Intrathecal delivery of ketorolac loaded in situ gels for prolonged analgesic and anti-inflammatory activity in vertebral fracture

Abstract

Purpose: To develop biodegradable, polymeric in situ gels based on sodium alginate and hydroxypropyl methylcellulose for intrathecal delivery of ketorolac tromethamine (KT) for effective management of pain and inflammation in vertebral fracture. Method: Ion activated in situ gels were used as implants and were prepared from sodium alginate and hydroxypropyl methylcellulose. The fabricated gels were evaluated for visual appearance, clarity, pH, gelling capacity, drug content, viscosity (using Brookfield viscometer), in vitro drug release (using a fabricated KC cell) and in vivo analgesic and anti-inflammatory activity (by intrathecal administration of in situ gel near the fractured vertebra in a rat model). Results: The physicochemical properties (visual appearance, clarity, pH, gelling capacity, drug content and viscosity) of in situ gels were acceptable for therapeutic use. KT-loaded gels demonstrated high drug encapsulation efficiency (98.3 - 103.3 %). Further, KT-loaded gels exhibited viscosity in the range of 1.11 to 6 cps at 50 rpm and shear thinning property (rheology testing). Additionally, the gels demonstrated 84.43 to 96.98 % drug release at the end of 12 h. In particular, in situ gels prepared from 1.2 % alginate/0.4 % HPMC (G7) exhibited excellent analgesic (54.28 %) and anti-inflammatory activity (51.6 % inhibition of rat paw edema) in the animal model of vertebral fracture. Conclusion: The formulated in situ gels can potentially be used as implants for the treatment of patients with vertebral fracture.