| Objectives:In recent years,the incidence of depression is increasing year by year.According to the degree of the depression,it can be divided into mild,moderate,severe depression.Major depressive disorder（MDD）is a kind of long-term emotional nerve disease,and it is accompanied by some physical symptoms.It is not only the severity of the depression,one of the most important feature is that it attacks repeatly and periodically.Desvenlafaxine succinate（DVS）is a potent and selective 5-HT and NA reuptake inhibitor.It can effectively inhibit the brain’s reuptake function of 5-HT and NA,so it can be used to treat the patients with MDD.Desvenlafaxine succinate sustained-release tablets approved by the FDA in the year of 2008,but there is no research report in China.The purpose of this study was to prepare desvenlafaxine succinate sustained-release tablets,making it localization.Methods:1 The preparation of desvenlafaxine succinate sustained-release tablets:We will establish the method to determine the vitro release degree of desvenlafaxine succinate sustained-release tablets,and do methodological study,refering to the FDA relevant regulations and literatures.To determine the type and dosage of skeleton material,the type of filler,the dosage of lubricant,preparation process and the pressure,we investigate the prescription and preparation process factors by the index of the in vitro release degree.After several preliminary experiments monitoring the process of coating,we should determine the optimum parameters for coating machine,with the coating film appearance and weight gain as index.We will prepare three batches of desvenlafaxine succinate sustained-release tablets according to the best prescription and preparation process,and study the stability of the preparation process with the in vitro release degree as index.The in vitrorelease profile are fitted with different release equations,and further exploring the release mechanism of desvenlafaxine succinate sustained-release tablets.2 The research on quality control of desvenlafaxine succinate sustained-release tablets: we establish the method to determine the content and content uniformity of desvenlafaxine succinate sustained-release tablets,and do methodological study.The self-made desvenlafaxine succinate sustained-release tablets will be studied influence factors test and accelerated test to investigate the formulation stability by the index of appearance,content,the gain in weight after moisture absorption and the in vitro release degree.3 The pharmacokinetics study of desvenlafaxine succinate sustained-release tablets: we make two formulations and two period crossover experiment on six healthy beagle dogs and collect vein blood samples at the design time after the beagle dogs oral administration of desvenlafaxine succinate sustained-release tablets or normal tablets.Referring to the relevant literatures,we determine the processing method and analytical methods of plasma samples,and study methodology.We calculate the pharmacokinetic parameters of the two kinds of tablets and compare them.Results:1 We have established the method to determine the in vitro release degree of desvenlafaxine succinate sustained-release tablets.According to the first method（Basket）operation of Chinese Pharmacopoeia,the release medium is 900 ml 0.9% NaCl aqueous solution;the temperature is 37℃;rotation speed is100 r·min-1.The samples of the time of 2,4,8,12,24 h are detected by UV spectrophotometry and detection wavelength is 274 nm.Methodological study results show that the precision and recovery are good.There is a good linear relationship between the absorbance（A）and concentration（C）at the concentration rage of 10 μg·ml-1160 μg·ml-1.2 With the in vitro release degree as an index,the best prescription and preparation process of desvenlafaxine succinate sustained-release tablet have been determined by single factor investigation.After several preliminary experiments monitoring the coating process,we have determined the optimummachine parameters and coating time.The coating weight gain is 5%;the coating film is uniform and smooth.Preparation Process:We weigh the prescription amount of drugs and excipients and mix them.We add appropriate amount of binder（10% PVP K30）to them to make soft material,and then make wet granulations through the 40 mesh sieve.After the granules dried,we take the uniform granules between 32 mesh and 40 mesh.Adding magnesium stearate to the granules,we compress tablets with 70 KN pressure.Tablet diameter is 9 mm;weight is 242 mg.The coating machine parameters:When the coating pan reaches to 40℃,we put the tablets into the coating pan.The first stage: the mass temperature is 40 ℃;inlet air temperature is 60 ℃;coating pan’s speed is 5 rpm;liquid ejection pressure is 1.5 kg;the blower speed is 2500 rpm;the coating liquid speed is 2 rpm(4 ml·min-1),coating for 20 min.The second stage: when the tablet’s surface covered with uniform film,we accelerate the coating liquid speed to 4 rpm(8 ml·min-1),coating for 40 min.The third stage: when the film completely covers the edges of the tablets,we slow the liquid ejection to 2 rpm(4 ml·min-1),coating for 20 min.The tablets continues to rotate for 30 min in the pan to make them dry.3 The in vitro release behavior of self-made desvenlafaxine succinate sustained-release tablets is consistented with the first-order equation.The drug release mechanism is diffusion and matrix erosion.4 We have established the HPLC method to determine the content and content uniformity of desvenlafaxine succinate sustained-release tablets.Methodological study results show that the specificity,precision,recovery and reproducibility are good.There is a good linear relationship between concentration（C）and peak area（A）in the concentration range of 96μg·ml-1144 μg·ml-1.5 The appearance,content,release degree of self-made desvenlafaxine succinate sustained-release tablets don’t change significantly after putting them at 60℃ for 5 days and 10 days.After putting the self-made tablets in the condition of 92.5% relative humidity for 5 days and 10 days,the moisture weight gain is greater than 5%,which don’t meet the quality requirements.After putting the tablets in the condition of 75% relative humidity for 5 days and 10 days,the moisture weight gain is less than 5%.The appearance and content show no significant change;the release degree slightly reduce at 2h.The above results indicate that this formulation should be kept in the condition avoiding high humidity.After putting the self-made tablets in the condition of4500±500 Lx illuminance for 5 days and 10 days,the appearance,content,release degree of self-made tablets don’t change significantly.6 We have established the HPLC method to determine the plasma samples.Methodological study results show that the specificity is good.There is a good linear relationship between the plasma samples’ concentration（C）and peak area（A）in the concentration range of 25 ng·ml-11250 ng·ml-1.In high,medium and low concentrations,the precision,recovery,repeatability and stability of plasma samples are good.7 We have used non-compartmental model to process plasma concentration-time data,and calculated the pharmacokinetic parameters.The Tmax,Cmax and MRT0→∞ of self-made desvenlafaxine succinate sustained-release tablets and normal tablets are 8.33±1.03 h,315.63±15.22ng·ml-1,17.02±1.70 h and 2.33±0.82 h,987.03±56.10 ng·ml-1,4.26±0.23 h,respectively.The results shows that the Tmax,MRT0→∞ of sustained-release tablets prolong and the Cmax of sustained-release tablets decrease;and it have a good sustained release effect in the body.Conclusion:This study have successfully prepared desvenlafaxine succinate sustained-release tablets,and preparation process is simple,reliable and repeatable.In vitro release tests shows that the sustained-release tablets can release drug for 24 h,and the release process meets the first order equation.The content and content uniformity of the self-made sustained-release tablets are meet the quality requirements.When storage the tablets for long term,we should pay attention to moisture.The pharmacokinetic study proves that the sustained release tablets also has a good sustained release effect in vivo. |
