title: Intra-articular bioactivity of a p38 MAPK inhibitor and development of an extended-release system.
abstract: In the treatment of arthritic diseases, oral or systemic administration of anti-inflammatory substances, such as p38 MAPK inhibitors, is hampered by numerous side effects. To overcome them, formulations of rapid and extended drug delivery systems were studied in intra-articular administration. For the first time, VX-745, a highly selective p38 MAPK inhibitor, demonstrated in vivo bioactivity, similar to dexamethasone activity, following intra-articular administration in an antigen-induced arthritic (AIA) mouse model. The in vitro bioactivity of VX-745 was also shown on synoviocytes, reducing the IL-6 concentration. Process and formulation parameters (i.e., polymer concentration, aqueous/organic phase ratio, emulsification speed and process, and evaporation pressure) and particle characterisation (i.e., drug loading, size of particle, and surface aspect) were extensively examined to produce optimised formulations. Indeed, a burst release provides a rapid saturation of intracellular p38 MAPK to relieve patients from pain and inflammation. Then, drug diffusion would be sufficient to maintain an effective dose over 2-3 months. This study confirms the effectiveness of encapsulated p38 MAPK inhibitors in extended drug delivery systems and seems to be a promising strategy for intra-articular treatment.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Pradal
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Maria-Fernanda
authors.initials: MF
authors.lastname: Zuluaga
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Maudens
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University Hospital and Department of Pathology and Immunology, University of Geneva, School of Medicine, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Waldburger
authors.affiliation: Novartis Pharma AG, Postfach, Basel, Switzerland.
authors.forename: Christian Alexander
authors.initials: CA
authors.lastname: Seemayer
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Doelker
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University Hospital and Department of Pathology and Immunology, University of Geneva, School of Medicine, Switzerland.
authors.forename: Cem
authors.initials: C
authors.lastname: Gabay
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Jordan
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland. Electronic address: Eric.allemann@unige.ch.
authors.forename: Eric
authors.initials: E
authors.lastname: Allémann
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004058:Diffusion; D004337:Drug Carriers; D006801:Humans; D007270:Injections, Intra-Articular; D007596:Joints / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007700:Kinetics; D008297:Male; D008810:Mice, Inbred C57BL; D010316:Particle Size; D011108:Polymers / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D011724:Pyridazines / Q000008:administration & dosage* / Q000737:chemistry; D011743:Pyrimidines / Q000008:administration & dosage* / Q000737:chemistry; D012995:Solubility; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013678:Technology, Pharmaceutical / Q000379:methods; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D011108:Polymers; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D048051:p38 Mitogen-Activated Protein Kinases; C464966:VX-745
keywords: Drug delivery system; Intra-articular; Liposomes; Long-term release; Microparticles; P38 MAPK inhibitors; PLA; PLGA