Preparation Of Dexlansoprazole Pulse Enteric Capsules

Objective:Dexlansoprazole is the dextro isomer of lansoprazole,which is a kind of traditional proton pump inhibitor?PPI?.Compared with the racemate,dexlansoprazole has the advantages of long retention time,fast elimination rate,significant effect in vivo etc.It is mainly used for the treatment of heartburn and erosion of esophageal inflammation?EE?associated with gastroesophageal reflux disease?GERD?in clinic.The study aims to prepare two different enteric pellets which can release drug at different parts in intestine,using two different pH sensitive Eudragit materials,and developping a kind of dexlansoprazole capsules which can extend in vivo retention time and significantly efficient to heartburn symptoms of patients with GERD.Methods:1 Establishment and evaluation of in vitro analysis method of dexlansoprazole pulse enteric capsules: Through access to relevant literature,content and related substances methodologies by HPLC and release degree methodology by UV spectrophotometry are established respectively in the study,including detection wavelength,chromatographic conditions and system suitability,specificity,linearity and range,recovery rate,precision,repeatability and stability,and the content,related substances and release degree of three batchs of capsules are determined.2 Preparation of dexlansoprazole pulse enteric capsules: Blank microcrystalline cellulose pellets are coated with drug layer,isolation layer and enteric layer by fluidized bed spray coating technology,and two kinds of pH sensitive enteric coated pellets are prepared,mixed with a certain proportion and loaded in capsules.Finally,we sieve the best prescription with drug ratio and release degree as indexes in every coating process.In the drug coating,HPMC as the binder,sodium dodecyl sulfate?SDS?as the solubilizing agent,Mg?OH?₂ as pH regulator and water as solvent,and the best distribution of three kinds of accessories are determined by designing three factors three levels orthogonal experiment,and the drug loading rate as index.In isolation coating,we use opadry as insulation material,water as solvent,and screen the best weight gain with release degree as index.In the enteric coating,in isolation pellets are coated with different types of Eudragit materials,respectively,and enteric pellets A,B are prepared.In the preparation progress of enteric pellets A,we use talcum powder as anti-adhesion agent,triethyl citrate as plasticizer,Eudragit L30D-55 as coating material,water as solvent,and investigate the optimum weight gain,as to enteric pellets B,we use talcum powder as anti adhesion agent,95% ethanol as solvent,Eudragit S100 and Eudragit L100 as coating materials,and investigate of the ratio of two materials and the best coating weight gain,and screen the plasticizer.Meantime,the best technology parameters are explored and determined in the whole process of coating,including inlet air temperature,into air volume,material temperature,atomization pressure and spray speed,etc.Finally,two kinds of pellets are mixed with different proportions and loded into capsule shells,and the optimal proportion are determined finally.3 Stability investigation of dexlansoprazole pulse enteric capsules: The stability test optimal formulation of the dexlansoprazole pulse enteric capsules are carried out by examining the appearance,content,related substances determination and in vitro drug release degree through influencing factors test and accelerated test.The influencing factors test include high temperature?60?±2??test,high humidity?90%±5%?test and high light illuminate?4500Lx?test;the accelerated test is the three batchs of capsules placing under the temperature of 40?,relative humidity of 75%±5% for 6 months.4 Dexlansoprazole pulse enteric capsules pharmacokinetic study in Beagle dogs: This study establishs and evaluates plasma treatment method and content determination method by HPLC.Through two period two formulation crossover study design with Beagle dogs as experimental animals,we feed Beagle dogs with self-made and commercial capsules,and draw blood from the hind limb vein and treat and analyze the plasma samples,record and plot the drug-time curve of two formulations.Finally,we calculate the relevant pharmacokinetic parameters by DAS software,and study the relative bioavailability and bioequivalence.Results:1 This study establishes the content and related substances methodologies by HPLC and release degree methodology by UV spectrophotometry of dexlansoprazole pulse enteric capsules.And the accessories and impurities have no interference with main drug after the methodology validation.The content,related substances and release degree of three batch preparations meet the requirements.2 The best prescription of dexlansoprazole pulse enteric capsules as follows:Drug layer coating liquid: MCC 200g,dexlansoprazole 20g,HPMC 3.5%,SDS 1.0%?0.16g?,Mg?OH?₂ 0.5%,purified water as solvent,including 6 batches.The isolation layer coating liquid: drug pellets 200 g,Obadry,purified water as solvent,coating weight gain of 15%.Enteric layer A coating liquid: isolated pellets 200 g,Eudragit L30D-55,plasticizer triethyl citrate as plasticizer,purified water as solvent,weight gain of 40%.Enteric layer B coating liquid: isolated pellets 200 g,Eudragit S100,plasticizer triethyl citrate as plasticizer,95% ethanol as solvent,weight gain of 55%.Capsules: calculation of content of A and B,according to the drug content proportion of 25%:75%?A:B?in No.2 capsule shells,dose: 30mg/capsule.The optimum crafts:200g material,inlet air temperature of 45-50?,air volume of 110-130m3·h^-1 material temperature of 35-36 ?,atomization pressure of 1.8-2.0kg·cm3,spray speed of 15-20r·min^-1.In the enteric coating progress,inlet air temperature of 42-45?,the material temperature of 30-33?,spray speed of 5-8r·min^-1.3 In the influence factors of high temperature test,pellets color deepens,impurities increase,content,acid resistance decreases and cumulative release rate decrease under the condition of high temperature?60??for 5 days and 10 days.In high humidity?90% RH?test,pellets show serious hygroscopicity and adhesion phenomenon.And in the light illuminate?4500 LX?test,drug are stable.In the accelerated test,all the indexes are relatively stable within 6 months,under the condition of temperature of 40?±2?,relative humidity of 75%±5%.4 In the pharmacokinetic study of Beagle dogs,The plasma treatment method and content determination method by HPLC are established,and the results meet the requirements.The drug concentration-time curve shows behavior consistency of two capsules,self-made preparation drug release behavior is slightly ahead of schedule,the relative bioavailability is 90.86%.Bioequivalence study is carried out through comparing main pharmacokinetic parameters of two kind capsules,including AUC_0-??C_max and T_max.Two formulations are biological equivalent,without significant difference.Conclusion:The dexlansoprazole pulse enteric capsules that we prepare is similar to commercial capsules in vitro drug release behavior,and the preparation progress is simple,easy operation with good reproducibility,simple and feasible prescription.Methods for capsules of content,related substances and release are established.Through the experiment of stability test,the prepared capsules were not resistant to high temperature,high humidity and strong light,should be placed in cool and dry conditions,and stored in foil material.The self-made capsules have the same drug concentration-time curve to commercial ones,and high relatively bioavailability,by the pharmacokinetic study of Beagle dogs.And the self-made capsules is bioequivalent with the reference preparations.