The Application Of Solid Dispersion Technology In Preparation Of Felodipine Sustained-Release Tablets

Background: Felodipine(felodipine, FEL) is a dihydropyridine of calcium antagonist,it can selectively affect vascular. FEL selectively decreases peripheral resistance and blood pressure,in the same time it won’t affect the state of heart.FEL can treat different kinds of hypertension and the related cardiovascular diseases.FEL is almost insoluble in water(0.6ng/L), which affects the dissolution and bioavailability of drug.Solid dispersion(SD) is a decentralized system that a drug is evenly dispersed in a solid carrier in the formation of such as molecules, colloid,amorphous or microcrystalline. When difficult soluble drug formed SD with suitable carrier, can increase its solubility and dissolution rate,promote the drug absorption, improve its bioavailability.In order to promote the drug’s solubility,the research used PVP K29/32, PEG6000, Poloxamer as carrier to prepare FEL-SD through solvent method,then prepared sustained-release tablets with SD as medium and HPMC as skeleton material.Objective: Prepare FEL-SD to promote the drug’s solubility, research the suitable prescription and method to prepare FEL sustained-release tablets that has the similar in vitro and vivo release behaviors with Plendil.Method:(1) To investigate the solubility of drug in different solutions.To set up HPLC method measuring FEL and UV method determining the in vitro release rate.(2)To prepare FEL-SD with solvent method. The solution rate was chosen as an indicator for the kinds of carrier dosage and method, and then optimized the formulation and preparation by orthogonal methodology.(3) Prepare FEL tablets by compressing the power directly.Choose the cumulative release rate as a standard to measure the formulation.And better the formulation by orthogonal methodology.(4)Make a method to determine the related substance.Check the quality and stability of self-made tablets.(5)To establish the HPLC/MS method to detect plasma concentration,use the self-made tablets and Plendil to carry pharmacokinetic experiments,and compare their differences.Result:(1) Establish HPLC method and UV method to determine FEL content and release rate.(2) FEL solid dispersion(SD) were prepared by solvent method.Compared with physical mixture and the draw drug, all SDs significantly increased the dissolution of FEL.When made with polyvidone(PVP) K29/32 as carriers at drug/carrier weight ratios of1∶6,the solution rate increased fast. The results of differential scanningcalorimetry and X-ray diffraction analyses indicated that the drug existed in an amorphous form in the prepared SDs.(3) Prepare the FEL tablet by compressing the powder directly. Check the cumulative release rate of the tablet.To pick out the best formulation and method of preparation by design an orthogonal methodology. Compare the release behavior of the self-made tablets and Plendil.The results come out to show that the two tablets have the similar in vitro release rate.(4)The method of detecting the related substance was specific, repeatable and accurate; Measured three batch of pilot samples the content and release rate and the related substances of FEL were within the rules. The influencing factors test showed us that when FEL is under bright light and high temperature, it is a little unstable.Therefor we should store it under dark and room temperature;The tests of accelerated stability showed us when stored at high temperature, the related substance will increase, but still at the eligible range.The content and release of FEL can meet the specification.(5)This HPLC/MS analysis was specific, sensitive, repeatable and accurate. The result shows that Tmax, Cmax, and AUC are similar, and relative bioavailability of test product is 112.8%. From the result, we can infer that the self-made tablets have the similar in vivo pharmacokinetic behavior to Plendil.Conclusion: Solid dispersion which prepared by solvent method could improve the solubility of felodipine. HPMC was used as skeleton materialto prepare the sustained-release tablets which have the similar in vitro dissolution and in vivo pharmacokinetic data like Plendil.