Dataset Information

Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative-lipid complex.

ABSTRACT: In this study, a system for oral delivery of etoposide (ETP) was designed to avoid the problems associated with low and variable bioavailability of a commercially available ETP emulsion comprised of polyethylene glycol, glycerol, and citric acid anhydrous. ETP was complexed with low-molecular-weight methylcellulose (ETP/LMC) and loaded into a water-in-oil-in-water multiple nanoemulsion to formulate an ETP/LMC-nanoemulsion (ELNE). To further enhance the oral bioavailability, an ionic complex formed by anionic lipid 1,2-didecanoyl-sn-glycero-3-phosphate (sodium salt) and cationic N ^α-deoxycholyl-l-lysyl-methylester was incorporated into ELNE, yielding ELNE#7. As expected, ELNE#7 showed 4.07- and 2.25-fold increases in artificial membrane and Caco-2/HT29-MTX-E12 permeability (P_app ), respectively, resulting in 224% greater oral bioavailability compared with the commercially available ETP emulsion. In contrast, inhibition of clathrin- and caveola-mediated endocytosis, macropinocytosis, and bile acid transporters by chlorpromazine, genistein, amiloride, and actinomycin D in Caco-2/HT-29-MTX-E12 monolayers reduced the P_app by 45.0%, 20.5%, 28.8%, and 31.1%, respectively. These findings suggest that these routes play important roles in enhancing the oral absorption of ELNE#7. In addition, our mechanistic study suggested that P-glycoprotein did not have an inhibitory effect on the permeation of ELNE#7. Notably, ELNE#7 showed significantly enhanced toxicity in LLC and A549 cells compared with ETP-E. These observations support the improved oral absorption of ETP in ELNE#7, suggesting that it is a better alternative than ETP emulsion.

SUBMITTER: Jha SK

PROVIDER: S-EPMC7594851 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative-lipid complex.

Jha Saurav Kumar SK Han Hee-Soo HS Subedi Laxman L Pangeni Rudra R Chung Jee Young JY Kweon Seho S Choi Jeong Uk JU Byun Youngro Y Kim Yong-Hee YH Park Jin Woo JW

Drug delivery 20201201 1

In this study, a system for oral delivery of etoposide (ETP) was designed to avoid the problems associated with low and variable bioavailability of a commercially available ETP emulsion comprised of polyethylene glycol, glycerol, and citric acid anhydrous. ETP was complexed with low-molecular-weight methylcellulose (ETP/LMC) and loaded into a water-in-oil-in-water multiple nanoemulsion to formulate an ETP/LMC-nanoemulsion (ELNE). To further enhance the oral bioavailability, an ionic complex form ...[more]

PMID: 33107339

Similar Datasets

Project description:AimCanagliflozin (CFZ), a novel SGLT II antagonist, exhibits erratic absorption after oral administration. The current study entails development and evaluation of spray dried lipid based formulation (solid SMEDDS) for enhancing oral bioavailability and anti-diabetic activity of CFZ.MethodsSolid SMEDDS developed through spray drying containing Neusilin US2 as an adsorbent. The formed solid SMEDDS were characterized for physicochemical and solid state attributes. Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) were used to confirm the spherical morphology. In vitro dissolution, ex vivo permeability and in vivo pharmacokinetic studies were conducted to determine the release rate, permeation rate and absorption profile of CFZ, respectively. Pharmacodynamic studies were done as per standard protocols.ResultsThe optimized solid SMEDDS exhibited acceptable practical yield and flow properties and is vouched with enhanced amorphization, nanoparticulate distribution and acceptable drug content. The spherical morphology of solid SMEDDS and reconstituted SMEDDS were confirmed in SEM and TEM, respectively. In vitro dissolution studies revealed multi-fold release behavior in CFZ in various dissolution media, whereas, remarkable permeability was observed in jejunum segment of rat intestine. Pharmacokinetic studies of CFZ in solid SMEDDS demonstrated 2.53 and 1.43 fold enhancement in Cmax and 2.73 and 1.98 fold in AUC 0-24h, as compared to pure API and marketed formulation, respectively. Pharmacological evaluation of solid SMEDDS revealed enhanced anti-diabetic activity of CFZ through predominant SGLT II inhibition in rats, as evident from evaluation of biochemical levels, urinary glucose excretion studies and SGLT II expression analysis.ConclusionThe current work describes significant improvement biopharmaceutical properties of CFZ in solid SMEDD formulation. Graphical abstract Graphical Abstract: Enhanced oral bioavailability and anti-diabetic activity of canagliflozin through a spray dried lipid based oral delivery: a novel paradigm.

Project description:Dolutegravir's therapeutic effectiveness in the management of neuroAIDS is mainly limited by its failure to cross the blood-brain barrier. However, lipid-based nanovesicles such as nanoemulsions have demonstrated their potential for the brain targeting of various drugs by intranasal delivery. Thus, the purpose of this study was to develop a Dolutegravir-loaded nanoemulsion-based in situ gel and evaluate its prospective for brain targeting by intranasal delivery. Dolutegravir-loaded nanoemulsions were prepared using dill oil, Tween® 80, and Transcutol® P. Optimization of the nanoemulsion particle size and drug release was carried out using a simplex lattice design. Formulations (F1-F7 and B1-B6) were assessed for various pharmaceutical characteristics. Ex vivo permeation and ciliotoxicity studies of selected in situ gels (B1) were conducted using sheep nasal mucosa. Drug targeting to the brain was assessed in vivo in rats following the nasal delivery of B1. The composition of oil, surfactant, and cosurfactant significantly (p < 0.05) influenced the dependent variables (particle size and % of drug release in 8 h). Formulation B1 exhibits pharmaceutical characteristics that are ideal for intranasal delivery. The mucosal steady-state flux noticed with BI was significantly greater (p < 0.005) than for the control gel. A histopathology of nasal mucosa treated with BI showed no signs of toxicity or cellular damage. Intranasal administration of B1 resulted in greater Cmax (~six-fold, p < 0.0001) and AUC0-α (~five-fold, p < 0.0001), and decreased Tmax (1 h) values in the brain, compared to intravenous administration. Meantime, the drug level in the plasma was relatively low, suggesting less systemic exposure to Dolutegravir through intranasal delivery. In summary, the promising data observed here signifies the prospective of B1 to enhance the brain targeting of Dolutegravir by intranasal delivery and it could be used as a feasible and practicable strategy for the management of neuroAIDS.

Project description:Resveratrol (RES) is a biopharmaceutical classification system (BCS) class II compound with low solubility and high permeability. Several strategies have been explored to overcome the low bioavailability of RES, making the formation of solid dispersions (SDs) one of the most promising. This study aimed at the development of a RES third-generation SD prepared by lyophilization as a strategy to improve RES solubility, dissolution, and oral bioavailability. Eudragit E PO was selected as the hydrophilic carrier in a 1:2 (RES:carrier) ratio, and Gelucire 44/14 as the surfactant, at 16% (w/w) of RES. Differential scanning calorimetry (DSC), scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), polarized light microscopy (PLM), X-ray powder diffraction (XRPD), and particle size distribution (Morphologi 4 Malvern) were used for solid-state characterization and to confirm the conversion of RES to the amorphous state in the SD. Third-generation SD presented an 8-, 12-, and 8-fold increase of RES solubilized compared to pure RES at pH 1.2, 4.5, and 6.8, respectively, and a 10-fold increase compared to the physical mixture (PM), at pH 6.8, after 24 h. In the gastric environment, the dissolution rate of third-generation SD and PM was similar, and 2-fold higher than pure RES after 30 min, while at pH 6.8, third-generation SD presented approximately a 5-fold increase in comparison to pure RES and PM. Third-generation SD presented higher in vitro intestinal permeability compared to its PM and second-generation SD (without Gelucire 44/14). A 2.4 and 1.7-fold increase of RES permeated, respectively in Caco-2 and Caco-2/HT2-MTX models, was obtained with third-generation SD compared to PM, after 3 h. Third-generation SD allowed a 3-fold increase of RES bioavailability compared to second-generation SD, after oral administration of 200 mg/kg of RES to Wistar rats. Enhanced RES oral bioavailability was obtained not only by solubility and dissolution improvement, but also by the interference of Gelucire 44/14, with RES metabolism, and inhibition of P-gp-mediated efflux. The presence of excipients like Gelucire 44/14 in the SD allows for greater bioavailability of orally administered RES, making it easier to obtain some of the physiological benefits demonstrated by this molecule.

Dataset Information

Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative-lipid complex.

Publications

Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative-lipid complex.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets