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US-20260124220-A1 - COMPOSITIONS AND METHODS RELATED TO ISOMERS OF CURCUMIN

US20260124220A1US 20260124220 A1US20260124220 A1US 20260124220A1US-20260124220-A1

Abstract

Various aspects of this disclosure relate to compositions comprising anions produced from curcumin, containers containing compositions comprising anions produced from curcumin, and methods of using compositions comprising anions produced from curcumin. Without limiting this disclosure or any patent claim that matures from this disclosure, anions produced from curcumin display improved bioavailability relative to molecular curcumin.

Inventors

  • C. Russell Thomas
  • Douglas G. Metcalf

Assignees

  • Natural Extraction Systems, LLC

Dates

Publication Date
20260507
Application Date
20260102

Claims (20)

  1. 1 . A composition, comprising: an anion, wherein the anion has the chemical formula C 21 H 19 O 6 1- ; the anion has the chemical structure set forth in Compound XXX; Compound XXX contains exactly 10 double bonds; R1 is hydroxy, oxide, or oxo; R2 is hydroxy, oxide, or oxo; R3 is hydroxy or oxide; and the 3 dotted lines in Compound XXX depict 0, 1, or 2 double bonds; a cation at a concentration of at least 10 nanomolar and no greater than 1 molar, wherein the cation is a metal cation or an ammonium cation; and a protic polar solvent at a concentration of at least 5 molar and no greater than 55.5 molar, wherein the anion and the cation are solutes that are dissolved in the protic polar solvent.
  2. 2 . The composition of claim 1 , wherein the anion is either: 2-methozxy-4-[3-hydroxy-5-oxo-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3-dienyl]phenolate; 2-methoxy-4-[5-hydroxy-3-oxo-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,4-dienyl]phenolate; 2-methoxy-4-[5-hydroxy-3-oxo-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,5-dienyl]phenolate; 2-methoxy-4-[3,5-dioxo-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hept-1-en-1-yl]phenolate; 2-methoxy-4-[3,5-dihydroxy-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3,5-trienyl]phenolate; 5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3,5-triene-3-oxide; 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3,5-triene-5-oxide; 5-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3-diene-3-oxide; 3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,4-diene-5-oxide; 3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,5-diene-5-oxide; 3-hydroxy-5-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3-dien-6-ide; 5-hydroxy-3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,4-dien-6-ide; 5-hydroxy-3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,5-dien-4-ide; 3,5-dioxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hept-1-en-4-ide; or 3,5-dioxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hept-1-en-6-ide.
  3. 3 . The composition of claim 1 , wherein either: the anion is 2-methoxy-4-[3-hydroxy-5-oxo-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3-dienyl]phenolate, and the composition further comprises 3-hydroxy-5-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3-diene; the anion is 2-methoxy-4-[5-hydroxy-3-oxo-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,4-dienyl]phenolate, and the composition further comprises 5-hydroxy-3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,4-diene; the anion is 2-methoxy-4-[5-hydroxy-3-oxo-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,5-dienyl]phenolate, and the composition further comprises 5-hydroxy-3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,5-diene; the anion is 2-methoxy-4-[3,5-dioxo-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hept-1-en-1-yl]phenolate, and the composition further comprises 3,5-dioxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hept-1-ene; the anion is 2-methoxy-4-[3,5-dihydroxy-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3,5-trienyl]phenolate, and the composition further comprises 3,5-dihydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3,5-triene; the anion is 5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3,5-triene-3-oxide, and the composition further comprises 3,5-dihydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3,5-triene; the anion is 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3,5-triene-5-oxide, and the composition further comprises 3,5-dihydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3,5-triene; the anion is 5-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3-diene-3-oxide, and the composition further comprises 3-hydroxy-5-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3-diene; the anion is 3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,4-diene-5-oxide, and the composition further comprises 5-hydroxy-3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,4-diene; the anion is 3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,5-diene-5-oxide, and the composition further comprises 5-hydroxy-3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,5-diene; the anion is 3-hydroxy-5-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3-dien-6-ide, and the composition further comprises 3-hydroxy-5-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,3-diene; the anion is 5-hydroxy-3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,4-dien-6-ide, and the composition further comprises 5-hydroxy-3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,4-diene; the anion is 5-hydroxy-3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,5-dien-4-ide, and the composition further comprises 5-hydroxy-3-oxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hepta-1,5-diene; the anion is 3,5-dioxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hept-1-en-4-ide, and the composition further comprises 3,5-dioxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hept-1-ene; or the anion is 3,5-dioxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hept-1-en-6-ide, and the composition further comprises 3,5-dioxo-1-(4-hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-oxocyclohexa-2,5-dienylidene)hept-1-ene.
  4. 4 . A composition, comprising: an anion, wherein the anion has the chemical structure set forth in either Compound III, which depicts 2-methoxy-4-[3-hydroxy-5-oxo-7-(4-hydroxy-3-methoxyphenyl)hepta-1,3,6-trienyl]phenolate, or Compound IV, which depicts 2-methoxy-4-[5-hydroxy-3-oxo-7-(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trienyl]phenolate; a cation at a concentration of at least 10 nanomolar and no greater than 1 molar, wherein the cation is a metal cation or an ammonium cation; and a protic polar solvent at a concentration of at least 5 molar and no greater than 55.5 molar, wherein the anion and the cation are solutes that are dissolved in the protic polar solvent.
  5. 5 . A composition, comprising: an anion, wherein the anion has the chemical structure set forth in Compound V, which depicts 2-methoxy-4-[3,5-dioxo-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-dienyl]phenolate; a cation at a concentration of at least 10 nanomolar and no greater than 1 molar, wherein the cation is a metal cation or an ammonium cation; and a protic polar solvent at a concentration of at least 5 molar and no greater than 55.5 molar, wherein the anion and the cation are solutes that are dissolved in the protic polar solvent.
  6. 6 . A container that contains a composition according to claim 4 .
  7. 7 . A method to change the color of a liquid, comprising: providing the composition of claim 4 , wherein the composition has an initial color; and contacting the composition with a Brønsted acid such that the initial color changes to a final color.
  8. 8 . A method to administer the composition of claim 4 , comprising: providing the composition; and consuming a portion of the composition, wherein a human consumes the portion of the composition by either swallowing or otherwise orally administering it.
  9. 9 . The composition of claim 4 , comprising a molecule, wherein: the composition comprises the anion at a concentration of at least 1 micromolar and no greater than 1 molar; the anion has a conjugate acid; the molecule is the conjugate acid of the anion; the solutes comprise the molecule; the molecule is dissolved in the protic polar solvent at a concentration of at least 10 nanomolar and no greater than 100 millimolar; and the composition comprises the molecule and the anion at a molar ratio of at least 1:100,000 and no greater than 10:1.
  10. 10 . The composition of claim 4 , comprising a Brønsted base, wherein: the protic polar solvent has a conjugate base; the Brønsted base is the conjugate base of the protic polar solvent; the solutes comprise the Brønsted base; the Brønsted base is dissolved in the protic polar solvent at a concentration of at least 1 nanomolar and no greater than 5 molar; and the molar concentration of the solvent in the composition is at least 10 times greater than the molar concentration of the Brønsted base that is dissolved in the protic polar solvent.
  11. 11 . The composition of claim 4 , comprising a Brønsted base, wherein: the protic polar solvent has a conjugate base; the Brønsted base is the conjugate base of the protic polar solvent; the solutes comprise the Brønsted base; the Brønsted base is dissolved in the protic polar solvent at a concentration of at least 1 nanomolar and no greater than 5 molar; the molar concentration of the solvent in the composition is at least 10 times greater than the molar concentration of the Brønsted base that is dissolved in the protic polar solvent; and the Brønsted base is selected from hydroxide; ethoxide; 1-hydroxy-propane-2-oxide; 2-hydroxy-propane-1-oxide; 3-hydroxy-propane-1-oxide; 1,3-dihydroxy-propane-2-oxide; and 2,3-dihydroxy-propane-1-oxide.
  12. 12 . The composition of claim 4 , comprising a cosolvent and a second cosolvent, wherein: the protic polar solvent, the cosolvent, and the second cosolvent are different chemical species; the composition comprises the solvent at greater concentration by mass than the cosolvent; the composition comprises the cosolvent at greater concentration by mass than the second cosolvent; the solvent is selected from propane-1,2-diol, propane-1,3-diol, and propane-1,2,3-triol; the cosolvent is ethanol; and the second cosolvent is water.
  13. 13 . The composition of claim 4 , comprising a cosolvent and a second cosolvent, wherein: the protic polar solvent, the cosolvent, and the second cosolvent are different chemical species; the composition comprises the solvent at greater concentration by mass than the cosolvent; the composition comprises the cosolvent at greater concentration by mass than the second cosolvent; the solvent is water; the cosolvent is selected from propane-1,2-diol, propane-1,3-diol, and propane-1,2,3-triol; and the second cosolvent is ethanol.
  14. 14 . The composition of claim 4 , comprising a cosolvent and a second cosolvent, wherein: the protic polar solvent, the cosolvent, and the second cosolvent are different chemical species; the composition comprises the solvent at greater concentration by mass than the cosolvent; the composition comprises the cosolvent at greater concentration by mass than the second cosolvent; the solvent is water; the cosolvent is ethanol; and the second cosolvent selected from either propane-1,2-diol, propane-1,3-diol, and propane-1,2,3-triol.
  15. 15 . The composition of claim 4 , comprising a cosolvent and a second cosolvent, wherein: the protic polar solvent, the cosolvent, and the second cosolvent are different chemical species; the composition comprises the solvent at greater concentration by mass than the cosolvent; the composition comprises the cosolvent at greater concentration by mass than the second cosolvent; the solvent is ethanol; the cosolvent is water; and the second cosolvent is selected from propane-1,2-diol, propane-1,3-diol, and propane-1,2,3-triol.
  16. 16 . The composition of claim 4 , comprising a cosolvent, wherein: the protic polar solvent and the cosolvent are different chemical species; the composition comprises the solvent at greater concentration by mass than the cosolvent; the solvent is water or ethanol; and the cosolvent is selected from propane-1,2-diol, propane-1,3-diol, and propane-1,2,3-triol.
  17. 17 . The composition of claim 4 , comprising a cosolvent, wherein: the protic polar solvent and the cosolvent are different chemical species; the composition comprises the solvent at greater concentration by mass than the cosolvent; the solvent is selected from propane-1,2-diol, propane-1,3-diol, and propane-1,2,3-triol; and the cosolvent is either water or ethanol.
  18. 18 . The composition of claim 4 , wherein the cation is selected from ammonium (“NH4+”); protonated ethanolamine; choline; protonated sphingosine; protonated lysine; and protonated arginine.
  19. 19 . The composition of claim 4 , wherein the cation is selected from sodium cation (“Na+”); potassium cation (“K+”); magnesium cation (“Mg++”); calcium cation (“Ca++”); zinc cation (“Zn++”); manganese cation (“Mn++”); iron (II) cation (“Fe++”); iron (III) cation (“Fe+++”); copper (I) cation (“Cu+”); and copper (II) cation (“Cu++”).
  20. 20 . The composition of claim 4 , comprising propylene glycol or glycerol.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Division of U.S. patent application Ser. No. 17/751,409, which granted as U.S. Pat. No. 12,514,864, and claims priority to U.S. Provisional Patent Application No. 63/191,818, filed May 21, 2021, U.S. Provisional Patent Application No. 63/191,836, filed May 21, 2021, U.S. Provisional Patent Application No. 63/191,849, filed May 21, 2021, U.S. Provisional Patent Application No. 63/191,880, filed May 21, 2021, U.S. Provisional Patent Application No. 63/194,815, filed May 28, 2021, and U.S. Provisional Patent Application No. 63/254,437, filed Oct. 11, 2021, each of which is incorporated by reference in its entirety. BACKGROUND Curcumin is the major bioactive molecule of turmeric, which is an ingredient and dietary supplement. Curcumin is known to be effective at treating cancer and inflammation. Numerous attempts to develop curcumin pharmaceuticals nevertheless failed in part because curcumin has limited solubility and limited bioavailability and because curcumin is thought to have limited chemical stability. Curcumin formulations with improved solubility, bioavailability, and stability are desirable. SUMMARY Various aspects of this disclosure relate to anionic forms of structural isomers of curcumin. Without limiting this disclosure or any patent claim that matures from this document, anionic forms of curcumin and its structural isomers display improved solubility in water relative to molecular forms because anionic forms carry negative charges, which favors hydrogen bonding to water; because charge-charge repulsion maximizes surface area in liquid formulations, which generally improves bioavailability and pharmacokinetics; because the administration of anionic forms of curcumin and its structural isomers to subjects converts the anionic forms to molecular forms, which partition out of liquid formulations and into the epithelial lining of a subject for rapid absorption, which improves bioavailability and pharmacokinetics; and because the molecular forms avoid first-pass metabolism, for example, when the molecular forms partition into the epithelial lining of the mouth or esophagus, which improves bioavailability and pharmacokinetics. Without limiting this disclosure or any patent claim that matures from this document, those skilled in the relevant arts generally believed that liquid formulations comprising curcumin generally, and the anionic forms of curcumin specifically, lacked sufficient stability to be pharmaceutically relevant; the perceived instability of curcumin generally, and the anionic forms of curcumin specifically, arose in part from the conversion of curcumin into one or more structural isomers of curcumin, which decreases measured curcumin concentrations in curcumin formulations. This patent document discloses anionic forms of structural isomers of curcumin that can be manufactured from curcumin using acid-base chemistry. The anionic forms of structural isomers of curcumin display improved solubility, bioavailability, and pharmacokinetics relative to known curcumin formulations, and they are expected to display comparable or improved efficacy at treating the health conditions that curcumin is known to treat. Various aspects of this disclosure relate to structural isomers of curcumin and their conjugate bases. Curcuma longa (turmeric) biosynthetically produces curcumin, which is a tautomer that exists as the enol structure of Compound I and the keto structure of Compound II. The molecule of Compound I can be deprotonated to produce the anions of Compounds III and IV. The molecule of Compound II can be deprotonated to produce the anion of Compound V. The anion of Compound III has the resonance structures of Compounds VI, VII, and VIII. The anion of Compound VI can be reprotonated to produce the molecule of Compound IX. The anion of Compound VII can be reprotonated to produce the molecule of Compound X. The anion of Compound VIII can be reprotonated to produce the molecule of Compound XI. The anion of Compound IV has the resonance structure of Compound XII. The anion of Compound XII can be reprotonated to produce the molecule of Compound XIII. The anion of Compound V has the resonance structure of Compound XIV. The anion of Compound XIV can be reprotonated to produce the molecule of Compound XV. The molecule of Compound IX can be deprotonated to produce the anion of Compound XVI. The anion of Compound XVI has the resonance structures of Compounds XVII and XVIII. The anion of Compound XVII can be reprotonated to produce the molecule of Compound XIX. The anion of Compound XVIII can be reprotonated to produce the molecule of Compound XX. The molecule of Compound X can be deprotonated to produce the anion of Compound XXI. The anion of Compound XXI has the resonance structures of Compounds XXII and XXIII. The anion of Compound XXII can be reprotonated to produce the molecule of Compound XXIV. The anion of Compound XXIII can be reprotonated to