Background: Palbociclib and ribociclib are substrates of efflux transporter, P-glycoprotein 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.

The objective of the study was to evaluate the possible pH-dependent interaction of ribociclib succinate with acid-reducing agents, which are concomitantly administered as supportive care medicines in cancer. Quality by Design-based analytical method development for a weakly basic drug ribociclib succinate supposedly having the characteristic ability of pH-dependent solubility was carried out for analyzing micro-dissolution experiment samples in biorelevant media to study pH-dependent interaction. An accurate and robust analytical method was developed using a three-level three-factorial box–behnken design for quantification of ribociclib succinate in micro-dissolution samples by the implementation of the Analytical Quality by Design approach. Here, pH of aqueous mobile phase and flow rate proved to be critical process parameters. The gastric compartment solubility was found to be 814.05 μg/mL, which dropped down to 494.71 μg/mL after a pH shift from pH 1.2–6.5. In the intestinal compartment, initial solubility was 717.58 μg/mL, which reduced to 463.20 μg/mL after a pH shift from 6.5 to 6.8. Concluded results state that pH shift does not impact the solubility or the absorption of the drug to a significant extent in the presence of acid-reducing agents. However, the study would prove to be a practical approach for examination of the behavior of the drugs at the initial stages.

No abstract

Introduction: Miconazole Nitrate is prescribed as an antifungal agent in conventional dosage forms. To mask the disadvantages of sticky creams and their tendency to rub off, an intelligent dosage regimen needs to be designed. Objectives: The present study aimed to design, develop, and characterize Miconazole Nitrate (0.5% w/v) film-forming spray for the treatment of superficial fungal infections in nails, such as Tenia and Onychomycosis. Materials and Methods: Eutectic mixture of Menthol and Camphor in the ratio of 1:1 was used to enhance permeation and solubilize film-forming polymers, i.e., Eudragit L-100 and Ethyl Cellulose, and provide a cooling effect. Results: The prepared formulations were evaluated for various critical parameters, and based on the results obtained, Formulation F1 exhibited a drug content of 91.82% and 83.75% of % Cumulative drug release through Eggshell membrane and was found to be the best-suited formulation. Formulation F1 was further chosen for carrying out in-vitro permeation studies through shed snakeskin of Ophiophagus Hannah (Cobra), which gave % a cumulative drug release of 72.453 %, exhibited pH of 5.8 and evaporation time of four minutes yielding a non-sticky film. The prepared formulations were clear in appearance and formed Uniform, non-sticky, flexible films. The average time required for the release of 50% drug was found to be 120-180 min, and the drug transport kinetic was best fitted into the Korsmeyer's-Peppas model. Conclusion:The study concluded that the prepared transdermal film-forming spray formulations would be efficient for treating fungal infections of superficial nature and will prove to be a practical approach in the delivery of topical antifungal agents.

Introduction: Alectinib, an anaplastic lymphoma kinase inhibitor of BCS class IV, is said to have pH-dependent solubility and is susceptible to interactions with co-prescribed acid-reducing agents. Objectives: A micro-dissolution study was performed to determine the effect of modulations in gastrointestinal pH using biorelevant media and a sensitive RP-HPLC technique was developed for quantification of alectinib in the same using quality by design approach. Materials and Methods: Analytical method was developed and optimized in accordance with box-behnken design followed by micro-dissolution experiment mimicking physiological pH shift. Results: The solubility of alectinib in FaSSGF decreased from 0.648 µg/ml to 0.270 µg/ml whereas in FaSSIF it dropped down from 0.574 µg/ml to 0.108 µg/ml at the end of the micro-dissolution experiment. This reveals that elevation of pH from 1.2 to 6.8 has no significant impact on its solubility and hence will not influence drug absorption. Conclusion: Nonetheless, the study would be useful for therapeutic medication monitoring, dose adjustment of co-administered drugs, proactively driving clinical research design, and obtaining a readout on pH liability for high-risk anticancer medications.