Construction Of Carvedilol Transdermal Patches Based On Binary Ethsomes And Silk Fibroin And Evaluation Of Its Antihypertensive Performance

Carvedilol(CL)is a lipophilic drug and a clinical first-line drug for the treatment of hypertension.However,CL has a short half-life and poor bioavailability after oral administration.Transdermal administration can avoid the first pass effect of the liver and gastrointestinal irritation.It is expected to overcome the above-mentioned shortcomings of CL and be better applied to the treatment of hypertension.This research aims to construct a transdermal drug delivery patch(TDDP)based on glycol plastid(BES)and silk fibroin fiber matrix,and use CL as a model drug to investigate whether the system and its use with the assistance of metal microneedles(MNs)can significantly improve the bioavailability of the drug and lower blood pressure.The main research contents and results of this paper are as follows:(1)BES formulation optimization and its characterization.The BBD(Box-Benhnken Designes)method was used to optimize the BES formula,with lecithin,octadecylamine,ethanol and propanediol as independent variables,and particle size,zeta potential,encapsulation efficiency and 24 h cumulative drug release as dependent variables to obtain the BES The optimal formula is: 0.1 g lecithin,0.01 g octadecylamine,20% v/v ethanol,10% v/v propanediol.The corresponding response values are: particle size 506.5±50.85 nm,zeta potential 11.3±1 m V,encapsulation efficiency 73.499±2.51%,and cumulative drug release volume of 361.038±38.91μg in 24 hours.The blank BES is round,and the particle size becomes larger after loading CL.The deformability of CL@BES is 70.58%.There is no significant difference in particle size and electric potential when placed at 4℃ for one month,and the stability is good.Within a certain concentration range(0～5% v/v),BES has good cell compatibility.(2)Preparation and characterization of TDDP.The silk fibroin fiber matrix(SFM)was prepared by the one-step soaking method of ternary solution.SFM has good hydrophilicity and good mechanical properties.The CL-wrapped BES is mixed with the PVP ethanol aqueous solution and then electrosprayed onto the SFM to obtain TDDP.Scanning electron micrographs showed that the diameter of the SFM fibers was uniform,and the drug-loaded microspheres were evenly distributed on the fibers.In vitro transdermal experiments show that TDDP has good transdermal performance,and MNs-assisted TDDP(MNs-TDDP)can significantly improve the transdermal efficiency.(3)Animal experiments.Pharmacokinetic studies with rats as experimental animals show that compared with oral administration,the administration of MNs-TDDP can significantly delay the attenuation of CL plasma concentration.Blood pressure monitoring experiments show that TDDP administration can effectively reduce the arterial blood pressure in hypertensive model rats.Further studies have shown that MNs-TDDP can significantly increase serum NO levels and achieve better blood pressure lowering effects.These results indicate that MNs-TDDP can effectively enhance the bioavailability of CL.The staining results of pathological sections showed that the administration of TDDP had no obvious toxicity to the main organs of animals.