HM30181A, a potent P-glycoprotein inhibitor, potentiates the absorption and in vivo antitumor efficacy of paclitaxel in an orthotopic brain tumor model.

Objective: Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma, owing to the presence of the blood-brain barrier and the activity of P-gp, which pumps its substrate back into the systemic circulation. The aim of the present study was to develop an intravenous formulation of HM30181A (HM) to inhibit P-gp in the brain to effectively deliver paclitaxel (PTX) for the treatment of malignant glioma. Methods: Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies: i) spray-drying [polyvinlypyrrolidone (PVP)-HM] and ii) solvent evaporation [HP-ß-cyclodextrin (cyclodextrin)-HM]. The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer cells. Blood and brain pharmacokinetic parameters were also determined, and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse model. Results: Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro, cyclodextrin-HM had a higher maximum tolerated dose in mice than did PVP-HM. Pharmacokinetic study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg, and the mice began to lose weight at doses above this level. Cyclodextrin-HM (10 mg/kg) administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model, according to both tumor volume measurement and survival time (P < 0.05). Conclusions: In a mouse orthotopic brain tumor model, the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.

Application of near-infrared spectroscopy to the determination of the sites of manufacture of proprietary products.

Reflectance near-infrared (NIR) spectroscopy has been investigated as a method to distinguish between the sites of manufacture of a number of proprietary tablets. As test samples, parallel imports which are pharmaceutically equivalent products manufactured at different sites have been used. Three products: Aremis/Besitran, Renitec and Voltarol Retard originating from two or more sites and Adalat from a single site were examined. The principal component analysis (PCA) score plots showed that spectra of tablets originating from different sites of manufacture often gave rise to statistically different populations. PCA loadings indicated that the differences were related to moisture content and excipients. Spectra were used to construct a library for the classification of tablets to predict the site of manufacture based on the method of residual variance of the principal components. Where a large data set was available (Aremis/Besitran tablets) prediction rates for the successful identification of the two sites of manufacture, Madrid and Barcelona, were 95.7 and 98.1%, respectively for the validation set with all errors encountered of Type I.