The Mesylate Dihydroergotoxine Nasal Brain Targeting Agents

Ergoloid mesylate(EM)is received as nootropics or "smart drug" for cognition enhancement in well persons of all ages.EM is also a prescription drug for the treatment of senileity and cerebrovascular insufficiency.The most common forms of EM currently used are the oral administration which has a low bioavailability,mainly resulting from first-pass effect, and injection which raises poor patient compliance and topical painfulness.Therefore,EM emulsion for nasal administration(EME)was prepared and compared to EM solution for nasal administration(EMS)to evaluate the brain target efficacy.The HPLC method was established to determine the EM concentration in EME and various pH buffer solutions.The related property of EM was investigated as well.It shows that EM is most stable in pH4.5 buffer,with slow but not significant increase of degradation in the range of pH3.5-5.1,while out of this range,the degradation goes up rapidly.High pressure homogenizer was used to prepare EME.The effects of homogenizer condition,oil phase,emulsifier and pH on the physicochemical stability of emulsion were investigated respectively,taking pH,mean diameter,particle size distribution,zeta potential, drug distribution as index.The final formulation and procedure were determined:4%egg leithin was added to the oil phase composed of 20%MCT and 0.4%tween-80,and stirred at 80℃until totally dispersed,followed by adding and dispersing of 0.5%EM.0.05%EDTA-2Na,0.01% benzalkonium bromide and 2.5%glycerol were heated and dissolved into double-distilled water. Coarse emulsion was achieved by mixing the oil and aqueous phases for 10 min using a high-shear mixer 10,000 rev/min.After adjusting the pH to about 5.0,final emulsion were obtained by passing the coarse emulsion through a high pressure homogenizer.The homogenization condition was 40℃,80 MPa and 6-10 cycles.The final product was bubbled with nitrogen gas before being sealed.The main physicochemical index of EME were about 100 nm in mean diameter,30 nm in particle size distribution,+26 mV in zeta potential,and the entrapment efficiency was above 75%. Stability study indicated that EME was stable in 6 months in respective of appearance,pH, content and entrapment efficiency.To assess the nasal ciliary toxicity of EME,the hoptoad in situ maxilla mucosa method was used by determining the ciliary movement time after in.administration.The toxicity of EME was very little and obviously lower than that of EMS.The viscosity of EME was higher than EME in the range of 5-40℃,which guaranteed that the residence time of the administered formulation.HPLC fluorometric method was performed to detect the concentration of EM in rat plasma, which was simple and precise.EME and EMS had been nasally administrated to rats, respectively.Non-compartment statistical moment method had been used in pharmacokinetics study.The results were compared with those of EM i.v..T_max,C_maxvalues and absolute bioavailability of EME and EMS were 62 and 107min;284.0 and 257.8ng/ml;56.8%and 47.4 %,respectively.T-test showed that the absolute bioavailability of EME was significantly higher than that of EMS,which indicated that EME had better bioavailability following intranasal administrationHPLC fluorometric method was performed to detect the concentration of EM in rats CSF, EM concentration in CSF were examined.Probe recovery was 24.25%by concentration difference method,recovery in vivo was 35.78%by retrodialysis.Non-compartment statistical moment method had been used in pharmacokinetics study.After nasal administration of EME and EMS and intravenous administration,T_max,C_maxand AUC_CSF/AUC_plasmain CSF were 20,20 and 60min;79.20,65.66 and 36.98ng/ml;0.73,0.61 and 0.15,respectively.DTP%(Direct transport percentage)of EME and EMS were 69.2 and 70.5%,with no significant difference from the result of t-test.However,other pharmacokinetic data showed significant difference(P＜0.05).It was clear that EM could directly enter brain through nasal mucosa due to shorter T_max and the greater value of AUC_CSF/AUC_plasma.And EME was considered to be better nasal dosage form since better results of bioavailability and lower toxicity.The site of action and recipient of EM were in the pars encephalica,this research supplied the evidence of EM nasally administration to cure Binswanger and the dosage selection of nasal administration.