Cyanocobalamin low viscosity aqueous formulations for intranasal delivery

• US 9,415,007 B2
• Filed: 09/12/2014
• Issued: 08/16/2016
• Est. Priority Date: 03/04/2003
• Status: Active Grant

• Current Assignee: Endo Pharmaceuticals Incorporated (Endo International PLC)
• Original Assignee: Par Pharmaceutical, Inc. (Endo International PLC)
• Inventors: Quay, Steven C., Aprile, Peter C., Go, Zenaida O., Sileno, Anthony P.
• Primary Examiner(s): Lundgren, Jeffrey S
• Assistant Examiner(s): SCHMITT, MICHAEL J
• Application Number:
  US14/485,228
• Publication Number:
  US 20150004198A1
• Time in Patent Office: 704 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/714 Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/186 Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A stable pharmaceutical mercury-free aqueous solution of cyanocobalamin comprised of cyanocobalamin and water wherein said solution of cyanocobalamin is suitable for intranasal administration, has a viscosity less than about 1000 cPs, and wherein said solution of cyanocobalamin has a bioavailability of cyanocobalamin when administered intranasally of at least about 7% relative to an intramuscular injection of cyanocobalamin with the proviso that the solution is essentially free of mercury and mercury-containing compounds. The present invention is also directed towards a method for elevating the vitamin B12 levels in the cerebral spinal fluid (CSF) comprising administering intranasally a sufficient amount of a mercury-free cyanocobalamin solution so as to increase the average ratio of vitamin B12 in the CSF to that in the blood serum (B12 CSF/B12 Serum×100) to at least about 1.1 comprising intranasally administering an aqueous solution of a cyanocobalamin, wherein said solution of cyanocobalamin has a bioavailability of at least 7% relative to an intramuscular injection of a cyanocobalamin.

Claims

1. A method for elevating a level of vitamin B12 in a subject having vitamin B12 deficiency associated with gastric surgery, comprising:

administering an aqueous solution of cyanocobalamin to the subject having vitamin B12 deficiency associated with gastric surgery,

wherein the aqueous solution of cyanocobalamin comprises;

cyanocobalamin;

water;

a buffer selected from the group consisting of citric acid, sodium citrate, monopotassium phosphate, disodium phosphate, potassium biphthalate, sodium hydroxide, sodium acetate, acetic acid, and combinations thereof;

optionally, a humectant selected from the group consisting of sorbitol, propylene glycol, and glycerin, and combinations thereof; and

optionally, a preservative selected from the group consisting of benzyl alcohol, parabens thimerosal, chlorobutanol, benzethonium chloride, and benzalkonium chloride, and combinations thereof;

wherein the aqueous solution of cyanocobalamin is suitable for intranasal administration, has a viscosity of less than about 1000 cPs, and a bioavailability of cyanocobalamin when administered intranasally of at least about 7% relative to an intramuscular injection of cyanocobalamin.

2. The method of claim 1, wherein the cyanocobalamin is at a concentration of about 0.5% by total weight of solution.

3. The method of claim 1, wherein the buffer comprises citric acid at a concentration of about 0.12% by total weight of solution and sodium citrate at a concentration of about 0.32% by total weight of solution.

4. The method of claim 3, wherein the pH of the aqueous solution of cyanocobalamin is about 4 to about 6.

5. The method of claim 4, wherein the aqueous solution of cyanocobalamin contains a humectant.

6. The method of claim 5, wherein the humectant is glycerin at a concentration of about 2.23% by total weight of solution.

7. The method of claim 1, wherein the aqueous solution of cyanocobalamin contains a preservative.

8. The method of claim 7, wherein the preservative comprises chlorobutanol or benzalkonium chloride, or combinations thereof.

9. The method of claim 8, wherein the preservative is benzalkonium chloride at a concentration of about 0.02% by total weight of solution.

10. The method of claim 1, wherein the aqueous solution of cyanocobalamin contains no mercury or mercury-containing compounds.

11. The method of claim 1, wherein the aqueous solution of cyanocobalamin comprises:

cyanocobalamin at a concentration of about 0.5% by total weight of the solution, citric acid at a concentration of about 0.12% by total weight of the solution, sodium citrate at a concentration of about 0.32% by total weight of the solution, glycerin at a concentration of about 2.23% by total weight of the solution, benzalkonium chloride at concentration of about 0.02% by total weight of the solution, and water.

12. The method of claim 1, wherein the aqueous solution of cyanocobalamin comprises:

cyanocobalamin at a concentration of about 0.5% by total weight of the solution, citric acid at a concentration of about 0.12% by total weight of the solution, sodium citrate at a concentration of about 0.32% by total weight of the solution, glycerin at a concentration of about 2.23% by total weight of the solution, and water.

13. A method of using a kit for elevating a level of vitamin B12 in a subject having vitamin B12 deficiency associated with gastric surgery, the kit comprising:

an aqueous solution of cyanocobalamin in a container; and

an actuator coupled to the container, the actuator comprising a tip for producing a spray of the aqueous solution of cyanocobalamin when the actuator is engaged;

the method comprising, administering the spray from the tip to a nose of a subject having vitamin B12 deficiency associated with gastric surgery,

wherein the aqueous solution of cyanocobalamin comprises;

cyanocobalamin;

water;

a buffer selected from the group consisting of citric acid, sodium citrate, monopotassium phosphate, disodium phosphate, potassium biphthalate, sodium hydroxide, sodium acetate, acetic acid, and combinations thereof;

optionally, a humectant selected from the group consisting of sorbitol, propylene glycol, and glycerin, and combinations thereof; and

optionally, a preservative selected from the group consisting of benzyl alcohol, parabens thimerosal, chlorobutanol, benzethonium chloride, and benzalkonium chloride, and combinations thereof;

wherein the aqueous solution of cyanocobalamin has a viscosity of less than about 1000 cPs and a bioavailability of cyanocobalamin when administered intranasally of at least about 7% relative to an intramuscular injection of cyanocobalamin.

14. The method of claim 13, wherein the spray has a spray pattern ellipticity ratio of about 1.0 to about 1.4 when measured at a height of 3.0 cm from the actuator tip.

15. The method of claim 13, wherein the spray comprises droplets, and wherein less than about 5% of the droplets are less than about 10 μ

m in size.

16. The method of claim 13, wherein the spray comprises droplets, and wherein less than about 50% of the droplets are less than about 26.9 μ

m in size.

17. The method of claim 13, wherein the spray has a spray pattern major axis and minor axis of about 25 to about 40 mm each.

18. The method of claim 13, wherein the cyanocobalamin is at a concentration of about 0.5% by total weight of solution.

19. The method of claim 13, wherein the aqueous solution of cyanocobalamin comprises:

cyanocobalamin at a concentration of about 0.5% by total weight of the solution, citric acid at a concentration of about 0.12% by total weight of the solution, sodium citrate at a concentration of about 0.32% by total weight of the solution, glycerin at a concentration of about 2.23% by total weight of the solution, benzalkonium chloride at concentration of about 0.02% by total weight of the solution, and water.

20. The method of claim 13, wherein the aqueous solution of cyanocobalamin comprises:

cyanocobalamin at a concentration of about 0.5% by total weight of the solution, citric acid at a concentration of about 0.12% by total weight of the solution, sodium citrate at a concentration of about 0.32% by total weight of the solution, glycerin at a concentration of about 2.23% by total weight of the solution, and water.