Synthesis of hydrophilic intra-articular microspheres conjugated to ibuprofen and evaluation of anti-inflammatory activity on articular explants.
The main limitation of current microspheres for intra-articular delivery of non-steroidal anti-inflammatory drugs (NSAIDs) is a significant initial burst release, which prevents a long-term drug delivery. In order to get a sustained delivery of NSAIDs without burst, hydrogel degradable microspheres were prepared by co-polymerization of a methacrylic derivative of ibuprofen with oligo(ethylene-glycol) methacrylate and poly(PLGA-PEG) dimethacrylate as degradable crosslinker. Microspheres (40-100 μm) gave a low yield of ibuprofen release in saline buffer (≈2% after 3 months). Mass spectrometry analysis confirmed that intact ibuprofen was regenerated indicating that ester hydrolysis occurred at the carboxylic acid position of ibuprofen. Dialysis of release medium followed by alkaline hydrolysis show that in saline buffer ester hydrolysis occurred at other positions in the polymer matrix leading to the release of water-soluble polymers (>6-8000 Da) conjugated with ibuprofen showing that degradation and drug release are simultaneous. By considering the free and conjugated ibuprofen, 13% of the drug is released in 3 months. In vitro, ibuprofen-loaded MS inhibited the synthesis of prostaglandin E2 in articular cartilage and capsule explants challenged with lipopolysaccharides. Covalent attachment of ibuprofen to PEG-hydrogel MS suppresses the burst release and allows a slow drug delivery for months and the cyclooxygenase-inhibition property of regenerated ibuprofen is preserved.
Occlugel, Archimed, 12 rue Charles de Gaulle, 78350 Jouy en Josas, France.
Laurent
L
Bédouet
UMR CNRS 8612, IFR 141-ITFM, Université Paris Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
Laurence
L
Moine
AP-HP, INRA, Center for Research of Interventional Imaging (CR2i), Jouy en Josas 78352, France.
Florentina
F
Pascale
UMR CNRS 8612, IFR 141-ITFM, Université Paris Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
Van-Nga
VN
Nguyen
UMR CNRS 8612, IFR 141-ITFM, Université Paris Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
Denis
D
Labarre
Occlugel, Archimed, 12 rue Charles de Gaulle, 78350 Jouy en Josas, France; AP-HP, INRA, Center for Research of Interventional Imaging (CR2i), Jouy en Josas 78352, France; AP-HP Hôpital Lariboisière, Department of Interventional Neuroradiology, 2 rue Ambroise Paré, 75475 Paris Cedex 10, France. Electronic address: alex.laurent@lrb.aphp.fr.
Alexandre
A
Laurent
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry*; D002358:Cartilage, Articular / Q000187:drug effects* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003692:Delayed-Action Preparations; D003956:Dialysis; D015232:Dinoprostone / Q000378:metabolism; D006868:Hydrolysis; D007052:Ibuprofen / Q000008:administration & dosage / Q000737:chemistry*; D007270:Injections, Intra-Articular; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid; D008070:Lipopolysaccharides / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008863:Microspheres; D009924:Organ Culture Techniques; D010316:Particle Size; D011092:Polyethylene Glycols; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012756:Sheep; D013583:Synovial Membrane / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D003692:Delayed-Action Preparations; D008070:Lipopolysaccharides; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D007770:L-Lactate Dehydrogenase; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007052:Ibuprofen
DDS; Hydrogel; Ibuprofen; Microspheres; Osteoarthritis; Prodrug