Preparation And In Vitro And Vivo Evaluation Of Prednisone Oral Pulsatile Release Tablets

Rheumatoid arthritis（RA）is a chronic autoimmune disease.The main clinical symptoms of RA including joint pain and morning stiffness show a significant circadian rhythm characteristics,which occur seriously in the early morning.Based on the principles of chronopharmacology and chronotherapeutics,oral pulsatile drug delivery system releases an effective dose of drug in a programmed time to reduce drug resistance and improve drug treatment and patients’ compliance by selecting a reasonable administration time and dosage form.It can rapidly or slowly release effective amounts of drug after a delayed time（T5%,that is,the corresponding time of cumulative drug release of 5%）,which is suitable for the diseases immediately needing a peak plasma concentration at night or after waking in the morning.Prednisone is widely used for RA.Based on the circadian rhythm exhibited in RA,the compression-coated pulsatile release formulation was applied to prednisone and shown to effectively prevent and treat the joint pain,morning stiffness and other clinical symptoms caused by RA.The formulation was aimed to conform with the internal changes of the cytokines by making a rapid drug liberation following a designed lag time,and thus reducing side effects and increasing patient’s compliance,as well as achieving optimal treatment efficacy.Firstly,the high performance liquid chromatography methods were developed for the determinations of in vitro dissolution,the drug concentration and related substances of the tablets.The results of method validation were in accordance with the requirements of the methodological study.The physical-chemical properties of prednisone were also studied.Prednisone showed nearly the same solubilities in various pH fluids.The in vitro dissolution method was screened and finally established.The pulsatile release tablet containing 5 mg prednisone was prepared by compression coating technology using lactose and microcrystalline cellulose as fillers,glyceryl behenate（Gly）as main coating material,citric acid/sodium bicarbonate as disintegrants while crosslinked polyvinylpyrrolidone（PVPP XL）as additional disintegrants.The effects of varieties and amounts of disintegrants,the hardness of tablet core,the composition and ratio of the coating films,the hardness of the compressible tablet and the thickness of the coating films on lag time and release profiles were investigated.The results of these experiments indicated that the lag time and release profiles of the press-coated tablet were obviously affected by the mounts of additional disintegrants,the hardness of tablet core,the composition and ratio of the coating films and the hardness of the compressible tablet,while the thickness of the coating films,at some extent,had no significant effects.The system with 16% Gly and 8% of PVPP XL was chosen as the optimal formulation.The relationship between T5% and the hardness of the compression-coated tablet containing 16% Gly was linear（r=0.9867）.Combined with the requirements of the delayed time,the hardness of the press-coated tablet was controlled at 190 N.The high performance liquid chromatography-mass spectrometer（HPLC/MS/MS）method of plasma concentrations of prednisone and prednisolone was established.And the studies of methodology were conducted to validate the bio analytical method.According to a randomized cross-over trial scheme,the plasma concentrations of immediate release tablets（IRT）and pulsatile release tablets（PRT）would be compared.The parameters of pharmacokinetics were obtained by DAS 2.1.1 software.The results showed that the HPLC/MS/MS method used for determining plasma concentrations was convenient,accurate,and sensitive.By comparing the statistical analysis,it was easy to see that there was no significant differences of area under the concentration-time curve(AUC_0-t,AUC_0-∞)and peak concentration(C_max)as compared to remarkable differences of Peak time(T_max)and T5% between two preparations.The above results indicated that only the start time of drug liberation of PRT was changed in comparison with that of IRT.However,the drug release behavior and relevant pharmacokinetic parameters such as AUC_0-t,AUC_0-∞ and C_max showed no significant differences.The influence factors study of preparation demonstrated that the temperature had little effect on press-coated tablets.But the tablets were sensitive to light and humidity.The tablets had significant moisture absorption under high humidity,which showed remarkable changes of in vitro release profiles.So the tablets should be stored in dry condition and avoid light.