Studies On Nimodipine Sedds Soft Capsule

Nimodipine Self-Emulsifying Drug Delivery System(NMSEDDS), choosing nimodipine as the main drug, oils and surfactants as vehicles, was a thermodynamically stable system. Nimodipine (NM), as one of the dihydropyridine calcium channel antagonists, has been used as an essential drug for the treatment of cerebral ischemia, vascular disease, angina pectoris and hypertension in clinic. Pharmacokinetics tests show that NM is well absorbed in the gastrointestinal tract after oral administration, but it is subject to extensive first-pass effect that results in very low plasma concentration, poor absolute bioavailability and significant inter-indiviual. Therefore, SEDDS was selected as the carrier to prepare NMSEDDS soft capsule (NMSESC) to increase dissolution, promote absorption and enhance bioavailability of NM.The solubilities of NM in Ethyl Linoleate was higher than other choosed oils. NM, the apparent partition coefficients in octanol/water was 17.78, was lipophilic. Two methods, UV spectrophotometry and HPLC, were developed for in vitro assay. HPLC could eliminate the disturbance of excipients on analysis.Ethyl Linoleate was selected for oil phase. Different surfactants and cosolvents were tested with Ethyl Linoleate, by means of investigating emulsifying time and the stability of the emulsion, Tween 80 was selected as surfactant and Transcutol as cosolvent. The pseudo-ternary phase diagrams was studied, the results show that NM had no apparent effect on the self-emulsifying region. We determined the optima formula for NMSEDDS, then investigate the affects of temperature, mill rate, different vehicle contents and volume on the self-emulsifying efficiency. We also studied the drug release by bulk- equilibrium reverse dialysis bag technique.The qualities of NMSESC were studied. Zeta potential was about -20 mV. The particle size was about 200 nm and the size distribution was narrow. We determined the content, the related substances and drug release of NMSESC, the results indicated they all meet the standard. The content was reduced in the highlight test, which show NM should kept under darkness. The stability of NMSESC was good in the cold-hot cycling test, accelerated test and long-term test under darkness.The pharmacokinetics of NMSESC was compared with commercial NM capsule and soft capsule in dogs. Their T_max were 0.799, 0.815 and 1.099 h, C_max were 588.41, 317.27 and 286.20 ng/ml respectively. The bioavailabilities of NMSESC was 160.09% and 139.13% compared with NM capsules and soft capsule. The results of variance analysis and two one side t-test showed that the absorption degree of NMSESC, NM capsule and soft capsule were unequal, SEDDS can promote the absorption of NM.In this report, we also study the distribution of NM in mice and evaluate its targeting performance. After oral administration for NMSESC, commercial NM capsules and soft capsules, the concentration of NM in different tissues was determined by HPLC. The results showed that AUC and C_max of NM in plasma had been raised significantly, which indicate the relative bioavailability of NMSESC had been raised. In contrast with NM capsules and soft capsules group, the NM distribution in plung, brain and heart had been raised significantly in the NMSESC group. The relative tissue exposure to the brain is 1.60 and 1.26 respectively, which indicated that NMSEDDS could alter the NM distribution in mice and had the tendency of plasma, plung, brain and heart targeting in vivo.