New Quaternary Ammonium Oxicam Derivatives Targeted toward Cartilage:  Synthesis, Pharmacokinetic Studies, and Antiinflammatory Potency

Abstract

Analogues of nonsteroidal antiinflammatory drugs (NSAIDs) oxicams, in which the active group was linked to a quaternary ammonium function [(4-hydroxy-2-methyl-2H-1,2-benzothiazine-1, 1-dioxide-3-carboxamido)2-methylpyridinium iodide or piroxicam-N(+) and [3-(4-hydroxy-2-methyl-2H-1,2-benzothiazine-1, 1-dioxide-3-carboxamido)propyl]trimethylammonium iodide or propoxicam-N(+)] were synthesized. Compounds were labeled with tritium for piroxicam-N(+) and carbon-14 for propoxicam-N(+). Pharmacokinetic studies conducted on rats showed that these molecules were able to highly concentrate in joint cartilages but their bioavailability by the oral way was low. Only propoxicam-N(+) exhibited a sufficient water solubility to be administered intravenously. This molecule was able to restore proteoglycans biosynthesis in cultured articular chondrocytes treated with Interleukin-1beta with an efficiency identical to that of indomethacin. These results suggest that the functionalization of oxicam derivatives by a quaternary ammonium group greatly increases their affinity toward articular cartilage without eliminating their pharmacological activity. New drugs synthesized according to this scheme could be useful to obtain a significant decrease of the efficient administered dose and consequently an attenuation of adverse effects such as digestive toxicity.

Intra‐articular depot formulation principles: Role in the management of postoperative pain and arthritic disorders

“…Based on these early observations efforts have been devoted to exploit the ion exchange properties of the ECM to enhance drug accumulation in the cartilage tissue. Various positively charged organic molecules have been observed to distribute into cartilage 138–147. This includes (i) radiodiagnostic agents for joint imaging containing a N‐quaternary functional group,142, 143 (ii) N‐quaternary analogues of anti‐inflammatory oxicams,140, 144 and (iii) a derivative of the potential DMOAD doxycycline 147…”

Complexation between low‐molecular‐weight cationic ligands and negatively charged polymers as studied by capillary electrophoresis frontal analysis

“…Upon ingestion the ions of the stomach fluid caused liberation of the drugs from the polyelectrolyte making them available for absorption into the body. Derivatives of anti-inflammatory drugs carrying a positive charge were designed in order to obtain selective drug accumulation in cartilage [51]. Accumulation in cartilage was observed as a result of the ionic interactions of the drug derivatives with sulfate and carboxylate groups of the cartilage polymer substructures that are part of the cartilage.…”

Cartilage targeted chemical delivery of naproxen and ibuprofen for the treatment of arthritis

“…It could be concluded that site specific delivery of these quaternary ester derivatives could prove to be an effective strategy for long term therapy of inflammatory conditions like arthritis. [23]…”