Correlation of in vitro and in vivo paracetamol availability from layered excipient suppositories.

An in vivo investigation of paracetamol availability was carried out on eight healthy volunteers, comparing two paracetamol suppository formulations prepared using two different gliceride bases, a fast drug-releasing one and a slow drug-releasing one, i.e. Witepsol H15 and W35, respectively. The formulations were selected on the basis of a previous in vitro drug release study, which showed that, by superimposing the excipients in two layers within the same suppository, the drug release kinetics could be modulated using different ratios between the two layers. The comparison between the two different formulations in terms of plasma profiles and total amounts of drug excreted in urine revealed an increase in the extent of drug absorption from the layered excipient suppository. As the W35 has a higher monoglyceride content than the H15, this improved paracetamol availability could be ascribed to the absorption-enhancing effect of the monoglycerides. Moreover, the W35 has also a higher viscosity, which could possibly cause the suppository to be retained for a longer time in the lower part of the rectum, where the blood is drained directly to the systemic circulation. It was therefore hypothesized that the enhanced paracetamol availability could be also due to a liver bypass mechanism. For a further examination of the paracetamol absorption kinetics after rectal administration, a one-compartment model was fitted to the drug plasma concentration data. This approach allowed to draw absorption versus time profiles, which showed that a retardation actually occurred in paracetamol absorption when using suppositories containing the slow drug releasing excipient W35. These absorption data were then employed for an A level in vitro-in vivo correlation testing, and a linear relationship was found between in vitro release rate and in vivo absorption rate, both for fast releasing and for the layered excipient suppositories.

Experimental design for a pharmaceutical formulation: optimisation and robustness.

In pharmaceutical industries, the formulator is usually faced with the optimisation of the excipient mixture composition aimed to prepare a product with the required characteristics. Experimental research methodology represents an efficient approach for solving such optimisation problems. Planning mixture experiments using specific designs allows to analyse the blending properties of each mixture component and estimate an empirical model approximating the response of interest as a function of excipient proportions. In this study the evolution of theophylline solubility in a four-component system with constraints was analysed using two mixture design approaches: a classical mixture component proportion approach and a mathematically independent variable approach. An optimal region characterised by high solubility values was found and further explored in order to verify the insensitivity of theophylline solubility to slight variations of the excipient mixture composition.

Experimental design applied to the formulation of lipsticks with particular features.

In our work a non-classical experimental design was applied to obtain lipsticks endowed with particular characteristics. Our aim was to formulate lipsticks that leave a brilliant and shiny colour application and have a transparent look. The emollient substances and the waxes (consistency factors) were identified as the main variables of the system. A two phase experimental strategy was thought out: the optimal quantities of consistency factors were selected using a Doehlert experimental matrix, whereas the correct mixtures of emollients were determined using a Scheffé simplex-centroid design. These two design were combined and a set of 49 experiments was obtained. The experiments carried out allowed the definition of a zone of two phases in which the objectives were attained: the correct types and appropriate quantities of emollients and waxes were determined. To find a possible correlation between some mixtures and the lipsticks' sensorial behaviour, differential scanning calorimetry was used. These results, in addition to those obtained using the experimental design allowed us to select the best lipstick formula. (c) Rapid Science Ltd. 1998.

Formulation and evaluation of vinylpyrrolidone/vinylacetate copolymer microspheres with griseofulvin.

Regular spherical microspheres of 220-260 microns average size have been prepared from vinylpyrrolidone/vinylacetate copolymer using a solvent evaporation method. Griseofulvin has been incorporated into these microspheres and its physical characterization has been carried out by differential scanning calorimetry (DSC), X-ray diffractometry and X-ray photoelectron spectroscopy. An increase of solubility was observed only with the 1:3 drug/polymer microspheres and the comparison of the dissolution profiles of microspheres with pure griseofulvin resulted in an enhancing effect. Furthermore the release rate of griseofulvin, incorporated into the microspheres, was shown to be biphasic and dependent upon the penetration of water into the microspheres, hydration and dissolution of the polymer and finally dissolution of the drug.

Chemometric differentiation of raw and commercial milk by trace elements using principal component analysis.

Nine trace elements (Cr, Mn, Fe, Ni, Cu, Zn, Mo, Cd, and Pb) were determined in the dissolved ash of 36 samples of raw milk. The distribution of the concentration of each element was first investigated by means of a test of normality. The matrix of the correlation between the concentrations of the elements was then used as a starting matrix for principal component analysis. Nine variables were reduced to four principal components, accounting for 75% of the total variance. The biophilic elements Mn-Fe and Cu-Mo were positively associated with the first two principal components, while Cr was correlated to the third and Ni and Cd with the fourth principal component. Pb and Zn are both negatively correlated to the first principal component. Comparison with 42 samples of a commercial milk, by using a two-dimensional plot of the principal component scores, rendered possible the differentiation between raw and commercial milk.