| Objectives:Dexlansoprazole, a proton pump inhibitor used for the treatment of ulcer, is one of the effective drugs in the clinical treatment of digestive disease.It is optical isomers Proton pump inhibitors,and it is the R-isomer of lansoprazole.It has a poor water solubility and is sensitive to light, acid and high temperature. Therefore, Dexlansoprazole often comes as a enteric-coated capsules and lyophilized preparation. Duplex delayed release capsule is a novel delayed-release solid dosage form. It could significantly improve improve the traditional drug AUC PPI formulations for the treatment of gastroesophageal reflux disease defect, through the two pulse administration of the drug at an average residence time in vivo. This study would like to make Dexlansoprazole duplex delayed release capsules, which would improve the deficiencies of traditional PPI formulations, sustained suppression of gastric acid secretion, and the effect is significant, well tolerated, and can effectively improve patient symptoms.Methods:1 In this prescription, taking the drug loading rate as the index, screen the best formulation of coating solution through L9(33) orthogonal experiment design. Preparation of drug-containing coating solution and using the fluidized bed to coat dexlansoprazole on the surface of sucrose pellets. Then continue to coat on the drug loaded pellets, using 2.5% HPMC aqueous solution as barrier coating material, L30D-55 aqueous dispersion as the enteric-coated material B, and L100-55 and S100(1:5) aqueous ethanol solution as the enteric-coated material A. In order to determine the optimum parameters of the equipment,the single factor experiments was made to investigate fluidized bed process,the investigation object is spray speed,spray pressure, the temperature of the material and the air volume. Observe and study release degree of the pellets, investigate the effect of different thicknessof enteric layer, determine the optimal weight gain. Screen the best prescription through inspecting the relaease, morphology and color of the capsules. 2 The quality control study of Dexlansoprazole duplex delayed release capsules: establish HPLC methods for the content uniformity, determination of content and related substance. Investigate the release of enteric-coated pellets and duplex enteric-coated capsules with the methods about lansoprazole enteric-coatde capsules in the New Drug Official Standard. In the meantime, carried out the related methodological study, prepare Dexlansoprazole duplex enteric-coated capsules in accordance with the best prescription, and then study the stability of preparation by the influencing factor test and accelerate test with the indexes of dissolution, content and the related substance. 3 Beagles for test animals, commercial preparations for the reference, a single-dose, two-treatment, two-sequence and randomized crossover study was carried out on four adult beagle dogs. Establish HPLC method to determine Dexlansoprazole in the plasma of beagle dogs, calculate the pharmacokinetic parameter of Dexlansoprazole and study the relative bioavaibility and the bioequiavailability.Results: 1 According to the orthogonal test, best prescription of the coating liquid of drug loading layer : Dexlansoprazole 20 g, HPMC E10 6g, SDS 1.92 g, Ethanol 30 g, water 240 m L. Fluidized bed parameters: Air volume 190m3·h-1,material temperature 30℃, Spray pressure 30-35 psi, Spray speed 5.0m L·min-1. Coating liquid of the isolation layer: The aqueous solution of HPMC E10(3%). Fluidized bed parameters: Air volume 190m3·h-1,material temperature 30℃, Spray pressure 30-35 psi, Spray speed 5.0m L·min-1. Coating liquid of the enteric coated layer B: Eudragit L30D-55(the solid weight 83g), Triethyl citrate 0.5g, Water 260Ml; Fluidized bed parameters: Air volume 190m3·h-1, material temperature 28℃,Spray pressure 30-35 psi, Spray speed5.0m L·min-1.Coating liquid of the enteric coated layer A: Eudragit L100-55 3g, Eudragit S100 15 g, Triethyl citrate 1g, Ethanol 635g; Fluidized bed parameters: Air volume 190m3·h-1,material temperature 25℃,Spray pressure 30-35 psi, Spray speed 5.0m L·min-1. 2 Established the methond of determinating release of pellet cores, enteric-coated granules and Dexlansoprazole duplex enteric-coated capsules with UV. And the wavelength was 284 nm and 286 nm where without any interference from excipients and solvents. This methond was verified to determinat the dissolution of Dexlansoprazole duplex enteric-coated capsules by methodology. 3 Established the methond of content uniformity, determination of content and release of Dexlansoprazole, wavelengths were 294 nm where without any interference from excipients. The method is accurate and sensitive. It is applicable to the quality control of the Dexlansoprazole duplex enteric-coated capsules. 4 Established the methond of determinating content and related substances of Dexlansoprazole, wavelengths were 285 nm. This methond was verified as simple, accurate and sensitive, and suitable for the quality control of Dexlansoprazole, without interference from excipients and solvents. The specificity test was also carried out for the determination of the related substances. The impurities produced by the damages of acid, alkali, light, high temperature and oxidation didn’t interfere the determination of main drug. 5 In the influence factor test, the sample which is placed 5 days have hygroscopic, 10 days hygroscopic phenomenon is more serious in the relative humidity of 92.5% and 75%, and the drug is released slower. Part pellets brick red color, the impurities increase in glare(4500lx) under the capsule, was reduced, release has been affected. For 10 days at 60℃, and its related substances were not significantly changed. Experimental results show that selfmade preparations for heat and light are unstable and should be taken away from light, moisture, room temperature and storage conditions. 6 Established an HPLC method for the determination of Dexlansoprazoleblood drug concentration, wavelength was 284 nm. Blank plasma was no interference on determination of main drug.Compared with reference formulation, the relative bioavailability of tested formulation was 94.24%.Conclusions: The prescription of Delansoprazole duplex enteric-coated capsules and preparation process are simple, feasible, and a good reproducibility. Duplex enteric-coated capsules should be stored transport. The determination methonds built for dissolution, content and related substances provide safeguard for the quality of the preparation. The experimental results show that it is suitable to be stored at room temperature and in the dark moisture. Results of pharmacokinetics indicate that the test preparation has a high bioavailability, and it is bioequivalence with the reference preparation. |
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