title: Crystal suspensions of poorly soluble peptides for intra-articular application: a novel approach for biorelevant assessment of their in vitro release.
abstract: Crystal suspensions of 3 poorly soluble peptides (MSC1, 2 and 3), intended for intra-articular administration were prepared and in vitro release was tested by a modified USP IV apparatus, combined with a dialysis system. Half-lives of release profiles were ∼5 days for MSC1 and ∼0.5 days for MSC2 and MSC3, showing the potential to achieve sustained exposure from crystal suspensions after intra-articular administration. The in vitro release setup discriminated between (i) different formulations, (ii) different concentrations of API and (iii) different APIs. In addition it was shown that this method allows the modification of release conditions in order to gain more biorelevance for in vitro release testing in the field of intra-articular application: the influence of synovial fluid components hyaluronic acid and albumin was demonstrated, showing prolonged half-lives for suspensions containing 2.5% bovine serum albumin (5 days) and accelerated release rates for suspensions containing 1% sodium hyaluronate (2.5 days) in comparison to a suspension in phosphate buffered saline (4 days). Furthermore, it was demonstrated that release rates of a suspension containing an artificial synovial fluid were in accordance with suspensions containing bovine synovial fluid (t1/2∼4 days).
authors.affiliation: Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany; Pharmbiotec GmbH, Campus C 2.2, 66123 Saarbruecken, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Sterner
authors.affiliation: Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany; Department of Molecular Biotechnology and Pharmaceutical Technology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Harms
authors.affiliation: Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Weigandt
authors.affiliation: Pharmbiotec GmbH, Campus C 2.2, 66123 Saarbruecken, Germany; Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University, Campus A 4.1, 66123 Saarbruecken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland, Campus 2.3, 66123 Saarbruecken, Germany. Electronic address: m.windbergs@mx.uni-saarland.de.
authors.forename: M
authors.initials: M
authors.lastname: Windbergs
authors.affiliation: Pharmbiotec GmbH, Campus C 2.2, 66123 Saarbruecken, Germany; Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University, Campus A 4.1, 66123 Saarbruecken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland, Campus 2.3, 66123 Saarbruecken, Germany.
authors.forename: C M
authors.initials: CM
authors.lastname: Lehr
mesh_terms: D000818:Animals; D002417:Cattle; D003460:Crystallization; D003692:Delayed-Action Preparations; D003956:Dialysis; D006207:Half-Life; D006820:Hyaluronic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D007270:Injections, Intra-Articular; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000378:metabolism*; D012995:Solubility; D013535:Suspensions; D013582:Synovial Fluid / Q000378:metabolism*
chemical_list: D003692:Delayed-Action Preparations; D010455:Peptides; D013535:Suspensions; D012710:Serum Albumin, Bovine; D006820:Hyaluronic Acid
keywords: ArtSF; BSA; BSF; Cartilage; Flow-through-cell; HA; IA; Osteoarthritis; PBS; Prolonged release; SF; SH; SM; Synovial joint; Synovial membrane; USP; United States Pharmacopeia; artificial synovial fluid; bovine serum albumin; bovine synovial fluid; hyaluronic acid; intra-articular; phosphate buffered saline; sodium hyaluronate; synovial fluid; synovial membrane