The objective of this study was to formulate novel painless combined hyaluronic acid (HA)-ketorolac (KT) membrane for the management of osteoarthritis with rapid analgesic onset, thus avoiding HA frequent invasive intra-articular injections and KT gastrointestinal complaints associated with all non-steroidal anti-inflammatory drugs. HA was chemically crosslinked with carbodiimide/glutaraldehyde to yield membrane of low water content. Different in vitro aspects (mechanical properties, water content and in vitro release) were studied leading to an optimized soft, flexible K8 HA membrane containing 30 mg KT that achieved the desired balance of excellent elasticity and low water content. Moreover, a successful retardation of KT release rate was achieved (82%) after 48 h with favored initial fast drug release in the first hour (32.7%) to attain rapid analgesic effect. The clinical assessments in arthritic rats revealed apparent improvement in joint space narrowing, highest increase in bone mineral density at the proximal tibia and distal femur joints with the absence of osteophytosis only in animal group treated with combined HA-KT membrane. Application of K8 membrane was able to preserve KT plasma concentration above its minimum effective concentration for 48 h therefore, would able to replace six commercial tablets each of 10 mg KT.

Ciclesonide (CIC), an inhaled corticosteroid for bronchial asthma is currently available as metered dose inhaler (CIC-MDI) which possesses a major challenge in the management of the elderly, critically ill patients and children. In this work, nebulized CIC nano-structure lipid particles (CIC-NLPs) were prepared and evaluated for their deep pulmonary delivery and cytotoxicity to provide additional clinical benefits to patients in controlled manner and lower dose. The bio-efficacy following nebulization in ovalbumin (OVA) induced asthma Balb/c mice compared to commercial (CIC-MDI) was also assessed. The developed NLPs of 222.6 nm successfully entrapped CIC (entrapment efficiency 93.3%) and exhibited favorable aerosolization efficiency (mass median aerodynamic diameter (MMAD) 2.03 lm and fine particle fraction (FPF) of 84.51%) at lower impactor stages indicating deep lung deposition without imparting any cytotoxic effect up to a concentration of 100 lg/ml. The nebulization of 40 mg dose of the developed CIC-NLPs revealed significant therapeutic impact in the mitigation of the allergic airways inflammations when compared to 80 mg dose of the commercial CIC-MDI inhaler (Alvesco V R ). Superior anti-inflammatory and antioxidative stress effects characterized by significant decrease (p< .0001) in inflammatory cytokines IL-4 and 13, serum IgE levels, malondialdehyde (MDA), nitric oxide (NO), TNF-a, and activated nuclear factor-jB (NF-jB) activity were obvious with concomitant increase in superoxide dismutase (SOD) activity. Histological examination with inhibition of inflammatory cell infiltration in the respiratory tract was correlated well with observed biochemical improvement.