Study On The Inclusion Complex Of Lansoprazole And Its Enteric - Coated Pellets

Lansoprazole（LPZ）was a substituted benzimidazole and selectively inhibits the H⁺/K⁺-ATPase of the parietal cell of the stomach.It was a representative proton pump inhibitor and had been clinically used in the therapy of gastric and duodenal ulcerative disease.According to the physicalchemial properties and absorbtion characteristic of LPZ in vivo,The enteric-coated pellets were studied in this paper.HPLC was utilized to determine the LPZ content in the pellets,and UV spectrophotometry was applied for determining the release of LPZ from pellets.The methods was proved to be reliable and simple.The preformulation research showed the equilibrium solubility and stability of LPZ in different pH phosphate buffer.The compatibility between LPZ and excipients under the different condition was also investigated by HPLC,which provided references and theoretical basis for formulation design.LPZ had a low water solubility,the clinical dose of which was relatively low.According to these characteristics,LPZ pellets were prepared by means of liquid phase layering with a Fluidized bed equipment,the optical processing parameters were obtained by the orthogonal experiment. Then the lansoprazole pellets were coated with OPADRY（YS- 1-7006）and Eudragit L30D-55 as coating materials,also the effects of coating level on the drug release characteristics was studied. The resulted products had perfect shape and surface characteristics,the acid resistance of pellets was satisfactory and the drug release in artificial intestinal liquid was rapid at the first fime,but at the last time,the commulative dissolution was lower than the market preparation.To investigate the complexation of lansoprazole（LPZ）withβ-cyclodextrin（β-CD）or hydroxylpropyl-β-cyclodextrin（HP-β-CD）,The phase solubility diagrams were plotted.The results showed:total drug solubility（free ionized drug + free un-ionized drug + ionized drug complex + unionized drug complex）was evidently enhanced under pH 11 by combined using cyclodextrin（CD） and NaHCO₃.Solid inclusion complexes of LPZ/CD were prepared in 1:1 or 1:1.5 ratios with the addition of NaHCO₃ by the Co-evaporating method（CE）and Spray drying method（SD）,the characteristics of which were studied preliminarily by in vitro dissolution test,differential scanning calorimetry（DSC）and Fourier transform infrared（FTIR）spectroscopy.In vitro study,the complexes prepared by CE or SD both enhanced the dissolution rate and accumulate dissolution of LPZ in pH 6.8 buffer solution comparing with LPZ and the physical mixture of LPZ and CD.At the basis of preparing of solid inclusion complexes of LPZ/β-CD,the LPZ pellets were prepared by extrusion-spheronization technology,Then the LPZ pellets were coated with same coating materials as above mentioned.Process parameters of preparing LPZ pellets and formulation factors were studied by the influence factors experiment and the orthogonal experiment.The final products appeared spherical with smooth surface.The formulation and process had a good reproducibility. Dissolution test showed:the drug release rate of LPZ enteric-coated pellets prepared by extrusion-spheronization was better than that of pellets prepared by liquid phase layering and the market preparation.With the market LPZ enteric-coated pellets capsule as the reference preparation,the pharmacokinetic properties of self-made enteric-coated pellets capsule were performed in three dogs.The main pharmacokinetic parameters of the test and reference formulation were as follow: C_maxwere 763.69 and 828.55 ng·ml^-1,T_maxwere both 1 h,MRT were 2.76 and 1.95 h,AUC_{0→t}were 1460.94 and 1410.22 ng·h·ml^-1,and Relative bioavailobility was 103.6%.