Physicochemical interaction of rifampicin and ritonavir-lopinavir solid dispersion: an in-vitro and ex-vivo investigation.

OBJECTIVE: To investigate the in-situ physicochemical interaction of Rifampicin and Ritonavir - Lopinavir Solid dispersion administered for the treatment of comorbid conditions i.e. Tuberculosis and HIV/AIDS. METHODS: pH-shift dissolution of Rifampicin (RIF) in presence of Ritonavir-Lopinavir solid dispersion (RL-SD) was carried out in USP phosphate buffer 6.8 and FaSSIF. Equilibrium and amorphous solubility were determined for the drugs. Pure drugs, their physical mixtures, and pH-shifted co-precipitated samples were characterized using DSC, PXRD, and FTIR. Fluorescence spectroscopy was used to investigate drug-rich and drug-lean phases. In-vitro and ex-vivo flux studies were also carried out. RESULTS: The results showed significant differences in the solubility and dissolution profiles of RTV and LOP in the presence of RIF, while RIF profile remained unchanged. Amorphicity, intermolecular interaction and aggregate formation in pH-shifted samples were revealed in DSC, XRD and FTIR analysis. Fluorescence spectroscopy confirmed the formation of drug-rich phase upon pH-shift. In-vitro and ex-vivo flux studies revealed significant reduction in the flux of all the drugs when studied in presence of second drug. CONCLUSION: RIF, RTV and LOP in presence of each other on pH-shift, results in co-precipitation in the amorphous form (miscible) which leads to reduction in the highest attainable degree of supersaturation. This reduction corresponds to the mole fraction of the RIF, RTV and LOP within the studied system. These findings suggest that the concomitant administration of these drugs may lead to physicochemical interactions and possible ineffective therapy.

Molecular Insights into the Mechanism of Modulatory Effects of Proton Pump Inhibitors on P-glycoprotein Mediated Drug Transport of Palbociclib and Ribociclib.

BACKGROUND: Palbociclib and ribociclib are substrates of efflux transporter P-glycoprotein which plays a key role in absorption and transport of these drugs. Proton pump inhibitors, when co-administered with them are known to show inhibitory effect on P-glycoprotein. OBJECTIVE: Therefore, this study aims to investigate the role of proton pump inhibitors in inhibition of P-glycoprotein mediated efflux of palbociclib and ribociclib. METHOD: A combined approach of molecular docking and ex vivo everted gut sac model was implemented to predict the potential of proton pump inhibitors i.e., omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole to inhibit the P-glycoprotein mediated intestinal transport of palbociclib and ribociclib and study the molecular basis of interaction taking place. RESULTS: Molecular docking studies revealed that omeprazole, rabeprazole and pantoprazole bound to the ATP site of nucleotide binding domain with binding energies of -27.53, -29.56 and -38.44 Kcal/mol respectively. In ex vivo studies, rabeprazole and omeprazole, affected the absorptive permeability of palbociclib by 3.04 and 1.26 and ribociclib by 1.76 and 2.54 folds, respectively. Results of molecular docking studies and ex vivo studies highlighted that proton pump inhibitors bound to the ATP binding site to block its hydrolysis thereby inhibiting the P-glycoprotein mediated efflux of palbociclib and ribociclib. CONCLUSION: The experimental evidence presented highlights the fact that proton pump inhibitors have potential to inhibit P-glycoprotein, giving rise to drug interactions with palbociclib and ribociclib. Hence, monitoring is required while proton pump inhibitors and cyclin-dependent kinase inhibitors are being co-administered to avoid adverse events.

Effervescence-induced amorphous solid dispersions with improved drug solubility and dissolution.

The current study aimed to investigate drug carrier miscibility in pharmaceutical solid dispersions (SD) and include the effervescent system, i.e. Effervescence-induced amorphous solid dispersions (ESD), to enhance the solubility of a poorly water-soluble Glibenclamide (GLB). Kollidon VA 64, PEG-3350, and Gelucire-50/13 were selected as the water-soluble carriers. The miscibility of the drug-carrier was predicted by molecular dynamics simulation, Hansen solubility parameters, Flory-Huggins theory, and Gibb's free energy. Solid dispersions were prepared by microwave, solvent evaporation, lyophilization, and Hot Melt Extrusion (HME) methods. The prepared solid dispersions were subjected to solubility, in-vitro dissolution, and other characterization studies. The in-silico and theoretical approach suggested that the selected polymers exhibited better miscibility with GLB. Solid-state characterizations like FTIR and 1H NMR proved the formation of intermolecular hydrogen bonding between the drug and carriers, which was comparatively higher in ESDs than SDs. DSC, PXRD, and microscopic examination of GLB and SDs confirmed the amorphization of GLB, which was higher in ESDs than SDs. Gibb's free energy concept suggested that the prepared solid dispersions will be stable at room temperature. Ex-vivo intestinal absorption study on optimized ESDs prepared with Kollidon VA64 using the HME technique exhibited a higher flux and permeability coefficient than the pure drug suggesting a better drug delivery. The drug-carrier miscibility was successfully studied in SDs of GLB. The addition of the effervescent agent further enhanced the solubility and dissolution of GLB. Additionally, this might exhibit a better bioavailability, confirmed by ex-vivo intestinal absorption study.

Implications of phase solubility/miscibility and drug-rich phase formation on the performance of co-amorphous materials: The case of Darunavir co-amorphous materials with Ritonavir and Indomethacin as co-formers.

The present study was designed to investigate the contribution of solid-state and the impact of composite drug-rich phase generated as a consequence of pH shift on the maximum achievable supersaturation of co-amorphous formulations. The co-amorphous phases of weak base-weak base-pair i.e. Ritonavir and Darunavir were prepared in anticipation of studying the effect of drug-rich phase consequent to pH shift. While the co-amorphous phases of weak base-Weak acid pair i.e. Darunavir and Indomethacin were studied to understand the manifestation of the solid-state drug: co-former miscibility in the absence of drug rich phase. Thermodynamically, the lowering of the supersaturation was found commensurate with the mole fraction of the respective component (Drug/Co-former) within the co-amorphous materials for both Darunavir: Ritonavir and Darunavir: Indomethacin pair. Kinetically, for Darunavir: Ritonavir co-amorphous materials, the shift in the pH from acidic to the neutral side led to the generation of drug-rich phase and subsequent LLPS. The free drug concentration achieved in the bulk of the solution was found dependent upon the mole fraction of the respective component within the drug-rich phase. The relative mole fraction of each component within the composite drug-rich phase is dictated by pH-dependent solubility and molecular weight of the individual components.