Utilization of Gelling Polymer to Formulate Nanoparticles Loaded with Epalrestat-Cyclodextrin Inclusion Complex: Formulation, Characterization, In-Silico Modelling and In-Vivo Toxicity Evaluation.

Epalrestat (EPL) is an aldose reductase inhibitor with poor aqueous solubility that affects its therapeutic efficacy. The research study was designed to prepare epalrestat-cyclodextrins (EPL-CDs) inclusion complexes to enhance the aqueous solubility by using beta-cyclodextrin (ß-CD) and sulfobutyl ether7 ß-CD (SBE7 ß-CD). Furthermore, polymeric nanoparticles (PNPs) of EPL-CDs were developed using chitosan (CS) and sodium tripolyphosphate (sTPP). The EPL-CDs complexed formulations were then loaded into chitosan nanoparticles (CS NPs) and further characterized for different physico-chemical properties, thermal stability, drug-excipient compatibility and acute oral toxicity studies. In-silico molecular docking of cross-linker with SBE7 ß-CD was also carried out to determine the binding site of the CDs with the cross-linker. The sizes of the prepared NPs were laid in the range of 241.5-348.4 nm, with polydispersity index (PDI) ranging from 0.302-0.578. The surface morphology of the NPs was found to be non-porous, smooth, and spherical. The cumulative percentage of drug release from EPL-CDs loaded CS NPs was found to be higher (75-88%) than that of the pure drug (25%). Acute oral toxicity on animal models showed a biochemical, histological profile with no harmful impact at the cellular level. It is concluded that epalrestat-cyclodextrin chitosan nanoparticles (EPL-CDs-CS NPs) with improved solubility are safe for oral administration since no toxicity was reported on vital organs in rabbits.

Biodegradable and biocompatible polymeric nanoparticles for enhanced solubility and safe oral delivery of docetaxel: In vivo toxicity evaluation.

Docetaxel (DTX) is a chemotherapeutic drug with poor hydrophilicity and permeability. Its lipophilic properties decrease its absorption in systemic circulation which hinders its therapeutic efficacy & safety. Cyclodextrins (CDs) with their unique structural properties enhance solubility of chemotherapeutic drugs. The study was designed to formulate docetaxel-cyclodextrins inclusion complexes for enhancement of solubility with sulfobutyl ether ß-cyclodextrin (SBE7-ß-CD), hydroxypropyl ß-cyclodextrin (HP-ß-CD) and ß-cyclodextrin (ß-CD). Further, by using ionic gelation method polymeric nanoparticles of docetaxel-cyclodextrins were prepared with sodium tri poly phosphate (STPP) and chitosan (CS). Optimization is performed by varying CS and STPP mass ratios. Nanoparticles were analyzed for their physicochemical properties, drug-excipient compatibility, thermal stability and oral toxicity. CDs enhanced the solubility of DTX. Nanoparticles were found within 144.8 ± 65.19 - 372.0 ± 126.9 nm diameters with polydispersity ranging 0.117-0.375. The particles were found round & circular in shape with smooth and non-porous surface. Increased quantity of drug release was observed from DTX-CDs loaded nanoparticles than pure drug loaded nanoparticles. Oral toxicity in rabbits revealed biochemical, histopathological profile with no toxic effect on cellular structure of animals.

Enhanced Oral Bioavailability of Epalrestat SBE7-ß-CD Complex Loaded Chitosan Nanoparticles: Preparation, Characterization and in-vivo Pharmacokinetic Evaluation.

BACKGROUND: Epalrestat (EPL) is a carboxylic acid derivative with poor aqueous solubility and its pharmacokinetic features are not fully defined. PURPOSE: Current research aimed to fabricate inclusion complexation of EPL with SBE7 ß-CD (IC) and EPL/SBE7 ß-CD CS NPs (NP). METHODS: EPL was complexed with SBE7 ß-CD using the co-precipitation method, and the prepared complex was fabricated into nanoparticles using the ionic gelation method. The prepared formulations were characterized for particle size analysis, surface morphology, and in vitro dissolution study. The % inhibition of EPL against α-glucosidase enzyme was also conducted to check the drug's antidiabetic activity. Finally, an in vivo pharmacokinetic investigation was carried out to determine the concentration of EPL in rabbit plasma of the prepared formulation. In vivo pharmacokinetic studies were conducted by giving a single dose of pure EPL, IC, and NP. RESULTS: The size of NP was found to be 241.5 nm with PDI 0.363 and zeta potential of +31.8 mV. The surface of the prepared NP was non-porous, smooth and spherical when compared with pure EPL, SBE7 ß-CD and IC. The cumulative drug release (%) from IC and NP was 73% and 88%, respectively, as compared to pure drug (25%). The % inhibition results for in vitro α-glucosidase was reported to be 74.1% and the predicted binding energy for in silico molecular docking was calculated to be -6.6 kcal/mol. The calculated Cmax values for EPL, IC and NP were 4.75±3.64, 66.91±7.58 and 84.27±6.91 µg/mL, respectively. The elimination half-life of EPL was 4 h and reduced to 2 h for IC and NP. The AUC0-α for EPL, IC and NP were 191.5±164.63, 1054.23±161.77 and 1072.5±159.54 µg/mL*h, respectively. CONCLUSION: Taking these parameters into consideration it can be concluded that IC and NP have prospective applications for greatly improved delivery and regulatedt release of poorly water soluble drugs, potentially leading to increase therapeutic efficacy and fewer side effects.

Antidiabetic Activities of an LC/MS Fingerprinted Aqueous Extract of Fagonia cretica L. in Preclinical Models.

Diabetes mellitus is a chronic disease and one of the most important public health challenges facing mankind. Fagonia cretica is a medicinal plant used widely in the Punjab in Pakistan. A recent survey has demonstrated that traditional healers and herbalists frequently use this plant to treat diabetes. In the current study, the traditional medicine was prepared as a tea, and the profile of the main metabolites present in the traditional medicine was analysed via LC/MS/MS. The extract was shown to contain a number of phenolic glycosides including quercetin-3-O-rutinoside, kaempferol-3-O-rutinoside, kaempferol-3-O-glycoside, kaempferol-3(6'-malonylglucoside), isorhamnetin-3-O-rutinoside, and isorhamnetin 3-(6″-malonylglucoside) in addition to two unidentified sulphonated saponins. The traditional medicine inhibits α-glucosidase in vitro with an IC50 of 4.62 µg/mL. The hypoglycaemic effect of the traditional medicine was evaluated in normoglycaemic and streptozotocin-treated diabetic rats, using glibenclamide as an internal control. The preparation (250 or 500 mg/kg body weight) was administered once a day for 21 consecutive days. The dose of 500 mg/kg was effective in the management of the disease, causing a 45 % decrease in the plasma glucose level at the end of the experimental period. Histological analysis of pancreatic sections confirmed that streptozotocin/nictotinamide treatment caused destruction of pancreatic islet cells, while pancreatic sections from the treatment groups showed that both the extract and glibenclamide partially prevented this deterioration. The mechanism of this protective effect is unclear. However, such a finding suggests that ingestion of the tea could confer additional benefits and should be investigated further.