| Objectives:Hypertension is a common disease.It can include other severe diseases such as myocardial infarction,strokes. The complications and mortality can be dramatically reduced by blood pressure control.H-160 is a dihydropyridine calcium ion antagonist and is a first-choice treatment for high blood pressure and angina in clinical application.Sustaind and controlled release preparation in recent yesrs,with its significant advantages more and more get the attention of people. And the drug release behavior of OS preparation is one of the most ideal dosage forms in oral slow controlled release preparations.The purpose of this study is with H-160 as the medel drug,to prepare a OS tablets,daily use a dose can get the purpose of treatment and reduce the incidence of adverse reactions at the same time.Methods:1 Preparation of OS tablets of H-160:H-160 mixed with PEG6000,use hot melt-squeeze machine to preparate the solid dispersion,then through by 40 mesh.The solid dispersion mixed with other accessories,use anhydrous ethanol to stick all,then through by 30 mesh.Dry the granule in 45 ℃for 30 minutes.Lastly,let them pass by 30 mesh again.The medicine containing layer is preparaed.Then use the same method to prepare the push layer. The medicine containing layer and push layer were compressed twice to prepare core tablets by 9mm die.Tablets were coating by Y6 which is soluted by acetone.At last,punch the medicine containing layer with the laser punching after 12 h,then the OS tablets of H-160 were prepared. The best prescription and process of core tablets was determined by a series of single factor experiments and L9(33) orthogonal experimental design.2 Research on quality control of OS controlled release tablets: established UV spectrophotometric method and HPLC method for the determination of dissolution of H-160 controlled release tablets and evaluated the consistency of the two methods; established HPLC method for the determination of content of H-160 and carried out the methodological studies.. And studied the stability of the self-made preparation with the evaluation indexes of appearance,content,and dissolution.3 Bioavailability studies: Developed HPLC method for the determination of H-160 in Beagle dog plasma. Adalat was taken as the reference preparation, a single-dose, two-treatment, two-sequence and randomized crossover study was Y6 rried out on four adult beagle dogs, studying its pharmacokinetics, relatively bioavailability,bioequivalence and the in vitro-in vivo correlation.Results:1 The best prescription and preparation process of the OS tablets of H-160 were selected through the single factor test and orthogonal test design.(1) medicine containing layer:H-160 30mg PEG6000 60mg Q8 47mg W9 12mg Lactose 35mg Magnesium stearate 0.5%(2) push layer Q9 10mg W9 20mg Na Cl 10mg M7 6.5mg Lactose 43.5mg Magnesium stearate 0.5% Coating liquid Y6 30g N5 3g Triethyl citrate 4.5g Acetone 1000ml Weight gain 10%Process: The solid dispersion mixed with other accessories,use anhydrous ethanol to stick all,then through by 30 mesh.Dry the granule in 45 ℃ for 30 minutes.Lastly,let them pass by 30 mesh again.The medicine containing layer is preparaed.Then use the same method to prepare the push layer. The medicine containing layer and push layer were compressed twice to prepare core tablets by 9mm die.Tablets were coating by Y6 which is soluted by acetone.At last,punch a 0.8mm hole in the medicine containing layer with the laser punching after 12 h,then the OS tablets of H-160 were prepared.2 Established a UV spectrophotometric method and a HPLC method for the determination of dissolution rate of controlled-release tablets of H-160:The detection wavelength was 238 nm with no interference of excipients. The methodological study results showed that within the concentration range of 2μg·m L-1~12μg·m L-1, the linear relationship between absorbance and concentration,area and concentration of H-160 was good. The regression equation were:UV method A=0.06C+0.0433,γ=0.9997;HPLC method A=82461C+5256.1,γ=0.9994. RSD of precision value respectively were 0.08% and 0.54%. low, medium, and high concentrations of recoveries of UV and HPLC mean of 98.93% and 98.74%.H-160 solution is stable away from light. The result showed that UV method and HPLC nethod were consistent after using the two methods to determine the dissolution rate of self-made tablets. The UV method Y6 n be used for the determination of the dissolution rate of controlled-release tablets of H-160.3 Established a HPLC method for the determination of the content of controlled-release tablets of H-160: The detection wavelength was 238 nm with no interference of excipients and mobile phase. The methodological study showed that within the concentration range of 4~24 μg·m L-1, the linear relationship between peak area and concentration of metoprolol succinate was perfect. The regression equation was A=82477C+5086.3,γ=0.9997.RSD of precision value was 0.34%.low, medium, and high concentrations of recoveries mean of 99.42%. This method can be used for the determination of the content of controlled-release tablets of H-160.4 Study on stability of self-made tablets:Under the condition of high temperature(60℃),the tablets would soon melt. Under the condition of 40℃,RH 92.5% and 75%, there was no significant change in the appearance,content and dissolution.Under the strong light(4500LX),tablets were unstabilite. The preservation of the tablets should avoid high temperature and light.5 Established a HPLC method for determination of H-160 blood drug concentration: wavelength was 238 nm, blank determination had no interference on H-160. The linear relationship was good in range of 2~100ng/m L, linear, the regression equation was A = 74.261C+884.26, γ=0.9990. Relatively bioavailability of test preparation was 95.95%, and there was a good correlation between absorption in vivo and drug release in vitro.Conclusions:The formulation and preparation of OS tablets of H-160 was feasible, with good reproducibility, and Y6 n achieve controlled release effect.The methods were established for the determination of dissolution rate and content. Experiments showed that H-160 controlled release tablets should be kept to avoid high temperature and humidity. The vivo pharmacokinetic studies had shown that compare to reference preparation, self preparation had good bioavailability,and there was a good correlation between absorption in vivo and drug release in vitro(γ=0.9297). |
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