Precision engineering designed phospholipid-tagged pamidronate complex functionalized SNEDDS for the treatment of postmenopausal osteoporosis.

Disodium pamidronate, a second-generation bisphosphonate is a potent drug for the treatment of osteoporosis, which has been very well established by previous literature. It has very low oral permeability, leading to its low oral bioavailability, which restrict this drug to being administered orally. Therefore, the present research work includes the development of an orally effective nanoformulation of pamidronate. In this work, disodium pamidronate was complexed with phospholipon 90G for the enhancement of permeability and to investigate the phospholipon 90G-tagged pamidronate complex-loaded SNEDDS for oral delivery with promises of enhanced bioavailability and anti-osteoporotic activity. The rational design and optimization was employed using Central Composite Design (Design Expert® 12, software) to optimize nanoformulation parameters. In this work, a commercially potential self nano-emulsifying drug delivery system (SNEDDS) has been developed and evaluated for improved oral bioavailability and better clinical acceptance. The hot micro-emulsification and ultracentrifugation method with vortex mixing was utilized for effective tagging of phospholipon 90G with pamidronate and then loading into the SNEDDS nanocarrier. The optimized Pam-PLc SNEDDS formulation was characterized for particle size, PDI, and zeta potential and found to be 56.38 ± 1.37 nm, 0.218 ± 0.113, and 22.41 ± 1.14 respectively. Also, a 37.9% improved bioavailability of pamidronate compared to marketed tablet was observed. Similarly, in vivo pharmacokinetic studies suggest a 31.77% increased bone density and significant enhanced bone biomarkers compared to marketed tablets. The developed formulation is safe and effectively overcomes anti-osteoporosis promises with improved therapeutic potential. This work provides very significant achievements in postmenopausal osteoporosis treatment and may lead to possible use of nanotherapeutic-driven emerging biodegradable carriers-based drug delivery.

In silico identification of viper phospholipaseA2 inhibitors: validation by in vitro, in vivo studies.

Snake venom, particularly of vipers from the Indian subcontinent, contains Phospholipase A2 (PLA2) as one its constituents which is widely implicated in hemorrhagic, cardiac arrest and death. Development of inhibitors of the protein can facilitate the weakening or annihilation of the venom toxicity and save many human lives. In the present communication, our studies relate to the design and development of structure-based ligands as inhibitors of PLA2 of Viper venom. The study involves the computational approach towards evaluating a library of molecules comprising of natural products, and synthetic molecules through docking studies on the venom protein PDB ID: 1OXL (a dimer, available in the literature). In silico experiments have resulted in the identification of several of them as PLA2 inhibitors. The inhibitory effect of PLA2 by these compounds is attributed to a great extent to their interaction with the residues Phe 46 and Val47 of chain B of the target protein and hence these two residues are identified as the key contributor for the said activity. In order to validate the in silico findings, a selected panel of compounds have been tested by in vitro and in vivo experiments against the venom, which has led to the observance of significant corroboration between the wet lab and in silico findings, validating thereby the in silico approach used in the present study.