Preparation Of Nimodipine Ophthalmic Ointment And Study On Its Systemic Transport

Objective:The calcium ion antagonist nimodipine was used as a model drug to prepare ophthalmic ointment,and the best prescription was selected and evaluated its quality;To observe the changes of plasma concentration and tissue distribution of nimodipine in rats after different routes of administration,in order to explore the feasibility of drug delivery through ocular administration to achieve systemic transport;To investigate the effect of different doses of borneol on the blood and brain after nimodipine by intraocular administration,in order to provide a theoretical basis for the study of drug transfer across the ocular barrier.Methods:?1?Different matrix and different concentrations of nimodipine ophthalmic ointments were prepared by melting method.Screening for the best ointment prescription with release as an indicator and evaluating its quality?including pH,uniformity,stability,viscosity,residence time,etc.?.?2?Totally 135 SD rats were randomly divided into three groups according to drug administration routes:intraocular?i.o.group?,intravenous?i.v.group?,and intragastric?i.g.group?.The doses were 5 mg/kg for i.o.and i.v.groups and 10 mg/kg for i.g.group.The concentration of nimodipine in plasma and brain tissue was analyzed by high performance liquid chromatography.The main pharmacokinetic parameters were calculated and compared.?3?Using saline as a control,the irritation of nimodipine ophthalmic ointment and borneol-containing ophthalmic ointments on rabbit eyes after single and multiple administrations was investigated;The rats were given nimodipine?5 mg/kg?ophthalmic ointments?including borneol 1.2%,2.4%,3.6%?,the concentration of nimodipine in plasma and brain tissue was measured at different time points,and the main pharmacokinetic parameters were calculated and compared with the nimodipine ophthalmic ointment group;Intraperitoneal injection of sodium nitrite induced cerebral hypoxia in rats.Observe the effect of ophthalmic ointment on the survival time of cerebral hypoxia in rats after ocular administration,and compare with nimodipine ophthalmic ointment with different doses of borneol and saline by ocular administration,nimodipine solution by oral administration.Results:?1?The best prescription is vaseline:lanolin:liquid paraffin=8:1:1,the drug concentration is 1.2%;pH is about 6.9,the uniformity and stability are good,the viscosity is suitable,and the residence time is longer than that of normal saline.?2?The pharmacokinetic parameters in i.o.group were as follows:Cmax:0.52?g/ml;tmax:5.0 min;and AUC0-t:21.14?g/ml·min.The main pharmacokinetic parameters in i.v.group were as follows:C_max:3.62?g/ml;and AUC_0-t:52.78?g/ml·min.The pharmacokinetic parameters in i.g.group were as follows:C_max:0.20?g/ml;t_max:5.0 min;and AUC_0-t:5.98?g/ml·min;The tissue distribution showed that NMD in tissues was rapidly distributed to various organ tissues after intravenous administration,and the distribution range was wide.It was distributed more in lung,kidney and heart,and then the drug concentration decreased rapidly;NMD is more distributed in the kidney and lung after intragastric administration,and less in the spleen,brain and other tissues;After ocular administration,NMD is more distributed in the lung,spleen and brain tissue,and the amount of drug in the kidney tissue is less.The peak concentrations of nimodipine in the heart,liver,spleen,lung,kidney and brain tissues of the same dose of the ocular administration route were 1.00,0.47,2.02,1.47,0.22,5.79 times of the gavage route,respectively,and the AUC values were respectively It is 0.59,0.76,1.83,1.84,0.25,and 4.78 times of the gastric route.From the results of pharmacokinetics and tissue distribution,it can be seen that nimodipine can be more efficiently absorbed into the systemic circulation through the ocular mucosa and transported to the brain tissue compared with the intragastric route.?3?Nimodipine ophthalmic ointment and borneol-containing ophthalmic ointments were not irritating to rabbit eyes;The effect of borneol on the pharmacokinetics of nimodipine in rats:the Cmax of nimodipine in the control group,low,medium and high dose borneol group were 0.52,0.43,0.24,0.22?g/ml,respectively,tmax was 5.00,4.005.67,8.33 min respectively,AUC_0-t were 15.93,15.26,11.73,8.97?g/ml·min,respectively;The effect of borneol on the distribution of nimodipine in rat brain tissue:the Cmax of nimodipine in the control group,low,medium and high dose borneol group were 1.12,1.18,1.88,2.18?g/ml,respectively,tmax was 15.00,11.67,6.67,2.00 min,respectively,and AUC_0-t were 49.88,50.05,79.59,84.11?g/ml·min,respectively;The BTE of the low,medium and high dose borneol group after ocular administration was1.04,2.17,2.98,respectively.The statistical results showed that compared with the low-dose borneol group and the control group,the high-dose borneol significantly reduced the amount of nimodipine absorbed into the blood by ocular administration?P<0.05?,and the amount absorbed into the brain was significantly increased?P<0.05?,while there was no significant difference between the low dose group and the control group,medium dose and high dose?P>0.05?.Borneol could affect the distribution of NMD in rat plasma and brain tissue after ocular administration to a certain extent.The t_max and C_max of NMD in brain tissue exhibited borneol dose dependence.Borneol increased the absorption rate of NMD in brain tissue and increased the absorption of NMD in brain tissue,and also reduced the concentration of NMD in plasma;Compared with the saline group,the 5 mg/kg NMD ophthalmic ointment in the eyes can significantly prolong the survival time after sodium nitrite poisoning in rats?P<0.01?.Although the oral administration group of nimodipine?10 mg/kg?prolonged the survival time after poisoning in rats,there was no significant difference?P>0.05?.Compared with the NMD ophthalmic ointment group,there was no significant difference in the low dose borneol group?P>0.05?,while the medium and high dose groups significantly prolonged the survival time?P<0.01?.Conclusion:Compared with the intragastric route,nimodipine can significantly improve bioavailability after ocular administration,and has certain targeting to brain tissue,indicating that it is feasible to achieve systemic transport of nimodipine via ocular administration.The combination of borneol and nimodipine found that borneol can significantly increase the intake of nimodipine into brain tissue,reduce the blood concentration of nimodipine in rats,and reduce its systemic toxic side effects,which is beneficial for the treatment of ischemic brain disease with nimodipine.