Transdermal Absorption Of Rutaecarpine LCNP And Its Application Microneedle-assisted Treatment

Evodia rutaecarpa is dry near mature fruit of Euodia Rutaecarpa(Juss.)of Rutaceae.Benth.,stone tiger,Euodia Rutaecarpa(Juss.).Benth var.Officinalis(Dode)Huang or Euodia Rutaecarpa(Juss.)Benth.Var.bodinieri(Dode)Huang [1].Rutaecarpine(Rut)is one of the main components of rutaecarpine,the research had shown that rutaecarpine had extensive pharm-acological effects,such as improving cardiovascular,anti-inflammatory,function,preventing thrombosis,pain relief etc.In spite of the good pharmacological activity and application prospects,the rutaecarpine had the problems,such as hydrophobic,poor oral absorption and low bioavailability in vivo,which exerted a serious influence on its clinical use.Therefore,this paper was aimed to improve the transdermal absorption and bioavailability of rutaecarpine from two aspects: first,for the low solubility in the water and low bioavailability,the rutaecarpine liquid cubic crystalline nanoparticles(Rut-LCNP)was established,Secondly,the transdermal efficiency of Rut-LCNP was improved based on physical penetration-microneedle method.The content of the paper mainly included: the preparation,pharmaceutical characterizatio,release behavior and transdermal absorption of Rut LCNP,microneedle mechanical model,microneedle penetration enhancement.1.Preparation of Rut-LCNP.On the basis of screening different entrapment efficiency(EE)measuresment method of Rut-LCNP.Precursor injection-high pressure homogenization for the preparation of the Rut-LCNP.The influence of stirring temperature,speed,time and high pressure homogenization pressure,time on the EE and particle size of Rut-LCNP was investigated by single factor experiment.The optimum preparation technology parameters of Rut-LCNP were identified.Finally,the prescription optimization model of Rut-LCNP was optimized by Box-Behnken designs-response surface methodology,and EE,drug loading,mean particle size and particle size distribution of Rut-LCNP were measured to investigate the model.2.Pharmacological characteristics and release behavior of Rut-LCNP.Firstly,And then the polarizing microscope,transmission electron microscopy,laser particle size instrument was adopted to the characterization of Rut-LCNP by the optical properties,morphology,particle size.The p H value,leakage,the release rate in vitro,the transdermal absorption in vitro of Rut-LCNP,and the results showed that the p H and the leakage rate of Rut-LCNP is relatively stable.The results showed that 30% PEG400 and 30%ethanol-saline solution had significant difference in the release rate of Rut-LCNP,and the release rate of LCNP in vitro was significantly different between the two mediators,and the results showed that there was a significant difference in the release rate of Rut-LCNP between the two mediators in vitro.Moreover,the drug release of LCNP was in accordance with the Higuchi equation.In the in vitro percutaneous permeation experiment,the transdermal permeation of Rut-LCNP obeys the zero-order kinetic equation.3.In vitro percutaneous absorption of Rut-LCNP with the aid of blank polymer microneedle.First of all,biological tissue(mouse abdominal skin)was used to investigate the true puncture performance of microneedle.Histological section method was used to evaluate the performance of microneedle puncture.By histological section staining,it was found that after microneedle treatment,the abdominal skin of mice was deformed,and there were indeed micropore channels.The experimental method of microneedle promoting percutaneous permeation of drugs in vitro was established by using Franz diffusion cell.The effects of the length of microneedle,the time of microneedle pretreatment and the force of microneedle on skin pretreatment on the efficiency of penetration were studied by means of transdermal experiment in vitro.The results showed that the strength of microneedle pretreatment and the time of microneedle pretreatment were two important factors affecting drug penetration compared with the passive diffusion control group,and the length of microneedle had no obvious effect on the penetration efficiency.Among the effects of microneedle pretreatment on skin,30 N had the strongest effect on the permeability of Rut-LCNP,20 N was the second,and 10 N was the worst.The penetration rates of Rut-LCNP were 4.5979,5.1538 and 6.0726 ?g/(cm2·h)at different pressures,respectively.The cumulative penetration for 12 h was 26.98.5,31.3567 and 38.3634 ?g/cm2,respectively.The comparison between the two groups showed that the force of 30 N in the microneedle group was higher than that in the 20 N microneedle group.There was a significant difference in the action of 10 N in the microneedle group(P < 0.05).The retention time of microneedle pretreatment was in the range of 3 ~ 10 min,and the longer the time was,the greater the permeation rate of the drug was.The transdermal penetration rates of Rut-LCNP were3.9786,4.5979,5.3258 ?g/(cm2·h)for 12 h,The cumulative penetration for 12 h was23.6996,26.96,32.9847?g/cm2,respectively.After comparison between the two groups,the transdermal penetration rates were 3.9786,4.5979,5.3258?g/(cm2·h),respectively.The results showed that there was also a significant difference between the microneedle group with 10 min retention time and the 3 min microneedle group(P < 0.05).There was no significant difference in the permeability of Rut-LCNP between the differences of microneedle length.4.Percutaneous absorption of Rut-LCNP in vitro under different cosmetic microneedle-assisted conditionsFirst,biological tissue(mouse abdominal skin)was used to investigate the true puncture performance of cosmetology microneedle,and then histological section method was used to evaluate the puncture performance of cosmetology microneedle.It was found that after pretreatment with nanocrystalline microneedle,the abdominal skin of mice became invisible,and after the treatment of ordinary metal microneedle,the skin of the abdomen of mice was deformed and deep microporous channels were produced.Franz diffusion cell was used to establish different cosmetic microneedles to promote percutaneous penetration of drugs in vitro,and the effect of different cosmetic microneedles on the penetration efficiency of evodipine LCNP was studied by means of in vitro transdermal experiment.The experimental results show that,compared with the passive diffusion control group,ordinary metal microneedles have a significant effect on the penetration enhancement efficiency,but nano-crystal micro-needle has no obvious effect on the penetration enhancement efficiency.The transdermal rates of Rut-LCNP were 2.1503,2.0817 ?g/(cm2·h),the cumulative penetration for 12 h was 11.6946 and 10.99507?g/cm2,after pretreatment with circular and square nanocrystalline microneedles,respectively.The penetration rates of Rut-LCNP were6.4643,7.0176,5.7948,6.0726 ?g/(cm2·h),the cumulative penetration were 64.7244,64.7244,63.4686,67.5607 ?g/cm2 for 12 h,respectively,among the four needle numbers(42 G,36 G,12 G,9 G)of ordinary metal microneedles.However,there was no significant difference between the needle number of microneedles and the transdermal rate and permeability of Rut-LCNP.