| Peptic ulcer is a common chronic disease of the digestive tract.Patients suffer from abdominal pain and acid reflux for a long time,which seriously affects the quality of life.Peptic ulcers have a variety of mechanisms,and drug therapy to inhibit gastric acid is still the main treatment option.The chronological pharmacological study found that the gastric acid secretion of the human body has the characteristics of time rhythm.If the dosing plan is designed for the peak gastric acid release,the purpose of minimum dose,best curative effect,and minimum toxicity can be achieved.Designing a suitable pulsed drug delivery system to control the drug release time by means of preparations to match the changes in human gastric acid secretion rhythm has broad clinical application prospects.Clinically,proton pump inhibitors are widely used in the treatment of gastric acid-related gastrointestinal disorders,which can act selectively on parietal cells H+/K+-ATP enzyme inhibition of gastric acid secretion.EMZ-Mg is a second-generation proton pump inhibitor.The commercially available formulation of Nexium recommends taking it once a day in the morning,and the effect cannot be sustained until the peak of gastric acid secretion at night,which may easily cause a night-time acid breakthrough.Patients have poor compliance if taking another dose before bedtime.The design of the project refers to the product characteristics and mechanism of action of dexlansoprazole sustained-release capsules(Dexilant)marketed by Takeda Corporation in Japan.Taking EMZ-Mg as model drug,pulse capsules were prepared with different pH-dependent film-controlled coating pellets.The subject is based on the analysis results of Dexilant.Firstly,MCC blank pellets were prepared by a centrifugal granulation method,and EMZ-Mg pellets were prepared by a powder layering method;Secondly,two different pH-dependent enteric pellets were prepared by fluidized bed spray coating method to prepare isolation layer and enteric layer.Based on the drug loading,plused capsules were prepared by filling 0#capsules at a certain ratio of the two enteric pellets,and quality evaluation and preliminary stability investigation were carried out.Finally,through the study of the in vivo and in vitro release behavior of homemade pulse capsules and commercially available preparations,the rationality of the formulation process design of EMZ-Mg pulse pellet capsules was evaluated.Finally,through the study of the in vivo and in vitro release profiles of pulsed capsules and commercially preparations,the rationality of the prescription process design of EMZ-Mg pulse pellet capsules was evaluated.1 Analysis of dexlansoprazole sustained release capsulesA method for determining the content and release of dexlansoprazole enteric-coated pellets was established by ultraviolet spectrophotometry.The methodological investigation was carried out through specificity,linearity and range,intra-day precision.Dexlansoprazole has a good linear relationship in pH7.0 PBS,with high precision within the day.The excipients do not interfere with the determination of dexlansoprazole.The Dexilant product was analyzed,and it was determined that the capsule content is composed of two kinds of pellets with a ratio of 1:3,and the appearance,particle size and content are different;the capsule shell is a gastric-soluble material;microscopic cross-section observation and prescription analysis results show that both types of pellets contain four-layer structure of pellet core,drug layer,isolation layer,and enteric layer,which are membrane-controlled pellets and the drug layer is prepared by powder lamination;the in vitro release test results showed that the rapid release of pellet I was complete,and that pellet II began to release after 50 min,resulting in two pulsed drug release behaviors,which provided a basis for the design of EMZ-Mg pulsed pellets.2 Preparation and evaluation of EMZ-Mg pelletsA method for measuring the content and release of EMZ-Mg pellets was established by ultraviolet spectrophotometry.The methodological investigation was carried out through specificity,linearity and range,day-to-day precision,and recovery rate.The results show that EMZ-Mg has a good linear relationship in pH11.0 PBS,with high precision and high recovery rate,and the excipients do not interfere with the determination of EMZ-Mg.The method meets the requirements for determination of EMZ-Mg pellets and release profiles.MCC blank pellet cores were prepared by centrifugal granulation method.A single-factor inspection of process factors was conducted with the total yield,target yield,and roundness as the evaluation indicators to determine the optimal process conditions for the blank pellet cores.The blank pellet cores produced had high roundness and the yield is(82.1±2.00)%,and the target yield is(51.1 ± 3.11)%.EMZ-Mg pellets were prepared on the basis of self-made blank pellet cores.With yield,target yield,roundness and release profiles as the evaluation indicators,the results of optimal formulation were blank core:EMZ-Mg:MCC:sucrose:magnesium carbonate:L-HPC 150:20:15:35:8:2.4,and the binder is 3%HPMC E5 aqueous solution.Orthogonal experimental design was used to optimize process factors,and the optimal process factors were determined as rotating speed 200 rpm,spraying speed 8 rpm,polishing time 3 min.Three batches of pellets were prepared according to the optimal formulation and processing and the EMZ-Mg-containing pellets had roundness(0.94±0.01),the yield(98.0 ± 0.42)%,the target yield(81.5±0.83)%and drug content(8.03 ± 0.06)%,which shows stable prescription process and good reproducibility.3 Preparation and Evaluation of EMZ-Mg Enteric Coated PelletsOn the basis of the EMZ-Mg pellets,two different pH-dependent EMZ-Mg enteric-coated pellets were prepared by using a fluidized bed bottom spray coating method to prepare the isolation layer and the enteric layer.Isolation layer coating solution was selected 5%HPMC E5 aqueous solution,and the weight gain of the isolation layer was screened by using drug content variation and appearance as evaluation indexes.It was determined that the isolating layer weight gain of enteric-coated pellets ? and ? was 8%and 5%.Two different pH-dependent enteric-coated pellets were prepared,and the weight gain of the enteric layer was screened based on the release profiles and acid resistance.Enteric-coated pellets I use Eudragit L30D-55 as the enteric material,the enteric layer weight gains 30%;Enteric-coated pellets ? use 1:3 mixture of Eudragit L100 and Eudragit S100 as the enteric material,the enteric layer weight gains 60%.The three batches results showed that the cumulative release of the enteric pellets ? was over 85%in 15 min,and the similarity factors among the three batches of enteric pellets ? were 79.49,72.97,and 91.11.The release profles of enteric pellet ? and ? were similar,and the prescription and processing were stable and reproducible.4 Preparation and preliminary stability study of EMZ-Mg pulsed capsulesThe quality standards for EMZ-Mg pulsed capsules were established,and three batches of EMZ-Mg pulsed pellets were evaluated.The results showed weight varied within 95.0?105.0%;drug content varied within 95.0?105.0%;similarity factors between three batches were 59.80?79.20?58.54,the cumulative release of 20 min is not more than 20%,the cumulative release of 50 min is not more than 35%,and the cumulative release of 105 min is not less than 85%.It was considered that EMZ-Mg pulsed capsules were qualified and reproducible,enteric pellet ? and ? were released completely in 20 and 105 min with no burst release of enteric pellet ?.Preliminary stability tests were performed,including high temperature tests,high humidity tests,and light tests.The content reduced by 4%in high temperature tests;the surface of the enteric pellets ? appears reddish luster,and the cumulative release of 50 min varied from(29.6±2.41)%to(45.8±2.47)%in high humidity tests of RH 75%;the surface of the enteric pellets ? appears light blue luster in light tests,which indicated the preparation should be kept away from light and stored in a dry and cool place.5 Pharmacokinetics study on EMZ-Mg pulsed capsules in ratsA method for the determination of EMZ-Mg in rat plasma was established.The method has a good linear relationship,high precision and accuracy.Using commercially available EMZ-Mg enteric-coated tablets(Nexium)as a control,pharmacokinetic studies in Wistar rats were performed on EMZ-Mg pulsed capsules.The plasma drug concentration-time curve was measured and the main pharmacokinetic parameters were calculated as follows:Tmax?Cmax?AUC 0-24h?MRT 0-24h?t1/2 of the test group were 2.00hand6.00h?1.79mg/L and3.35mg/L?25.24mg/L*h?8.70h?7.82h;Tmax?Cmax?AUC0-24h?MRT0-24h?t1/2 of the control group were 1.50 h?3.47 mg/L?20.54 mg/L*h?7.57 h?10.46 h;relative bioavailability was 122%.The results showed that,unlike the control group,EMZ-Mg pulsed capsules produced two pulsed drug releases in vivo,which improves bioavailability.The dosing plan could be redesigned as once a day before dinner to match the second release of the preparation in vivo with the peak of gastric acid secretion in human bodies,which could inhibit stomach acid with effect.In summary,it was determined that the prescription and process of EMZ-Mg pulsed capsules were stablt and reliably.Dosing plan could be redesign to target to human gastric acid secretion according to the pulsed release characteristics,which has good application prospects. |
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