Formulation of controlled release microspheres containing nicardipine: therole of pharmacokinetic modeling and computer simulation

Nicardipine is an antihypertensive drug of the dihydropyridine series. It h as high solubility in an acidic and low solubility in an alkaline medium. I t is rapidly absorbed, extensively presystemically metabolized and excreted in the urine and faeces, mainly as inactive metabolites. Since the duratio n of its action can be extended by prolonging the absorption interval, the design of controlled release formulation is reasonable. The aim of the pres ent study was to prepare microspheres which would release nicardipine at a decreased rate in gastric and increased rate in intestinal juice during a 1 2 h interval. Pharmacokinetic modeling based on compartment analysis and su pported by analog computer and digital simulation technique showed that the target steady state peak plasma concentrations of 32 mu g/l and trough pla sma concentration of 7 mu g/l would be maintained if nicardipine were incor porated in a formulation releasing the drug as follows: 25% after 1 h, 40% after 2 h, 65% after 4 h, 80% after 6 h, 90% after 8 h and 100% by 12 h. Mi crospheres have been prepared from hydroxypropylmethylcellulose phthalate p olymer using the solvent evaporation method. Drug content, scanning electro n micrographs, particle size distribution and dissolution profile were dete rmined. In vitro nicardipine release was described by a biphasic square roo t of time kinetics and was in accordance with the above values relating to the dissolution. Furthermore, a composed first-pass pharmacokinetic model w ith derived release function as an input was developed to predict nicardipi ne plasma concentrations after single- and 12 h multiple-dosage-regimen sch eme administration of controlled release microspheres.