The Preparation Of Amoxicillin And Clavulanate Potassium Enteric Capsule And In Vitro And In Vivo Evaluation

Amoxicillin clavulanate potassium compound preparation is a commonly used broad-spectrum antibiotic,can be used to treat oral,respiratory,digestive and other parts of the infection.As of March 2020,the website of the state food and drug administration has approved 86 amoxicillin clavulanate potassium compound preparation Numbers,73 domestic drug Numbers,with a ratio of 2:1,4:1,7:1,8:1,14:1,16:1 and 13 imported drug Numbers,all with a ratio of 7:1.In this study,amoxicillin and potassium clavulanate enteric pellets were prepared respectively to prevent potassium clavulanate from being decomposed by gastric acid and reduce related substances.Amoxicillin potassium clavulanate enteric capsules(2:1)were prepared and their qualities,stability and pharmacokinetic studies were conducted.Compared with amoxicillin clavulanate potassium film coating tablets(2:1,specification 0.375g),the bioavailability is expected to be improved.Part one Study on the formulation of amoxicillin clavulanate potassium enteric solution capsuleObjective:The optimal prescription and preparation process of amo xicillin potassium clavulanate enteric capsule were selected based on the dissolution curve and content.Methods:The pellets were prepared by extrusion spherification and centrifugal granulation,and then coated by fluidized bed.Finally,amoxicillin enteric pellets and clavulanate enteric pellets were prepared.The particle size distribution,diameter,yield,roundness,crispness and main drug content were used as evaluation indexes to determine the main drug content.Results:According to prescription screening,determine the preparati on of pellets by centrifugal granulation method,Centrifugal granulator parameters:The disc rotate speed 350 rpm Atomization pressure 0.1 mpa Spray volume 13 rpm Air volume 20%Adhesive 5%PVPK30??????Isolation layer prescription and coating parameters:Enteric layer prescription and coating parameters:Conclusions:Pellet preparation by centrifugal granulation is simple and feasible with uniform particle size distribution and high yield.Amoxicillin enteric-soluble pellets and potassium clavulanate enteric-soluble pellets were prepared by encapsulating the isolation layer and enteric-soluble layer in a fluidized bed.Part two Study on the quality of amoxicillin clavulanate potassium enteric solution capsuleObjective:According to the properties of amoxicillin and potassium clavulanate,to establish a simple and reliable method of in vitro analysis,to study the quality control of amoxicillin and potassium clavulanate enteric-soluble capsule,to ensure its safety,effectiveness and controllable quality.Methods:HPLC method was used to determine the release,content and related substances of amoxicillin clavulanate potassium enteric capsule in vitro.The potassium clavulonate polymer and other fluorescent impurities were determined by fluorescence detection.Results:The results of methodological investigation showed that specificity,linearity,precision,repeatability and recovery were good.The related substances and fluorescent impurities in the preparation were tested and the results met the requirements.Conclusions:The method of in vitro analysis of amoxicillin clavula nate potassium enteric capsule was established,which can be used for d etermination.The related substances and fluorescent impurities in the preparation all meet the qualified requirements.Part three Study on the stability of amoxicillin clavulanate potassium enteric-soluble capsuleObjective:The changes of the preparation with the change of temperature,humidity and light are studied to provide a basis for the produc tion,packaging and storage conditions of the drug.Methods:The stability of the preparation was determined by the a ppearance of the preparation,the contents of main drugs and related sub stances.Results:The preparation was unstable when placed at a high temperature of 60? for 10 days,and all the inspection items met the requirements under the condition of 40?.The preparation is unstable in 90%and 75%of the high humidity environment for 10 days,the product is sensitive to humidity;The preparation was kept stable for 10 days under the condition of strong light 4500Lx,and all inspection items met the requirements.Conclusions:The preparation is susceptible to high temperature and humidity,so the sample should be stored in a high temperature environment,and pay attention to moisture.Part four Pharmacokinetics of amoxicillin and clavulanate potassium enteric-soluble capsule in vivoObjective:To study the pharmacokinetics of amoxicillin clavulanate potassium enteric capsule(2:1)and amoxicillin clavulanate potassium membrane tablet(2:1)in Beagle dogs.Methods:HPLC method for the determination of amoxicillin clavul anate potassium in plasma was established in Beagle dogs.Pharmacokinetic experiments were carried out with the double period crossover design of two preparations,and the drug-time curves of the two preparations were recorded and plotted.Finally,the pharmacokinetic parameters were calculated by DAS software and analyzed.Results:The AUC and Cmax of amoxicillin and clavulanic acid in the self-made preparation were significantly higher than that the reference preparation,indicating that the preparation of enteric capsule reduced the decomposition of clavulanic acid and improved the bioavailability of amoxicillin.Conclusions:Compared with amoxicillin clavulanate potassium tablets,amoxicillin clavulanate potassium enteric capsule has higher bioavailability.