Pharmacokinetic Study Of New Formulations Of Two Synthetic Glucocorticoids

Background:Synthetic glucocorticoid is the first-line anti-inflammatory drug.However,the problem of the side effects associated with these drugs have aroused great concern and remained unresolved.Nowadays,budesonide as a potent glucocorticoid has been developed into various formulations intended to delivery the drag to the lesions without causing systemic side effects. Betamethasone dipropionate is always administrated percutaneously to treat skin diseases.The low plasma concentration and the interferences derived from endogenous glucocorticoids constitute challenges to the pharmacokinetic study of these drags.Objective:In the present study,the pharmacokinetics of budesonide enteric controlled release pellets and the compound tazarotene-betamethasone cream in animals will be studied using sensitive and selective liquid chromatography-tandem mass spectrometric methods(LC-MS/MS) to support the development of these two new formulations.Method:The in vitro release of budesonide from the enteric controlled release pellets(test formulation)was study using basket method in comparison with Entocort EC as the reference formulation.The pharmacokinetics ofbudesonide enteric controlled release pellets was studied in a cross-over experiment by single or repeat oral administration of budesonide enteric controlled release pellets(test formulation)and Entocort EC(reference formulation)to 6 beagle dogs with a wash-out period of one week.The pharmacokinetics of compound tazarotene-betamethasone 0.05%cream was conducted with 8 groups of rabbits(n=6/group)after single(0.5 g,1.0 g and 2.0 g)or repeat(2.0 g×5 d)percutaneous administration of the compound cream.The comparison was made between the compound cream and betamethasone dipropionate 0.05%cream and tazarotene 0.05%cream separately.Plasma(and rabbit skin)concentrations were determined by validated LC-MS/MS methods.Pharmacokinetic parameters were obtained using standard non-compartmental methods.In addition,skin irritancy was studied with rabbit and average scores were obtained.Results:Sensitive and selective LC-MS/MS methods were developed and applied in the pharmacokinetic study of budesonide enteric controlled release pellets and compound tazarotene-betamethasone 0.05%cream.Maximal budesonide plasma level was observed in dog plasma after 3.8±3.2 h and the C_maxwas 1056±659 pg/mL after a single oral administration of 9 mg budesonide enteric controlled release pellets(test formulation).Budesonide showed approximately 3-fold greater accumulation on day 5 compared with day 1 after repeat dose. Significant interindividual variability was observed in both the test and reference group.For the compound tazarotene-betamethasone 0.05%cream,the terminal t_1/2was 30.0-36.8 h (betamethasone)and 12.5-17.4 h(tazarotene acid)in three dosage groups.The increase of C_maxand AUC_0-∞for betamethasone were proportional more than the increase of the dose while the increase of these values were less than the dose increase for tazarotene acid.Mean C_maxranged from 167-910 pg/mL(betamethasone)and 8.96-28.0 ng/mL(tazarotene acid)and drug accumulations of betamethasone and tazarotene acid were observed after 5 day repeat dose.The systemic exposure of betamethasone(AUC_0-t17.8±10.3 ng·h/mL)in rabbit was lower in compound cream group than that of betamethasone dipropionate cream(AUC_0-t33.4±12.6 ng·h/mL)group,and the skin concentrations of betamethasone and tazarotene acid show no statistical differences in the comparison groups(P＞0.05).The compound cream scored 0 in the skin irritancy study which was lower than both the tazarotene cream and betamethasone dipropionate cream.Conclusion:The newly developed budesonide enteric controlled release pellets had s similar in vitro release profile with that of Entocort EC.The pharmacokinetic study showed a sustained T_max of the test formulation which indicate a controlled release profile.However,the pharmacolinetics of this pH-dependent drug delivery system was known to be affect by many factors such as the physical activity and gastrointestinal motion of tested animal which lead to the significant interindividual variability observed in this study,this will compromise the therapeutic effect of the formulation.The systemic adsorption of betamethasone from compotmd tazarotene-betamethasone cream was less than that of betamethasone dipropionate cream without compromise the skin accumulation of the drug,besides,skin irritancy study showed that the compound cream had no irritancy on skin,which indicate a lower incidence of adverse effects and ensure the topical effect of the drugs thus proved the safety of the compound cream.