Preparation And In Vivo/In Vitro Evaluation Of An Enteric Dry Suspension System Of Esomeprazole Porous Ion Exchange Resin

Background:Esomeprazole（ESO）is an S-isomer Proton Pump Inhibitor（PPI）developed on the basis of omeprazole,which is mainly used for the treatment of gastroesophageal reflux disease.Among all PPI drugs,ESO has high safety and small individual differences.Acid inhibition ability is the strongest,since the market has achieved excellent economic benefits.However,only relevant injections,enteric-coated capsules and enteric-coated tablets have been approved for market in China.However,injections have some problems such as pain in injection and inconvenience in use.Capsules and tablets are difficult to accurately divide doses and there is a risk of loss of enteric-coated effect due to chewing,so they are not suitable for people with swallowing difficulties,especially children.Objective:This project is dedicated to the development of safe and effective Esomepazole resin enteric dry suspension suitable for children and patients with dysphagia,to serve the majority of Chinese children,to enrich the related research of Esomepazole pharmaceutical preparations and excipients ion exchange resin,and to make efforts and attempts to get rid of the application restrictions of children patients as soon as possible.Method:In this paper,a novel porous anion exchange resin was prepared by seed swelling polymerization,chloromethylation reaction and quaternization reaction.Using the porous anion exchange resin as the carrier,the drug resin complex of Esomepazole was prepared on the ion exchange resin.The intestinal coating was carried out by fluidized bed coating technology.To prevent the drug from being destroyed by gastric acid in the stomach and improve the stability of the drug in vivo.Then,the intestinal coated microcapsules were mixed with excipients to prepare a dry suspension,and the esomeprazole intestinal solution was prepared by adding pure water and shaking it well before use.The quality of self-made Esomeprazole resin enteric dry suspension was evaluated by in vitro release,in vivo pharmacokinetics and stability tests.In addition,in vivo imaging experiments were carried out on the quantum dots labeled fluorescent resin enteric-dry suspension to realize the in vivo tracer of the resin,and the transport process of the resin carrier in vivo was directly studied by obtaining fluorescence signals.Results:The self-made porous anion exchange resin was a uniform and well-shaped porous microsphere with a particle size of about 5μm,and the pore size of the microsphere was distributed in the range of 3～20 nm.The infrared results and chlorine content of the self-made resin were basically consistent with that of the imported resin,and the specific surface area was up to 757.95 m²/g.The influence of drug concentration,resin dosage,temperature,time and other factors in the preparation process of drug resin complex was investigated based on resin loading capacity and drug utilization,and the optimal drug loading process was determined as follows:200 mg ESO was continuously stirred in 50 m L Na OH solution with pH=9 at 35℃until the drug was completely dissolved.The self-made porous resin with the same amount of the drug was added and stirred at a constant temperature for 120 minutes.The drug loading capacity of the resin was up to 0.93 mg/mg,and the drug utilization rate was 92.30%.The intestinal resin coated microcapsules were prepared by fluidized bed coating method.In vitro release results showed that the release of the intestinal resin coated microcapsules was less than 10%in the acidic medium for the first 2 h,and about 80%in the pH 6.8 medium within 45 min,indicating that the intestinal dissolution effect of the coated microcapsules was obvious.Suspension content,in vitro release,leakage and stability were investigated.The results showed that the content of self-made ESO enteric dry suspension ranged from 90 to 100%,and there was no obvious leakage after standing at room temperature for 7 days.Combined with the results of acceleration experiment and room temperature retention experiment,it was found that self-made enteric dry suspension and coated microcapsules had consistent enteric solubility and good stability.In vivo pharmacokinetic study of self-made Esomepazole enteric dry suspension and commercial enteric coated tablets was conducted in SD rats.The results showed that compared with commercial enteric coated tablets,the absorption of self-made enteric dry suspension was faster,the peak time of T_max was advanced from 2 h to 1.5 h,and the maximum blood concentration increased from 2.36μg/m L to 2.77μg/m L.The half-life of t_1/2 was 2.67 h and 2.38 h,respectively.The area under the curve was 8.99μg·h/m L and 8.45μg·h/m L,respectively.The relative bioavailability of the self-made ESO enteric dry suspension was 93.99%.The in vivo tracer test results of quantum dot fluorescein resin-coated suspension in mice showed that within 20 min of administration,fluorescein resin-coated microcapsules were mainly distributed in the oral cavity to the esophagus,and were transported to the stomach,small intestine and large intestine about 0.5 to 1 h after administration,and were distributed in both the stomach and intestine.After 1 to 2 h,some of them were excreted by urethra and anal.At 4 h,the fluorescence resin-coated microcapsules were basically excreted completely.Conclusions:The self-made porous anion-exchange resin medicinal excipients have uniform particle size,high specific surface area,and good drug loading performance.The Esomeprazole enteric dry suspension prepared by using it as a key carrier has shown good enteric dissolution effect in both in vivo and in vitro tests,and its stability has been verified by accelerated test and room temperature retention test.It can help reduce the risk of loss of enteric dissolution effect of enteric solid preparations due to breaking and chewing,improve the existing problems of swallowing difficulty,dose-dividing difficulty,injection pain and inconvenient use of existing solid preparations and injections,improve the application scope of drugs and patients’compliance,and bring convenience to the elderly and children patients with swallowing difficulties.