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Lipid-based nanosystem of edaravone: development, optimization, characterization and in vitro/in vivo evaluation.

ABSTRACT: Edaravone (EDR) is a well-recognized lipophilic free radical scavenger for diseases including neurodegenerative disease, cardiovascular disease, and cancer. However, its oral use is restricted due to poor oral bioavailability (BA). The aim of present research was to enable its oral use by developing a lipid-based nanosystem (LNS). The components of LNS including oil, surfactants, and co-surfactants were selected based on their potential to maximize the solubilization in gastrointestinal (GI) fluids, reduce its glucuronidation and improve transmembrane permeability. The liquid LNS (L-LNS) with Capryol™ PGMC (Oil), Cremophor^® RH 40:Labrasol^®:TPGS 1000 (1:0.8:0.2) (Surfactant) and Transcutol P^® (Co-surfactant) were optimized to form microemulsion having droplet size (16.25 nm), polydispersity index (0.039), % Transmittance (99.85%), and self-emulsification time (32 s). It significantly improved the EDR loading as well as its metabolism and permeability profile during transport across the GI tract. To overcome the possible drawbacks of L-LNS, Aerosil^® 200 was used to formulate solid LNS (S-LNS), and its concentration was optimized based on flow properties. S-LNS possessed all quality attributes of L-LNS confirmed by solid-state characterization, reconstitution ability, and stability study. The dissolution rate of EDR was significantly enhanced with L-LNS and S-LNS in simulated gastric, and intestinal fluids. The pharmacokinetic study revealed significant improvement in relative BA, C_max, and t_1/2 with L-LNS and S-LNS against EDR suspension. Moreover, S-LNS showed superior cellular uptake and neuroprotective effect compared to EDR in SH-SY5Y695 cell line. An appropriate selection of the components of LNS could enable effective oral delivery of challenging therapeutics that are conventionally used by the parenteral administration.

SUBMITTER: Parikh A

PROVIDER: S-EPMC8241028 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and purposeNiosomes are nonionic surfactant-based vesicles that exhibit certain unique features which make them favorable nanocarriers for sustained drug delivery in cancer therapy. Biodistribution studies are critical in assessing if a nanocarrier system has preferential accumulation in a tumor by enhanced permeability and retention effect. Radiolabeling of nanocarriers with radioisotopes such as Technetium-99m (99mTc) will allow for the tracking of the nanocarrier noninvasively via nuclear imaging. The purpose of this study was to formulate, characterize, and optimize 99mTc-labeled niosomes.MethodsNiosomes were prepared from a mixture of sorbitan monostearate 60, cholesterol, and synthesized D-?-tocopherol polyethylene glycol 1000 succinate-diethylenetriaminepentaacetic acid (synthesis confirmed by 1H and 13C nuclear magnetic resonance spectroscopy). Niosomes were radiolabeled by surface chelation with reduced 99mTc. Parameters affecting the radiolabeling efficiency such as concentration of stannous chloride (SnCl2·H2O), pH, and incubation time were evaluated. In vitro stability of radiolabeled niosomes was studied in 0.9% saline and human serum at 37°C for up to 8 hours.ResultsNiosomes had an average particle size of 110.2±0.7 nm, polydispersity index of 0.229±0.008, and zeta potential of -64.8±1.2 mV. Experimental data revealed that 30 µg/mL of SnCl2·H2O was the optimal concentration of reducing agent required for the radiolabeling process. The pH and incubation time required to obtain high radiolabeling efficiency was pH 5 and 15 minutes, respectively. 99mTc-labeled niosomes exhibited high radiolabeling efficiency (>90%) and showed good in vitro stability for up to 8 hours.ConclusionTo our knowledge, this is the first study published on the surface chelation of niosomes with 99mTc. The formulated 99mTc-labeled niosomes possessed high radiolabeling efficacy, good stability in vitro, and show good promise for potential use in nuclear imaging in the future.

Project description:Background and methodsA new cyclosporin A-loaded, PEGylated chitosan-modified lipid-based nanoparticle was developed to improve upon the formulation of cyclosporin A. PEGylated chitosan, synthesized in three steps using mild reaction conditions, was used to modify the nanoparticles. Cyclosporin A-loaded, PEGylated chitosan-modified nanoparticles were prepared using an emulsification/solvent evaporation method. The drug content and encapsulation efficiency of the cyclosporin A-loaded, PEGylated chitosan-modified nanoparticles were measured by high-performance liquid chromatography. The average size of the nanoparticles was determined by transmission electron microscopy and dynamic light scattering. The pharmacokinetic behavior of the nanoparticles was investigated in rabbits after intravenous injection. Cyclosporin A concentrations in a whole blood sample were analyzed by high-performance liquid chromatography using tamoxifen as the internal standard. The pharmacokinetic parameters were calculated using the 3p87 software program.ResultsFourier transform infrared spectroscopy and nuclear magnetic resonance confirmed the structure of PEGylated chitosan. The drug content and encapsulation efficiency of the cyclosporin A-loaded, PEGylated chitosan-modified nanoparticles were 37.04% and 69.22%, respectively. The average size of the nanoparticles was 89.4 nm. The nanoparticles released 30% cyclosporin A-loaded in 48 hours in vitro, with no initial burst release. The mode of release in vitro was prone to bulk erosion. The in vivo results showed the biological half-life of the elimination phase (t(1/2β)) of the nanoparticles was 21 times longer than that of the cyclosporin A solution, and the area under the curve for the nanoparticles was 25.8 times greater than that of the cyclosporin A solution.ConclusionModification of PEGylated chitosan prolonged the retention time of the nanoparticles in the circulatory system and improved the bioavailability of cyclosporin A.

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Lipid-based nanosystem of edaravone: development, optimization, characterization and in vitro/in vivo evaluation.

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