| Objective: Immunosuppressive agent is a class of immunosuppressive effects drugs.It can inhibit the body's abnormal immune response.It has been widely used in anti-organ transplant rejection and autoimmune disease treatment.Medicine A is a kind of synthesis of purine nucleoside immunosuppressant.It can inhibit division and proliferation of the rapid growth of specific lymphocytes,such as T-cell and B-cell.So it can creat the immunosuppressive effects.At present,it is conventional immunosuppressive drug.In the domestic and foreign market medicine A only has ordinary tablets.The ordinary tablet should administer three times each day.It's plasma concentration is not stable and side effect is obvious.Osmotic pump tablet as a typical example of controlled release preparation can release drug at the rate of approximate zero-order and reduce or even eliminate the adverse reaction.This study aimed at preparing A-osmotic pump controlled-release tablets.Formulation and process were optimized.Quality control method was established.And the release kinetics in vivo was studied.Methods: On the basis of pretest and scientific literatures,quality control method was established.Detection wavelength of drug A was decided.At this wavelength absorption of drug was obtained and its cumulative release was also obtained.Drug A is a model drug.On the basis of pretest and scientific literatures,drug A,osmotic agent,blocker,lubricator were mixed with adhesives-the ethanol solution of PVP.And we prepared soft wood,made granula,then tableted the core.Then composition of the coating solution and coating technology were studied and decided.A coated core tablets wereprepared by coating.The amount of osmotic agent,block ag-ent,PVP,plasticizer,thickness of coating membrane,weight of tablet,orifice,release media,rate of rotation were investigated.The orthogonal experiment was designed to optimize formulation in which the amount of bolck agent,plasticizer and thickness of coating membrane were taken as three influential factors.And three different levels were selected.By analysis of range,the optimization of technique and formulation was decided.Then release profile was fitted with zero-order release equation.The quality control studies of the osmotic pump contr-olled-release tablets were researched.A series of experiments were carried out,including description,recovery,precision,ass-ay,and dissolution.Stability experiment: The optimal formulation was inv-estigated under following circumstances: high temperature, high humidity,strong light and long natural store condition. Dissolution test and content assay were taken to examine at different time.Pharmacokinetics study in vivo: High-performance Liquid Chromatograph was adopted in examining concentration of plasma.The ordinary tablet was used as reference.the relative bioavailability and pharmacokinetics of osmotic pump controlled release tablets were studied.We select the dogs as laboratory animal,which were divided into 2 groups in random.One group was given osmotic pump tablets and the other was given market tablets.Crossover experiment was taken after two weeks.Plasma samples were determined by HPLC which were obtained at different time.Pharmacokinetics parameters were calculated with 3p97.Results: The results were defined through simple factor test and orthogonal experiments.The optimal formulation were as follows: weight of tablet,450mg;drug,200mg;lactose,232mg;PEO,13.5mg;PVP in the ethanol,3%;magnesium stearate,4.5mg.The coating solution were as follows: CA,2g;PEG 400,0.4g;acetone,100ml;talc powder,0.1g.The coating conditions were as follows: coating temperature,40-45℃;spray pressure,10bar;speed of wind,4m/s;flow rate of coating solution,0.25ml/min;gain of weight,2%.UV spectrophotometry was used on assay of medicine A in vitro.Detection wavelength of drug A was 278 nm.Excipients had no interference with the results at this wave.The linearity range of drug was 2.5μg/ml～17.5μg/ml.Regression equation was: A=0.0509C-0.0016(r=0.9997).The recoveries were 97.8~102.5%.The within-day precision was 1.28~2.14%.The between-day precision was 1.19~2.02%.The result showed that the method can meet the C-HP,and this method can accurately detect drug A in osmotic pump tablets.Release profile of A-osmotic pump was fitted with zero-order release equation: y = 7.9824x + 6.0426(r=0.9977), The results show that it meets the zero-release requirements.There was no change in physical appearance,drug content and drug release characteristics after being stored at high temperature(60℃) and strong illumination (4500Lx).It showed that drug was stable on temperature,illumination.The result of high humidity test showed that when osmotic pump release tablets were placed in humidity(RH 92.5%),the weight highly increased.But in humidity(RH 75%),the weight were hardly increased.The result of accelerated experiment and long natural store condition experiment showed that the data were not significantly different from before.Pharmacokinetic study: we took the experiment according to defined HPLC condition.The main pharmacokinetics parameters were respectively as following: Compared with market conventional capsule,peak time of osmotic pump tablet was extended,plasma concentration of osmotic pump tablet was decreased and bioavailability was almost equivalent.Conclusions: A osmotic pump tablets had good effect of controlled release property and repetition in vitro.The quality is independent from temperature,illumination and was stable in accelerated experiment. The experiment in vivo showed that peak time of osmotic pump tablet was extended,plasma concentration of osmotic pump tablet was decreased and bioavailability was almost equivalent. |
