WO2009045735A2 - Method for stabilizing quercetin - Google Patents

Method for stabilizing quercetin Download PDF

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Publication number
WO2009045735A2
WO2009045735A2 PCT/US2008/076795 US2008076795W WO2009045735A2 WO 2009045735 A2 WO2009045735 A2 WO 2009045735A2 US 2008076795 W US2008076795 W US 2008076795W WO 2009045735 A2 WO2009045735 A2 WO 2009045735A2
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WO
WIPO (PCT)
Prior art keywords
quercetin
vitamin
mixture
weight ratio
solution
Prior art date
Application number
PCT/US2008/076795
Other languages
French (fr)
Other versions
WO2009045735A3 (en
Inventor
Thomas Christian Lines
Original Assignee
Quercegen Pharma Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Quercegen Pharma Llc filed Critical Quercegen Pharma Llc
Priority to EP08835871A priority Critical patent/EP2200605A4/en
Priority to CA2700867A priority patent/CA2700867C/en
Priority to RU2010117350/15A priority patent/RU2476217C2/en
Publication of WO2009045735A2 publication Critical patent/WO2009045735A2/en
Publication of WO2009045735A3 publication Critical patent/WO2009045735A3/en
Priority to ZA2010/02110A priority patent/ZA201002110B/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • antioxidants such as quercetin
  • certain natural antioxidants inhibit both acute and chronic phases of free-radical induced diseases.
  • some natural antioxidants exhibit synergy in their reactions with biologically relevant oxygen species, e.g., hydroxyl radicals, superoxides, oxysulfurs, sulfur dioxide, and nitrogen dioxide.
  • quercetin is unstable when placed in an aqueous solution. It is therefore desirable to develop a method to increase quercetin stability.
  • the present invention is based on the unexpected finding that quercetin is much more stable in a solution also containing vitamins B3 and C than in a solution containing only quercetin.
  • this invention features a method for stabilizing quercetin by placing it in a solution (e.g., an aqueous solution) containing vitamin B3 and vitamin C to form a mixture and then assessing the stability of the quercetin in the mixture after an extended period of time (e.g., two weeks, two month, or one year).
  • a solution e.g., an aqueous solution
  • quercetin, vitamin B3, and vitamin C preferably have a weight ratio of 1 : 0.02-1 : 0.2-2.5 (e.g., 1 : 0.08 : 1).
  • the concentration of quercetin can range from 20 mg/L to 10 g/L (e.g., 500 mg/L to 2 g/L).
  • FIG. 1 is a chart showing stability of quercetin in two aqueous solutions containing quercetin alone (QP2-Q), and quercetin, vitamin B3, and vitamin C (QPl- QB3C), respectively, and an acidic solution containing quercetin alone (QP3-Q).
  • the weight ratio between quercetin, vitamin B3, and vitamin C in the mixture can be 1 : 0.02-1 : 0.2-2.5, or any ratio in between.
  • the weight ratio can be 1 : 0.04-0.5 : 0.3-2.0, 1 : 0.05-0.3 : 0.4-1.5, 1 : 0.05-0.2 : 0.5-1, and 1 : 0.1-0.2 : 0.5-1.
  • Preferred ratios include 1 : 0.02 : 1, 1 : 0.04 : 1, 1 : 0.08 : 1, 1: 0.05: 1.5, and 1: 0.16: 1.
  • quercetin refers to both quercetin aglycon and quercetin derivatives, e.g., quercetin-3-O-glucoside, quercetin-5-O-glucoside, quercetin-7-O- glucoside, quercetin-9-O-glucoside, quercetin-3-O-rutinoside, quercetin-3-O-[ ⁇ - rhamnosyl-(l ⁇ 2)- ⁇ -rhamnosyl-(l ⁇ 6)]- ⁇ -glucoside, quercetin-3-O-galactoside, quercetin-7-O-galactoside, quercetin-3-O-rhamnoside, and quercetin-7-O-galactoside.
  • quercetin derivatives After digestion, quercetin derivatives are converted to quercetin aglycon and other active derivatives, which are absorbed in the body.
  • the quantity of quercetin mentioned above refers to that of quercetin aglycon or the quercetin moiety of a quercetin derivative.
  • Quercetin can be added to the composition either in a pure form or as an ingredient in a mixture (e.g., a plant extract). Examples of commercially available quercetin include QU995 (containing 99.5% quercetin) and QU985 (containing 98.5% quercetin) from Quercegen Pharma LLC (Newton, MA) and Merck KGaA (Brazil).
  • vitamin B3 includes vitamin B3 in its various forms, including niacinamide, nicotinic acid, nicotinamide, inositol hexaniacinate.
  • vitamin C i.e., L-ascorbic acid, D-ascorbic acid, or both
  • salts e.g., sodium ascorbate
  • the vitamin B3/vitamin C solution can be prepared by dissolving vitamin B3 and vitamin C in a suitable solvent, such as a pure solvent (e.g., water) or a mixture of two or more solvents. One or more quercetins are then dissolved or suspended in the vitamin B3/vitamin C solution to form a mixture.
  • the mixture can be stored at a suitable temperature (e.g., 20 or 25 0 C) for an extended period of time (e.g., two weeks or two month). During the storage, the quercetin content in the mixture is determined periodically (e.g., every 24 hours or every week) via conventional methods, e.g., HPLC, to assess quercetin stability.
  • a suitable solvent such as a pure solvent (e.g., water) or a mixture of two or more solvents.
  • One or more quercetins are then dissolved or suspended in the vitamin B3/vitamin C solution to form a mixture.
  • the mixture can be stored at a suitable temperature (e.g.
  • quercetin contents in QP1-QB3C remained unchanged during the 12-day incubation period.
  • the quercetin contents in QP2-Q and QP3-Q decreased by about 15% and 10% respectively during the 12-day incubation.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Saccharide Compounds (AREA)

Abstract

This invention relates to a method for stabilizing quercetin by placing it in a solution containing vitamin B3 and vitamin C and assessing stability of the quercetin in the mixture.

Description

Method for Stabilizing Quercetin
BACKGROUND
It is known that certain natural antioxidants, such as quercetin, inhibit both acute and chronic phases of free-radical induced diseases. Further, some natural antioxidants exhibit synergy in their reactions with biologically relevant oxygen species, e.g., hydroxyl radicals, superoxides, oxysulfurs, sulfur dioxide, and nitrogen dioxide.
However, quercetin is unstable when placed in an aqueous solution. It is therefore desirable to develop a method to increase quercetin stability.
SUMMARY The present invention is based on the unexpected finding that quercetin is much more stable in a solution also containing vitamins B3 and C than in a solution containing only quercetin.
Accordingly, this invention features a method for stabilizing quercetin by placing it in a solution (e.g., an aqueous solution) containing vitamin B3 and vitamin C to form a mixture and then assessing the stability of the quercetin in the mixture after an extended period of time (e.g., two weeks, two month, or one year). In the mixture, which can be in suspended form, quercetin, vitamin B3, and vitamin C preferably have a weight ratio of 1 : 0.02-1 : 0.2-2.5 (e.g., 1 : 0.08 : 1). The concentration of quercetin can range from 20 mg/L to 10 g/L (e.g., 500 mg/L to 2 g/L).
The details of one or more embodiments of the invention are set forth in the description below. Other features or advantages of the present invention will be apparent from the following drawing and detailed description of several embodiments, and also from the appending claims.
DESCRIPTION OF THE DRAWING
FIG. 1 is a chart showing stability of quercetin in two aqueous solutions containing quercetin alone (QP2-Q), and quercetin, vitamin B3, and vitamin C (QPl- QB3C), respectively, and an acidic solution containing quercetin alone (QP3-Q). DETAILED DESCRIPTION
One can stabilize quercetin by either dissolving or suspending it in a solution containing vitamin B3 and vitamin C to form a mixture.
The weight ratio between quercetin, vitamin B3, and vitamin C in the mixture can be 1 : 0.02-1 : 0.2-2.5, or any ratio in between. For example, the weight ratio can be 1 : 0.04-0.5 : 0.3-2.0, 1 : 0.05-0.3 : 0.4-1.5, 1 : 0.05-0.2 : 0.5-1, and 1 : 0.1-0.2 : 0.5-1. Preferred ratios include 1 : 0.02 : 1, 1 : 0.04 : 1, 1 : 0.08 : 1, 1: 0.05: 1.5, and 1: 0.16: 1. The term "quercetin" refers to both quercetin aglycon and quercetin derivatives, e.g., quercetin-3-O-glucoside, quercetin-5-O-glucoside, quercetin-7-O- glucoside, quercetin-9-O-glucoside, quercetin-3-O-rutinoside, quercetin-3-O-[α- rhamnosyl-(l→2)-α-rhamnosyl-(l→6)]-β-glucoside, quercetin-3-O-galactoside, quercetin-7-O-galactoside, quercetin-3-O-rhamnoside, and quercetin-7-O-galactoside. After digestion, quercetin derivatives are converted to quercetin aglycon and other active derivatives, which are absorbed in the body. The quantity of quercetin mentioned above refers to that of quercetin aglycon or the quercetin moiety of a quercetin derivative. Quercetin can be added to the composition either in a pure form or as an ingredient in a mixture (e.g., a plant extract). Examples of commercially available quercetin include QU995 (containing 99.5% quercetin) and QU985 (containing 98.5% quercetin) from Quercegen Pharma LLC (Newton, MA) and Merck KGaA (Brazil). "Vitamin B3" mentioned herein includes vitamin B3 in its various forms, including niacinamide, nicotinic acid, nicotinamide, inositol hexaniacinate. "Vitamin C" mentioned herein includes vitamin C (i.e., L-ascorbic acid, D-ascorbic acid, or both) and its salts (e.g., sodium ascorbate).
The vitamin B3/vitamin C solution can be prepared by dissolving vitamin B3 and vitamin C in a suitable solvent, such as a pure solvent (e.g., water) or a mixture of two or more solvents. One or more quercetins are then dissolved or suspended in the vitamin B3/vitamin C solution to form a mixture. The mixture can be stored at a suitable temperature (e.g., 20 or 25 0C) for an extended period of time (e.g., two weeks or two month). During the storage, the quercetin content in the mixture is determined periodically (e.g., every 24 hours or every week) via conventional methods, e.g., HPLC, to assess quercetin stability. Without further elaboration, it is believed that the above description has adequately enabled the present invention. The following example is, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
Stability of Quercetin and Quercetin/Vitamine B3/Vitamine C in Aqueous Solutions An aqueous solution containing 0.1% (w/v) quercetin (coded "QP2-Q") was prepared, kept in 12 sealed 60-ml glass bottles, i.e., bottles 1-12, and incubated at 75 0C. More specifically, 50 ml of the solution were placed in each glass bottle. Quercetin contents in bottles 1-12 were determined by HPLC on day 1 to day 12, respectively. They were compared with the quercetin content on day 0 to obtain "%
Recovery Relative to Control," shown in FlG 1. as follows:
% Recovery Relative to Control = (Quercetin content on day X) /(Quercetin content on
day O)
The same analysis as described above was applied to an aqueous solution containing quercetin, vitamin B3, and vitamin C at a ratio of 1:0.08:1 by weight (coded "QP1-QB3C") and to an acidic solution (pH 2.6) containing 0.1% (w/v) quercetin (coded "QP3-Q"). Based on the results thus obtained, stability curves were prepared. Also see FIG. 1.
The quercetin contents in QP1-QB3C remained unchanged during the 12-day incubation period. By contrast, the quercetin contents in QP2-Q and QP3-Q decreased by about 15% and 10% respectively during the 12-day incubation. These results indicate that quercetin was stabilized by the presence of vitamin B3 and vitamin C in the solution.
OTHER EMBODIMENTS
All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.
From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A method for stabilizing quercetin, comprising placing quercetin in a solution containing vitamin B3 and vitamin C to form a mixture and assessing stability of the quercetin in the mixture.
2. The method of claim 1, wherein a weight ratio between quercetin, vitamin B3, and vitamin C is 1: 0.02-1: 0.2-2.5.
3. The method of claim 2, wherein the weight ratio is 1: 0.05-0.2: 0.5-1.
4. The method of claim 2, wherein the weight ratio is 1: 0.1-0.2: 0.5-1.
5. The method of claim 2, wherein the weight ratio is 1: 0.04: 1.
6. The method of claim 2, wherein the weight ratio is 1: 0.08: 1.
7. The method of claim 1, wherein the mixture is in suspended form.
8. The method of claim 1, wherein quercetin has a concentration in the mixture from 20 mg/L to 10 g/L.
9. The method of claim 8, wherein the concentration is 500 mg/L to 2 g/L.
10. The method of claim 1, wherein the solution is an aqueous solution.
11. The method of claim 10, wherein a weight ratio between quercetin, vitamin B3, and vitamin C is 1: 0.02-1: 0.2-2.5.
12. The method of claim 11, wherein the weight ratio is 1: 0.05-0.2: 0.5-1.
13. The method of claim 11, wherein the weight ratio is 1: 0.1-0.2: 0.5-1.
14. The method of claim 11, wherein the weight ratio is 1: 0.04: 1.
15. The method of claim 11, wherein the weight ratio is 1: 0.08: 1.
16. The method of claim 10, wherein the mixture is in suspended form.
17. The method of claim 10, wherein quercetin has a concentration in the mixture from 20 mg/L to 10 g/L.
18. The method of claim 8, wherein the concentration is 500 mg/L to 2 g/L.
PCT/US2008/076795 2007-10-01 2008-09-18 Method for stabilizing quercetin WO2009045735A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP08835871A EP2200605A4 (en) 2007-10-01 2008-09-18 Method for stabilizing quercetin
CA2700867A CA2700867C (en) 2007-10-01 2008-09-18 Use of vitamin b3 and vitamin c to stabilize quercetin in an aqueous solution
RU2010117350/15A RU2476217C2 (en) 2007-10-01 2008-09-18 Method of quercetin stabilisation
ZA2010/02110A ZA201002110B (en) 2007-10-01 2010-03-25 Method for stabilizing quercetin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US97671907P 2007-10-01 2007-10-01
US60/976,719 2007-10-01

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WO2009045735A2 true WO2009045735A2 (en) 2009-04-09
WO2009045735A3 WO2009045735A3 (en) 2009-05-28

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EP (1) EP2200605A4 (en)
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ZA (1) ZA201002110B (en)

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CN102766180B (en) * 2012-06-01 2015-12-02 贵州师范大学 The purposes of the method for purification and products thereof of two active monomer compound in saxifrage

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Also Published As

Publication number Publication date
CA2700867C (en) 2016-05-31
US8202900B2 (en) 2012-06-19
ZA201002110B (en) 2010-11-24
CA2700867A1 (en) 2009-04-09
RU2476217C2 (en) 2013-02-27
US20090088580A1 (en) 2009-04-02
EP2200605A2 (en) 2010-06-30
EP2200605A4 (en) 2011-03-23
WO2009045735A3 (en) 2009-05-28
RU2010117350A (en) 2011-11-10

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