Design and development of an injectable in situ forming drug delivery system of methotrexate for the treatment of rheumatoid arthritis

Methotrexate (MTX) is the drug of choice for the treatment of rheumatoid arthritis (RA). At present there exists a lacuna in delivering methotrexate in suitable dosage form to maintain optimum plasma concentration to achieve therapeutic efficacy during the treatment period. Exposure of MTX at higher concentrations resulted in severe side effects. Moreover, the treatment modality (initial and maintenance dose) of RA is not clinically uniform. Biodegradable injectable in situ gels offer versatility in delivering drug at predetermined rates, and maintaining plasma concentration with a possibility of dose adjustment. They can be developed to optimize the therapeutic properties of a drug product, render them safe, effective and reliable during therapy. The aim of the present study was to formulate a biodegradable injectable in situ gel system for methotrexate sodium in the treatment of rheumatoid arthritis. The formulations were prepared by "cold technique" using thermosensitive polymer, Pluronic F-127 (20 %) and varying concentration of co-polymers, Pluronic F-68 (2–6 %) and Carbopol 934 (1.0-1.5 %). The prepared in situ gels were evaluated in vitro for drug interactions by FT-IR, sterility, gelation characteristics, content uniformity, viscosity, syringeability and in vitro drug release. MTX was evenly distributed in all formulations, which were sterile and syringeable through an 18 gauze needle. The gels were thermosensitive and thermoresponsive, and were dependent on the concentration of co-polymers. Drug release from in situ gels was sustained for 96 h to 120 h, and influenced by the type and concentration of co-polymers employed. Drug release was significantly higher in dynamic diffusion state in comparison with static state as ascertained by student t-test. The drug release was by non-fickian diffusion mechanism and followed first-order kinetics. These findings suggested that in situ gels can be effectively used to achieve controlled drug release; are easy to administer, are effective with reduced frequency of dosage, and result in increased patient compliance and comfort. It may be concluded that methotrexate in situ gels are ideally suitable in the treatment of RA.