The Studies On Aspirin And Esomeprazole Magnesium Compound Enteric-Coated Pellet Capsules

The incidence of cardiovascular disease trends to rise year by year around the world, which have brought great fear and worry to patient due to its high probability of death and disability. Thrombus is one of the major factors to cause cardiovascular disease that could affect our whole body capacity including artery, vein and microvascular thrombosis. Antiplatelet, anticoagulation and thrombolytic agents are commonly used drugs and one of the most classical and widely used antiplatelet agents is aspirin which has advantages of low cost and good effects. Therefore, low-dosage aspirin has been regarded as first-line drug to prevent cardiovascular diseases.However, aspirin has the common side effects that it can stimulate the gastrointestinal tract even cause stomach bleeding after long-term use. Therefore, the proton pump inhibitors are usually chosen to protect gastrointestinal mucosa against side effects brought by aspirin. However, drug combination has some deficiency that patients need take multiple drugs with different dosages and times, which has bad patient compliance. Therefore, the compound preparation of aspirin and esomeprazole magnesium was developed to promote patient compliance and provide more choices for clinic treatment.Firstly, the methods of content assay and in vitro release tests of aspirin (ASA) and esomeprazole magnesium (EMZ-Mg) single enteric-coated pellets and compound enteric-coated pellets were respectively carried out. Secondly, the aspirin and esomeprazole magnesium compound enteric-coated pellet capsules were prepared by two kinds of schemes and the formulation and process were systematically studied. Thirdly, the drugs release in vivo of compound enteric-coated pellet capsules prepared by two kinds of schemes was studied by animal experiments in order to evaluate the quality and stability of compound enteric-coated pellet capsules.1. Establishment of determination method for drug content and release of compound enteric-coated pellet capsulesThe content assay and in vitro release test of aspirin and esomeprazole magnesium single enteric-coated pellets were carried out by UV, and compound enteric-coated pellet capsules was determined by HPLC. The methodology of UV and HPLC spectrophotometry was validated by specificity, linearity and range, precision, accuracy, etc. The results showed that methods for content assay and in vitro release tests of aspirin in water and pH6.8 PBS and esomeprazole magnesium in pH11.0 PBS was specific with no interference of excipients, showing good linearity within the appropriate concentration range, good precision of the reference or test solutions and high accuracy on the basis of recovery determination meeting with the requirements. Therefore, the method of UV spectrophotometry for content assay and in vitro release tests of aspirin and esomeprazole magnesium single enteric-coated pellets were feasible and the method of HPLC spectrophotometry for content assay and in vitro release tests of compound enteric-coated pellet capsules showed good system suitability, linearity, precision and high accuracy in pH6.8 and pH11.0 PBS, meeting with the requirements.2. Preparation and Quality specification study of compound enteric-coated pellet capsulesThe compound enteric-coated pellet capsules were designed with two schemes. The first scheme was that aspirin and esomeprazole magnesium single enteric-coated pellets were prepared respectively and then were filled into hard capsules based on dosages. The second scheme was that aspirin and esomeprazole magnesium compound enteric-coated pellets were prepared by films coating technology and then were filled into hard capsules based on dosages.2.1 The first scheme:The ASA pellets were prepared by extrusion-spheronization equipment and EMZ-Mg were layered on the MCC pellets which were prepared by centrifugal granulation. Then ASA pellets and EMZ-Mg pellets were coated by enteric-coated films to prepare enteric-coated pellets that were filled into hard capsules based on dosages.ASA pellets were prepared by extrusion-spheronization. The roundness, yield and dissolution were employed to select and optimize formulations including filler, adhesive and stabilizer, and process including diameter of sieve plate, extrusion rate, spheronization rate and time. Finally, reproducibility test was conducted to verify the rationality of formulation and stability of process. The results indicated that the optimal formulation included ASA(47%), MCC(47%), L-HPC(3%) and tartaric acid(3%), and the optimal process was 0.5mm of sieve plate,12Hz of extrusion rate and 20Hz of spheronization rate in 3min. Three batches of pellets were prepared by the optimal formulation and process, which performed high roundness that the ratio of long radius and short radius was 0.96±0.01, high yield of (96.4±0.66)% and rapid dissolution above 80% in 45min.MCC pellets were prepared by centrifugal granulation. The roundness and yield were employed to select and optimize the process parameters including rotor rotation speed, slit air flow rate and spray air rate. Then the MCC pellets were coated by EMZ-Mg and isolated layers. The yield and content uniformity were employed to select and optimize formulation and process parameters of drug and isolated layers. The results indicated that the optimal process is:spray air rate is 15rpm, slit air flow rate is 15Hz and rotor rotation speed is 450rpm. Three batches of MCC pellets were prepared by optimal process with high yield of (81.5±0.78)% and roundness of 0.91± 0.02. The drug layer with formulation including EMZ-Mg(7.5%), HPMC E5(3%) and NaHCO3 (5%) was prepared with the process parameters:0.15MPa of spray pressure, 1.5 to 2.0rpm of spray air rate and 35Hz of air flow rate, which performed high yield above 90% and high content uniformity(RSD<2.0%). The isolate layer with formulation including HPMC E5(7.5%), GMS(10%) and TEC(20%) was prepared with process parameters:0.15MPa of spray pressure,1.2rpm of spray air rate and 35Hz of air flow ratewhich performed high yield above 90%. Therefore, the formulation and process of EMZ-Mg pellets were suitable and stable with highly reproducibility.The enteric-coated layers with Eudragit L30D-55 including GMS(5%) and TEC(10%) were coated on ASA and EMZ-Mg pellets. The release profiles in vitro and yield were employed to screen the coating process and thickness of layer. The results indicated that ASA pellets and EMZ-Mg pellets were coated by enteric-coated layers with 30% and 40% weight gain respectively in the process:0.12MPa of spray pressure,2.0rpm of spray air rate and 35 to 40Hz of air flow rate. Three batches of enteric-coated pellets were prepared by optimal formulation and process, drug in which released at intestinal tract and had high yield of (95.5±0.8%) and (90.6±1.66)%.The drug content of ASA and EMZ-Mg enteric-coated pellets were determined to ensure the amount of capsule (size 1) filled corresponding to ASA 81mg and EMZ-Mg 20mg. Three batches of compound enteric-coated pellet capsules were prepared, of which drug release percentage in artificial gastric fluid in 2 h was less than 5%, while drug release percentages of ASA and EMZ-Mg in artificial intestinal fluid in 45min was 72.8% and in 30min was 89.8%. The release profiles of compound enteric-coated pellet capsules were quite well and similarity of which was high with the factor of f2 above 70.2.2 The second scheme:ASA pellets were also prepared by extrusion-spheronization and then isolated layer Ⅰ, drug layer of EMZ-Mg, isolated layer Ⅱ and enteric-coated layer were coated to prepare compound enteric-coated pellet capsules, the amount filled in which was ensured by drug content determination.The formulation and process of ASA pellets were unaltered. The release profiles in vitro were employed to screen the formulations and processes of isolated layer Ⅰ, drug layer, isolated layer Ⅱ and enteric-coated layer. Finally, reproducibility of three batches of compound enteric-coated pellet capsules was evaluated with similarity factor method. The result indicated that isolated layer Ⅰ with 40% weight gain of eudragit and 10% weight gain of HPMC were applied to isolate two drugs; the drug layerconsisted of EMZ-Mg(7.5%), HPMC E5(3%) and NaHCO3(5%); the isolated layer Ⅱ mainly consisted of HPMC; the outermost layer of compound enteric-coated pellets mainly consisted of eudragit with 40% weight gain. This designed scheme not only isolated two drugs sufficiently but also made the drug release at intestinal tract. Three batches of compound enteric-coated pellet capsules were prepared, and drug release percentages of ASA and EMZ-Mg in artificial intestinal fluid was(5.9±1.1)% and (78.5±1.4)% in 15min, and (77.4±3.3)% and (83.5±1.9)% in 60min. The release profile of compound enteric-coated pellet capsules was quite well and similarity factor between two of three batches was above 50, which demonstrated the high stability of formulations and process.Isolated layer Ⅰ with eudragit can not only avoid drugs degradation causing by interaction, but also control drug release profiles. The lag-time between ASA and EMZ-Mg release had an advantage that gastrointestinal tract mucosa was protected by rapid drug release of EMZ-Mg and then ASA released largely to play an efficient role of antithrombosis. This design scheme was more reasonable and advanced, which could exploit the advantages nearly to the full of synergism of compound preparation.3. The pharmacokinetic study of two kinds of compound enteric-coated pellet capsulesFirstly, the methodology of HPLC spectrophotometry which was used to determine the plasma drug concentrations was validated by specificity, linearity and range, precision, accuracy, etc. The capsules were orally administered to the rats and blood samples were collected from jugular vein at 0.5,1,1.5,2,2.5,3,3.5,4,5,6,8, 10,12,24h after administration. The plasma was processed and the drug content was determined by HPLC. The diagrams with time and plasma drug concentration of SA and EMZ-Mg were drawn. And then the pharmacokinetic parameters were calculated by non-compartmental analyses using the software program DAS2.0. The drug release in vivo of two kinds of compound pellet capsules was compared. The result indicated that the method was specific, good linearity within the appropriate concentration range, good precision of the reference or test solutions and high accuracy, meeting with the requirements. After orally administrated, the peak time of EMZ-Mg was same but the peak time of SA was one hour apart between two kinds of compound pellet capsules. Therefore, the drug release of ASA from the second scheme of compound pellet capsules in vivo was slower, which could protect gastrointestinal tract mucosa by EMZ-Mg.In conclusion, two schemes had been applied to prepare compound pellet capsules, which can make ASA play an efficient role of antithrombosis and avoid side effect of stimulating gastrointestinal tract. This compound formulation would increase patient compliance and provide more choices for clinic treatment. It could be transformed into large scale of manufacture because of stabilized fomulations and processes. Especially, the second scheme of compound enteric-coated pellet capsules combined two drugs in one pellet, which can not only avoid the complicated process of capsules filling but also control the lag-time of two drug release to exploit the advantages nearly to the full of synergism of compound preparation. Since the film coating equipment was excellent and the process was proficient, this subject has application prospects to pharmaceuticals industry and clinical applications.