Sustained-release formulations of colchicine and methods of using same

• US 10,610,488 B2
• Filed: 10/19/2018
• Issued: 04/07/2020
• Est. Priority Date: 04/16/2013
• Status: Active Grant

• Current Assignee: Murray & Poole Enterprises, Ltd.
• Original Assignee: Murray & Poole Enterprises, Ltd.
• Inventors: Riel, Susanne
• Primary Examiner(s): Barsky, Jared
• Application Number:
  US16/165,696
• Publication Number:
  US 20190054028A1
• Time in Patent Office: 536 Days
• Field of Search: None
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• 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
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Pharmaceutical compositions of colchicine for once-a-day oral administration are provided. The formulations comprise a sustained-release component and an optional immediate-release component, the compositions of which can be selectively adjusted, respectively, to release the active ingredient along a pre-determined or desired release profile. Methods of treating or preventing cardiovascular disease and/or inflammatory disease in mammalian subjects comprising the administration of the novel formulations disclosed herein are also provided.

Claims

1. A sustained release formulation of colchicine, comprising:

(a) granules comprising 0.6 mg of colchicine or a pharmaceutically acceptable salt thereof and a binder comprising a first hydroxypropyl methylcellulose (HPMC) in an amount of 1% to 30% (w/w) of the formulation, wherein the first HPMC has a viscosity of 6 mPa·

s;

(b) a release retarding agent admixed with, or blended with, the granules in an amount of between about 20% and about 30% w/w of the formulation, which comprises equal proportions of a second HPMC and lactose monohydrate, wherein the second HPMC has a viscosity that is different from the first HPMC; and

(c) at least one pharmaceutically acceptable excipient admixed with, or blended with, the granules,

wherein the sustained release formulation is in a form of a tablet or liquid, and

wherein when the sustained release formulation is in the form of a tablet, the sustained release formulation further comprises a coating that is a taste-masking coating, enteric coating, seal coating, film coating, barrier coating, and/or a compression coating, wherein the coating is not a release retarding coating.

2. The formulation of claim 1, wherein less than between about 23% and about 74% of colchicine is released in vitro into water within about 2 hours at 37°

C., or wherein less than about 70% of colchicine is released in vitro from said formulation within about 2 hours at 37°

C.

3. The formulation of claim 1, wherein the release retarding agent further comprises one or more of cellulose ethers, cellulose esters, acrylic acid copolymers, waxes, gums, glyceryl fatty acid esters, and sucrose fatty acid esters.

4. The formulation of claim 1, wherein the at least one pharmaceutically acceptable excipient is starch, gelatin, polyvinylpyrrolidone (PVP), polyvinyl alcohol, microcrystalline cellulose, hydroxypropyl cellulose (HPC), or a mixture thereof.

5. The formulation of claim 1, wherein the pharmaceutically acceptable excipient is one or more of a binder, a filling agent, a glidant, and a lubricant.

6. The formulation of claim 1, wherein the pharmaceutically acceptable excipient is one or more of starches, gelatin, polyvinylpyrrolidone, cellulose derivatives, and polyvinyl alcohol.

7. The formulation of claim 6, wherein the cellulose derivative is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl cellulose (HPC).

8. The formulation of claim 1, wherein the second HPMC in the release retarding agent has a viscosity of 4000 mPa·

s.

9. The formulation of claim 1, wherein the pharmaceutically acceptable excipients is a filling agent selected from one or more of sucrose, lactose, trehalose, maltose, mannitol, sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, methacrylic acid divinyl benzene, cross-linked polyvinylpyrrolidone, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, and pregelatinized starch.

10. The formulation of claim 5, wherein the total amount of filling agent in the formulation is between about 5.0 wt % and 90.0 wt % of the formulation.

11. The formulation of claim 1, wherein the pharmaceutically acceptable excipient is a glidant selected one or more of colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, and tribasic calcium phosphate.

12. The formulation of claim 11, wherein the total amount of glidant in the formulation is between about 0.5 wt % to about 5 wt % of the formulation.

13. The formulation of claim 1, wherein the pharmaceutically acceptable excipient is a lubricant selected from one or more of glyceryl behenate, stearic acid, hydrogenated vegetable oils, stearyl alcohol, leucine, polyethylene glycol, magnesium stearate, glyceryl monostearate, polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, and colloidal silica.

14. The formulation of claim 13, wherein the lubricant is included in an amount between about 0.5 wt % to about 5 wt % of the formulation.

15. The formulation of claim 1, wherein the formulation is in a dosage form selected from one or more of a tablet, a pill, a capsule, a caplet, a suppository, a dermal patch, a cream, sublingual formulation, eye drops, gel, ointment, a troche, a pouch, sprinkles, or in fixed combination with a surgically insertable medical device.

16. The formulation of claim 1, wherein the colchicine is uniformly distributed throughout the formulation.

17. The formulation of claim 1, wherein when the formulation is a tablet, the compression strength of the tablet is between about 30N and about 130N.

18. The formulation of claim 1, wherein the total amount of colchicine in the formulation is between about 0.25 wt % and about 0.75 wt % of the formulation.

19. A composition, consisting of:

0.5 mg to 0.75 mg colchicine or a salt thereof, per 100 mg total composition;

5 mg to 40 mg of a 50/50 w/w % mixture of a first hydroxypropyl methylcellulose (HPMC) and lactose monohydrate, per 100 mg total composition;

5.0 wt % and 90.0 wt % of one or more filling agents selected from sucrose, lactose, m particular lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, methacrylic acid divinyl benzene (DVB), cross-linked polyvinyl pyrrolidone (PVP), microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, and pregelatinized starch;

0.5 wt % to about 5 wt % of one or more glidants selected from colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, and tribasic calcium phosphate;

0.5 wt % to about 5 wt % of one or more lubricants selected from glyceryl behenate, stearic acid, hydrogenated vegetable oils, stearyl alcohol, leucine, polyethylene glycol, magnesium stearate, glyceryl monostearate, polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, and colloidal silica;

1 wt % to 30 wt % of one or more binders comprising a second HPMC, wherein the first HPMC has a higher viscosity rating than the second HPMC; and

water.

20. The composition of claim 19, wherein the filling agent is lactose monohydrate, the glidant is talk, and the lubricant is stearic acid.

21. The composition of claim 19, wherein the composition comprises 10 mg, 15 mg, or 20 mg of the 50/50 w/w % of the first hydroxypropyl methylcellulose (HPMC) and lactose monohydrate, per 100 mg total composition.

22. The composition of claim 19, wherein the first HPMC has a viscosity rating between 1000 mPa·

s and 10000 mPa·

s.

23. The composition of claim 19, wherein the composition is a compressed tablet or a liquid or a gel.

24. The composition of claim 23, wherein the composition is a compressed tablet, wherein the compressed tablet comprises a non-functional coating, and wherein non-functional coating is a taste-masking coating, enteric coating, seal coating, film coating, barrier coating, and/or a compress coating, and wherein the coating is not a release retarding coating.

25. The composition of claim 19, further comprising a statin.

26. The composition of claim 19, wherein less than between about 23% and about 74% of colchicine is released in vitro into water within about 2 hours at 37°

C., or wherein less than about 70% of colchicine is released in vitro from said formulation within about 2 hours at 37°

C.

27. A sustained release formulation of colchicine, comprising:

(a) granules comprising 0.6 mg of colchicine or a pharmaceutically acceptable salt thereof and a binder comprising a first hydroxypropyl methylcellulose (HPMC) in an amount of 1% to 30% (w/w) of the formulation;

(b) a release retarding agent admixed with, or blended with, the granules in an amount of between about 20% and about 30% w/w of the formulation, which comprises equal proportions of a second HPMC having a viscosity of 4000 mPa·

s and lactose monohydrate, and wherein the second HPMC has a viscosity that is different from the first HPMC; and

(c) at least one pharmaceutically acceptable excipient admixed with, or blended with, the granules,

wherein the sustained release formulation is in a form of a tablet or liquid, and

wherein when the sustained release formulation is in the form of a tablet, the sustained release formulation further comprises a coating that is a taste-masking coating, enteric coating, seal coating, film coating, barrier coating, and/or a compression coating, wherein the coating is not a release retarding coating.