Preparation, Characterization And Pharmacokinetics Of Nimodipine Micelle

Nimodipine (NM), as the1,4-dihydropyridine calcium channel blocker, having highlyselective on brain receptors.NM is used for the prevention and treatment of subarachnoidhemorrhage, hypertension, ischemic cerebrovascular disease and migraine in clinical. NMis currently approved for its benefit to ameliorate memory degeneration and has highclinical value on Alzheimer’s disease. However, this drug has a poor oral bioavailabilitybecause of its high hepatic first pass effect and it has a short elimination half-life.In this study, Biodegradable hydrophobic material polylactic acid (PLA) approved bythe FDA.Hydrophilic polymer materials polyethylene glycol (PEG) can be injected andwater-soluble vitamin E(TPGS) were chosen to prepare NM micelles. Thus, the solubilityof NM was improved. In order to improve the bioavailability and reduced toxicity of NMformulations, compare the results of vivo pharmacokinetics, which were givenintraperitoneally the NM micelles and NM injection of rats.Rotary evaporation method was applied for prepare NM m PEG-PLA micelles. Theeffect of several factors including the type of organic solvent stirring time, stirring speed,polymer concentration, the ratio of solvent to aqueous, the amount of NM were investigatedon entrapment, drug-loading rate, particle diameter and PDI by single-factorial experiments.Then, optimize the formulation by orthogonal experiment. The optimum preparationprocedure was as follows:20mg mPEG-PLA and3.5mg NM are dissolved in2ml THF, by750rpm stirring conditions to dissolve completely. Continue to stir while the THF solutionis dropwise into round bottom flask with6ml of distilled water. Continue stirring for30min,and then rotary evaporator at40℃3min.The drug-loading rate of NM mPEG-PLAmicelles is12.89%.In the same way, The optimum preparation procedure of NMmPEG-PLA TPGS mixed micelles was as follows:20mg mPEG-PLA and6mg NM are dissolved in2ml THF, by1000rpm stirring conditions to dissolve completely. Continue tostir while the THF solution is dropwise into round bottom flask with8ml of10mg TPGSdistilled water. Continue stirring for30min, and then rotary evaporator at40℃3min.Thedrug-loading rate of NM mPEG-PLA/TPGS micelles is14.80%.The CMC of NM mPEG-PLA micelles and NM mPEG-PLA TPGS mixed micelleswere0.525μg/mL and0.661μg/mL respectively. The particle diameter of NM mPEG-PLAmicelles and NM mPEG-PLA TPGS mixed micelles were74.6nm and174.7nm. The vitrorelease of NM mPEG-PLA micelles was studied and the drug releasing performance couldbe described by first-order-model. And the vitro release of NM mPEG-PLA/TPGS micelleswas studied and the drug releasing performance could be described by Niebergull andHixson-crowell model. The drug release was gentle and no burst release phenomenon.A RP-HPLC method was established to determine the concentration of NM in plasma.To calculate the pharmacokinetic parameters by DAS3.0and describe the mainpharmacokinetic parameters by non-compartment model and compartment model Resultsshowed that three of the formulations were metabolic fast. The bioavailability of NMmPEG-PLA micelles and NM mPEG-PLA/TPGS mixed micelles were similar to the NMsolution. Micelles were not achieve the desired release effect.