| Except oral administration,transdermal administration is one of the most important routes of administration in traditional chinese medicin,it has the advantages of convenient administration,avoiding first pass effect,long maintenance time,as so on.However,the Complex component and excessive dose seriously restrict the application and development of modern preparation technology.This article from the perspective of biopharmaceutics,according to the academic view that "Systemic effects of external application of Chinese medicine should be transdermal resorption in order to play a role",developed an liposome artificial skin membrane for the first time and separated the active substance based from Xiangfu Siwu Decoction,which can treat dysmenorrhea by transdermal administration.To carry out the analysis of components,pharmacodynamics studies and percutaneous absorption of pharmacokinetic studies comparing to the unseparated Xiangfu Siwu Decoction part.Employ water extraction and alcoholprecipitation,macroreticular adsorbent and ethanol elution to prepare the 40%and 60%ethanol elution site,the yield were 0.957%and 0.325%.Mixing the 40%and 60%site at a ratio of 1:1 to prepare the Xiangfu Siwu Decoction part(XFD).Applying the UPLC-MS/MS to determine the content of main active components in the XFD,the contents of ferulic acid,paeoniflorin,albiflorin,tetrahydrocolumbamine,pprotopine and tetrahydropalmatine were(4.73 ± 0.88)%,(12.5 7 ± 2.03)%,(3.09±0.49)%,(0.26±0.09)%,(0.26±0.11)%and(0.41±0.18)%.The liposome-based artificial skin membrane(LASM)was prepared by liposome technology,combined with porous membrane material,centrifugal and freezing thawing.The model drug was formed by main active compounds mixed at the ratio in XFD,taking the rat skin as a control to carry out in vitro transdermal absorption test.Prescription screening and optimization were carried out in terms of phospholipid content and phospholipid composition.The best prescriptions showed that the phospholipid content was 11.58 mg/cm2 and the egg lecithin:cholesterol was 77:23.The composition and structure of LASM were investigated by attenuated total reflection Fourier transform infra-red spectrum(ATR-FTIR)and scanning electron microscopy(SEM).The result of ATR-FTIR analysis showed that the composition of LASM was closer to the real skin.SEM analysis displayed that the small particle size liposome can block the pore of the nylon membrane,and the large particle size of the liposome is close to the surface of LASM,forming a"brick-wall" structure,which was similar to the stratum corneum.The stability of LASM in the receiving solution was investigated by the method of resistance.The results showed that 20%ethanol water as the receiving solution could not destroy the integrity of LASM.In vitro permeation test was carried out by modified Franz diffusion cell method.The permeation of the model drugs in LASM,rat skin and commercial Strat-MTM membrane was compared.The results showed that the simulated effect of LASM on real skin was significantly better than that of Strat-MTM membrane.The optimal LASM was used to enrich percutaneous absorption site(XFD-L)from XFD,with a rate of 18.92±2.12%(n=3),and the components in XFD and XFD-L were analyzed.A total of 18 compounds in XFD were identified by UPLC-TOF/MS,including terpenoids and their glycosides,aromatic acids,alkaloids and peptides.The peak area of 18 components in before and after membrane separation was compared and the composition of active ingredient in XFD-L was changed.At the same time applying the UPLC-MS/MS method determined the content of main components in before and after part by membrane separation.The content of paeoniflorin and albiflorin reduced by about 90%,and the content of ferulic acid increased from 5.91%to 17.00%,increasing by 3 times,and the contents of three alkaloids decreased.According to the percutaneous absorption properties,for example,paeoniflorin and albiflorin,with larger molecular weight and large polarity,are difficult to penetrate the skin,and ferulic acid,with small molecular weight and polarity,is easily to penetrate the skin.Therefore,LASM is able to enrich the components that are easily absorbed through the skin and remove about 81%of the components that are difficult to penetrate through the skin.Prepared mouse primary dysmenorrhea model,and The effects of XFD and XFD-L on the contraction of isolated uterus were studied in vitro,The effect of XFD and XFD-L transdermal administration were evaluated by writhing test in mice,with the number of writhing times and the concentrations of PGF2?,Ca2+and NO in the uterus as indicators and oral ibuprofen as a positive control.The results of In vitro uterine contraction test showed that compared with XFD,the inhibitory effect of XFD-L on the mean contraction frequency and tension of the uterus was enhanced with the same dose(P<0.05,P<0.01).The results of the writhing test showed that XFD-L significantly reduced the number of writhing in mice(P<0.01),which was comparable to that of the positive control ibuprofen.And the number of writhing times of XFD-L group under half dose was lower than that of XFD group.The results showed that XFD-L could significantly reduce the concentration of Ca2+and PGF2?(P<0.001,P<0.05),and increase the concentration of NO(P<0.05),and the regulation of the three indexes was stronger than that of XFD Compared with XFD,the inhibition effect of XFD-L on dysmenorrhea was improved significantly.Ferulic acid is the main active component of principal drug "Angelica" in Xiangfu Siwu Decoction,with the effect of anti-platelet aggregation and thrombus,anti-inflammatory and diastolic blood vesselsIn order to further investigate the effect of membrane separation on the percutaneous absorption of ferulic acid,XFD and XFD-L in gel form was transdermal administered by rat abdominal and determined the plasma concentration of ferulic acid,calculated pharmacokinetic parameters.The results showed that compared with the XFD group,the AUC and Cmax values in the XFD-L group were increased by 1.70 times and 1.88 times(P<0.05),respectively,indicating that the relative bioavailability of ferulic acid was increased significantly. |
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