Sustained-release formulations of colchicine and methods of using same

• US 10,105,319 B2
• Filed: 12/08/2014
• Issued: 10/23/2018
• 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:
  US14/563,503
• Publication Number:
  US 20150094322A1
• Time in Patent Office: 1,415 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 colchicine or a pharmaceutically acceptable salt thereof in an amount of not more than 0.6 mg, and a binder comprising hydroxypropyl methylcellulose (HPMC) 6 mPa·

s 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 25% and about 30% w/w of the formulation, wherein the retarding agent comprises a combination of equal parts hydroxypropyl methylcellulose (HPMC) with a viscosity grade of 4000 mPa*s and lactose monohydrate; and

(c) at least one additional pharmaceutically acceptable excipient admixed with or blended with the granules, wherein the at least one additional pharmaceutically acceptable excipient is starch, gelatin, polyvinylpyrrolidone (PVP), polyvinyl alcohol, microcrystalline cellulose, hydroxypropyl cellulose (HPC) or a mixture thereof,

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

wherein the formulation is homogeneous.

2. The formulation of claim 1, wherein colchicine is included in an amount of about 0.55 mg.

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

4. The formulation of claim 1, wherein less than between about 23% and about 74% of colchicine is released in vitro into water within the first 120 minutes, or wherein less than about 70% of colchicine is released in vitro from said formulation within about 2 hours at 37°

C.

5. The formulation of claim 3, wherein the compression strength of the tablet is between about 50N and about 130N.

6. The formulation of claim 3, wherein said compression strength is at least about 50N.

7. The formulation of claim 1, wherein the granules additionally comprise a first filling agent comprising lactose monohydrate in an amount of 10% to 80% (w/w) of the formulation, and wherein a second filling agent is admixed or blended with the granules, which comprises lactose monohydrate in an amount of 10% to 30% (w/w) of the formulation.

8. The formulation of claim 1, wherein less than about 70% of colchicine is released in vitro from said formulation within about 2 hours at 37°

C.

9. The formulation of claim 1, wherein the sustained release formulation further comprises a filling agent, and wherein the filling agent is one or more of sucrose, lactose monohydrate, trehalose, maltose, mannitol, sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, methacrylic acid divinylbenzene (DVB), cross-linked PVP, polacrilin potassium, sodium starch glycolate, and pregelatinized starch.

10. A sustained release formulation of colchicine, comprising:

(a) granules comprising colchicine or a pharmaceutically acceptable salt thereof in an amount of not more than 0.6 mg, and a binder comprising hydroxypropyl methylcellulose (HPMC) 6 mPa·

s 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 25% and about 30% w/w of the formulation, wherein the retarding agent comprises a combination of equal parts hydroxypropyl methylcellulose (HPMC) with a viscosity grade of 4000 mPa*s and lactose monohydrate; and

(c) at least one additional pharmaceutically acceptable excipient admixed with or blended with the granules, wherein the at least one additional pharmaceutically acceptable excipient is starch, gelatin, polyvinylpyrrolidone (PVP), polyvinyl alcohol, microcrystalline cellulose, hydroxypropyl cellulose (HPC) or a mixture thereof,

wherein the granules additionally comprise a first filling agent comprising lactose monohydrate in an amount of 10% to 80% (w/w) of the formulation,

wherein a second filling agent is admixed or blended with the granules, which comprises lactose monohydrate in an amount of 10% to 30% (w/w) of the formulation,

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

wherein the formulation is homogeneous.

11. The formulation of claim 10, wherein less than about 70% of colchicine is released in vitro from the sustained formulation within about 2 hours at 37°

C.

12. The formulation of claim 10, wherein colchicine is included in an amount of about 0.55 mg.

13. The formulation of claim 10, wherein the compression strength of the tablet is between about 30N and about 130N.

14. The formulation of claim 10, wherein said compression strength is at least about 30N.