Study On The Sustaind-relaese Matrix Tablets Of Oxaceprol

Arthritis is a common chronic disease with osteoarthritis(OA) and rheumatoid arthritis(RA) as the main form.It is a systemic disease with a quite high disability ratio which has the characteristics of joint synovitis and bone and cartilage undermine.It is listed into the three most serious deseases that are threatening human lives by the World Health Organization in 1999.The main treatment drugs are non-steroidal anti-inflammatory analgesic drugs(NSAIDs),which give anti-inflammatory and analgesic effects via inhibiting cyclooxygenase and reduce the formation of prostaglandin to ease arthritis symptoms.As these drugs do not affect the pathological mechanism of arthritis,and they have no therapeutic effect on the joint destruction.1/3 of all drug adverse reactions are caused by NSAIDs(mainly gastrointestinal ulcers and bleeding,gastric perforation,etc.) which limit their clinical applications.However,the incidence of arthritis is not regularity but continually,and prolonged medication is called which cause obvious drug toxicity and decrease the patient medication compliance. Therefore,the development of non-steroidal anti-inflammatory drugs with safety, effectiveness,but less side effects is on the need for clinical therapy and lowering gastrointestinal side effects of NSAIDs is a new basic starting point.Oxaceprol is an amino acid derivative.It has been verified in large number of pre-clinical and clinical trials that the drug has a significant anti-inflammatory effect which is superior to the current clinical NSAIDs widely used.It is used for the treatment of osteoarthritis and rheumatoid arthritis to ease the pain and limb rigidity with better gastrointestinal safety.It has been widely used more than 20 years in Germany and France.It is soluble in water,with a good stability and easily absorbed after oral administration,then excreted in urine and faeces as a prototype drug without metabolism. Experiment data indicate that this drug inhibit neutrophil extravasations selectively via reducing the adsorption of leukocyte to endothelial tissues.As not inhibiting the synthesis of cyclooxygenase(COX) and PG,it gives less gastrointestinal side effects and good clinical tolerance.Its effective blood concentration is high and elimination half-life is short so that a large quantity and frequency administration is needed.Therefore,we designed Oxaceprol sustained-release preparations which administrated twice daily.Firstly,a HPLC method was established to determine the content and related substance of Oxaceprol and to study the stability characteristic of the Oxaceprol sustained release tablets.Ultraviolet spectrophotometry(UV) was developed to assay drug release characteristic in vitro.The equilibrium solubility value of Oxaceprol at 37℃in distilled water,0.1mol/LHCl and pH6.8 phosphate buffer(PBS) was356,362, 354mg/ml respectively,which were all higher than 1g/ml.It can be concluded that the solubility of Oxaceprol was independent with pH.Secondly,single factor experiments were performed and the release rate in vitro was used as an evaluation index.The viscosities & dosages of matrix material HPMC;the species & dosages of blocking agent;the species & dosages of bonding agent;different granulating method;different tablet weight and hardness;different dissolution medium and stirring rate were evaluated respectively.The release rate of Oxaceprol sustained release(SR) tablets decreased as the content of HPMC increased.The viscosity of HPMC had unconspicuous influence on the release rate of Oxaceprol SR tablets.When the hydrophobic material such as EC and Eudragit were used in matrix,the release rate of Oxaceprol SR tablets decreased greatly.The release rates of Oxaceprol sustained release tablets decrease greater when the more hydrophobic material was used.The species of bonding agent,granulating method,tablet weight and hardness had influence on the release rate of Oxaceprol SR tablets,while dissolution medium and stirring rate had unconspicuous influence on the release rate of Oxaceprol SR tablets.Based on the studies of single factor experimentations,optimal formulation and techniques were selected by orthogonal design test.When using HPMC and EC as multi-matrix,Oxaceprol SR tablets of twice daily administration had significantly sustained-release characteristics in vitro.The release behavior of the Oxaceprol SR tablets followed the Higuchi equation.The rationality and stability of the formulation and techniques of Oxaceprol SR tablets were validated by the release determination of 3 batches of Oxaceprol SR tablets.Stability experiments results indicated that Oxaceprol SR tablets were stable to light and high temperature,while the moisture absorption character in high humidity was observed.These results indicated that Oxaceprol SR tablets were instable to high humidity,so the Oxaceprol SR tablets must be stored in airproof containers.The stability experiments results of Oxaceprol SR tablets indicated that Oxaceprol SR tablets were stable at 25℃,RH75%and 25℃,RH92.5%for six month. The experiments results of selecting the coating material of Oxaceprol SR tablets showed that coating had no effect on the release characteristics of Oxaceprol SR tablets.