Preparations And Studies Of Esomeprazole Magnesium-naproxen Enteric-coated Tablets

Objectives:May.5.2010,the US Food and drug administration（FDA）have already approved a tablet which contains extended release enteric coated naproxen and quick release of esomeprazole magnesium（commercial name is vimovo produced by AstraZeneca and Pozen Inc.）.Those nonsteroidal anti-inflammatory drugs（NSAIDs）and proton pump inhibitor compounds preparation used to alleviate the symptoms of osteoarthritis,rheumatoid rheumatoid arthritis and ankylosing spondylitis.At the same time,it can reduce the patients’ risk of gastric ulcers disease which induced by the NSAIDs.Based on the foreign product already marketed,the purpose of this study is to prepare the esomeprazole magnesium-naproxen enteric-coated tablets,and establish the evaluation methods to detect the content and related substances.Methods:1 The preparations for esomeprazole magnesium – naproxen enteric-coated tablets: in this study,we mixed the raw material of naproxen and suitable excipients evenly.After the wet granulation,the naproxen tablet core was prepared.Based on this tablet core,we used the efficient coating machine to coat the other layers,followed by isolation layer,enteric layer,isolation layer,the ESO layer and shading isolation layer,and finally we got the final tablets.During the preparation process,we used an aqueous solution of hydroxypropyl methyl cellulose as isolation layer coating material;Eudragit L30D-55 dispersions as enteric coating material;an aqueous solution of hydroxypropyl methyl cellulose as ESO dispersion medium.Meanwhile,we took the inlet air temperature,material temperature,pot body speed,pump speed,spray pressure,pressure thimble,fan speed as the single factors,sothat we can determine the best equipment parameters.With the release degree as an index,we selected the prescription of every coating layers,and determined the optimal coating weight gain.2 The quality control research of esomeprazole magnesium – naproxen enteric-coated tablets: We established a high performance liquid chromatography（HPLC）method to determine the drugs’ release,content,and related substances,and did the methodological study.Then we studied the stability of the preparations by the influencing factor test and the accelerated test with the indexes of release,content and appearance.Results:1 According to the prescription selections,we determined the optimal prescription for naproxen tablet core as followed:Naproxen 375 g,PVPP 16.35 g,PVP 16.35 gStearic acid magnesium 1 gThe tablet is compressed by 10 mm die.The hardness is qualified with the range of 6-8kg.Isolation layer coating solution:HPMC 16 gH₂O 160 g.Enteric layer coating solution:L30D-55 66.67 gTriethyl citrate 2 gH₂O 130 g.ESO layer coating solution:ESO 20 gHPMC 8 gH₂O 200 g Shading isolation layer:HPMC 16 gTIO₂ 1.6 gH₂O 160 mL2 The best coating process is as followed:The inlet air temperature 60 ℃ Material temperature 45 ℃Pot body speed 5 rpm Pump speed 3 rpmSpray pressure 1 kg Pressure thimble 1 kgFan speed 2500 rpm3 The determination methods of HPLC for esomeprazole magnesium –naproxen enteric-coated tablets:The detection wavelength for naproxen is 300 nm,with no interference of excipients and mobile phase.The methodological study shows that within the concentration range of 270⁴50 μg/mL,the linear relationship between peak area and concentration of naproxen is good.The regression equation is A =3217C + 8673,R2=0.9994,RSD of precision value is 0.35%.Low,medium and high concentrations of recoveries mean is 99.36%,RSD=0.36%.Stability and repeatability are both perfect.Therefore,this method can be used for the determination of the content of naproxen.The detection wavelength for esomeprazole magnesium is 302 nm,with no interference of excipients and mobile phase.The methodological study shows that within the concentration range of 10.28⁵1.40 μg/mL,the linear relationship between peak area and concentration of esomeprazole magnesium is good.The regression equation is A = 56444 C + 21807,R2=0.9992,RSD of precision value is 0.27%.Low,medium and high concentrations of recoveries mean is 97.92%,RSD=0.91%.Stability and repeatability are both perfect.Therefore,this method can be used for the determination of the content of esomeprazole magnesium.4 The determination methods of HPLC for esomeprazole magnesium –naproxen related substances:Naproxen’s related substances is 6-methoxy-2-acetonaphthone（impurityA）.The detection wavelength for naproxen is 311 nm,with no interference of excipients and mobile phase.The methodological study showsthat within the concentration range of 0.2⁰.8 μg/mL,the linear relationship between peak area and concentration of naproxen is good.The regression equation is A = 93425C-166,R2=0.9998,RSD of precision value is 0.27%.Low,medium and high concentrations of recoveries mean is 96.90%,RSD=1.99%.Stability and repeatability are both perfect.Therefore,this method can be used for the determination for the impurityA.The detection wavelength for esomeprazole magnesium’s related substances is 305 nm,with no interference of excipients and mobile phase.Within the limited range of impurityB,C and D,the linearity,precision,recovery,stability and repeatability are all good.Therefore,this method can be used for the determination for the impurityB,C and D.5 The influencing factors test and the accelerated test of self-made preparation:Under the condition of high temperature 60 ℃ ± 2 ℃,high humidity 90%± 5%,illumination 4500 Lx for ten days,the appearance,content and release determination results met the requirements.The results of accelerated test showed that the preparation was stable,with less influence by the high temperature,high humidity and illumination,so that the storage conditions can be relatively easy.Conclusions:The preparation method of esomeprazole magnesium – naproxen enteric-coated tablets is simple,feasible and reproducible.The tablets have suitable hardness,on one hand,it is convenient for manufacturers to produce,preserve and transport the tablets;on the other hand,it’s easy to take the tablets for patients.This study also establish method to detect the content and related substances,which can make the preparations safe and easily controlled.