| Epilepsy is a common chronic neurological disease with high disease incidence, ranking second among the nervous system diseases, of which refractory epilepsy accounted for 25%. The refractory epilepsy is that appropriate antiepileptic drugs are used for reasonable and regular treatment under the premise of a clear diagnosis. The plasma concentration of the body reaches the effective therapeutic range, but the drug concentration of pathogenesis of epilepsy is lower than the effective therapeutic concentrations, so the condition of epileptic can not be satisfactorily controlled. Therefore, the mortality rate of refractory epilepsy is 4-7 times higher than the general epilepsy, which seriously affect the quality of life of patients, and bring a great burden and harm to the family of patient and society.The aim of this study was to develop a novel nasal drug delivery system to improve lamotrigine(LTG) distribution in hippocampus which is the region most affected by epilepsy and expected to enhance pharmacodynamics by intranasal(IN) administration and minimize side effects. Two micelles were formulated, the prescription and the preparation technology were studied using the single factor investigation followed with the orthogonal design. In briefly,a mixture composed of mPEG-PLA and LTG of different proportions was dissolved in 2 ml of methanol. TPGS was dissolved in appropriate amount of water in a round-bottom flask. The mixture was added into the TPGS solution dropwise and stirred at different rotate speed for 0.5 to 4 hours. The solvent was subsequently evaporated using a rotary evaporator under vacuum and a clear micelle solution was formed. Distilled water was added and the solution was filtered by a 0.22 μm filter membrane to remove the unincorporated LTG. Eight factors of this method included stirring rate, stirring time, stirring temperature, evaporation temperature, ration between organic solvent and water, ratio between mPEG-PLA and TPGS, concentration of mPEG-PLA, and drug dosage were taken into accounted. Preparation of LTG-incorporated mPEG-PLA micelles were similar to the mixed micelle. The drug loading of LTG-loaded micelle and LTG-loaded mixed micelle were 36.44 ± 0.14% and 39.28 ± 0.26 %, respectively. Dynamic light scattering(DLS) was employed to research the particle size of the two micelles, the mean size of LTG-loaded micelle and LTG-loaded mixed micelle were 122.9 nm and 183.5 nm, respectively. The data of LTG micelle and mixed micelle were fitted according to the zero order equation, first-order equation, Higuchi equation, Ritger-peppas equation, biexponential and biphase equation, respectively. The release behavior of LTG micelles was most similar to biexponential and biphase equation, which means the release of LTG from micelles could be divided into two stages, the first stage was rapid drug release and the second stage was slow drug release.Then, a microdialysis technique coupled with a validated chromatographic system was formed for the measurement of protein-unbound form LTG in rat blood and brain. The pharmacokinetic data demonstrated that the area under the concentration–time curve(AUC0-t) of the LTG solution, the LTG micelle and the LTG mixed micelle were 23.17 ± 3.6, 49.34 ±4.2 and 61.32±2.3 min·mg/L in rat blood after LTG intranasal administration(2 mg/ kg) and 5383.578 ± 196, 16500.479 ± 153 and 25245.019±172 min·μg/L in rat hippocampus, respectively.To study the distribution of LTG mixed micelle and LTG solution administered by intranasal and oral in heart, liver, spleen, lung, kidney and brain, a high performance liquid chromatography was created. The results showed the the concentration in brain of LTG-loaded mixed micelle was 1.50~1.90 times higher than LTG solution.The results revealed that LTG micelles especially the LTG mixed micelle can enhance the drug across the BBB into the brain and also showed that the potential of LTG mixed micelle to overcome epilepsy. |
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