Improved Solubility of Quercetin by Preparing Amorphous Solid with Transglycosylated Rutin and Isoquercitrin

Uchiyama, Hiromasa; Wada, Yuhei; Takamatsu, Marina; Kadota, Kazunori; Tozuka, Yuichi

doi:10.2525/ecb.56.161

Cited by 6 publications

(5 citation statements)

References 19 publications

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“…However, all flavonoids have at least one O atom in the skeletal structure, indicating that CAGE could improve the solubility of flavonoids other than NOB. In particular, improvements in compounds that are poorly water-soluble and have poor oral BA, such as quercetin 45,46 (solubility in water: 0.0014 mg/mL, BA in men: 1%) and kaempferol 8 (solubility in water: 0.18 mg/mL, BA 2%) could be expected.…”

Section: Discussionmentioning

confidence: 99%

Transdermal delivery of nobiletin using ionic liquids

Hattori

Tagawa

Inai

et al. 2019

Sci Rep

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Nobiletin (NOB), a flavonoid, has extremely low water solubility and low oral bioavailability; however, despite these problems, various physiological effects have been investigated in vitro. In the present study, we investigated the transdermal delivery of NOB using choline and geranic acid (CAGE), which is a biocompatible material that has been reported to be a promising transdermal delivery approach. The feasibility was evaluated by a set of in vitro and in vivo tests. A solubility evaluation demonstrated that CAGE induced excellent solubility of NOB induced by multipoint hydrogen bonding between NOB and CAGE. In vitro transdermal tests using a Franz diffusion cell showed that CAGE was effective in enhancing transdermal absorption of NOB, compared to other penetration enhancers. Subsequent in vivo tests demonstrated that CAGE significantly improved area under the concentration-time curve of NOB in vivo and NOB/CAGE sample showed 20-times higher bioavailability than oral administration of NOB crystal. Furthermore, NOB/CAGE sample also showed significant drops of the blood glucose level in rats derived from hypoglycemic activity of NOB. Thus, transdermal administration of NOB using CAGE was shown to be feasible, which indicates that the use of CAGE may be adapted for other flavonoids that also show both low water solubility and low permeability.

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Section: Discussionmentioning

confidence: 99%

Transdermal delivery of nobiletin using ionic liquids

Hattori

Tagawa

Inai

et al. 2019

Sci Rep

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“…The O -glycosylation of resveratrol was reported to increase both its solubility in water and bioavailability while preventing oxidation [ 12 ]. The glycosylation of rutin has been extensively studied and is considered an efficient and available method to increase solubility [ 13 , 14 , 15 ]; however, information on the changes in its properties and efficacy is not fully understood. This study was conducted to investigate whether rutin and rutin glycoside with different solubilities may have different effects on antioxidant, anti-inflammation and antithrombotic activities (such as platelet aggregation and blood coagulation).…”

Section: Introductionmentioning

confidence: 99%

A Comparative Study of Rutin and Rutin Glycoside: Antioxidant Activity, Anti-Inflammatory Effect, Effect on Platelet Aggregation and Blood Coagulation

2021

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The effects of rutin and rutin glycoside with different solubility were compared on antioxidant activity and anti-inflammatory effects in vitro and the effects on platelet aggregation and blood coagulation in vitro and in vivo. Rutin glycoside (consisting of rutin mono-glucoside and rutin di-glucoside) was prepared via enzymatic transglycosylation from rutin. Rutin glycoside showed a higher effect than rutin on radical scavenging activity in antioxidant assays. Rutin showed a higher toxicity than rutin glycoside in murine macrophage RAW264.7 cells. They had similar effects on the levels of nitric oxide (NO), prostaglandin E (PGE) 2 and pro-inflammatory cytokines (such as tumor necrosis factor (TNF)-α, and interleukin (IL)-6) in the cells. Both rutin and rutin glycosides similarly reduced the rate of platelet aggregation compared to controls in vitro. They also similarly delayed prothrombin time (PT) and activated partial thromboplastin time (APTT) in an in vitro blood coagulation test. The effect of repeated administration of rutin and rutin glycoside was evaluated in vivo using SD rats. The platelet aggregation rate of rutin and the rutin glycoside administered group was significantly decreased compared to that of the control group. On the other hand, PT and APTT of rutin and rutin glycoside group were not significantly delayed in vivo blood coagulation test. In conclusion, rutin and rutin glycoside showed differences in antioxidant activities in vitro, while they were similar in the reduction of NO, PGE2, TNF-α and IL-6 in vitro. Rutin and rutin glycoside also showed similar platelet aggregation rates, and blood coagulation both in vitro and in vivo condition. Comparing in vitro and in vivo, rutin and rutin glycoside were effective on platelet aggregation both in vitro and in vivo, but only in vitro on blood coagulation.

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“…The products received after the previously described [ 20 ] lyophilization procedure (Que-Me-β-CD and Que-HP-β-CD) were two light, slightly yellow powders. They were further blended with the spray-dried mannitol/lecithin microparticles produced and characterized in previous work [ 35 ].…”

Section: Resultsmentioning

confidence: 99%

“…The complexation of Que with Me-β-CD and HP-β-CD has been found to increase the solubility of the flavonoid 6–50 times in a wide range of pHs, from 1.2 to 7.4 [ 30 , 31 , 32 ]. In particular, at less acidic conditions, i.e., pHs of 6.8 and 7.4, the solubilizing effect of HP-β-CD was superior to that of Me-β-CD, probably due to the formation of a second 1:2 (Que/CD) complex, according to the phase solubility study at a pH of 6.8 [ 20 ]. In the context of this PK study, the oral administration of pure Que was not performed due to the low solubility of the compound (0.004–0.016 mg/mL), which made intragastric delivery impossible to an aqueous solution at the required concentration.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the primary metabolites of Que in serum and the brain, i.e., glucurono-sulfo conjugates, also possess antioxidant and anti-inflammatory properties, as well as neuroprotective activity [ 15 , 16 , 17 , 18 ]. Several approaches for enhancing Que solubility have been reported in the literature, including the formation of inclusion complexes with cyclodextrin (CD) derivatives, as well as its formulation into amorphous solid or emulsion/nanoemulsion systems [ 19 , 20 , 21 , 22 ]. Hydrogels, cocrystals and amorphous solid dispersions have been also evaluated for improving Que systemic bioavailability using rodent animal models [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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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

Manta,

Papakyriakopoulou,

Nikolidaki

et al. 2023

Pharmaceutics

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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.

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Improved Solubility of Quercetin by Preparing Amorphous Solid with Transglycosylated Rutin and Isoquercitrin

Cited by 6 publications

References 19 publications

Transdermal delivery of nobiletin using ionic liquids

Transdermal delivery of nobiletin using ionic liquids

A Comparative Study of Rutin and Rutin Glycoside: Antioxidant Activity, Anti-Inflammatory Effect, Effect on Platelet Aggregation and Blood Coagulation

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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