Stabilized sulforaphane

• US 7,879,822 B2
• Filed: 01/23/2008
• Issued: 02/01/2011
• Est. Priority Date: 01/23/2007
• Status: Active Grant

• Current Assignee: PharmAgra Labs, Inc.
• Original Assignee: PharmAgra Labs, Inc.
• Inventors: Dagan, Ido Dov, Newsome, Peter Wyatt, Baudet, Michel Pierre, Frisbee, Albert Roger
• Primary Examiner(s): Maier; Leigh C
• Application Number:
  US12/009,874
• Publication Number:
  US 20080176942A1
• Time in Patent Office: 1,105 Days
• Field of Search: None
• US Class Current: 514/58
• CPC Class Codes: A61K 31/26 Cyanate or isocyanate esters; Thiocyanate or isothiocyanate esters
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/42 the bicyclo ring system containing seven carbon atoms
• CPC Class Codes: C07C 331/20 of a saturated carbon skeleton
• CPC Class Codes: C07C 331/26 having isothiocyanate groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07F 9/025 Purification; Separation; Stabilisation; Desodorisation of organo-phosphorus compounds of natural phosphatides C07F9/103; phosphines C07F9/5095
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C08B 37/0015 Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
• CPC Class Codes: C08L 5/16 Cyclodextrin; Derivatives thereof

Abstract

A method of stabilizing sulforaphane is provided. The method includes contacting sulforaphane, or an analog thereof, and a cyclodextrin to form a complex between the sulforaphane, or analog thereof, and the cyclodextrin.

Claims

1. A method of stabilizing sulforaphane, or an analog thereof, the method comprising:

contacting sulforaphane or an analog of sulforaphane selected from one or more of 6 isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1′

-hydroxyethyl)-5-isothiocyanatonorborane, exo-2-acetyl-5-isothiocyanoatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, and cis- or trans-3-(methylsulfonyl)-cyclohexylmethyl-isothiocyanate, and mixtures thereof, and at least one cyclodextrin to form a complex between the sulforaphane, or analog of sulforaphane, and the at least one cyclodextrin.

2. A method according to claim 1, wherein the at least one cyclodextrin is selected from the group consisting of W6 (alpha) cyclodextrin, W7 (beta) cyclodextrin, W8 (gamma) cyclodextrin, and mixtures thereof.

3. A method according to claim 1, wherein the step of contacting sulforaphane, or an analog thereof, and at least one cyclodextrin comprises:

dissolving or suspending the at least one cyclodextrin in a solvent or mixture of solvents to form a solution or suspension; and

dissolving or suspending the sulforaphane, or an analog thereof, in the solution or suspension.

4. A method according to claim 3, wherein the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec-butanol, iso-butanol, tert-butanol, high molecular weight alcohols, dimethyl formamide, diethyl formamide, ethylene glycol, triethyleneglyclol, glycerin, polyethyleneglycol, formic acid, acetic acid, formamide, acetone, tetrahydrofuran, dioxane, methyl ethyl ketone, high molecular weight ketones, ethyl acetate, acetonitrile, N,N-dimethylacetimide, dimethyl sulfoxide, carbon disulfide, hexane, hexane isomers, cyclohexane, heptane, heptane isomers, C₈-C₁₆ solvents, mineral oil, diethyl ether, methyl tert-butyl ether, methylene chloride, chloroform, carbon tetrachloride, benzene, nitrobenzene, toluene, and mixtures thereof.

5. A method according to claim 3, further comprising the step of separating the complex from the solution or suspension.

6. A method according to claim 5, wherein the step of separating the complex from the solution or suspension comprises isolation of the solid from the suspension or precipitation of the complex from the solution followed by isolation of the resulting solid.

7. A method according to claim 5, wherein the step of separating the complex from the solution or suspension comprises evaporation, or partial evaporation, of the solvent or solvents, followed by isolation of the resulting solid.

8. A method according to claim 5, wherein the step of separating the complex from the solution or suspension comprises saturating the solvent or solvents with cyclodextrin to decrease the solubility of the complex in the solvent or solvents.

9. A method according to claim 1, wherein the step of contacting sulforaphane, or an analog thereof, and at least one cyclodextrin comprises:

dissolving or suspending the sulforaphane, or an analog thereof, in a solvent or mixture of solvents to form a solution or suspension; and

dissolving or suspending the at least one cyclodextrin in the solution or suspension.

10. A method according to claim 9, wherein the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec-butanol, iso-butanol, tert-butanol, high molecular weight alcohols, dimethyl formamide, diethyl formamide, ethylene glycol, triethyleneglyclol, glycerin, polyethyleneglycol, formic acid, acetic acid, formamide, acetone, tetrahydrofuran, dioxane, methyl ethyl ketone, high molecular weight ketones, ethyl acetate, acetonitrile, N,N-dimethylacetimide, dimethyl sulfoxide, carbon disulfide, hexane, hexane isomers, cyclohexane, heptane, heptane isomers, C₈-C₁₆ solvents, mineral oil, diethyl ether, methyl tert-butyl ether, methylene chloride, chloroform, carbon tetrachloride, benzene, nitrobenzene, toluene, and mixtures thereof.

11. A method according to claim 9, further comprising the step of separating the complex from the solution or suspension.

12. A method according to claim 11, wherein the step of separating the complex from the solution or suspension comprises isolation of the solid from the suspension or precipitation of the complex from the solution followed by isolation of the resulting solid.

13. A method according to claim 11, wherein the step of separating the complex from the solution or suspension comprises evaporation, or partial evaporation, of the solvent or solvents, followed by isolation of the resulting solid.

14. A method according to claim 11, wherein the step of separating the complex from the solution or suspension comprises saturating the solvent or solvents with cyclodextrin to decrease the solubility of the complex in the solvent or solvents.

15. A method according to claim 1, wherein the step of forming a complex between sulforaphane, or an analog thereof, and a cyclodextrin is conducted at room temperature.

16. A method according to claim 1, wherein the step of forming a complex between sulforaphane, or an analog thereof, and a cyclodextrin is conducted at a temperature above room temperature.

17. A method according to claim 1, wherein the step of forming a complex between sulforaphane, or an analog thereof, and a cyclodextrin is conducted at a temperature below room temperature.

18. A method according to claim 1, wherein the step of contacting sulforaphane, or an analog thereof, with at least one cyclodextrin to form a complex with cyclodextrin comprises contacting sufficient amounts of sulforaphane and a cyclodextrin to give a weight load of between about 0.01% wt/wt and about 30% wt/wt sulforaphane to cyclodextrin in the complex.

19. A method according to claim 1, wherein the step of contacting sulforaphane, or an analog thereof, and at least one cyclodextrin comprises:

dissolving or suspending at least one cyclodextrin in a first solvent or mixture of solvents to form a first solution or suspension;

dissolving or suspending sulforaphane, or an analog thereof, in a second solvent or mixture of solvents to form a second solution or suspension; and

combining the first solution or suspension with the second solution or suspension.

20. A composition comprising a complex of sulforaphane and a cyclodextrin.

21. A composition according to claim 20, wherein said cyclodextrin is selected from the group consisting of W6 (alpha) cyclodextrin, W7 (beta) cyclodextrin, W8 (gamma) cyclodextrin, and mixtures thereof.

22. A composition comprising a complex of an analog of sulforaphane and a cyclodextrin, wherein the analog of sulforaphane is selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanoat-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1′

-hydroxyethyl)-5-isothiocyanatonorborane, exo-2-acetyl-5-isothiocyanoatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, and cis- or trans-3-(methylsulfonyl)-cyclohexylmethyl-isothiocyanate, and mixtures thereof.

23. A composition according to claim 22, wherein said cyclodextrin is selected from the group consisting of W6 (alpha) cyclodextrin, W7 (beta) cyclodextrin, W8 (gamma) cyclodextrin, and mixtures thereof.

24. A pharmaceutical composition comprising a complex of cyclodextrin and sulforaphane, or an analog of sulforaphane selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanoat-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1′

-hydroxyethyl)-5-isothiocyanatonorborane, exo-2-acetyl-5-isothiocyanoatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, and cis- or trans-3-(methylsulfonyl)-cyclohexylmethyl-isothiocyanate, and mixtures thereof, and an excipient.

25. A composition according to claim 24, wherein the cyclodextrin is selected from the group consisting of W6 (alpha) cyclodextrin, W7 (beta) cyclodextrin, W8 (gamma) cyclodextrin, and mixtures thereof.

26. A composition according to claim 24, wherein the excipient is suitable for one or more of oral, topical, parenteral, injectable, buccal, sublingual, intramuscular, or intravenous administration.

27. A composition according to claim 26, wherein the oral administration form is one or more of a dietary supplement, a food product, a food supplement, or a food additive.

28. A composition according to claim 26, wherein the topical administration form is one or more of a cream, jelly, ointment, or suspension.

29. A nutraceutical composition comprising a complex of cyclodextrin and sulforaphane, or an analog of sulforaphane one or more of 6 isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1′

-hydroxyethyl)-5-isothiocyanatonorborane, exo-2-acetyl-5-isothiocyanoatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, and cis- or trans-3-(methylsulfonyl)-cyclohexylmethyl-isothiocyanate, and mixtures thereof, and an excipient.

30. A composition according to claim 29, wherein the cyclodextrin is selected from the group consisting of W6 (alpha) cyclodextrin, W7 (beta) cyclodextrin, W8 (gamma) cyclodextrin, and mixtures thereof.

31. A composition according to claim 29, wherein the excipient is suitable for one or more of oral, topical, parenteral, injectable, buccal, sublingual, intramuscular, or intravenous administration.

32. A composition according to claim 31, wherein the oral administration form is one or more of a dietary supplement, a food product, a food supplement, or a food additive.

33. A composition according to claim 31, wherein the topical administration form is one or more of a cream, jelly, ointment, or suspension.