Controlled-release in-situ gel forming formulation of tramadol containing chitosan-based pro-nanogels

Chronic pain is one of the most prevalent health problems worldwide. Tramadol is a synthetic semi-opioid analgesic, interacting with serotonergic, adrenergic and opioid receptors to reduce the pain but its short half-life in vivo may reduce patient compliance in case of chronic pains. To overcome this problem, novel drug delivery systems have been investigated. This study focuses on a chitosan based thermoresponsive in-situ gel forming formulation intended to subcutaneous injection. To evaluate further drug release, a reversed phase high performance liquid chromatography method was developed. Then two formulations (with and without TPP) were optimized by D-optimal plan using Design-Expert statistical software and were characterized in terms of morphology, release phenomenon, texture, swelling and stability as well as in vivo response. AFM images show approximately spherical nanocavities in the homogenous TPP containing gel structure, which explain the different patterns of drug release between the two formulations. This implies that changing TPP concentration can control formation of these cavities and hence drug release rate and kinetics. Not present in the sol state, nanostructures lead to emerge of a new concept: pro-nanogels. Finally, the formulations with proper texture qualities, stability and rapid sol-gel transition in vivo could be a candidate for controlled release of therapeutic agents following subcutaneous injection.