Saccharide free, storage stable thyroid hormone active drug formulations and methods for their production

• US 8,779,000 B1
• Filed: 07/20/2013
• Issued: 07/15/2014
• Est. Priority Date: 07/20/2013
• Status: Active Grant

• Current Assignee: Famygen Life Sciences Incorporated
• Original Assignee: Nilesh Parikh, William Hite
• Inventors: Parikh, Nilesh, Hite, William
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US13/947,022
• Time in Patent Office: 360 Days
• Field of Search: 514/567, 424/400, 424/464, 424/465, 424/468, 424/489, 424/499, 424/502
• US Class Current: 514/567
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Abstract

Embodiments of the present invention provide pharmaceutical compositions in unit dosage form that comprise a therapeutically effective amount of levothyroxine sodium; an antioxidant in an amount sufficient to stabilize the levothyroxine sodium against oxidation; an amount of an alditol sufficient to stabilize the levothyroxine sodium; and at least two excipients selected from a filler, a binder, and a lubricant. Such compositions are free of added monosaccharide, disaccharide, and an oligosaccharide and are storage stable.

Claims

1. A pharmaceutical composition in unit dosage form that comprises:

a therapeutically effective amount of a levothyroxine sodium;

an antioxidant in an amount sufficient to stabilize the levothyroxine sodium against oxidation;

an amount of an alditol sufficient to stabilize the levothyroxine sodium; and

at least two excipients selected from the group consisting of a filler, a binder, and a lubricant, wherein;

the alditol is at least one member selected from the group consisting of a mannitol, a sorbitol, a maltitol, and a xylitol;

the composition is free of added saccharide selected from the group consisting of a monosaccharide, a disaccharide, and an oligosaccharide; and

the composition is storage stable.

2. The composition of claim 1, wherein the filler is present in the composition and is at least one member selected from the group consisting of a calcium phosphate, a cellulose, a magnesium carbonate, a calcium carbonate, and a calcium sulfate.

3. The composition of claim 1, wherein the binder is present in the composition and is at least one member selected from the group consisting of a polyvinylpyrrolidone, an alginate, a gelatin, a chitosan, a kaolin, an acacia, a methyl cellulose, a liquid glucose tragacanth, a starch, a starch paste, a pregelatinized starch, an ethyl cellulose, a hydroxypropylmethyl cellulose, a hydroxypropyl cellulose, a sodium carboxymethyl cellulose, an alginic acid, a polyvinyl pyrrolidone, a cellulose, a polyethylene glycol, a polyvinyl alcohol, and a polymethacrylate.

4. The composition of claim 1, wherein the lubricant is present in the composition and is at least one member selected from the group consisting of a talc, a calcium stearate, a sodium stearyl fumarate, a stearic acid, a magnesium stearate, a solid polyethylene glycol, a cocoa butter, a hydrogenated vegetable oil, a mineral oil, a glyceryl palmitostearate, and a glyceryl behenate.

5. The composition of claim 1, wherein the antioxidant is at least one member selected from the group consisting of a butylated hydroxyanisole, a vitamin E (alpha tocopherol), a butylated hydroxytoluene, an ascorbic acid, a sodium ascorbate, a sodium bisulfate, and a sodium metabisulfite.

6. The composition of claim 1, further comprising at least one additional excipient selected from the group consisting of a glidant and a surfactant.

7. The composition of claim 6, wherein the glidant is present in the composition and is at least one member selected from the group consisting of a talc, a silica, a fumed silica, and a colloidal silicon dioxide.

8. The composition of claim 6, wherein the surfactant is present in the composition and is at least one member selected from the group consisting of a polysorbate, a sodium lauryl sulfate, a lauryl dimethyl amine oxide, a cetyltrimethylammonium bromide, a polyethoxylated alcohol, a polyoxyethylene sorbitan, an octoxynol, a n,n-dimethyldodecylamine-n-oxide, a hexadecyltrimethylammonium bromide, a polyoxyl 10 lauryl ether, a BRIJ 721, a bile salt, a polyoxyl castor oil, a nonylphenol ethoxylate, a cyclodextrin, a lecithin, and a methylbenzethonium chloride.

9. A pharmaceutical composition in unit dosage form that comprises:

a levothyroxine sodium in one amount selected from the group consisting of 25 μ

g, 50 μ

g, 75 μ

g, 88 μ

g, 100 μ

g, 112 μ

g, 137 μ

g, 150 μ

g, 175 μ

g, 200 μ

g, and 300 μ

g;

1%-70% w/w of an alditol;

1%-80% w/w of a filler;

0.001%-10% w/w of a binder;

0.001%-5% w/w of an antioxidant;

0.1%-5% w/w of a glidant; and

0.001%-5% w/w of a surfactant, wherein the composition is free of added saccharide selected from the group consisting of a monosaccharide, a disaccharide, and an oligosaccharide, and wherein the composition is storage stable.

10. The composition of claim 9, wherein the filler and is at least one member selected from the group consisting of a calcium phosphate, a cellulose, a magnesium carbonate, a calcium carbonate, and a calcium sulfate.

11. The composition of claim 9, wherein the binder is present in the composition and is at least one member selected from the group consisting of a polyvinylpyrrolidone, an alginate, a gelatin, a chitosan, a kaolin, an acacia, a methyl cellulose, a liquid glucose tragacanth, a starch, a starch paste, a pregelatinized starch, an ethyl cellulose, a hydroxypropylmethyl cellulose, a hydroxypropyl cellulose, a sodium carboxymethyl cellulose, an alginic acid, a polyvinyl pyrrolidone, a cellulose, a polyethylene glycol, a polyvinyl alcohol, and a polymethacrylate.

12. The composition of claim 9, wherein the lubricant is at least one member selected from the group consisting of a talc, a calcium stearate, a sodium stearyl fumarate, a stearic acid, a magnesium stearate, a solid polyethylene glycol, a cocoa butter, a hydrogenated vegetable oil, a mineral oil, a sodium lauryl sulfate, a glyceryl palmitostearate, and a glyceryl behenate.

13. The composition of claim 9, wherein the antioxidant is at least one member selected from the group consisting of a butylated hydroxyanisole, a vitamin E (alpha tocopherol), a butylated hydroxytoluene, an ascorbic acid, a sodium ascorbate, a sodium bisulfate, and a sodium metabisulfite.

14. The composition of claim 9, wherein the glidant is at least one member selected from the group consisting of a talc, a silica, a fumed silica, and a colloidal silicon dioxide.

15. The composition of claim 9, wherein the surfactant is at least one member selected from the group consisting of a polysorbate, a sodium lauryl sulfate, a lauryl dimethyl amine oxide, a cetyltrimethylammonium bromide, a polyethoxylated alcohol, a polyoxyethylene sorbitan, an octoxynol, a n,n-dimethyldodecylamine-n-oxide, a hexadecyltrimethylammonium bromide, a polyoxyl 10 lauryl ether, a BRIJ 721, a bile salt, a polyoxyl castor oil, a nonylphenol ethoxylate, a cyclodextrin, a lecithin, and a methylbenzethonium chloride.

16. A pharmaceutical composition in unit dosage form that comprises:

a levothyroxine sodium in one amount selected from the group consisting of 25 μ

g, 50 μ

g, 75 μ

g, 88 μ

g, 100 μ

g, 112 μ

g, 137 μ

g, 150 μ

g, 175 μ

g, 200 μ

g, and 300 μ

g;

20%-60% w/w of an alditol;

10%-70% w/w of a filler;

1%-5% w/w of a binder;

0.1%-1% w/w of an antioxidant;

0.1%-3% w/w of a glidant; and

0.01%-1% w/w of a surfactant, wherein the composition is free of added saccharide selected from the group consisting of a monosaccharide, a disaccharide, and an oligosaccharide, and wherein the composition is storage stable.

17. The composition of claim 16, wherein the filler and is at least one member selected from the group consisting of a calcium phosphate, a cellulose, a magnesium carbonate, a calcium carbonate, and a calcium sulfate.

18. The composition of claim 16, wherein the binder is present in the composition and is at least one member selected from the group consisting of a polyvinylpyrrolidone, an alginate, a gelatin, a chitosan, a kaolin, an acacia, a methyl cellulose, a liquid glucose tragacanth, a starch, a starch paste, a pregelatinized starch, an ethyl cellulose, a hydroxypropylmethyl cellulose, a hydroxypropyl cellulose, a sodium carboxymethyl cellulose, an alginic acid, a polyvinyl pyrrolidone, a cellulose, a polyethylene glycol, a polyvinyl alcohol, and a polymethacrylate.

19. The composition of claim 16, wherein the lubricant is at least one member selected from the group consisting of a talc, a calcium stearate, a sodium stearyl fumarate, a stearic acid, a magnesium stearate, a solid polyethylene glycol, a cocoa butter, a hydrogenated vegetable oil, a mineral oil, a sodium lauryl sulfate, a glyceryl palmitostearate, and a glyceryl behenate.

20. The composition of claim 16, wherein the antioxidant is at least one member selected from the group consisting of a butylated hydroxyanisole, a vitamin E (alpha tocopherol), a butylated hydroxytoluene, an ascorbic acid, a sodium ascorbate, a sodium bisulfate, and a sodium metabisulfite.

21. The composition of claim 16, wherein the glidant is at least one member selected from the group consisting of a talc, a silica, a fumed silica, and a colloidal silicon dioxide.

22. The composition of claim 16, wherein the surfactant is at least one member selected from the group consisting of a polysorbate, a sodium lauryl sulfate, a lauryl dimethyl amine oxide, a cetyltrimethylammonium bromide, a polyethoxylated alcohol, a polyoxyethylene sorbitan, an octoxynol, a n,n-dimethyldodecylamine-n-oxide, a hexadecyltrimethylammonium bromide, a polyoxyl 10 lauryl ether, a BRIJ 721, a bile salt, a polyoxyl castor oil, a nonylphenol ethoxylate, a cyclodextrin, a lecithin, and a methylbenzethonium chloride.

23. A pharmaceutical composition in unit dosage form that comprises:

a levothyroxine sodium in one amount selected from the group consisting of 25 μ

g, 50 μ

g, 75 μ

g, 88 μ

g, 100 μ

g, 112 μ

g, 137 μ

g, 150 μ

g, 175 μ

g, 200 μ

g, and 300 μ

g;

37.50%-42.50% w/w of a mannitol;

0.75%-1.50% w/w of a polyvinylpyrrolidone;

1.00%-2.00% w/w of a magnesium stearate;

52.50%-62.50% w/w of a microcrystalline cellulose, a dicalcium phosphate, or a combination of microcrystalline cellulose and dicalcium phosphate;

0.20%-1.00% w/w of a colloidal silicon dioxide;

30.00%-35.00% w/w of a dicalcium phosphate;

0.0075%-0.015% w/w of a butylated hydroxyanisole; and

0.075%-0.15% w/w of a sodium lauryl sulfate, and

wherein the composition is free of added saccharide selected from the group consisting of a monosaccharide, a disaccharide, and an oligosaccharide, and wherein the composition is storage stable.