Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3, a highly dosed poorly water-soluble weak base.

Ucb-35440-3 is a new drug entity under investigation at UCB S.A. Due to its physicochemical characteristics, the drug, a poorly water-soluble weak base, shows poor solubility and dissolution characteristics. In rat, the low oral bioavailability (F < 10%) is largely due to poor absorption. In order to enhance the solubility and dissolution characteristics, formulation of ucb-35440-3 as nanocrystals has been achieved in this study. Nanoparticles were prepared using high pressure homogenization and were characterized in terms of size and morphology. In vitro dissolution characteristics were investigated and compared to the un-milled drug in order to verify the theoretical hypothesis on the benefit of increased surface area. In vivo pharmacokinetic evaluation of ucb-35440-3 nanoparticles was also carried out on rats. Crystalline state evaluation before and following particle size reduction was conducted through polarized light microscopy and PXRD to denote any possible transformation to an amorphous state during the homogenization process. Drug chemical stability was also assessed following homogenization. The dissolution rate increased significantly at pH 3.0, 5.0 and 6.5 for ucb-35440-3 nanoparticles. However, the pharmacokinetic profile obtained yielded lower systemic exposure than the un-milled compound (in fed state), this although being thought to be the consequence of the drug and formulation characteristics.

Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement of nifedipine.

Poorly water-soluble drugs such as nifedipine (NIF) (approximately 20 microg/ml) offer challenging problems in drug formulation as poor solubility is generally associated to poor dissolution characteristics and thus to poor oral bioavailability. In order to enhance these characteristics, preparation of nifedipine nanoparticles has been achieved using high pressure homogenization. The homogenization procedure has first been optimized in regard to particle size and size distribution. Nanoparticles were characterized in terms of size, morphology and redispersion characteristics following water-removal. Saturation solubility and dissolution characteristics were investigated and compared to the un-milled commercial NIF to verify the theoretical hypothesis on the benefit of increased surface area. Crystalline state evaluation before and following particle size reduction was also conducted through differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) to denote eventual transformation to amorphous state during the homogenization process. Through this study, it has been shown that initial crystalline state is maintained following particle size reduction and that the dissolution characteristics of nifedipine nanoparticles were significantly increased in regards to the commercial product. The method being simple and easily scaled up, this approach should have a general applicability to many poorly water-soluble drug entities.

Correlation of extrusion forces, raw materials and sphere characteristics.

This communication reports on the correlation between extrusion forces and sphere characteristics. Dicalcium phosphate dihydrate, alpha-lactose monohydrate and anhydrous beta-lactose were models for respectively an insoluble, a medium soluble and a highly soluble drug and were used to produce spheres. Phase diagrams for ternary mixtures consisting of microcrystalline cellulose, water and a third excipient were constructed. The region where good spheres were obtained correlated well with the area of extrusion forces between 630 and 1260 N. This correlation was seen for the insoluble, the medium and the highly soluble products.

Instrumentation of a gravity feed extruder and the influence of the composition of binary and ternary mixtures on the extrusion forces.

A gravity feed extruder was adapted to monitor the extrusion forces, the temperature during processing and the rotational speed of the extruding cylinders. The extruder was used to evaluate the influence of particle size of insoluble material and of product solubility on the extrusion forces. Microcrystalline cellulose, dicalcium phosphate dihydrate and different lactoses were used as model compounds. Difference in lactose and microcrystalline cellulose particle size did not influence extrusion forces. The amount of water in the mixtures to be processed and the initial difference in solubility for some of the lactose types investigated influenced the extrusion forces dramatically. Extrusion forces recorded during processing of a mixture previously granulated in a high shear granulator were higher than when processed in a planetary mixture. Loss of water during high shear granulation is probably the main cause of this phenomenon.

Comparison of techniques for detection of domestic infestations with Triatoma infestans in Brazil.

The detection of infestations of Triatominae in houses in regions endemic for Chagas's disease is a criterion frequently used in the selection of areas, or of individual houses, for treatment in insecticide campaigns as well as in the evaluation of insecticide performance. Several different methods for detecting domestic infestations with Triatominae were compared: night capture, capture of five bugs with the aid of a flushing-out agent and use of card boxes of the Gómez-Núñez type. The flushing-out and Gómez-Núñez box methods were found to be equally sensitive, although each failed to detect some infestations which the other detected. The night capture method was slightly more sensitive but was found to be impractical for insecticide trials. Improvement to the flushing-out method, notably the introduction of a systematic search technique, made it much more sensitive than the Gómez-Núñez box method for heavily infested houses and for houses three months after insecticide treatment. Although the sensitivity of the Gómez-Núñez box method increases when the boxes are left in place for a long time, this also limits the value of the information obtained regarding the evaluation of insecticides. On the basis of the results presented, the flushing-out method using a systematic search of the house was found to be the most suitable sampling technique, but it is recognized that this method still has limitations.