| Imidazolium ionic liquid is a new green solvent with low toxicity and high solubility,which is used in chemical reaction,organic phase separation,surfactant and solubilizer of pharmacy field.Although the penetration enhancing effects of imidazolium ionic liquids have been reported in literatures,the relationship between imidazolium ionic liquid molecular structure and the penetration enhancing activity is not been studied,furthermore,the specific permeation mechanism of ionic liquid microemulsion on skin is still not clear.Hence,in our research,the hydrophilic compound of panax notoginseng saponins(PNS)was used to investigate the permeation effects of imidazolium ionic liquids and the structure-activity relationship,then selected the representative imidazolium ionic liquids to the preparation of ionic liquid microemulsion,and studied the penetration effect and mechanism of microemulsion on PNS as an enhancer.After that,the cutaneous safety of imidazolium ionic liquid microemulsion was also investigated,the main research contents and results of this study were as follows:1.Male mouse abdominal skin was used to study transdermal permeation of the five main saponins in PNS by means of Franz diffusion cell in vitro,the result showed us that the accumulative penetration amount of the five saponins changed linearly with time,the order of penetration amount was kept as:Rg1>Rb1>R1>Re>Rd,and ginsenoside Rg1 was showed a highest penetration capacity among others in 24 h with a steady penetration rate and cumulative penetration of 0.114±0.017 mg·cm-2·h-1 and 2.718±0.365 mg·cm-2.Moreover,it found that the permeability coefficients of the five saponins were consistent.In order to easily study the later tests,ginsenoside of Rg1 was used as the main indicator to investigate the transdermal permeation of PNS in mouse skin.The method of Franz diffusion cell was also used in studying the effect of different concentrations of PNS(20,40,60,90 mg.mL-1)on the transdermal delivery of PNS,the result showed that the accumulation was proportional to the time in 24 h,and the best osmotic concentration of PNS in mouse skin was 60 mg.mL-1.2.In this study,the stable imidazolium ionic liquid[BMIM]Cl was used to preliminarily investigate the influence of ionic liquids on transcutaneous permeation of fluorescein sodium(hydrophilicity)by a confocal laser scanning microscopy.It found that compared with the control group,5%[BMIM]Cl could significantly promoted fluorescein sodium distribution into the deeper skin layer,and then increased the concentration of flurescent probe in skin.The result suggested that imidazolium ionic liquid showed a good penetration effect on hydrophilic compounds.Based on these results,we had studied that the best penetration concentration of ionic lqiuid was 5%,and ginsenoside of Rg1 was also used as the main indicator to investigate the influence of eleven imidazolium ionic liquids(5%)and three ordinary enhancers(5%,N-pyrrolidone,1,2-propylene glycol and azone)on the transdermal delivery of PNS(60 mg.mL-1)in mouse skin.It suggested that imidazolium ionic liquids had a certain penetration on PNS in vitro,and[HOEIM]Cl showed a best permeation effect(enhancing rate ER was 3.13).The penetration activity of imidazolium ionic liquids was related to the substituent number,chain length,location,kinds of cationic and the composition of anion.More importantly,imidazolium ionic liquid could increase the penetration activity by changing the specific structure of functional group.3.In our study,the hydrophilic ionic liquid[HOEIM]Cl,lipophilic ionic liquid[BMIM]PF6 and[BMIM]C12SO3 were served as one of water phase,oil phase and surfactant in microemulsion,and determined the best proportion of each component in microemulsions from the pseudo-ternary phase diagram to prepare three imidazolium ionic liquid microemulsions(Me 2,Me 3,Me 4).Then studied the physic-chemical properties of each microemulsion which included with particle size,viscosity,pH and stability.The result showed that three ionic liquid microemulsions were successfully prepared,and physically stable with the size smaller than 100 nm.After,we also studied that the three imidazolium ionic liquid microemulsions had a good effect on the penetration of PNS by means of Franz diffusion cell in vitro.4.Investigation means of confocal laser scanning microscopy(CLSM),transepidermal water loss(TEWL),atomic force microscopy(AFM),differential scanning calorimetry(DSC),attenuated total reflection fourier transform infrared spectroscopy(ATR-FTIR)were used to study the effect of imidazolium ionic liquid micreomulsions on mouse skin permeability.Combined with our results,the specific permeation mechanism of ionic liquid microemuslion on mouse skin could be summed up into two aspects:first,ionic liquid microemulsion could change the lipid bilayer structure by disrupting the order and intact structure to reduce the diffusion barrier of the stratum corneum,leading to the lipid bilayer become loosely and irregularly,thus increased the skin permeability.Second,after penetrated into the skin,ionic liquid microemulsions could also promoted drug distribution into the deeper skin layer and increased the concentration of drugs in skin tissue.5.Rats were used in the study of cutaneous safety,on one hand,skin irritation test of imidazolium ionic liquid microemulsions was assessed after single dose,and the results suggested that Me 3(oil acid/Tween-80+[BMIM]C12SO3/1,2-propanediol/50%[HOEIM]Cldistilled water)had no skin irritation from the observation of naked eye,however,the skin under a single dose of Me 4(oil acid/Tween-80+[BMIM]C12SO3/1,2-propanediol/distilled water)had a slight erythema from 24 h,and in the continual observation,the rat skin had recovered normally without any erythema and other adverse reactions at 144 h.There was not any inflammatory cell or other tissue lesion by Me 3 and Me 4 from the observation of histological section.But it was a remarkable fact that the stratum cornuems had a keratization after given Me 3 and Me 4.On the other hand,acute toxicity test on rats was carried out by giving them five times of the usual dose,fixed for 24 hours,after that,removed the drug residue and consecutively observed for 14 days.It found that Me 3 and Me 4 all showed no acute toxicity reaction.In conclusion,our research was studied that imidazolium ionic liquids and the microemulsions all showed a penetration effect on PNS,and we had also investigated the penetration mechanism and cutaneous safety of imidazolium ionic liquid microemulsions,these results provided theoretical references for the application of ionic liquid microemulsion in pharmaceutical field. |
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