P-Boronophenylalanine complexes with fructose and related carbohydrates and polyols

• US 6,169,076 B1
• Filed: 03/31/1999
• Issued: 01/02/2001
• Est. Priority Date: 03/31/1999
• Status: Expired due to Fees

• Current Assignee: Glycosyn Pharmaceuticals, Inc.
• Original Assignee: Glcosyn Pharmaceuticals Incorporated
• Inventors: Shull, Brian, Head, Gerald, Spielvogel, David
• Primary Examiner(s): Peselev, Elli
• Application Number:
  US09/282,847
• Time in Patent Office: 643 Days
• Field of Search: 514/64, 514/23, 568/6, 536/124, 536/1.11, 536/18.7
• US Class Current: 514/23
• CPC Class Codes: C07B 59/005 Sugars; Derivatives thereof; Nucleosides; Nucleotides; Nucleic acids
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07H 1/00 Processes for the preparation of sugar derivatives

Abstract

The present invention is directed to salt-free and essentially salt-free p-boronophenylalanine-carbohydrate or p-boronophenylalanine-polyol complexes, as well as methods for making such compounds. In addition, the present invention provides methods for substantially solubilizing freeze-dried p-boronophenylalanine-carbohydrate and p-boronophenylalanine-polyol complexes. The present invention further provides compositions and methods for enhancing the solubility of boronophenylalanine.

Claims

1. A method of making essentially salt-free carbohydrate and polyol (p-boronophenylalanine) complexes, comprising:

a) providing;

i) p-boronephenylalanine,

ii) water,

iii) a compound selected from the group consisting of carbohydrates and polyols,

iv) a base, and

v) an ion-exchange media;

b) mixing said p-boronophenylalanine, said water, said compound, and said base, to produce a basic solution, such that said p-boronophenylalanine and said compound are substantially dissolved in said basic solution;

c) adding said ion-exchange media to said basic solution, thereby adjusting the pH of said basic solution to the range of between about 7.3 and 7.5, to produce a mixture at physiological pH; and

d) removing said ion-exchange media from said mixture to produce an essentially salt-free (p-boronophenylalanine) complex in solution.

2. The method of claim 1, further comprising the step of:

e) freeze-drying said essentially salt-free (p-boronophenylalanine) complex in solution, to produce a freeze-dried essentially salt-free (p-boronophenylalanine) complex.

3. The method according to claim 1, wherein said removing step comprises filtration.

4. The method of claim 1, wherein said removing step comprises decanting.

5. The method according to claim 1, wherein said ion-exchange media comprises an ion-exchange resin.

6. The method according to claim 5, wherein said ion-exchange resin is Dowex 50WX4-50 ion-exchange resin.

7. The method according to claim 1, wherein said basic solution comprises 1 equivalent of said p-boronophenylalanine and approximately 1.1 equivalents of said compound.

8. The method according to claim 1, wherein said basic solution comprises 1 equivalent of said p-boronophenylalanine and an excess of up to 8 equivalents of said compound.

9. The method according to claim 1, wherein said basic solution has a pH of between about 8 and 10.

10. The method according to claim 1, wherein said compound is selected from the group consisting of monosaccharides, disaccharides, fructose, sorbose, ribose, galactose, glucose, mannose, 2-deoxygalactose, 2-deoxyglucose, maltulose, lactulose, palatinose, leucrose, turanose, lactose, maltose, sorbitol, mannitol, dulcitol, xylitol, adonitol and threitol.

11. The method according to claim 1, wherein said base is selected from the group consisting of NaOH, KOH, Ca(OH)₂ and Mg(OH)₂.

12. The method according to claim 1, wherein said p-boronophenylalanine is selected from the group consisting of (d,l)-p-boronophenylalanine and l-p-boronophenylalanine.

13. A composition comprising an essentially salt-free carbohydrate-(p-boronophenylalanine) complex synthesized using the method of claim 1.

21. A composition comprising an essentially salt-free polyol-p-boronophenylalanine) complex synthesized using the method of claim 1.

14. A freeze-dried essentially salt-free p-boronophenylalanine complex selected from the group consisting of l-p-boronophenylalanine-d-fructose complex, l-p-boronophenylalanine-d-sorbose complex, l-p-boronophenylalanine-d-maltulose complex, l-p-boronophenylalanine-d-lactulose complex, l-p-boronophenylalanine-d-palatinose complex, l-p-boronophenylalanine-d-sorbitol complex, l-p-boronophenylalanine-d-mannitol complex, l-p-boronophenylalanine-dulcitol complex, and l-p-boronophenylalanine-xylitol complex.

15. A method of solubilizing an essentially salt-free (l-p-boronophenylalanine)-carbohydrate complex, comprising the steps of:

a) providing, in any order;

i) a freeze-dried essentially salt-free (l-p-boronophenylalanine)-carbohydrate complex, and

ii) a solvent, said solvent is selected from the group consisting of water, isotonic saline, and dilute saline;

b) substantially solubilizing said freeze-dried salt-free (l-p-boronophenylalanine)-carbohydrate complex with said solvent, to provide an iso-osmotic solution.

16. The method of claim 15, wherein said freeze-dried salt-free (l-p-boronophenylalanine)-carbohydrate complex is complexed to a carbohydrate selected from the group consisting of monosaccharides, disaccharides, fructose, sorbose, ribose, galactose, glucose, mannose, 2-deoxygalactose, 2-deoxyglucose, maltulose, lactulose, palatinose, leucrose, turanose, lactose and maltose.

17. The method of claim 15, wherein said iso-osmotic solution is suitable for intravenous use.

18. A method comprising the steps of:

a) providing, in any order;

i) a freeze-dried essentially salt-free (l-p-boronophenylalanine)-polyol complex, and

ii) a solvent, said solvent is selected from the group consisting of water, isotonic saline, and dilute saline;

b) substantially solubilizing said freeze-dried salt-free (l-p-boronophenylalanine)-polyol complex with said solvent, to provide an iso-osmotic solution.

19. The method of claim 18, wherein said iso-osmotic solution is suitable for intravenous use.

20. The method of claim 18, wherein said essentially freeze-dried salt-free (l-p-boronophenylalanine)-polyol complex is complexed to a polyol selected from the group consisting of sorbitol, mannitol, dulcitol, xylitol, adonitol and threitol.