The Transcranial Absorption Of SU2237

Objective: To explore a new route of administration, patented active molecule SU2237 have been research through transcranial absorption in vivo in the rat.To predict the permeability of the drug by transcranial absorption and screen permeation enhancers, artificial infiltration devices have improved and SU2237 transcranial absorption in vitro have simulated.Methods: To study SU2237 transcranial absorption in rat, HPLC methodology have established first. Because SU2237, after it into the Liquid column,will separate ferulic acid(FA) and tetramethylpyrazine(TMP), ferulic acid(FA) and tetramethylpyrazine(TMP) methodology have investigated simultaneously.Specificity Investigation showed blank brain tissue in maximum absorption wavelength of SU2237(287nm) at no absorption.Ferulic acid(FA), standard curve regression equation is y = 61315 x + 19133,R2=0.999. In the low concentration(0.08 μg/ml), medium concentration(12.0 μg / ml),high concentration(28.0 μg/ml),the relative recovery were 98.3%, 108.4%,105.5%,they are in line with the requirements of methodology. In the low concentration(0.08 μg/ml), medium concentration(12.0 μg/ml), high concentration(28.0 μg/ml), the relative standard deviation(RSD) of day precision was 9.78%, 1.14%, 2.94%, and the relative standard deviation(RSD) of day precision was 8.85%, 1.65%, 2.91%, they are in line with the method learning requirements. RSD of stability at room temperature in 10 hours was 0.62%, it is in line with the methodology requirements.Tetramethylpyrazine(TMP), standard curve regression equation is y =60854x-2155.9, R2=0.9992. In the low concentration(0.2 μg/ml), medium concentration(1.0 μg / ml), high concentration(2.0 μg/ml),the relative recoverywere 104.1%, 109.3%, 103.3%,they are in line with the requirements of methodology.In the low concentration(0.2 μg/ml), medium concentration(1.0 μg/ml), high concentration(2.0 μg/ml), the relative standard deviation(RSD) of day precision was 3.24%, 1.90%, 3.81%, and the relative standard deviation(RSD) of day precision was 5.14%, 7.30%, 0.65%, they are in line with the method learning requirements. RSD of stability at room temperature in 10 hours was 0.38%, it is in line with the methodology requirements.The topic studies SU2237 pharmacokinetics, after apply SU2237 to rats’ head, in the 60, 90, 105, 120, 180, 240, 300 min obtain brain tissue respectively. Detecting the SU2237 concentration in brain tissue by HPLC and calculating the pharmacokinetic parameters by 3p97 program.The topic studies SU2237 were administered through the acupuncture, apply SU2237 to Baihui and Tianmen of rats with the capillaries, then obtain brain tissue in90 min, Detecting the SU2237 concentration in brain tissue by HPLC.To simulation SU2237 transcranial absorption in rats in vitro and screen permeation enhancers,UV methodology have established first.Specificity Investigation showed artificial cerebrospinal fluid(a CSF) in maximum absorption wavelength of SU2237(287 nm) at no absorption.SU2237, standard curve regression equation is y = 0.072 x + 0.0024, R2 = 0.9998. In the low concentration(1.0 μg/ml),medium concentration(4.0 μg / ml), high concentration(8.0 μg/ml),the relative recovery of SU2237 with azone were 100.7%, 98.1%, 97.8%, the relative recovery of SU2237 with azone, propylene glycol were105.4%, 97.9%, 97.9%,they are in line with the requirements of methodology. In the low concentration(0.2 μg/ml), medium concentration(1.0 μg/ml), high concentration(2.0 μg/ml), the relative standard deviation(RSD) of day precision was 2.60%, 0.54%, 0.85%, and the relative standard deviation(RSD) of day precision was 6.29%, 0.69%, 0.94%, they are in line with the method learning requirements. RSD of stability at room temperature in 12 hours was 0.31%, it is in line with the methodology requirements.This topic is intended to study drug SU2237 penetration in vitro. Using Franz diffusion device test, the rat‘skulls were fixed between diffusion chamber and theVII receiving chamber. Adding a magnetic stirrer and artificial cerebrospinal fluid(a CSF),so that the bottom of the skull in full contact with the receiving liquid to drain the bubble. Applied 2.25 ml of SU2237 to each rat’ skull, diffuse device have put into the collector thermostat heating magnetic stirrer, adjusted speed to 1000 r ? min-1 and the water bath temperature to 37.0 ± 1 ℃, start timing. At 0,0. 5,1,2,3,4,5,6,7,8,9,10 h remove 100 μl receiving fluid respectively into a 10 ml volumetric flask,and volume with a CSF. Then supplemented with an equal volume of a CSF to receiving chamber,and detect the concentration of SU2237 by UV measurement.Results: The topic studies SU2237 pharmacokinetics, after apply SU2237 to rats’ head.Detecting the SU2237 concentration in brain tissue by HPLC, data fitting by3p97 program and calculating the pharmacokinetic parameters by AIC minimum principle.FA is in accordance with two-compartment absorbing kinetic model in the brain.The Ka of FA is 2.30 h-1, T1 / 2α is 0.37 h, T1 / 2β is 21.60 h, Tmax is 0.49 h, Cmax is 1.18μg / m L, AUC is 2.45 μg * h * m L-1, V / F is 41.91 L / kg.TMP is in accordance with one-compartment absorbing kinetic model in the brain. The Ka of TMP is 1.35 h-1, T1 / 2Ka is 0.51 h, T1 / 2Ke is 0.86 h, Tmax is 0.94 h, Cmax is 0.23 μg / m L, AUC is 0.60 μg * h * m L-1, V / F is 247.44 L / kg.To explore SU2237 administration acupuncture points of the head, after administration SU2237 on the BAIHUI and TIANMEN of rats. Detecting the SU2237 concentration in brain tissue by HPLC, SU2237 can be penetrated the skull and absorb, Baihui and Tianmen absorb more than the blank.To simulate the absorption experiments in vitro,using modified Franz diffusion device, wherein the film change into a rat skull for screening permeation enhancers.According to linear equation, Calculation transdermal rate constants J, AR multiple Er and apparent permeability coefficient Kr of different penetration enhancers, compared with the blank, 1% azone, 4% azone, 2% azone + 10% PG and2% azone can increase the percutaneous absorption rate of SU2237 in proper order.Among them, 2% azone possess the best effect, is 1.71 times.Conclusion: From the parameters to observe, the peak time of SU2237 is about0.49 hours, indicating SU2237 penetration into the brain rapidly. AUC value of SU2237 in the brain, indicating that the amount of drug present in the brain, SU2237 can treat stroke and brain-related diseases.Comparative parameters of transcranial absorption and oral absorption, peak time of transcranial absorption is 0.49 hours, peak time of oral absorption is 0.5 hours,which show two paths penetration rate fairly. AUC value of transcranial absorption is2.45μg * h * m L-1, AUC value of oral absorption is 1.27 μg * h * m L-1, displayed former have more doses in the brain, meanwhile, transcranial absorption than oral absorption more effective. Cmax of transcranial absorption is 1.18 μg * m L-1, Cmax of oral absorption is 0.62 μg * m L-1, instructions former achieve greater concentration,transcranial absorption is more benefit for stroke and treatment of brain-related diseases.The results of administration in acupuncture point show that after SU2237 administration, transdermal acupuncture points are better than non-acupuncture points.Meanwhile, it prove stratum corneum of the skin of acupuncture points are thinner than non-acupuncture points, transdermal barrier of acupuncture points are low, so the skin of acupuncture points have good permeability, it is good for absord.Compared with the blank, 1% azone, 4% azone, 2% azone + 10% PG and 2%azone can increase the percutaneous absorption rate of SU2237 in proper order.Among them, 2% azone possess the best effect, is 1.71 times.