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Comparative Serum and Brain Pharmacokinetics of Quercetin after Oral and Nasal Administration to Rats as Lyophilized Complexes with β-Cyclodextrin Derivatives and Their Blends with Mannitol/Lecithin Microparticles.

ABSTRACT: Quercetin (Que) is one of the most studied flavonoids with strong antioxidant properties ascribed to its ability to bind free radicals and inactivate them. However, the low solubility of the compound along with its inadequate absorption after oral administration limit its beneficial effects. Que's complexation with two different cyclodextrin (CD) derivatives (hydroxypropyl-β-CD and methyl-β-CD) via the neutralization/lyophilization method has been found to improve its physicochemical properties. Moreover, blends of the lyophilized powders with mannitol/lecithin microparticles (MLMPs) have been proposed as candidates for intranasal (IN) administration after in vitro and ex vivo evaluations. In this context, a comparative pharmacokinetic (PK) study of the IN vs oral administration of Que lyophilized powders and their blends with MLMPs (75:25 w/w) was performed on Wistar rats. The PK parameters estimated by a non-compartmental analysis using the sparse data methodology in Phoenix^® 8.3 (Certara, Princeton, NJ, USA) illustrated the effectiveness of IN administration either in brain targeting or in reaching the bloodstream. Significant levels of the compound were achieved at both sites, compared to those after oral delivery which were negligible. These results favor the potential application of the prepared Que nasal powders for systemic and nose-to-brain delivery for the prevention and/or treatment of neuroinflammatory degenerative conditions, such as Parkinson's and Alzheimer's disease.

SUBMITTER: Manta K

PROVIDER: S-EPMC10459069 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

Comparative Serum and Brain Pharmacokinetics of Quercetin after Oral and Nasal Administration to Rats as Lyophilized Complexes with β-Cyclodextrin Derivatives and Their Blends with Mannitol/Lecithin Microparticles.

Manta Konstantina K Papakyriakopoulou Paraskevi P Nikolidaki Anna A Balafas Evangelos E Kostomitsopoulos Nikolaos N Banella Sabrina S Colombo Gaia G Valsami Georgia G

Pharmaceutics 20230728 8

Quercetin (Que) is one of the most studied flavonoids with strong antioxidant properties ascribed to its ability to bind free radicals and inactivate them. However, the low solubility of the compound along with its inadequate absorption after oral administration limit its beneficial effects. Que's complexation with two different cyclodextrin (CD) derivatives (hydroxypropyl-β-CD and methyl-β-CD) via the neutralization/lyophilization method has been found to improve its physicochemical properties. ...[more]

PMID: 37631250

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Project description:Background and objectiveHepcidin, an endogenous peptide hormone, binds to ferroportin and is the master regulator of iron trafficking. Rusfertide, a synthetic peptide, is a potent hepcidin mimetic. Clinical studies suggest rusfertide may be effective in the treatment of polycythemia vera. This study investigated the dose-ranging pharmacokinetics, pharmacodynamics, and safety of a lyophilized formulation of rusfertide.MethodsA randomized open-label crossover study was conducted in two groups of healthy adult subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous rusfertide doses that ranged from 10 to 60 mg of a lyophilized formulation and 20 mg of an aqueous prefilled syringe formulation that were used in clinical trials.ResultsRusfertide showed a rapid initial absorption. Median time to peak plasma concentrations for the lyophilized formulation was 24 h for doses of 10-30 mg and 2-4 h for doses of 45 and 60 mg. Mean terminal half-life ranged from 19.6 to 57.1 h. Rusfertide peak concentration and area under the concentration-time curve increased with an increasing dose, but in a less than dose-proportional manner. Metabolites M4 and M9 were identified as major metabolites. At the rusfertide 20-mg dose, the lyophilized formulation had an area under the concentration-time curve from time zero to infinity approximately 1.5-fold higher than the aqueous formulation. The elimination half-life was comparable for the two formulations. Dose-related decreases in serum iron and transferrin-iron saturation were seen following rusfertide treatment. The majority of treatment-emergent adverse events were mild; treatment-related treatment-emergent adverse events seen in ≥10% of subjects were injection-site erythema and injection-site pruritus.ConclusionsRusfertide was well tolerated; the pharmacokinetic and pharmacodynamic results indicate that lyophilized rusfertide is suitable for once-weekly or twice-weekly administration.

Dataset Information

Comparative Serum and Brain Pharmacokinetics of Quercetin after Oral and Nasal Administration to Rats as Lyophilized Complexes with β-Cyclodextrin Derivatives and Their Blends with Mannitol/Lecithin Microparticles.

Publications

Comparative Serum and Brain Pharmacokinetics of Quercetin after Oral and Nasal Administration to Rats as Lyophilized Complexes with β-Cyclodextrin Derivatives and Their Blends with Mannitol/Lecithin Microparticles.

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