RESUMO
Ibuprofen is classified as a non-steroidal anti-inflammatory drug (NSAID) that is employed as an initial treatment option for its non-steroidal anti-inflammatory, pain-relieving, and antipyretic properties. However, Ibuprofen is linked to specific well-known gastrointestinal adverse effects like ulceration and gastrointestinal bleeding. It has been linked to harmful effects on the liver, kidney, and heart. The purpose of the study is to create novel and potential IBU analogue with reduced side effects with the enhancement of their medicinal effects, so as to advance the overall safety profile of the drug. The addition of some novel functional groups including CH3, F, CF3, OCF3, Cl, and OH at various locations in its core structure suggestively boost the chemical as well as biological action. The properties of these newly designed structures were analyzed through chemical, physical, and spectral calculations using Density Functional Theory (DFT) and time-dependent DFT through B3LYP/6-31 g (d,p) basis set for geometry optimization. Molecular docking and non-bonding interaction studies were conducted by means of the human prostaglandin synthase protein (PDB ID: 5F19) to predict binding affinity, interaction patterns, and the stability of the protein-drug complex. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) and PASS (Prediction of Activity Spectra for Substances) predictions were employed to evaluate the pharmacokinetic and toxicological properties of these structures. Importantly, most of the analogues displayed reduced hepatotoxicity, nephrotoxicity, and carcinogenicity in comparison to the original drug. Moreover, molecular docking analyses indicated improved medicinal outcomes, which were further supported by pharmacokinetic calculations. Together, these findings suggest that the modified structures have reduced adverse effects along with improved therapeutic action compared to the parent drug.
RESUMO
Background: Solid dispersion (SD) has been used conventionally as a successful technique for improving the dissolution profile and bioavailability of poorly water-soluble drugs. The aim of this study was to progress the dissolution rate and bioavailability of naproxen (BCS class II) by SD technique. Materials & methods: In this study, hydrophilic carriers are used for preparing solid dispersion of naproxen by evaporation method. The prepared optimized SDNs were evaluated by in-vitro drug dissolution test, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The in-vivo analgesic effects tests of the optimized SDNs (SDN-2 and SDN-5) were performed by tail immersion method and writhing method. Results: All the prepared SDNs exhibited a significant increase in the dissolution of naproxen compared to that of the pure drug. Among them, SDN-2 (the dispersion with sodium starch glycolate at 1:2 ratio of naproxen and sodium starch glycolate) and SDN-5 (using the combination of PEG-8000 and sodium starch glycolate with naproxen at 1:1:1 ratio) showed faster dissolution rate as compared to other solid dispersions (SDNs) and pure naproxen. SDN-2 showed 5.4 times better dissolution rate and SDN-5 depicted 6.5-fold increment of dissolution rate compared to pure naproxen drug. DSC, PXRD and SEM microscopy showed that the drugs crystallinity was decreased during the preparation process. FTIR study revealed that naproxen was stable in polymeric dispersions and there was no interaction among the drug and polymers. In writhing method, the percentage inhibition of the number of writhes showed significantly greater (p < 0.01), (p < 0.0001) analgesic activity for the higher dose treatment groups SDN-2(H), and SDN-5(H), respectively, when contrasted to the pure drug naproxen. For tail immersion test, there is increase in latency time at 90 min which is significantly greater (P < 0.01), (P < 0.05), (P < 0.01) for treatment groups SDN-2(H), SDN-5(L), and SDN-5(H), respectively that ultimately authenticates that the optimized SDNs (SDN-2, SDN-5) showed better analgesic activity in mice in comparison with the pure drug. Conclusion: It can be concluded that dissolution of the naproxen could be improved by the making solid dispersion using sodium starch glycolate and/or combination of sodium starch glycolate and PEG 8000 due to the complete transformation of drug into amorphous form with the entire loss of crystallinity, as evidenced by DSC, PXRD, and SEM and also consequences the enhanced analgesic activity in mice.