| Cyclosporine A(CSA)is a third generation potent immunosuppressant.Due to its high specificity and strong action,CSA has been widely used in clinical practice since the 1980s for the treatment of organ transplant rejection and autoimmune diseases.However,due to the low bioavailability of cyclosporine A after oral administration,in order to improve the bioavailability of cyclosporine A.In this study,the preparation process and pharmacokinetics of transdermal patch of cyclosporine polypeptide A were investigated by applying electroporation technology to provide ideas for the development of transdermal drug delivery formulation of cyclosporine A.In the study on the optimization of the electrical parameters of the electroporation method,the cumulative permeation and transdermal absorption efficiency(ER)of cyclosporine A were taken as the indexes,and the electrical parameters of the electroporation were optimized by a four-factor,three-level orthogonal test after a single-factor investigation of pulse voltage,pulse time,number of pulses and pulse frequency,and the optimal electrical parameters of the electroporation were finally determined as follows:pulse voltage of 250 V,pulse time of 200 ms,number of pulses of 80 and pulse frequency of 40 pulses/min,which can significantly increase the transdermal permeation of cyclosporine A and are stable and feasible.In the study of the prescription and process of transdermal patches,the type of pressure-sensitive adhesive,the amount of pressure-sensitive adhesive,the type of plasticiser,the amount of plasticiser,the type of permeation promoter,the amount of permeation promoter and the drug loading capacity were investigated as single factors,and then a four-factor,three-level orthogonal test was carried out to optimise the prescription and process of transdermal patches,and the best preparation process was finally obtained The process is 1.50 g of pressure-sensitive adhesive(Eudragit E100),1.50 mL of tributyl citrate,8%menthol and 1%drug loading.In the study on the quality evaluation of transdermal patches,the appearance,adhesion and weight difference of the preparations were all in accordance with the pharmacopoeia requirements,as well as the uniformity of the colour of the patches,the surface finish of the patches,the presence or absence of de-paste and the flatness of repeated folding.The peeling strength test results showed that the peeling times of the three batches of transdermal patches were close to each other,with the average peeling time ranging from 58.00 to 62.00 min;the peeling strength test results showed that the peeling times of the three batches of transdermal patches were close to each other,with the average peeling time ranging from 8.24±1.15 min,and the peeling strengths of the three batches of preparations were also close to each other,with the average peeling time ranging from 3.50±0.28 N/cm;weight difference The weight difference of the 20 transdermal patches was less than 5%,and none of the patches exceeded the weight difference limit by a factor of one;the results of the cumulative permeation experiments:the cumulative permeation amounts within 8 h were basically the same,148.25±9.66 μg/cm2,152.65±4.66 μg/cm2 and 148.63±8.14μg/cm2 respectively,and their cumulative permeation amounts within 0-8 h The trend of changes in the cumulative permeation amounts from 0 to 8 h was also relatively stable,which can be used as a guarantee for the diffusion and absorption of the drug in vivo;the results of in vitro release experiments:all of them could reach more than 70%within 12 h;the results of content determination were:19.12±0.32 mg/sticker.In the in vivo pharmacokinetic study of transdermal patch rats,the maximum absorption concentration(Tmax for 5 h)of cyclosporine A was reached after transdermal administration of the drug under the effect of electroporation,the concentration Cmax was 2.430 μg/mL,the area under the drug-time curve(AUC(0-48))was 54.580 μg/mL*h and the mean retention time(MRT(0-48))was 18.719 h.Preliminary pharmacokinetic experiments showed that the electroporation group was able to effectively increase the drug transmission compared to the transdermal patch group,effectively increase the mean relative bioavailability(Fr of 322.74%)compared to the gavage group,and prolong the mean retention time of the drug molecules in the body and maintain relatively flat blood concentrations. |
