Methods of treating and/or preventing cardiovascular disease
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.
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.