Increased dissolution and physical stability of micronized nifedipine particles encapsulated with a biocompatible polymer and surfactants in a wet ball milling process.

Suspensions of nifedipine, a practically water-insoluble drug, were prepared in the presence of a biocompatible polymer, polyvinylpyrrolidone (PVP, K value 17), and three surfactants, sodium lauryl sulfate (SLS, anionic), cetyltrimethylammonium bromide (CETAB, cationic), polysorbate 80 (Tween 80, nonionic), by wet milling in ceramic ball mills. Nifedipine powders encapsulated with PVP and the surfactants were recovered from the suspensions after milling and evaluated for changes in particle size, morphology, sedimentation rate in aqueous suspensions, crystal form, and dissolution. Particle size analysis indicated that milling of suspensions in solutions of PVP and surfactants is an efficient method for reducing the particle size of nifedipine to below 10 microm. Furthermore, DSC and XPS analysis indicated that during milling the nifedipine crystals were coated with the PVP or surfactants and that milling with PVP stabilized the nifedipine crystal form during milling while nifedipine was gradually amorphisized when milled in a quaternary nifedipine/PVP/SLS/CETAB system. The decrease in particle size caused a significant decrease in sedimentation rate and increased the dissolution rate of nifedipine in simulated gastric fluid when compared to milled nifedipine and powder mixtures of the drug and the excipients.

Comparative evaluation of the severity of gastric ulceration by solid dispersions and coprecipitates of indomethacin.

The ulcerogenic activity of indomethacin was studied in rats following single and chronic doses of indomethacin in the form of pure drug, solid dispersions and coprecipitates. Each formulation was administrated as a suspension in a 2% methylcellulose solution. Gastrointestinal ulceration was assessed, four hours after a single dose and 24 hours following the last dose of a chronic four day dosing regimen, by counting the number of lesions and ulcers present. A rating scale was employed to evaluate the severity index. The coprecipitate formulation produced less severe ulceration than the solid dispersion and pure drug. This suggests that the severity of ulceration than the solid dispersion and pure drug. This suggests that the severity of ulceration may be related to the preparation methodology and drug release kinetics.

Effect of hyperbilirubinemia on the pharmacokinetics of diazepam in the rat.

The pharmacokinetics of intravenously-administered diazepam have been studied in heterozygous (non-jaundiced) and homozygous (jaundiced) Gunn rats following single doses of 10 mg/Kg. Plasma concentration time course data from heterozygous and homozygous animals can be described adequately by biexponential equations. A faster plasma clearance rate (Clp) and shorter elimination half life (t 1/2) as well as reduced volumes of distribution [Vp and Vd(area)] were observed in homozygous animals. These potential effects of bilirubin on the distribution and elimination of diazepam should be considered if diazepam is to be used in the therapy of neonatal hyperbilirubinemia.