Obtenção de pellets por extrusão e esferonização farmacêutica. Parte I. Avaliação das variáveis tecnológicas e de formulação / Production of pellets by pharmaceutical extrusion and spheronisation. Part I. Evaluation of technological and formulation variables

O processo de peletização consiste na aglomeração por via úmida de pós de uma substância ativa e excipientes sob a forma de umidades esféricas. Estas umidades esféricas, denominadas pela expressão anglo-saxônica pellets, diferem de grânulos obtidos pelo processo clássico de granulação no que respeita às características físicas conseguidas. Um dos processos de peletização usualmente empregado para a produção de pellets em duas operações unitárias fundamentais: a extrusão e a esferonização. O presente trabalho pretende apresentar um revisão da técnica de extrusão e esferonização para produção de pellets farmacêuticos abordando as implicações dos aspectos tecnológicos e de formulação que envolvem este processo

A simple method for nicardipine hydrochloride quantification in plasma using solid-phase extraction and reversed-phase high-performance liquid chromatography.

A simple and sensitive reversed-phase liquid chromatography method was developed and validated for the determination of nicardipine hydrochloride (NC) in rabbit plasma. Nicardipine hydrochloride and nimodipine, used as internal standard, were initially extracted from plasma by a rapid solid-phase extraction using C(18) cartridges. After extraction, nicardipine hydrochloride was separated by HPLC on a C(18) column and quantified by ultraviolet detection at 254 nm. A mixture of acetonitrile-0.02 M sodium phosphate buffer-methanol (45:40:15) with 0.2% of triethylamine of pH of 6.1 was used as mobile phase. The mean (+/-SD) extraction efficiency of NC was 77.56 +/- 5.4, 84.23 +/- 4.32 and 83.94 +/- 3.87% for drug concentrations of 5, 25 and 100 ng/mL, respectively. The method proved to be linear in the range of 5-100 ng/mL with a regression coefficient of 0.9993. The relative standard deviations of intra- and inter-day analysis for NC in plasma were 3.26-6.52% (n = 5) and 4.71-9.38% (n = 5), respectively. The differences of the mean value measured from the concentration prepared, expressed in percentages (bias percentage), were only - 5.2, 0.4 and 0.8% at NC 5, 25 and 50 ng/mL, which confirmed the accuracy of the method. The analytical technique was used to determine NC plasma concentration after drug oral administration to rabbits. The results inferred that NC is rapidly absorbed in rabbits and has a short half-life (t(1/2) = 1.34 h).

Hydrophilic and hydrophobic cyclodextrins in a new sustained release oral formulation of nicardipine: in vitro evaluation and bioavailability studies in rabbits.

The feasibility of using complexes with cyclodextrins (CDs) in nicardipine (NC) controlled delivery has been examined, with a view to extending the pharmaceutical applications spectrum of these carriers. For a fast release fraction, a hydrophilic beta-cyclodextrin derivative (hydroxypropyl-beta-cyclodextrin) was employed to form a water-soluble complex. For the sustained-releasing portion, triacetyl-beta-cyclodextrin (TAbetaCD) was used to provide complexes with appropriate hydrophobicity. An optimal formulation was designed by the combination of each fraction in different mixing ratios. The release behaviour of the complexes, as well as of their mixtures, was examined in simulated gastric (pH 1.2) and intestinal (pH 6.8) fluids. The formulations released the drug rapidly at the initial stage, followed by a slow release. The drug release rate was markedly retarded in the increasing order of the amount of NC/TAbetaCD complex. When NC was administered to rabbits, its absorption was very rapid with a short elimination half-life, while a prolonged maintenance of the plasma levels was obtained for the two selected formulations. The drug bioavailability was considerably improved especially after the administration of the mixture of hydrophilic and hydrophobic complexes, when compared with the NC/TAbetaCD complex. The results suggested that the critical combination of hydrophilic and hydrophobic CDs complexes, in appropriate ratios, could be a promising drug delivery system with a prolonged therapeutic effect coupled with a more balanced bioavailability.

Effect of the hydrophobic nature of triacetyl-beta-cyclodextrin on the complexation with nicardipine hydrochloride: physicochemical and dissolution properties of the kneaded and spray-dried complexes.

The inclusion ability of triacetyl-beta-cyclodextrin (TAbetaCD), a hydrophobic cyclodextrin (CD) derivative was examined, using nicardipine hydrochloride (NC) as model drug. The binary compounds were prepared in a 1 : 1 molar ratio by the kneading and the spray-drying techniques. In order to confirm the complexation between NC and TAbetaCD in the solid state, differential scanning calorimetry, X-ray diffractometry, Fourier transformation-infrared spectroscopy and scanning electron microscopy were carried out and the results were compared with the corresponding physical mixture in the same molar ratio. The kneaded product presented only slight modifications on the drug physicochemical and morphological properties, which could mean that no complex formation occurred during this process. In contrast, spray-drying was found to produce inclusion complexes with amorphous nature. In vitro dissolution studies were carried out in simulated gastric (pH 1.2) and intestinal (pH 6.8) fluids, according to the United States Pharmacopoeia (USP) basket method. The NC in vitro release from the kneaded and spray-dried products was markedly retarded in both dissolution media. However, this retarding effect was significantly more evident for the spray-dried compound. It was concluded that the formation of real inclusion complexes could only be achieved by the spray-drying method.