Sustained-release formulations of colchicine and methods of using same
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.
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,
(b) a binder comprising a first hydroxypropyl methylcellulose (HPMC) having a viscosity of 6 mPa·s in an amount of 1% to 30% (w/w) of the formulation;
(c) 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 of a second HPMC having a viscosity of 4000 mPa·s and lactose monohydrate; and
(d) at least one additional pharmaceutically acceptable excipient admixed with or blended with the granules, wherein the at least one additional pharmaceutically acceptable excipient is selected from starch, gelatin, polyvinylpyrrolidone (PVP), polyvinyl alcohol, microcrystalline cellulose, hydroxypropyl cellulose (HPC), and mixtures thereof, and
(e) one or more buffering agents, wetting agents, emulsifying agents, suspending agents, preserving agents, solvents, sweetening agents, flavoring agents, antifoaming agents, polymers, antioxidants, chelating agents, viscomodulators, tonicifiers, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and absorption-promoting agents,
wherein the sustained release formulation is in a form of a tablet,
wherein the sustained release formulation is homogeneous; and
wherein the sustained release formulation produces a plasma profile characterized by a Cmax for colchicine of between about 0.9 ng/ml to about 1.6 ng/mL.
2 . The sustained release formulation of claim 1 , which comprises about 0.50 mg of the colchicine.
3 . The sustained release formulation of claim 1 , wherein the compression strength of the tablet is between about 30N and about 130N.
4 . The sustained release formulation of claim 3 , wherein the compression strength of the tablet is between about 50N and about 130N.
5 . The sustained release formulation of claim 3 , wherein said compression strength is at least about 50N.
6 . The sustained release 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.
7 . The sustained release formulation of claim 1 , wherein the 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.
8 . 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,
(b) a binder comprising a first hydroxypropyl methylcellulose (HPMC) having a viscosity of 6 mPa's in an amount of 1% to 30% (w/w) of the formulation;
(c) 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 of a second HPMC having a viscosity of 4000 mPa·s and lactose monohydrate; and
(d) at least one additional pharmaceutically acceptable excipient admixed with or blended with the granules, wherein the at least one additional pharmaceutically acceptable excipient is selected from starch, gelatin, polyvinylpyrrolidone (PVP), polyvinyl alcohol, microcrystalline cellulose, hydroxypropyl cellulose (HPC), and mixtures thereof, and
(e) one or more buffering agents, wetting agents, emulsifying agents, suspending agents, preserving agents, solvents, sweetening agents, flavoring agents, antifoaming agents, polymers, antioxidants, chelating agents, viscomodulators, tonicifiers, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and absorption-promoting agents,
wherein the granules additionally comprise a first filling agent comprising lactose monohydrate in an amount of 10% to 80% (w/w) of the sustained release 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 sustained release formulation,
wherein the sustained release formulation is in a form of a tablet,
wherein the sustained release formulation is homogeneous; and
wherein the sustained release formulation produces a plasma profile characterized by a Cmax for colchicine of between about 0.9 ng/mL to about 1.6 ng/mL.
9 . The sustained release formulation of claim 8 , wherein colchicine is included in an amount of about 0.50 mg.
10 . The sustained release formulation of claim 8 , wherein the compression strength of the tablet is between about 30N and about 130N.
11 . The sustained release formulation of claim 8 , wherein said compression strength is at least about 30N.