Methods of treating and/or preventing cardiovascular disease

• US 10,130,585 B2
• Filed: 12/08/2014
• Issued: 11/20/2018
• 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:
  US14/563,537
• Publication Number:
  US 20150094323A1
• Time in Patent Office: 1,443 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

Methods of treating or preventing cardiovascular disease and/or inflammatory disease in mammalian subjects comprising the administration of the novel formulations disclosed herein are provided.

Claims

1. A method of treating cardiovascular disease in a subject, which comprises orally administering a sustained release formulation to the subject, wherein the sustained release formulation comprises:

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

s in an amount of 1% to 30% (w/w) of the formulation;

a release retarding agent admixed with or blended with the granules in an amount of between about 25% w/w and about 30% w/w of the sustained release formulation, wherein the release retarding agent comprises equal parts of hydroxypropyl methylcellulose (HPMC) having a viscosity grade of 4000 mPa·

s and lactose monohydrate; and

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

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

wherein the formulation is homogeneous.

2. The method of claim 1, wherein the cardiovascular disease is one or more of acute pericarditis, recurrent pericarditis, post-pericardiotomy syndrome (PPS), and cardiovascular events in subjects with stable coronary disease.

3. The method of claim 1, wherein the subject has acute cardiovascular disease and is concurrently administered an agent that treats acute cardiovascular events, and wherein said acute cardiovascular event is acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke.

4. The method of claim 3, wherein the agent that treats acute cardiovascular events comprises one or more of atorvastatin, rosuvastatin, simvastatin and pravastatin, and/or a salt thereof.

5. The method 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.

6. The method 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.

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

C.

8. The method 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 and sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, methacrylic acid divinylbenzene (DVB), cross-linked PVP, polacrilin potassium, sodium starch glycolate, and pregelatinized starch.

9. The method of claim 1, wherein the sustained release formulation further comprises a glidant, and wherein the glidant is one or more of colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, and tribasic calcium phosphate.

10. The method of claim 9, wherein the total amount of glidant in the sustained release formulation is between 0.5 wt % and 5 wt % of the sustained release formulation.

11. The method of claim 1, wherein the sustained release formulation further comprises a lubricant, and wherein the lubricant is 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.

12. The method of claim 11, wherein the total amount of lubricant the sustained release formulation is between 0.5 wt % and 5 wt % of the sustained release formulation.

13. A method of treating cardiovascular disease in a subject, which comprises:

administering a sustained release formulation to the subject, wherein the sustained release formulation comprises;

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

s in an amount of 1% to 30% (w/w) of the formulation;

a release retarding agent admixed or blended with the granules an amount of between about 25% w/w and about 30% w/w of the sustained release formulation, wherein the release retarding agent comprises equal parts of hydroxypropyl methylcellulose (HPMC) having a viscosity grade of 4000 mPa·

s and lactose monohydrate; and

at least one pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is a starch, gelatin, polyvinylpyrrolidone (PVP), microcrystalline cellulose, hydroxypropyl cellulose (HPC), polyvinyl alcohol, 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 50% (w/w) of the formulation,

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

wherein the formulation is homogeneous.

14. The method of claim 13, wherein the cardiovascular disease is one or more of acute pericarditis, recurrent pericarditis, post-pericardiotomy syndrome (PPS), and cardiovascular events in subjects with stable coronary disease.

15. The method of claim 13, wherein the subject has acute cardiovascular disease and is concurrently administered an agent that treats acute cardiovascular events, and wherein said acute cardiovascular event is acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke.

16. The method of claim 15, wherein the agent that treats acute cardiovascular events is one or more of atorvastatin, rosuvastatin, simvastatin and pravastatin, and/or a salt thereof.

17. The method of claim 13, wherein the sustained release formulation comprises not more than 0.50 mg of colchicine and/or the pharmaceutically acceptable salt thereof.

18. The method of claim 13, wherein the 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.

19. The method of claim 13, wherein the sustained release formulation further comprises a binder, and wherein the binder is one or more of starches, gelatin, polyvinylpyrrolidone, cellulose derivatives, and polyvinyl alcohol.

20. The method of claim 13, 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.

21. The method of claim 13, wherein the sustained release formulation further comprises a glidant, and wherein the glidant is one or more of colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, and tribasic calcium phosphate.

22. The method of claim 21, wherein the total amount of glidant in the sustained release formulation is between 0.5 wt % and 5 wt % of the sustained release formulation.

23. The method of claim 13, wherein the sustained release formulation further comprises a lubricant, and wherein the lubricant is 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.

24. The method of claim 23, wherein the sustained release formulation is formulated for once daily administration.

25. The method of claim 13, wherein less than about 70% of colchicine is released in vitro from the sustained formulation within about 2 hours at 37°

C.