Study On The Preparation And Sustained Release Properties Of The Betamethasone Microspheres/Chitosan-sodium Hyaluronate Thermosensitive Hydrogel Combined System

Obiective:Osteoarthritis is a chronicly regressive osteoarthrosis that severely hazard to the health of the elderly.There are60millions—70millions people got different degree of OA in our country.Intraarticular injection of Glucocorticosteroid and Hyaluronic acid is the commonly used treatment methods for OA.However, Elimination of drug is fast after the intraarticular injection. Thus, the local drug concentration falls quickly and the local concentration will be low, also needs frequent administration frequency. Aimed to the above problems This article innovationally designed an preparation betamethasone microspheres/chitosan—Sodium Hyaluronate thermosensitive hydrogel combination system for intraarticular injection to treatment of OA, which prapare betamethasone and sodium hyaluronate in the same dosage form in order to effect,also reduce the infection by injection respectively.These drug delivery systems are flowable aqueous solution before administration, but once injected, they rapidly form gel under physiological conditions and hence an in situ"drug deporf"forms, which could effectly contain the stable drug concentration, reduce administration frequency and side effect, enhanee the patient compliane.Methods:(1) The preparation of betamethasone microspheresThe betamethasone loaded sustained release microspheres were prepared using O/W emulsion solvent evaporation method under the consideration of the drug properties. The microscopy and structure of microspheres were characterized by Scanning electron microscopy(SEM) and Fourier transform infrared(FTIR), the content of drug was determined by Ultraviolet(UV) Spctrophotomatry method. Choosing diameter, drug loading and encapsulation efficiency as evaluating indexes, the best formulation and technological parameters were optimized based on the results of single factor study and the orthogonal. (2) The preparation of chitosan—Sodium Hyaluronate thermosensitive hydrogelCombined the Sodium Hyaluronate and chitosan-β-GP hydrogel system in order to prapare chitosan—Sodium Hyaluronate thermosensitive hydrogel. Investgating the effect of chitosan deacetulation、dissolved medium and mass percent fo chitosan、β-GP、Sodium Hyaluronate on the gelation time、 pH and syringeability, the optimied parameters were selected.(3) The preparation of betamethasone microspheres/chitosan-Sodium Hyaluronate thermosensitive hydrogel combination systemInvestigating the effect of administration dose of betamethasone microsphere in the hydrogel on the gelation time、pH and syringeability of the combined system,thus defining the mass of microspheres loaded.(4) Study on in vitro release of the preparationsChoosing PBS as mediun and selecting dialysis method,appliled High-perfprmace liquid chromatography (HPLC)method to detect drug reease of the praparation in vitro.Results:(1)The best preparation prescription of betamethasone microspheres was:betamethasone:PLGA1:10(W/W); the oil phase was5.00%(W/V) PLGA/DCM solution;water phase was2.0%PVA(W/V) aqueous solution;oil phase/water phase volume ratio=1:25;the stirring rate was700rpm,the temperature was room temperature. The prepared microspheres had an smooth surface and porous layer, with drug loading percent of10%,encapsulation efficiency of71.38%,middle diameter of41.05um.(2) The best preparation prescription of chitosan—Sodium Hyaluronate thermosensitive hydrogel was:2%(w/v) Chitosan solution of90%Deacetylation, with dissolve medium of0.1mol HCL, the maass percent ofβ-GP was30%, the maass percent of Sodium Hyaluronate was10mg/ml. which prepared in the ice stirring condition. The pH of the hydrogel is7.322, the gelation time in37℃was5’37".(3) The best administration dose of betamethasone microsphere in the hydrogel was:2.8ml chitosan—Sodium Hyaluronate thermosensitive hydrogel could load35mg betamethasone microspheres.(4) Betamethasone microspheres sustained released11d in vitro, with best release mathematical model of Higuchi equation, betamethasone microspheres/chitosan-Sodium Hyaluronate thermosensitive hydrogel combination system sustained released79%in17days, with best release mathematical model of first-order and Hixcon-crowell equation.Conclusion:In this subject, the preparation of betamethasone microspheres/chitosan-Sodium Hyaluronate thermosensitive hydrogel combination system had a good sustained-release property and sol to gel doage form change in vitro, which in comply with study objective.