Design And Pharmacokinetic Evaluation Of Long-Acting Drug-in-Adhesive Transdermal Patch Of Rivastigmine

Objective:The purpose of this study is to prepare a long-acting pressure-sensitive adhesive patch of Rivastigmine（RVS）with simple structure,constant release rate and gentle blood concentration by ion pair technology.Method:In this paper,rivastigmine tartrate was prepared into free base of rivastigmine.In order to achieve the purpose of long-term controlled release,ion-pair strategy was chosen to solve this problem.Firstly,the isolated abdominal skin of Wistar rats were used as the permeability barrier,six kinds of saturated fatty acids and aromatic acids:n-butyric acid（C₄）,n-octanoic acid（C₈）,lauric acid(C₁₂),ibuprofen（IB）,salicylic acid（SA）,benzoic acid（BA）and RVS were synthesized,and the formation of ion-pairs was characterized by Fourier transform infrared spectroscopy（FTIR）.Ion-pair was used as the main drug,the patch was prepared by organic solvent volatilization method,and the type and dosage of pressure-sensitive adhesive,drug loading and permeation enhancer were screened by single factor test in vitro,and the optimal prescription was obtained.The controlled release mechanism of ion pairs was characterized by in vitro release study,FTIR method,Raman spectroscopy method,computer molecular simulation,differential scanning calorimetry（DSC）and rheological experiments.The quality of the patch prepared by the optimized prescription was preliminarily evaluated,and its mechanical properties and uniformity were mainly investigated.Male rabbits were used as experimental animals to investigate the in vivo pharmacokinetic behavior of the optimized prescription patch and the commercially available Exelon^?patch.The high performance liquid chromatography（HPLC）method was used to determine the drug concentration in plasma samples.The pharmacokinetic data is calculated by Win Nonlin^?software.Result:The prescription composition of the optimized RVS patch is as follows:the main drug is rivastigmine-salicylate ion pair（RVS-SA）,the drug loading is 30%（RVS is 30%）,and the pressure-sensitive adhesive is self-made hydroxyl-containing polyacrylic acid Ester pressure sensitive adhesive（AAOH）,the accelerator is 15%POCC.The in vitro transdermal rate of RVS-SA long-acting patch remained relatively constant within 72 hours.The release study of RVS and RVS-SA showed that the rate-limiting step which mainly affected the transdermal permeation of RVS is the release process.The results of FTIR,Raman,computer molecular simulation,DSC and rheological experiments showed that the formation of RVS-SA ion pairs increased the molecular interaction between RVS and pressure-sensitive adhesive,and reduced the free volume formation ability and molecular mobility of pressure-sensitive adhesive,thus inhibiting the release of RVS from the adhesive.The RVS-SA patch had good adhesion to the skin,and the content of the drug in the patch was relatively uniform,which was in line with the regulations of the Chinese Pharmacopoeia.The results of in vivo pharmacokinetic experiments in rabbits showed that the relative bioavailability of the 72-hour long-acting rivastigmine patch to the marketed patch Exelon^?was 87.07%,and there was no significant difference in the AUC value between the two（P>0.05）.Compared with the Exelon^?patch,the C_max of the preferred prescription patch significantly reduces the delay of T_max,t_1/2 and the MRT_0-t is prolonged,which proves that the preferred prescription patch can effectively control the in vitro transdermal and in vivo absorption of RVS and achieve the long-term goal.Conclusion:In this paper,ion-pair technology was used to successfully prepare a RVS long-acting pressure-sensitive adhesive dispersion patch with simple structure,constant and rapid drug release and gentle blood concentration.The controlled release mechanism of ion pair technology was clarified from the molecular level:the formation of ion pair not only strengthens the interaction between RVS and pressure sensitive adhesive,but also reduces the fluidity of pressure sensitive adhesive and the ability to form free volume.It provides a reference for the development of long-acting patches.