ABSTRACT
Analogue design forms one of the mainstays of new drug discovery. A fast-follow on approach is commonly used by modern day drug discoverers on the quest of the best in class. Monitoring close structural analogues of the pioneering drug by an algorithm such as docking is fraught with the risk of returning false positives. In this paper, we present the case of two near-pharmacophoric analogues of the JAK3 inhibitor Tasocitinib which give positive docking prediction despite being inactive. Post-processing the docked poses with MM/GBSA and parallel computation of electrostatic potential maps point towards a potential weakening of one of the crucial hydrogen bonds (hinge) within the ATP-binding pocket of JAK3. Perturbing the bound ligands by molecular dynamics (MD) simulations show the complexes to be unstable with the analogues losing their original hold on the protein within 1.2 ns. A short post MD simulation dramatically improves the prediction value of docking runs, especially when dealing with 'me-too' analogues.
Subject(s)
Piperidines/chemistry , Pyrimidines/chemistry , Pyrroles/chemistry , Algorithms , Janus Kinase 3/antagonists & inhibitors , Molecular Dynamics Simulation , Piperidines/pharmacology , Protein Binding , Pyrimidines/pharmacology , Pyrroles/pharmacology , Quantitative Structure-Activity RelationshipABSTRACT
The aim of this study was to investigate the industrial feasibility of developing a co-formulated solid dispersion (SD) containing two antimalarial drugs artemether (ARTM) and lumefantrine (LUMF). Soluplus(®) (polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer) was used as primary carrier matrices via hot-melt extrusion processing to improve solubility profile and the oral bioavailability of the combination. Based on the preliminary screening, the optimized quantities of PEG 400, Lutrol F127 and Lutrol F68 were incorporated as surfactant with soluplus in different ratios to improve extrudability, increase wettability and the melt viscosity of the HME process. Soluplus(®) was proved to successfully stabilize both the drugs inside its polymeric network during extrusion via forming a stable solid dispersion. Physicochemical properties of the APIs and the SDs characterized by thermo-gravimetric analysis (TGA), differential scanning calorimetry (DSC), MDSC, FTIR spectroscopy and X-ray diffractometry (XRD) revealed the amorphous existence of the drug in all SDs developed. Molecular level morphology of solid dispersion characterized by using advanced physicochemical characterization techniques such as Raman spectroscopy, atomic force microscopy (AFM) and 2D NMR showed the transformation of the crystalline drugs to its stable amorphous state. All manufactured SDs retained their amorphicity even after a stability study conducted in accelerated condition over 6 months. The solubility and in vitro dissolution performance of both drugs in SD formulations was improved significantly when compared with pure drugs and marketed product while the in vivo studies revealed the same.The pharmacokinetic studies in rats revealed that the SD (AL1) shows a 44.12-65.24 folds increase in the AUC(0-72) and 42.87-172.61 folds increase in Cmax compared to that of pure drugs and a better bioavailability than that of commercial product.
Subject(s)
Antimalarials/administration & dosage , Artemisinins/administration & dosage , Chemistry, Pharmaceutical/methods , Drug Carriers/chemistry , Ethanolamines/administration & dosage , Fluorenes/administration & dosage , Administration, Oral , Animals , Antimalarials/chemistry , Antimalarials/pharmacokinetics , Area Under Curve , Artemether, Lumefantrine Drug Combination , Artemisinins/chemistry , Artemisinins/pharmacokinetics , Biological Availability , Crystallization , Drug Combinations , Drug Compounding/methods , Drug Stability , Drug Storage , Ethanolamines/chemistry , Ethanolamines/pharmacokinetics , Feasibility Studies , Fluorenes/chemistry , Fluorenes/pharmacokinetics , Male , Rats , Rats, Wistar , Solubility , Surface-Active Agents/chemistry , Viscosity , WettabilityABSTRACT
In the present study attempts were made to prepare metered dose inhalation of salbutamol in solution form and compared it with the marketed metered dose inhalation in suspension form. Solution form of the drug was found better than marketed suspension formulation with respect to homogeneity and content uniformity. Propellant blend P-11 and P-12 in the proportion 30:70 was selected as it gave optimum vapour pressure. Surfactant oleic acid in concentration 10 mg per can was selected as it gave best results with clarity, spray pattern, vapour pressure, content per spray and rate of evaporation. Ethyl alcohol 2 ml per can was used as a cosolvent to give a clear solution, optimum vapour pressure, maximum content per spray and fair rate of evaporation. The selected formulation was subjected to the physico-chemical evaluation tests as per the standard pharmacopoeial procedures and the characteristics of the formulations were further compared with a conventional marketed formulation. In vitro study reveled the net respirable fraction was better than marketed preparation.
