Enema composition for treatment of ulcerative colitis having long term stability

• US 8,809,308 B2
• Filed: 11/11/2013
• Issued: 08/19/2014
• Est. Priority Date: 11/09/2012
• Status: Expired due to Fees

• Current Assignee: Haz Two, LLC
• Original Assignee: SciDose LLC
• Inventors: Palepu, Nagesh R., Buxton, Philip Christopher
• Primary Examiner(s): Weddington, Kevin E
• Application Number:
  US14/076,560
• Publication Number:
  US 20140135299A1
• Time in Patent Office: 281 Days
• US Class Current: 514/169
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/385 having two or more sulfur atoms in the same ring
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Abstract

Long term storage stable budesonide-containing solutions are disclosed. The solutions can include budesonide or a pharmaceutically acceptable salt thereof, cromolyn sodium, antioxidizing agent, benzoic acid, and a pharmaceutically acceptable fluid including propylene glycol and water. Kits including the long term storage stable budesonide-containing solutions and methods of treating ulcerative colitis are also disclosed.

Claims

1. A long-term stable budesonide-containing solution, comprising

a) from about 0.1 mg to about 10 mg budesonide or a pharmaceutically acceptable salt thereof;

b) from about 5 mg to about 150 mg cromolyn or a pharmaceutically acceptable salt or solvate thereof;

c) from about 5 mg to about 25 mg of an antioxidizing agent;

d) from about 5 mg to about 50 mg benzoic acid; and

e) a pharmaceutically acceptable fluid comprising;

i) from about 20% (v/v) to about 90% (v/v) propylene glycol; and

ii) water.

2. The long-term stable budesonide-containing solution of claim 1, wherein the amount of the budesonide is from about 2.5 mg to about 7.5 mg.

3. The long-term stable budesonide-containing solution of claim 2, wherein the amount of the budesonide is about 5 mg.

4. The long-term stable budesonide-containing solution of claim 1, wherein the cromolyn is cromolyn sodium in an amount of from about 30 mg to about 125 mg.

5. The long-term stable budesonide-containing solution of claim 4, wherein the amount of the cromolyn sodium is about 100 mg.

6. The long-term stable budesonide-containing solution of claim 1, wherein the antioxidizing agent is selected from the group consisting of potassium metabisulfite, sodium metabisulfite, sulfurous acid, ascorbic/iso-ascorbic acid and their salts, thiols and mixtures thereof.

7. The long-term stable budesonide-containing solution of claim 6, wherein the antioxidizing agent is potassium metabisulfite.

8. The long-term stable budesonide-containing solution of claim 1, wherein the amount of the antioxidzing agent is from about 0.2 mg to about 20 mg.

9. The long-term stable budesonide-containing solution of claim 8, wherein the amount of the antioxidzing agent is about 10 mg.

10. The long-term stable budesonide-containing solution of claim 1, wherein the amount of benzoic acid is from about 0.2 mg to about 50 mg.

11. The long-term stable budesonide-containing solution of claim 10, wherein the amount of benzoic acid is about 10 mg.

12. The long-term stable budesonide-containing solution of claim 1, wherein the pharmaceutically acceptable fluid comprises from about 30% (v/v) to about 75% (v/v) propylene glycol.

13. The long-term stable budesonide-containing solution of claim 12, wherein the pharmaceutically acceptable fluid comprises about 50% (v/v) propylene glycol.

14. The long-term stable budesonide-containing solution of claim 1, further comprising a free radical scavenger or metal scavenger.

15. The long-term stable budesonide-containing solution of claim 14, wherein the metal scavenger is selected from the group consisting of EDTA and lactobionic acid.

16. The long-term stable budesonide-containing solution of claim 1, wherein the total volume of the solution is from about 5 ml to about 15 ml.

17. The long-term stable budesonide-containing solution of claim 16, wherein the total volume of the solution is about 10 ml.

19. A long-term stable budesonide-containing solution of claim 1, wherein the amount of total degradants in the solution after 3 months at 40°

C. is less than 5%.

20. A kit for the treatment of ulcerative colitis, comprising:

a) a first container comprising a therapeutically effective of amount of the long-term stable budesonide-containing solution of claim 1; and

b) a second container comprising;

i) from about 50 mg to about 5,000 mg mesalamine or a pharmaceutically acceptable salt thereof;

ii) from about 5 millimoles to about 50 millimoles sodium butyrate;

iii) from about 75 mg to about 150 mg citric acid;

iv) from about 40 mg to about 80 mg potassium metabisulfite;

v) from about 150 mg to about 250 mg sodium benzoate;

vi) from about 40 mg to about 70 mg EDTA;

vii) from about 500 mg to about 1.5 g of a mixture of microcrystalline cellulose and carboxymethylcellulose; and

viii) water.

21. A kit for the treatment of ulcerative colitis, comprising:

a) a first container comprising a therapeutically effective of amount of the long-term stable budesonide-containing solution of claim 1;

b) a second container comprising;

i) from about 50 mg to about 5,000 mg mesalamine or a pharmaceutically acceptable salt thereof;

ii) from about 5 millimoles to about 50 millimoles sodium butyrate;

iii) from about 75 mg to about 150 mg citric acid;

iv) from about 40 mg to about 80 mg potassium metabisulfite;

v) from about 150 mg to about 250 mg sodium benzoate;

vi) from about 40 mg to about 70 mg EDTA;

vii) from about 500 mg to about 1.5 g of a mixture of microcrystalline cellulose and carboxymethylcellulose; and

viii) water; and

c) a third container comprising from about 100 mg to about 1,000 mg lipoic acid.

22. The kit of claim 21, wherein the lipoic acid is alpha lipoic acid or R-dihydro-lipoic acid.

23. A kit for the treatment of ulcerative colitis, comprising:

a) a first container comprising a therapeutically effective of amount of the long-term stable budesonide-containing solution of claim 1,

b) a second container comprising;

i) from about 50 mg to about 5,000 mg mesalamine or a pharmaceutically acceptable salt thereof;

ii) from about 75 mg to about 150 mg citric acid;

iii) from about 40 mg to about 80 mg potassium metabisulfite;

iv) from about 150 mg to about 250 mg sodium benzoate;

v) from about 40 mg to about 70 mg EDTA;

vi) from about 500 mg to about 1.5 g of a mixture of microcrystalline cellulose and carboxymethylcellulose; and

vii) water; and

c) a third container comprising;

i) from about 5 millimoles to about 50 millimoles sodium butyrate; and

ii) water.

24. A kit for the treatment of ulcerative colitis, comprising:

a) a first container comprising a therapeutically effective of amount of the long-term stable budesonide-containing solution of claim 1,

b) a second container comprising;

i) from about 50 mg to about 5,000 mg mesalamine or a pharmaceutically acceptable salt thereof;

ii) from about 75 mg to about 150 mg citric acid;

iii) from about 40 mg to about 80 mg potassium metabisulfite;

iv) from about 150 mg to about 250 mg sodium benzoate;

v) from about 40 mg to about 70 mg EDTA;

vi) from about 500 mg to about 1.5 g of a mixture of microcrystalline cellulose and carboxymethylcellulose; and

vii) water;

c) a third container comprising;

i) from about 5 millimoles to about 50 millimoles sodium butyrate; and

ii) water; and

d) a fourth container comprising from about 100 mg to about 1,000 mg lipoic acid.

25. The kit of claim 24, wherein the lipoic acid is alpha lipoic acid or R-dihydro-lipoic acid.

26. A method of treating ulcerative colitis in a patient requiring such treatment, comprising:

a) providing the kit of claim 20;

b) combining the contents of the first and second containers; and

c) rectally administering the resulting combination of step b).

27. A method of treating ulcerative colitis in a patient requiring such treatment, comprising:

a) providing the kit of claim 21;

b) combining the contents of the first and second containers;

c) rectally administering the resulting combination of step b); and

d) orally administering the lipoic acid of the third container.

28. A method of treating ulcerative colitis in a patient requiring such treatment, comprising:

a) providing the kit of claim 23;

b) combining the contents of the first, second, and third containers;

c) rectally administering the resulting combination of step b).

29. A method of treating ulcerative colitis in a patient requiring such treatment, comprising:

a) providing the kit of claim 24;

b) combining the contents of the first, second, and third containers;

c) rectally administering the resulting combination of step b); and

d) orally administering the lipoic acid of the fourth container.

18. A long-term stable budesonide-containing solution, comprising

a) about 5 mg budesonide or a pharmaceutically acceptable salt thereof;

b) about 100 mg cromolyn sodium;

c) about 10 mg potassium metabisulfite;

d) about 10 mg benzoic acid; and

e) a pharmaceutically acceptable fluid comprising;

i) about 50% (v/v) propylene glycol; and

ii) water.