net (OFTARED) of the Institute of Health Carlos III, Madrid, Spain. Electronic address: rociohv@farm.ucm.es.
authors.forename: Rocío
authors.initials: R
authors.lastname: Herrero-Vanrell
mesh_terms: D000818:Animals; D002460:Cell Line; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008863:Microspheres; D011091:Polyesters / Q000008:administration & dosage* / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D011091:Polyesters
keywords: Dexamethasone; Intraocular injection; Microspheres; Ocular drug delivery; Poly(ester amide); Tolerance