The Study On The Optimized Formulation And Pharmacokinetic Of Oral Dapagliflozin Tablets

Dapagliflozin(DAPA)is the inhibitor of sodium-glucose transporter 2(SGLT2),which is clinically used to treat type-2 diabetes mellitus.DAPA selectively inhibits SGLT2,which increases urinary glucose excretion and controls glucose levels.It does not cause hypoglycemia and weight increase,thus delaying the development of diabetic syndrome.The tablet of DAPA is a common film-coated tablet,which is approved for market in 2012 and has owned by Alistair and Bristol-Myers Squibb.At present,the prescription technology of this product is still in 20 years'patent protection period,and the prescription is not clear.To realize the drug domestic accessibility and study the substitution,this subject is carried out to research of the prescription technology of DAPA tablets after the expiration of the patent.The research contents are as follows:(1)Pre-prescription study:A method for the determination of DAPA is established.The solubility and stability of DAPA in water,pH=1.2,pH=4.5 and pH=6.8 are investigated.The results show that the solubility of the four solutions is 1.58�0.26mg/mL,1.66�0.09mg/mL,1.32�0.37mg/mL,and 1.33�0.28mg/mL,respectively.There is no significant degradation within 90 minutes under 37?constant thermostatic waterbath.The physic-chemical characters of API and the compatibility of raw materials and excipients are studied by DSC,SEM,FT-IR and PXRD.The results show that the melting point of DAPA is 81~85.1?,the particle size distribution is uneven,and there is aggregation phenomenon.Pressure within 200kg does not change the crystal structure of API.Excessive rotational speed and high pressure will delay the inherent dissolution of API,and the effect of rotational speed is greater.The stability changes well under high temperature(40?/75%RH),high humidity(75%RH/25?),strong light(2000Lx/25?/74%RH).The compatibility of raw materials and excipients keep well.(2)Research on the original research,analysis and development objectives:Based on recently literatures,the basic information of the original research tablets,such as prescription composition,pharmacokinetics of the original research tablets is obtained.The dissolution methodologie is established.The linear regression equations of pH=1.2,pH=4.5,pH=6.8 and waterisy=65736x-85772(R~2=0.9986),y=71658x-70823(R~2=0.999),y=70364x-39880(R~2=0.9992)?y=68790x-53010(R~2=0.9985),respectively.Four dissolution curves of the original tablets are studied.The results show that the dissolution percentage of the four dissolution curves of the original tablets reach 85%or more at 15 min interval,and there is no pH dependence.Through the quality target product profile(QTPP),critical quality attributes(CQAs)and initial risk assessment of prescription variables,it is clear that the development aim of homemade products should be consistent with the formulation,administration mode and stability of the original tablets.(3)Prescription technology study:By comparing the advantages and disadvantages of conventional tablet pressing technology and aiming at the characteristics of API,powder direct pressing technology is selected,because of its good product stability,energy and time saving,high production efficiency and low cost.The effects of pressure,rotational speed and punch size on the quality of tablets are investigated.The results show that pressure has a significant effect on the quality of tablets,while rotational speed and punch size had no obvious influence on the quality of tablets.Finally,a pressure of 50 kg,a speed of 7 rpm and a punch size of 9 mm are selected.Mixture design using DOE in prescription design is according to the hardness,fragility,tablet weight variation and dissolution results in vitro.The best prescriptions are API(5%),MCC101(51.9%),anhydrous lactose Flowlac(37.5%),PVPP(3.6%),magnesium stearate(1%)and silicon dioxide(1%).When mixing,magnesium stearate is finally added to prevent the API from overmixing and affecting the dissolution.(4)Pharmacokinetic study:The methodology of blood concentration is established in healthy male SD rats.The linear equation is y=40834x+237288(R~2=0.9916).Eyeball blood is collected at 0.5h,1h,2h,3h,6h and 12h after oral administration in groups.Blood drug concentration at each time point is determined and blood drug concentration-time curve is drawn.The results show that the trend of blood concentration-time curve of self-made tablets keeps basically the same as that of original tablets.Within 0.5h-3h,the peak value of blood drug concentration is about 3h,the maximum concentration of homemade tablets is about 400ng/mL,and the maximum concentration of original tablets is around 500 ng/mL.After 3h,the blood drug concentration gradually declines,but no results in too low tissue concentration.Both the original and homemade groups of the body weight increase significantly,an average gain of about 2 g/d,which is much higher than that of the untreated group.Conclusion:Through the pre-prescription study and the analysis of the original DAPA tablets,the powder direct pressing process with simple and feasible technology,easy operation and low energy consumption is selected to prepare the optimized formulation of DAPA homemade tablets.The safety of the tablet preparation process was analyzed and accident prevention measures were given.The hardness,fragility and tablet weight variation of the homemade tablets meet the requirements of pharmacopoeia,and the trend of blood concentration-time curve of the tablets is basically consistent with that of the commercial tablets.It provides basic data for the research and development of domestic oral tablets of DAPA and carries on important guiding significance for the optimization of the preparation process.