Solid self-emulsifying drug delivery system (SSEDDS), which incorporates liquid SEDDS into a solid dosage form, has been recently introduced to improve the oral bioavail-ability of poorly water-soluble drugs. However, supersaturated drug generated by SSEDDS is thermodynamically unstable and tends to precipitate rapidly prior to absorption, resulting in compromised bioavailability. The aim of this study was to construct a novel supersaturated SSEDDS (super-SSEDDS) by combining SSEDDS with appropriate precipitation inhibitor. Fenofibrate (FNB), a sparingly soluble drug, was selected as a model drug in this study. An optimized SSEDDS was prepared by solvent evaporation by using mesoporous silica Santa Barbara Amorphous-15 as the inert carrier. Supersaturation assay was conducted to evaluate the precipitation inhibition capacity of different polymers, and the results showed that Soluplus
®
could retard the FNB precipitation more effectively and sustain a higher apparent concentration for ~120 min. This effect was also clearly observed in the dissolution profiles of FNB from SSEDDS under supersaturated condition. The study of the mechanism suggested that the inhibition effect might be achieved both thermodynamically and kinetically. The area under the concentration–time curve of the super-SSEDDS was 1.4-fold greater than that of SSEDDS in the absence of Soluplus, based on an in vivo pharmacokinetic study conducted in beagle dogs. This study has demonstrated that the approach of combining SSEDDS with Soluplus as a supersaturation stabilizer constitutes a potential tool to improve the absorption of poorly water-soluble drugs.
Dehydrogenative
coupling-based reactions have emerged as an efficient
route toward the synthesis of a plethora of heterocyclic rings. Herein,
we report an efficacious, nickel-catalyzed synthesis of two important
heterocycles such as quinoline and quinoxaline. The catalyst is molecularly
defined, is phosphine-free, and can operate at a mild reaction temperature
of 80 °C. Both the heterocycles can be easily assembled via double dehydrogenative coupling, starting from 2-aminobenzyl
alcohol/1-phenylethanol and diamine/diol, respectively, in a shorter
span of reaction time. This environmentally benign synthetic protocol
employing an inexpensive catalyst can rival many other transition-metal
systems that have been developed for the fabrication of two putative
heterocycles. Mechanistically, the dehydrogenation of secondary alcohol
follows clean pseudo-first-order kinetics and exhibits a sizable kinetic
isotope effect. Intriguingly, this catalyst provides an example of
storing the trapped hydrogen in the ligand backbone, avoiding metal-hydride
formation. Easy regeneration of the oxidized form of the catalyst
under aerobic/O2 oxidation makes this protocol eco-friendly
and easy to handle.
Background:
Postprandial hyperglycemia can be reduced by inhibiting major carbohydrate
hydrolyzing enzymes, such as α-glucosidase and α-amylase which is an effective approach in
both preventing and treating diabetes.
Objective:
The aim of this study was to synthesize a series of 2,4-dichloro-5-[(N-aryl/alkyl)sulfamoyl]
benzoic acid derivatives and evaluate α-glucosidase and α-amylase inhibitory activity
along with molecular docking and in silico ADMET property analysis.
Method:
Chlorosulfonation of 2,4-dichloro benzoic acid followed by reaction with corresponding
anilines/amines yielded 2,4-dichloro-5-[(N-aryl/alkyl)sulfamoyl]benzoic acid derivatives. For
evaluating their antidiabetic potential α-glucosidase and α-amylase inhibitory assays were carried
out. In silico molecular docking studies of these compounds were performed with respect to these
enzymes and a computational study was also carried out to predict the drug-likeness and ADMET
properties of the title compounds.
Results:
Compound 3c (2,4-dichloro-5-[(2-nitrophenyl)sulfamoyl]benzoic acid) was found to be
highly active having 3 fold inhibitory potential against α-amylase and 5 times inhibitory activity
against α-glucosidase in comparison to standard drug acarbose.
Conclusion:
Most of the synthesized compounds were highly potent or equipotent to standard
drug acarbose for inhibitory potential against α-glucosidase and α-amylase enzyme and hence this
may indicate their antidiabetic activity. The docking study revealed that these compounds interact
with active site of enzyme through hydrogen bonding and different pi interactions.
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