Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay.

Recent research on dipeptidyl peptidase-IV (DPP-IV) inhibitors has made it feasible to treat type 2 diabetes mellitus (T2DM) with minimal side effects. Therefore, in the present investigation, we aimed to discover and develop some coumarin-based sulphonamides as potential DPP-IV inhibitors in light of the fact that molecular hybridization of many bioactive pharmacophores frequently results in synergistic activity. Each of the proposed derivatives was subjected to an in silico virtual screening, and those that met all of the criteria and had a higher binding affinity with the DPP-IV enzyme were then subjected to wet lab synthesis, followed by an in vitro biological evaluation. The results of the pre-ADME and pre-tox predictions indicated that compounds 6e, 6f, 6h, and 6m to 6q were inferior and violated the most drug-like criteria. It was observed that 6a, 6b, 6c, 6d, 6i, 6j, 6r, 6s, and 6t displayed less binding free energy (PDB ID: 5Y7H) than the reference inhibitor and demonstrated drug-likeness properties, hence being selected for wet lab synthesis and the structures being confirmed by spectral analysis. In the in vitro enzyme assay, the standard drug Sitagliptin had an IC50 of 0.018 µM in the experiment which is the most potent. All the tested compounds also displayed significant inhibition of the DPP-IV enzyme, but 6i and 6j demonstrated 10.98 and 10.14 µM IC50 values, respectively, i.e., the most potent among the synthesized compounds. Based on our findings, we concluded that coumarin-based sulphonamide derivatives have significant DPP-IV binding ability and exhibit optimal enzyme inhibition in an in vitro enzyme assay.

QbD enabled optimization of solvent shifting method for fabrication of PLGA-based nanoparticles for promising delivery of Capecitabine for antitumor activity.

The key objective of the current research was to fabricate and optimize Capecitabine (Cap)-loaded [poly(lactic-co-glycolic acid)] PLGA-based nanoparticles (NPs) by enabling quality by design (QbD) approach for enhancing antitumor activity by promising delivery of the drug at the colonic site. The current research was based on fabricating PLGA-based nanoparticles along with Eudragit S100 as enteric polymer employing solvent shifting method followed by optimization using QbD approach. This approach was found to be useful for understanding the multiple factors and their interaction influencing the product by utilizing Design of Experiment (DOE). Box-Behnken design (BBD) was adopted to achieve the required critical quality attributes (CQAs), i.e., minimizing particle size, maximizing entrapment efficiency, and minimizing PDI value. The optimized nanoparticles were lyophilized and characterized by FT-IR, DSC, TEM, DLS, MTT assay using HT-29 cell lines, and in vivo pharmacokinetic studies. The optimized PLGA-based nanoparticles were found to possess average particle size, PDI, zeta potential, and entrapment efficiency of 195 nm, 0.214, -6.65 mV, and 65%, respectively. TEM analysis revealed the spherical nature of nanoparticles. The FT-IR and DSC studies revealed no interaction. The bioavailability of Cap-loaded nanoparticles was found to be two fold increased than the pure drug, and also, it exhibited significantly more cytotoxic to tumor cells as compared to pure drug as confirmed by MTT assay. The optimized PLGA-based nanoparticles found to possess enhanced bioavailability and significantly more cytotoxic potential as compared to pure drug.

Lyophilized SLN of Cinnacalcet HCl: BBD enabled optimization, characterization and pharmacokinetic study.

Objective: The objective of the present research is to formulate solid lipid nanoparticles (SLN) of CH to improve its oral bioavailability.Methods: Cinnacalcet hydrochloride (CH) exhibits poor oral bioavailability of 20 to 25% because of low aqueous solubility and first pass metabolism. The SLN formulations were optimized using Box-Behnken Design. SLN formulation was prepared using hot homogenization technique followed by ultra-sonication and evaluated. The optimized SLN formulation was lyophilized to improve the stability of the formulation further.Results: Compritol 888 ATO (COM), Soya lecithin (SL) and poloxamer 188 (POL) were selected as lipid, surfactant and co-surfactant respectively. For optimistaion, the desirable goal was fixed for variour responses vis-a-vis entrapment efficiency (EE), particle size (PS) and (time taken for diffusion of 85% drug) T85%. The optimized single dose of SLN obtained using BBD consisting of 30 mg of CH, 100 mg of COM, 150 mg of SL and 0.1% w/v of POL. The pharmacokinetic study revealed that optimized SLN and lyophilized SLN were found to increase the oral bioavailability nearly two times compared to an aqueous suspension of pure drug.Conclusion: Thus lyophilized SLN formulation explicated the potential of lipid-based nanoparticles as a potential carrier in improving the oral delivery and stability of CH.

Quality by Design Enabled Development of Oral Self-Nanoemulsifying Drug Delivery System of a Novel Calcimimetic Cinacalcet HCl Using a Porous Carrier: In Vitro and In Vivo Characterisation.

In this present research, work quality by design-enabled development of cinacalcet HCl (CH)-loaded solid self-nanoemulsifying drug delivery system (S-SNEDDS) was conducted using a porous carrier in order to achieve immediate drug release and better oral bioavailability. Capmul MCM (CAP), Tween 20 (TW 20) and Transcutol P (TRP) were selected as excipients. Cumulative % drug release at 30 min (Q30), emulsification times (ET), mean globule size (GS) and polydispersity index (PDI) were identified as critical quality attributes (CQAs). Factor mode effect analysis (FMEA) and Taguchi screening design were applied for screening of factors. The optimised single dose of S-SNEDDS obtained using Box-Behnken design (BBD) consisted of 30 mg of CH, 50 mg of CAP, 149.75 mg of TW 20, 55 mg of TRP and 260.75 mg of Neusilin US2. It showed an average Q30 of 97.6%, ET of 23.3 min, GS of 89.5 nm and PDI of 0.211. DSC, XRD and SEM predict the amorphous form of S-SNEDDS. In vivo pharmacokinetic study revealed better pharmacokinetic parameters of S-SNEDDS. The above study concluded that the optimised S-SNEDDS is effective to achieve the desired objective. Graphical Abstract.