Study On Of Compound Metformin Hydrochloride/saxagliptin Controlled Release Tablets

Diabetes mellitus is a chronic disease which is harmful to human health.At present,there are a lot of hypoglycemic medicines used in clinical,because it is not ideal to control the blood sugar with a certain type of hypoglycemic medicine,and the combination of drug used in clinical is more and more common in recent years.metformin hydrochloride that is a type of Biguanide antidiabetic drug by promoting glucose anaerobic glycolysis,increasing peripheral tissue to uptake glucose and glucose’utilization lowers blood sugar,protecting the damagedβcells’function from further damage,which is a basic treatment in patients with type 2 diabetes.Saxagliptin is a Dipeptidyl peptidase-4（DPP-4）inhibitor,which can improve the activity of GLP-1 by inhibiting the rapid degradation of endogenous GLP-1 and improving the function of islet.Two drugs are complementary in action mechanism,which can play the role of synergy.The combination of medication in Clinical can more effectively control blood sugar,reduce the risk of hypoglycemia,and not increase the weight.Therefore,in this paper,the osmotic pump controlled release technique was used,we combined metformin hydrochloride with saxagliptin as a model drug to study and prepare the compound metformin hydrochloride/saxagliptin osmotic pump controlled release tablets,for a chronic disease of long-term treatment,it has important clinical significance.The compound metformin hydrochloride/saxagliptin sustained-release tablets developed by the cooperation of Bristol Squibb Company and AstraZeneca has been listed in 2010 in the United States,the name of the commodity is Kombiglyze XR,but there is no report about preparation study or the listing of compound metformin hydrochloride/saxagliptin at home.A novel compound metformin hydrochloride/Saxagliptin osmotic pump controlled release tablets was prepared by osmotic pump technology.The Osmotic pump controlled release preparation compared other forms has the following advantages:?it can release drug at a constant rate in a certain time and is not affected by pH,gastric bowel peristalsis physiological factors;?the fluctuation of blood drug concentration is minimized which reduces toxic and side effect;?it can reduce the frequency of administration,improve the formulation’effectiveness and safety and compliance of patients;?it has high technical content,short development cycle,and is easy to industry.The specific composition of compound metformin hydrochloride/saxagliptin osmotic pump tablets:double-layer tablet core composed of containing layer and push layer,semi-permeable membrane coating layer,rapid-release coating layer containing the active drug.The drug core is divided into drug layer and boosting layer,bread a semi-permeable membrane layer outside the core,punch a hole in the drug layer side.After the medicine is taken,the rapid-release layer can be dissolved in body fluids,so the rapid-release coating layer in the drug can quickly from the surface of the tablet dissolute,the humoral fluid through a semipermeable membrane gradually infiltrate into the chip internal,the push layer in the core under the water swelling pushs drug from the hole at the constant speed.This study of the preparation of double-layer osmotic pump tablet has more obvious advantages:the rapid-release coating layer in the drug can quickly play a role of treatment;the drug in core can release slowly,the efficacy of drug is more durable;the blood drug concentration is stable;Reducing frequency of medication and reducing side effects;Zero order release characteristics is significant;the drug release compared to monolayer osmotic pump is more fully.In the establishment of the quality standard of the compound preparation,it was found that the conventional C₁₈ column can not separate metformin hydrochloride from Saxagliptin.In order to better control the quality,this study used a cyano column to establish the simultaneous determination method by HPLC for self-made osmotic pump controlled release tablets of metformin hydrochloride and saxagliptin content.The method can simultaneously determine the content of two principal components in compound metformin hydrochloride/Saxagliptin osmotic pump controlled release tablets,which is simple in operation and accurate in result,and can be used for quality control of the preparation.This study selected PEO and sodium chloride as the main supplementary material for the core,cellulose acetate（CA）and PEG1500 as coating material,acetone as organic coating solvent to prepare compound metformin hydrochloride/saxagliptin osmotic pump controlled release tablets.On the basis of the release mechanismthe of osmotic pump tablets,the f₂ similarity factor method FDA recommend was used as an evaluation index of drug release degree,the main investigation from the following several aspects:drug layer prescription,boost layer prescription,coating membrane prescription and drug release in vitro condition,etc.Through the single factor testing,We selected three important influential factors which affected the cumulative release rate（Y₁）within 12 hours and the drug release curve fitting degree（Y₂）of compound metformin hydrochloride/Saxagliptin osmotic pump tablets.The factors that have important influence on the above two indexes include:the content of PEO in the push layer（A）,the content of NaCl in the push layer（B）and the weight of coating film（C）.We took the above three factors as the dependent variable,the cumulative release of metformin and drug release curve linearity as independent variables,using the Box-Behnken design-response surface method（BBD-RSM）.We conducted the prescription optimization testing of compound metformin hydrochloride/Saxagliptin osmotic pump controlled release tablets via three factors and three levels,through the Design-Expert8.0.5b optimization software,we predicted the best prescription and the best prescription was as follows:the content of PEO in the push layer 99mg/tablets,the content of NaCl in the push layer 49mg/tablets,the gaining weight of coating 5%.And according to the best prescription to verify,we compared the measured value with the optimization value the software predicted,we can know the predictive effect by using the fitting model.In 12 hours average cumulative release of predictive value was 95.43%,the linearity of predictive value was 0.9736,in 12 hours average cumulative release of the measured value is 95.16%,the linear degree of the measured value is 0.9709,there was same basically between the measured value and the predictive value.This noted that the Box-Behnken design-response surface method can be used as an experimental method to optimize the prescription of compound metformin hydrochloride/Saxagliptin osmotic pump controlled release tabletsAt the end of this paper,the stability of compound metformin hydrochloride/saxagliptin osmotic pump controlled-release tablets was investigated.The influencing factors testing results showed that metformin hydrochloride/saxagliptin controlled release tablets under the condition of60℃for 10 days and 4500lx light intensity for 10 days were stable,various indexes were not significantly changed;under the condition of relative humidity of 92.5%for 10 days,The character had obvious change,tablets were softened by moisture absorption.Therefore,the follow-up samples should be kept in a closed,dry environment.The Accelerated testing results showed that:under the condition of 40℃,relative humidity of 75%,three batch samples simulated the listed packaging for an accelerated test,the examining indexes showed no obvious changes within 3 months,the follow-up testing is in progress.The Long-term testing results showed that:under the condition of 25℃,relative humidity 60%,three batch samples simulated the listed packaging for a long test,the examining indexes showed no obvious changes within 3months,the follow-up testing is in progress.