Research On Intranasal Delivery Of Tetrahydropalmatine Inspired By A Traditional Application Method Of Corydalis Rhizoma

Research on traditional application method of Chinese herb posses important significance for pharmacy of Chinese materia medica.In the present study,we focused on the nasal administration of Corydalis Rhizoma powder in treating headache,which was originally decribed in Ben Cao Gang Mu.Tetrahydropalmatine(THP),the major effector of Corydalis Rhizoma,was chose as model drug on behalf of Corydalis Rhizom.The experiments were performed to investigate pharmacokinetic properties and brain distribution of THP in rats following intranasal administration(IN).The effects on contents of serotonin(5-HT)and endothelin(ET)in brain of nitroglycerin-induced migraine rats.were also observed after IN administration of THP.This work would provide scientific basis of the traditional application methods of Corydalis Rhizoma.1.The rat nasal cavity recirculating perfusion method was employed to regulate THP nasal absorption.The nasal absorptions of THP dissolved in sulfate and acetate solutions were all investigated.And the influence given to the nasal mucosa absorption by concentration and pH value were also examined.The results showed that the nasal absorption rate of THP in sulfuric acid solution was significantly higher than that in acetate solutions.There were no significant differences of nasal THP absorption rate in the concentration range of 50 – 500 μg/mL.2.An LC-FLD analytical method for THP in rat plasma was established,and the pharmacokinetics of THP after IN,intravenous(IV)and oral administration were investigated.The results showed that the plasma concentration of THP peaked more rapidly after IN administration compared with oral administration.The calculated AUC of IN administration was remarkably higher than that of oral administration.Consequently,the bioavailability of intranasal THP(45.13%)was about 2.5 times that of oral THP(18.34%).3.The levels of THP after IN,IV and oral administration in different brain regions including olfactory bulb(OB),olfactory tract(OT),cerebrum(CR),and cerebellum(CL)were determined by LC-FLD analysis..And the value of drug targeting index(DTI)was calculated.The results showed that the concentration of THP in OB was significantly higher than that in OT,CR and CL at 0.083 h after IN administration.The concentrations in OB and OT were higher than those in CR and CL at 0.25 h.Furthermore,the DTIs of IN administration for OB,OT,CR and CL delivery were calculated to be greater than 1.indicating that IN administration achieved more effective brain delivery.Collectively,the brain pharmacokinetic data suggest that intranasal THP enters the brain by olfactory routes other than penetration of the BBB via systemic circulation.4.The rat model with migraine was build up by nitroglycerin.The levels of 5-HT and ET in brain of migraine model rats were determined following IN administration of THP.The results showed that the contents of 5-HT and ET in the brain of the model rats were significantly increased(p<0.05)The IN dosing of THP can significantly decrease the level of 5-HT and ET in the brain of the model rats(p<0.05),indicates that THP had therapeutic effects on migraine following IN administration.