| Amoxicillin and clavulanate potassium is a compound preparation of broad-spectrum antibiotics and enzyme inhibitors.It is widely used clinically for upper respiratory tract infections,lower respiratory tract infections,urinary tract infections,and skin and soft tissue infections caused by susceptible strains.The original preparation used in this project was amoxicillin and clavulanic acid tablets(2:1)developed by British company Glaxo Smith Kline(GSK)with a specification of 0.375 g.The product is not yet available in China and the preparation is very stable.In the production and storage process,the impurity content does not increase significantly.Currently,it is widely used in clinical practice abroad and the benefits are very good.The stability of the same kind of drugs produced by most domestic manufacturers is poor,and the content of impurities increases significantly after storage for a period of time,which affects the efficacy of drugs and is prone to adverse reactions.This project aims to explore different prescriptions and techniques to prepare an amoxicillin potassium clavulanate film-coated tablets for in vitro and in vivo experiments and quality studies in order to meet the quality control requirements and similar in vivo and in vitro studies.Part one Study on formulation and process of AMC film-coated tabletsObjectives: The optimal formulation and process for the screening of amoxicillin-clavulanate potassium film was chosen so that its in vitro dissolution profile was similar to that of the original study.Methods: The raw materials of amoxicillin and potassium clavulanate were mixed well with suitable excipients.After dry granulation,the tablets of amoxicillin and clavulanate potassium were compressed.On the basis of the existing cores,a film coat is prepared by using a high-efficiency coating machine to finally obtain a finished tablet.With dissolution rate as the evaluation index,the optimal prescription was screened and the optimal coating weight gain was determined.Results: According to the prescription screening,the optimal prescription for determining amoxicillin and clavulanate potassium core is:AML 250 mg CLA 125 mg MCC 230 mg PVPP 30 mg Aerosil(Inner)10 mg Magnesium stearate(extra)2 mg The optimum process parameters for dry granulation are: extrusion pressure 15 kg/cm2,feeding speed 9 ~ 10 rpm,extrusion speed 12 rpm,through 16 mesh screen,take 16-40 mesh particles for tableting.Tableting parameters: theoretical weight 695 mg,controlled at 680~710mg,using ?16*8 mm capsule type stamping,hardness of 17~23 kg/cm2.Film layer coating solution:Tablet 200 g Opadry 10 g100 m L water as solvent,coating weight gain of 3%The best parameters for the coating process:Inlet temperature 65oC Pot body temperature 35~40oC Pot rotation speed 7 rpm Coating liquid pump speed 2~4 rpm Spray pressure 1 kg Fan speed 1600 rpmConclusion: The preparation process of the amoxicillin potassium clavulanate film is simple and feasible,and the reproducibility is good.The in vitro dissolution profile of the homemade preparation is similar to the reference preparation.Part two Study on quality of AMC film-coated tabletsObjectives: The self-made AMC film-coated tablets were subjected to quality control studies to ensure its safety,efficacy and controllability.Methods: HPLC method was established to determine the content of self-made AMC film-coated tablets.HPLC,fluorescence spectrophotometry and GC were used to determine the contents of polymers,aliphatic amine impurities and related substances in homemade preparations.Results: The HPLC method was used to determine the content of main drug in AMC film-coated tablets.The methodological investigation results showed that the specificity,linearity,precision,repeatability and recovery were all good.The polymers,fatty amine impurities and related substances in the preparations were examined and the results were in compliance with the defined requirements.Conclusion: The method for determining the content of amoxicillin and clavulanic acid was simple and convenient,and the durability was good.The contents of the three batches of self-made preparations met the requirements and the content was uniform.The quality of the polymers,aliphatic amine impurities and related substances in the homemade preparations are controllable and meet the prescribed limits.Part three Study on Stability of AMC film-coated tabletsObjectives: Study the self-made preparations under the influence of temperature,humidity and light changes with time,provide the basis for the production of drugs,packaging forms and storage conditions.Methods: Taking the appearance of the preparation,the content of the main drug and the content of related substances as the inspection indicators,the influencing factor test and the accelerated test were conducted to examine the stability of the preparation.Results: The preparations were not stable at high temperature of 60oC for10 days,but all items under the conditions of 40oC met the requirements;the preparations were not stable under 90% and 75% high humidity environment for 10 days,indicating that the product was very sensitive to humidity;placed under high light 4500 Lx for 10 days,all the items studied meet the requirements.Accelerated test results of six months showed that according to the packaging conditions of the original preparation agent,various inspection items of homemade preparations were relatively stable.Conclusion: Preparations are susceptible to high humidity and high temperatures,so be careful when storing samples to prevent moisture and avoid placing them in high temperatures.Part four Study on pharmacokinetics of AMC film-coated tabletsObjectives: Study the bioequivalence of self-made preparations and reference preparations in Beagle dogs.Methods: Beagle dogs were used as experimental animals to establish HPLC method for the determination of amoxicillin and clavulanic acid in plasma.Pharmacokinetic tests were performed using a two-period dual-cycle crossover design,and drug-time curves for the two formulations were recorded and plotted.Finally,DAS software was used to calculate pharmacokinetic parameters and 3P97 software was used for bioequivalence analysis.Results: HPLC method for the determination of amoxicillin and clavulanate potassium in plasma was established.The pretreatment of blood samples was simple and feasible.The AUC0?? of amoxicillin in the self-made and reference preparations were(30.422 ± 1.347)and(31.526 ± 1.181)mg/L*h,respectively,and the Cmax was(11.425±0.568)and(11.6±0.517)?g/m L,respectively.The Tmax was(1.417±0.204)and(1.583±0.204)h,respectively;the AUC0?? of clavulanic acid were(24.881 ± 0.673)and(26.688±0.949)mg/L*h,respectively,and the Cmax was(11.31±0.584).)and(11.093 ± 0.514)? g/m L,Tmax were(1.167 ± 0.258)and(1.083 ±0.204)h,respectively.The 90% confidence intervals for the log ratios of AUC0-? and Cmax for amoxicillin and clavulanic acid in the reference preparations and test preparations were within 80% to 125% confidence intervals;ln(AUC0-?)and ln(Cmax)After two one side t test,t1?t1-?(v)and t2?t1-?(v)are established at the same time.Conclusion: The self-made formulation of AMC film-coated tablet is bioequivalent to the reference formulation. |
PDF Full Text Request