Stability Indicating Assay Method for the Quantitative Determination of Olaparib in Bulk and Pharmaceutical Dosage Form.

Objectives: Olaparib is an orally active poly (ADP-ribose) PARP (polymerases) inhibitor known to destroy cancer cells with BRCA1 or BRCA2 deficiency. An authentic, fast, distinct, and reliable reverse phase-high performance liquid chromatography (RP-HPLC) method was developed and promptly validated in tablet formulations for olaparib estimation. Materials and Methods: The proposed method focuses on the separation of olaparib in reverse phase mode using a Waters symmetry C18 (150 x 4.6 mm, 5 µm) analytical column with a flow rate of 1.0 mL/min and the injection volume was kept at 20 µL. The optimized mobile phase consists of ammonium acetate buffer (pH adjusted to 3.5 by glacial acetic acid): methanol in the ratio of 50:50 v/v. Results: The eluents were measured at 254 nm and the retention time for the drug encircled was about 4.32 min. The stress degradation studies of olaparib were conducted under acidic, alkaline, oxidative, photolytic and thermal conditions to demonstrate the stability of the drug. The regression value of 0.998 showed that the developed method was linear over the range of 80 µg/mL to 120 µg/mL. The developed RP-HPLC method is accurate and precise. The method was statistically validated as per International Conference on Harmonization guidelines. Conclusion: The proposed method is suitable and can be applied for the quantitative estimation of olaparib without any interference of the excipients used in the drug formulations.

Simultaneous Pharmacokinetics Estimation of Nateglinide and Pioglitazone by RP-HPLC: Computational Study to Unlock the Synergism.

Nateglinide (NAT) and Pioglitazone (PIO) are an antidiabetic drugs combination and currently under clinical trial in countries like Japan. In this study, an alternative, a simple, sensitive high-performance liquid chromatography method has been developed (limit of detection: 15 ng/mL and limit of quantification: 50 ng/mL) for simultaneous estimation of this drug combination in rat plasma. Most remarkably, bioavailability of NAT has been increased markedly on coadministration with PIO, than when it was administered alone. Thus, PIO is assumed to retard the catabolism of NAT by inhibiting metabolic liver-microsomal enzyme, especially CYP2C9. Using a Waters Nova-Pak C 18 column (150 × 3.9 mm, 4 µm) and a mobile phase of acetonitrile: 10 mM KH2PO4 (60: 40, V/V (volume by volume)) pH 3.5, the analysis was performed at 210 nm with a flow rate of 1.5 mL/min. In silico docking via molecular dynamics simulation revealed that NAT-CYP2C9 binding affinity may be reduced after PIO attachment, presumably due to the binding site overlapping of the two drugs. Thus, it has been proposed that NAT and PIO may be an efficient synergistic fixed dose combination against diabetes mellitus, and the above method can foster a simple but highly sensitive bioanalytical estimation for routine analysis.

Computational tool for immunotoxic assessment of pyrethroids toward adaptive immune cell receptors.

BACKGROUND: Pyrethroids have prominently known for their insecticidal actions worldwide, but recent reports as anticancer and antiviral applications gained a lot of interest to further understand their safety and immunotoxicity. OBJECTIVE: This encouraged us to carry out our present study to evaluate the interactions of pyrethroids toward adaptive immune cell receptors. MATERIALS AND METHODS: Type 1 and Type 2 pyrethroids were tested on T (CD4 and CD8) and B (CD28 and CD45) immune cell receptors using Maestro 9.3 (Schrödinger, LLC, Cambridge, USA). In addition, top-ranked tested ligands were too explored for toxicity prediction in rodents using ProTOX tool. RESULTS: Pyrethroids (specifically type 2) such as fenvalerate (-5.534 kcal/mol: CD8), fluvalinate (-4.644 and - 4.431 kcal/mol: CD4 and CD45), and cypermethrin (-3.535 kcal/mol: CD28) have outcome in less energy or more affinity for B-cell and T-cell immune receptors which may later result in the immunosuppressive and hypersensitivity reactions. CONCLUSION: The current findings have uncovered that there is a further need to assess the Type 2 pyrethroids with wet laboratory experiments to understand the chemical nature of pyrethroid-induced immunotoxicity. SUMMARY: Fenvalerate showed apex glide score toward CD8 immune receptor, while fluvalinate confirmed top-ranked binding with CD4 and CD45 immune proteinsIn addition, cypermethrin outcame in top glide score against CD28 immune receptorTop dock hits (Type 2) pyrethroids have shown probable toxicity targets toward AOFA: Amine oxidase (flavin-containing) A and PGH1: Prostaglandin G/H synthase 1, respectively. Abbreviations used: PDB: Protein Data Bank; AOFA: Amine oxidase (flavin-containing) A; PGH 1: Prostaglandin G/H synthase 1.

Fabrication of ß-cyclodextrin-mediated single bimolecular inclusion complex: characterization, molecular docking, in-vitro release and bioavailability studies for gefitinib and simvastatin conjugate.

OBJECTIVES: Introduction of multiple molecules in a single inclusion complex, albeit cheaper, lacks conclusive attempts in earlier drug delivery reports. This manuscript emphasizes simultaneous incorporation of two anticancer drugs, gefitinib (G) and simvastatin (S), in a single molecule of ß-cyclodextrin for the first time to achieve effective drug delivery. METHODS: The inclusion complex (GSBCD) was prepared by cosolvent evaporation technique using ß-cyclodextrin (BCD) as carrier. Characterization of GSBDC was performed by Fourier transform infrared spectroscopy, COSY, differential scanning calorimetry, X-ray diffraction and dynamic light scattering analyses, which were ascribed to the complex formation inside BCD cavity, micronization of drugs and conversion to amorphous state. KEY FINDINGS: The complex revealed entrapment of G and S in 3 ± 0.48: 2 ± 0.19 molar ratio and showed more than 3.5 and 10 fold increase in drug release in in vitro and in vivo, respectively. Docking and COSY studies revealed molecular alignment into BCD central cavity that been achieved via hydrogen bonding between certain groups of the ligands (G and S) and the polar heads of BCD. Partial incorporation of the molecular backbone inside inclusion complex suggests superficial contact with the solvent indicating slow steady release kinetics. CONCLUSIONS: This approach of forming inclusion complex with multiple molecules within a single cavity can be a landmark for further studies in drug delivery.