| Objective:Evodia extract is an effective multi-target analgesic which includes EVO and RUT.However, oral administration of Evodia extract may lead to headaches, severe abdominal pain, blurred vision and other adverse reactions. Topical formulations can reduce the system side effects. The subject of previous had maken Evodia extract into a topical preparation. But the results showed that the stratum corneum is the main barrier as to its percutaneous penetration. On the basis of preliminary work and in order to increase the amount of penertration, the subject is to study the effect of the kind of penetration enhancers on the cumulative penetration. The microdialysis technique was used for studying the transdermal formulations pharmacokinetic behavior of the Evodia extract ointment. The results of this study will provide theoretical and experimental evidence for the extract topical formulations research.Methods:(1) The method of HPLC for the determination of RUT and EVO in the ointment skin receive were established. Taking the pig skin as permeation barrier, the affects of the type and concentration of the penetration enhancers were researched by using the improved vertical Franz diffusion pool.(2)The influence of the concentration and the perfusion fluid velocity on the in vitro recovery of EVO and RUT were assayed by the loss and gain method, and the in vivo recovery was determined by the loss method. (3)18male SD rats were randomly divided into3groups on average, and the microdialysis probes were inserted into the abdomen subcutaneous. The0.5g0%anethole ointment,3%anethole ointment and5%anethole ointment were local administered. The EVO and RUT concentration-time curvy was monitored among the10h.(4) The quality control system of the evodia rutaecarpa ointment was establish. The appearance, pH value, content, cone into the degree and the preliminary stability were assayed.Results:(1) The results of percutaneous penetration in vitro shows that the promote infiltration agent of evodia rutaecarpa extract catalysed by EVO percutaneous ointment permeability order was:anethole>limonene>1,4-cineole> menthol> tetrahydro geraniol≈geraniol> nerolidol> farnesoid>borneol> negative control>glycyrrhizic acid potassium. The RUT order was:anethole>1,4-cineole>limonene>menthol>geraniol>tetrahydro geraniol>nerolidol>farnesoid>borneol>negative control>glycyrrhizic acid potassium.Among them, the anethole,1,4-cineole and limonene shortness of seepage effect were good. The Q24of EVO were1.78±0.13.1.49±0.10、1.60±0.12μg·cm-2respectively. And the ER were3.40,2.91,3.20respectively. In additions, the Q24of RUT were1.74±0.14、1.64±0.13、1.57±0.11μg·cm-2, and the ER were4.39,3.73,3.52respectively.The effects of concentration of the three promoting agent on percutaneous penetration in vitro were discussed. The results showed that the effect on promoting permeability enhanced with the increase of concentration in the scope of the1-5%concentration. But when the concentration increased from5%to8%, the Q24and ER did not increase any more. It indicated that the promote infiltration agent within the scope of the screening,5%anethole, extracts from evodia rutaecarpa ointment in vitro percutaneous penetration performance is best. The EVO Q24was1.81±0.11μg·cm-2, the ER is3.21; The RUT Q24was1.76±0.13μg·cm-2, the ER is3.84.(2) Probe results show that the recovery of perfusion fluid velocity of probe in vitro is inversely proportional to the rate. And the concentration of RUT and EVO have no effect on the probe recovery. the results of recovery in vitro measured by the increment method and decrement method showed that the recovery of EVO were46.09±3.74%,45.20±3.37%, and the recovery of RUT were56.23±4.63%,54.88±3.92%. The recovery of EVO in vivo was29.33±3.15%, and the RUT was36.36±3.21%.(3)Local pharmacokinetic experiments results showed that the Cmax, AUC0-10、AUC0-∞of the no promoting agent group,3%of anethole group,5%anethole extracts from evodia rutaecarpa ointment of subcutaneous increase respectively. Promote ooze agent concentration extracts of evodia rutaecarpa ointment and seepage effects from big to small in turn as follows:5%anethole>3%anethole> without promoting agent. Among them, the5%anethole group ointment on promoting effect is best.It indicated that5%of anethole as promoting the permeability agents can effectively promote the extract of percutaneous penetration, which is helpful for clinical treatment of pain.(4)The optimization evodia rutaecarpa extract ointment was with pale yellow uniform semi-solid, exquisite, pH6.71±0.11mm, cone into the degree was123.9±13.9, the viscosity of70.1±6.2Pa·S, the content is between99%-101%. The formulation does not appear statified phenomenon under the4000rpm centrifugal after30min. Ana the formulation maintain sable30days at40℃constant temperature. Conclusion:(1) The improved Franz upright transdermal diffusion pool and micro dialysis sampling technique were used to screen out the terpene class to promote infiltration agent, which can effectively improve evodia rutaecarpa extracts percutaneous penetration in vitro and in vivo.(2)5%extract of anethole ointment was stability, quality control and provide reference for external preparation of evodia rutaecarpa extract development.Which will provide a new way for the clinical treatment of analgesia. |
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