Injectable Sustained-release Gel Loaded Microsphere/Microcrystal For Osteoarthritis Therapy

Osteoarthritis(OA)is an age-related disease leading to a decline in quality of life of patients.Local injections of corticosteroids have historically been applied to rescue acute exacerbation of knee osteoarthritis.Oral non-steroidal anti-inflammatory drugs(NSAIDs)are also popularly recommended for prolonged improvement in chronic articular pain.So,the combination of the two kinds of drugs is commonly used to control the development of OA in clinical.However,long-term administrations of both medications may result in the osteonecrosis of knee due to the repeated injections of steroids and the side effects in gastrointestinal and cardiovascular system.For the purpose of conquering these unmet medical needs,we designed a sustained-release gel for intra-articular injection.Firstly,a hydrophilic corticosteroid,dexamethasone sodium phosphate(DSP),was encapsulated by microspheres to increase the retention time in the joint.Then,celecoxib(CLX)microcrystals were prepared in order to enhance the water solubility.Finally,the gel with highly efficient thermal-sensitivity was prepared via the esterification crosslinking.The contents of this study are as follows:DSP loaded microsphere(DM)was optimized by Plackett-Burman design and Taguchi orthogonal design in response to encapsulation efficiency,and effects of processing parameters were analyzed.CLX microcrystal(CM)was manufactured using an antisolvent-ultrasonic method.The results of X-ray diffraction pattern,differential scanning calorimetry and Fourier transform infrared spectroscopy illustrated that CM gained a decline of particle size and crystallinity compared to coarse powders,and the dissolution test confirmed the improvement of solubility.Moreover,a solvent-free method was employed to heating crosslink and synthesize a novel Poloxamer 407/Gantrez S97 based gel(GZF).Characterizations verified the occurrence of esterification reaction,and rheological studies demonstrated that GZF gel could be injected at room temperature and taken place sol-gel transition in lower concentration.The in vitro release of DSP and CLX was fast phase in 24 h followed by a controlled release of ～8 days with 98.6% and 92.2% of release amounts of DSP and CLX,respectively.The effects of OA therapy of DM/CM/Gel were evaluated in cytology and in vivo.Both non-loaded microspheres and GZF polymers displayed great biocompatibility against RAW264.7 macrophages.The most suitable dosages of 5 n M DSP and 125 n M CLX in the formulation were determined because of its significant effects against macrophage inflammation with less administrative amount.In vivo animal evaluation showed that DM/CM/Gel suppressed the release of inflammatory cytokines after 21 days treatment.In addition,histological evaluation revealed that DM/CM/Gel interrupted the progression of cartilage surface denudation and matrix loss.Therefore,DM/CM/Gel is a prospective strategy for OA therapy,which also provides an inspiration for the development of OA innovative formulations.