How to stop disproportionation of a hydrochloride salt of a very weakly basic compound in a non-clinical suspension formulation.

Our objectives were to stabilize a non-clinical suspension for use in toxicological studies and to develop methods to investigate the stability of the formulation in terms of salt disproportionation. The compound under research was a hydrochloride salt of a practically insoluble discovery compound ODM-203. The first of the three formulation approaches was a suspension prepared and stored at room temperature. The second formulation was stabilized by pH adjustment. In the third approach cooling was used to prevent salt disproportionation. 5 mg/mL aqueous suspension consisting of 20 mg/mL PVP/VA and 5 mg/mL Tween 80 was prepared for each of the approaches. The polymer was used as precipitation inhibitor to provide prolonged supersaturation while Tween 80 was used to enhance dissolution and homogeneity of the suspension. The consequences of salt disproportionation were studied by a small-scale in vitro dissolution method and by an in vivo pharmacokinetic study in rats. Our results show that disproportionation was successfully suppressed by applying cooling of the suspension in an ice bath at 2-8 °C. This procedure enabled us to proceed to the toxicological studies in rats. The in vivo study results obtained for the practically insoluble compound showed adequate exposures with acceptable variation at each dose level.

Ternary copper(II) complex: NCI60 screening, toxicity studies, and evaluation of efficacy in xenograft models of nasopharyngeal carcinoma.

Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4. The complex significantly inhibited tumor growth in nasopharyngeal carcinoma xenograft bearing mice models at doses which were well tolerated without causing significant or permanent toxic side effects. However, higher doses which resulted in better inhibition of tumor growth also resulted in toxicity.

Rational selection of structurally diverse natural product scaffolds with favorable ADME properties for drug discovery.

Natural product analogs are significant sources for therapeutic agents. To capitalize efficiently on the effective features of naturally occurring substances, a natural product-based library production platform has been devised at Aurigene for drug lead discovery. This approach combines the attractive biological and physicochemical properties of natural product scaffolds, provided by eons of natural selection, with the chemical diversity available from parallel synthetic methods. Virtual property analysis, using computational methods described here, guides the selection of a set of natural product scaffolds that are both structurally diverse and likely to have favorable pharmacokinetic properties. The experimental characterization of several in vitro ADME properties of twenty of these scaffolds, and of a small set of designed congeners based upon one scaffold, is also described. These data confirm that most of the scaffolds and the designed library members have properties favorable to their utilization for creating libraries of lead-like molecules.

Trypsin inhibitory activity of Lawsonia inermis.

The ethanolic extract of Lawsonia inermis leaves and lawsone tested for trypsin inhibitory activity showed an IC(50) value of 64.87 and 48.6 microg/ml, respectively.

alpha-Glucosidase inhibitory activity of Mangifera indica bark.

The ethanolic extracts of Lawsonia inermis leaves, Holarrhena antidysenterica bark, Swertia chirata whole plant and Mangifera indica bark were tested (in-vitro) for alpha-glucosidase inhibitory activity. M. indica extract was found to be the most potent, with an IC(50) value of 314 microg/ml.

Mast cell stabilising activity of Bacopa monnieri.

Successive petroleum ether, chloroform, methanol and water extracts of Bacopa monnieri were tested (in vitro) for mast cell stabilising effect. The methanolic fraction exhibited potent activity comparable to disodium cromoglycate, a known mast cell stabiliser.

Effect of certain plant extracts on alpha-amylase activity.

Ethanolic extracts of Punica granatum, Mangifera indica, Boerhaavia diffusa, Embelia ribes, Phyllanthus maderaspatensis, and Withania somnifera, were tested for their effect on alpha-amylase activity (in vitro). P. granatum and M. indica were found to exhibit interesting alpha-amylase inhibitory activity.