title: Polyanion based controlled release system for the GnRH-receptor antagonist degarelix.
abstract: The aim of this study was to investigate the interaction between the positively charged gonadotropin releasing hormone receptor antagonist degarelix and the two polyanions alginate and carboxymethyl cellulose (CMC). Light as well as transmission electron microscopy revealed that complexes formed by simple mixing of the peptide with one of the polymers had a nano-structure consisting of twisted fibers. The remarkable unique process of complex formation could be followed by isothermal titration calorimetry: We found that peptide self-aggregates dissolved upon the addition of polyanion and peptide-polymer-complexes formed thereafter with the anionic polymer as a template. Peptide release from the complexes was tested in vitro and in vivo and compared to the dissolution of drug from self-aggregates. In vitro the release was monitored over a period of three months. We could find only slight differences in the release kinetics for the alginate and the CMC complexes compared to the pure drug. An in vivo study in Sprague Dawley rats showed similar degarelix plasma concentration levels for the complex formulations and an aqueous degarelix solution following subcutaneous injection. Overall, our findings suggest a competition between complex formation and peptide aggregation, which did not increase the availability of free drug.
authors.affiliation: Department of Pharmaceutical Technology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Backofen
authors.affiliation: Early Stage Development, Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, 2300 Copenhagen, Denmark; Currently F. Hoffman-La Roche Ltd., Pharmaceuticals Division, Grenzacherstr. 124, CH-4070 Basel, Switzerland.
authors.forename: Gregoire
authors.initials: G
authors.lastname: Schwach
authors.affiliation: Non-clinical Development, Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, 2300 Copenhagen, Denmark.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koechling
authors.affiliation: Early Stage Development, Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, 2300 Copenhagen, Denmark.
authors.forename: Torsten
authors.initials: T
authors.lastname: Weiss
authors.affiliation: Department of Pharmaceutical Technology, University of Regensburg, 93053 Regensburg, Germany; University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany. Electronic address: achim.goepferich@chemie.uni-regensburg.de.
authors.forename: Achim
authors.initials: A
authors.lastname: Goepferich
mesh_terms: D000818:Animals; D002942:Circular Dichroism; D003692:Delayed-Action Preparations; D008297:Male; D046529:Microscopy, Electron, Transmission; D009842:Oligopeptides / Q000008:administration & dosage*; D000071228:Polyelectrolytes; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003692:Delayed-Action Preparations; D009842:Oligopeptides; D000071228:Polyelectrolytes; D011108:Polymers; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide
keywords: GnRH antagonist; ITC; In-vitro study; Polymer complex; Sustained release; TEM