| Gentiana macrophylla is the dried root of Gentiana,which has a variety of biological activities,such as anti-inflammation,liver protection,analgesia,cardiovascular protection and so on.Most of the traditional administration methods of Gentiana are oral administration,but iridoids are rapidly absorbed and eliminated in vivo,and oral bioavailability is low,which is not conducive to its efficacy.Cataplasm is a new type of transdermal drug delivery,which has the advantages of large drug loading and long action time.In this study,the split iridoid terpenes with high content in Gentiana macrophylla were taken as the research object,the rules of skin penetration in vitro were investigated and prepared into cataplasm,and then the pharmacodynamics and pharmacokinetics of split iridoid cataplasm were evaluated by animal experiments.Firstly,the in vitro permeation of gentiopicroside,swertiopicroside and swertioside was systematically studied by modified Franze diffusion cell method.The permeation efficiency of swertioside was the highest,followed by swertiopicroside and swertiside.After the addition of penetration enhancers,the permeation efficiency of the three iridoid terpenes was improved,and the best osmotic effects on gentiopicroside,swertiamarin and sweroside were1.5%azone+1.5%N-methylpyrrolidone,1.5%azone+1.5%menthol,respectively.The cumulative permeability reached 125.59±2.56,265.97±13.64,263.9±4.79μg/cm2,respectively.Secondly,gentiopicroside（GPS）and swertiopicroside（SWE）were used as main drugs to develop cataplasm.Taking adhesion and comprehensive sensory evaluation as evaluation criteria,and the contents of NP-700,carbopol,kaolin and EDTA as four factors,orthogonal experiments were designed to screen the best prescription of cataplasm matrix,that is,NP-700 content was4%,kaolin content was 1.2%,EDTA content was 0.01%,and carbopol content was 0.3%.The glycerol content is 30%,the hydroxyl aluminum content is0.3%and the best penetration enhancer is selected.The release rule of the prepared cataplasm was studied in vitro.the results showed that the prepared cataplasm could stably release the drug and pass through the skin,and the penetration time could be maintained for more than 12 hours.Finally,the pharmacodynamics and pharmacokinetics of the prepared cataplasm were studied.The anti-inflammatory activities of GPS and SWE cataplasm were detected by mouse foot swelling model,and the anti-inflammatory mechanisms of gentiopicroside and swertiamarin were studied by Elisa,HE section,q RT-PCR and Western Blotting experiments.It was found that GPS and SWE could reduce the content of inflammatory cytokines TNF-α,i NOS,IL-6 and increase the content of anti-inflammatory cytokines IL-10,which was consistent with the transcriptional trend of m RNA.GPS and SWE also decreased the expression of i NOS,COX-2,IκBα,p Mu65and p-p65,indicating that their significant anti-inflammatory effects may be achieved by inhibiting i NOS/COX-2/NF-κB signal pathway.Monitoring the concentration-time curve of GPS and SWE in rats after oral administration and cataplasm administration,it was found that compared with oral administration,the plasma concentration of Gentiana iridoid cataplasm was stable,and the time to reach the maximum plasma concentration was prolonged to 2 hours,and decreased slowly.Among them,the AUC（0∞）of GPS and SWE cataplasm increased to 99.51±1.71and135.34±2.33 mg/L×h,respectively,and the clearance rates were 1.84±0.03,1.35±0.02 L/h/kg,respectively.Through LC-MS analysis of drug-containing serum and skin homogenate,it was found that gentiopicroside and Swertiopicroside transformed each other after entering the systemic circulation through the skin,which may help to better exert their efficacy. |
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