Comparative Investigation On The Pharmacokinetics Of Polymorphic Nimodipine In Rats After Oral&Pulmonary Delivery

As the previous investigation have proved that their existed pharmacokinetic and bioavailability difference for polymorphic drug due to the difference in their crystal forms.How this difference would change if administration route are changed from oral delivery to the others?To investigate this bioavailability difference is of great significance for rational selection of dosage forms and administration route of polymorphic drugs in the clinical trials.Nimodipine is a kind of polymorphic drug.We used nimodipine as a model drug to investigate pharmacokinetic and bioavailability when it was delivered orally and pulmonary to rats.Polymorphic H and L of nimodipine with the particle size ranged from 125μm to150μm were made by recrystallization.Polymorphic L form of nimodipine microcrystals with the size of 8.25±0.05μm was obtained by anti-solvent recrystallization.The morphology,in vitro dissolution characteristics and stabilities of three nimodipine samples were investigated.Drug concentration in plasma was detected by HPLC.Base on it,nimodipine was delivered orally and pulmonary to rats to explore the effect of crystal forms on pharmacokinetic and bioavailability.The results of in vivo studies showed that C_max of H and L form were respectively 21.27ng/ml and 30.65 ng/ml;AUC_0-24h-24h of them were respectively 140.90ng/mL·h and 336.14 ng/mL·h and the ratio of them was 0.42;T_maxax of them were respectively 2.5h and 5.0h after intragastric administration at a dose of 40 mg/kg.The C_max of H and L form were respectively 26.23ng/ml and 39.60 ng/ml;AUC_0-24h-24h of them were respectively 261.77 ng/m L·h and 280.63 ng/mL·h and the ratio of them was 0.93;T_maxax of them were respectively 1.5h and 1.33h after pulmonary delivery at a dose of 15 mg/kg.Compare to oral administration,the C_max of H and L form nimodipine was increased although the dose of pulmonary delivery was reduced;the T_max both of H and L form nimodipine was shortened to different degrees.At the same time,the AUC_0-24h-24h of H form by pulmonary delivery was 1.85-fold higher than that by oral administration;however,the AUC_0-24h-24h of L form by pulmonary delivery was only 0.83-fold than that by oral administration.The difference of pharmacokinetic for polymorphic drugs was decreased when the administration was changed from oral to pulmonary delivery.As the results shown,the bioavailability of drugs in vivo increased while the particle size reduced.The C_max and AUC_0-24h-24h of L form nimodpine microcrystals was2.45-fold and 1.68-fold higher than that of L form nimodipine respectively after oral,and the C_maxax and AUC_0-24h-24h of L form nimodpine microcrystals was 5.53-fold and3.82-fold higher than that of L form nimodipine respectively after pulmonary delivery.Particle size decrease can significantly improve the bioavailability of nimodipine after oral and pulmonary delivery with the higher AUC_0-24h increase after pulmonary delivery.