Once daily formulations of tetracyclines
View Patent ↗Disclosed are once-daily formulations containing tetracyclines, especially doxycycline. Such formulations are useful, for instance, for the treatment of collagenase destructive enzyme-dependent diseases, such as periodontal disease and acne, and acute and chronic inflammatory disease states, such as rosacea and arthritis.
1. A method for treating rosacea in a mammal in need thereof, comprising administering an oral pharmaceutical composition consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline; (ii) a delayed release formulation (DR) comprising about 10 mg doxycycline; and (iii) a pharmaceutically acceptable excipient selected from the group consisting of binder, disintegration agent, filling agent, surfactant, solubilizer, stabilizer, plasticizer, lubricant, enteric polymers, and combinations thereof; and (iv) optionally, a controlling coat, overcoating layer, a core, and combinations thereof, wherein doxycycline is the sole active ingredient and the total amount of doxycyline in the composition is about 40 mg.
2. The method of claim 1 , wherein the mammal is a human.
3. The method of claim 1 , which at a once-daily dosage, administration of the composition will give blood levels of the doxycycline of between 0.1 μg/ml to 1.0 μg/ml.
4. The method of claim 3 , which at a once-daily dosage, administration of the composition will give blood levels of the doxycycline of between 0.3 μg/ml to 0.8 μg/ml.
5. The method of claim 1 , wherein the pharmaceutically acceptable excipient is incorporated in the IR formulation, the DR formulation, or both.
6. The method of claim 1 , wherein the binder is selected from the group consisting of methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyvinylpyrrolidone/vinyl acetate copolymer.
7. The method of claim 1 , wherein the disintegration agent is selected from the group consisting of cornstarch, pregelatinized starch, cross-linked carboxymethylcellulose, sodium starch glycolate, and cross-linked polyvinylpyrrolidone.
8. The method of claim 1 , wherein the filling agent is selected from the group consisting of lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, and polyethylene glycol.
9. The method of claim 1 , wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts, and glyceryl monostearate.
10. The method of claim 1 , wherein the solubilizer is selected from the group consisting of citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate, and sodium carbonate.
11. The method of claim 1 , wherein the stabilizer is selected from the group consisting of antioxidation agents, buffers, and acids.
12. The method of claim 1 , wherein the plasticizer is selected from the group consisting of acetyltriethyl citrate, triethyl citrate, acetyltributyl citrate, dibutylsebacate, triacetin, polyethylene glycols, and propylene glycol.
13. The method of claim 1 , wherein the lubricant is selected from the group consisting of talc, colloidal silica dioxide, magnesium stearate, calcium stearate, titanium dioxide, magnesium silicate, stearic acid, polyethylene glycol, leucine, glyceryl behenate, and hydrogenated vegetable oil.
14. The method of claim 1 , wherein the core comprises sugar spheres or microcrystalline spheres.
15. The method of claim 1 , wherein the overcoating layer is a protective coating, color coating, or both.
16. The method of claim 1 , wherein the composition is in the form of a granule, tablet, pellet, powder, sachet, capsule, gel, dispersion or suspension.
17. The method of claim 1 , wherein the DR formulation comprises at least one enteric polymer.
18. The method of claim 1 , wherein the enteric polymer is selected from the group consisting of cellulose acetate phthalate; hydroxypropyl methylcellulose phthalate; polyvinyl acetate phthalate; hydroxypropyl methylcellulose acetate succinate; cellulose acetate trimellitate; hydroxypropyl methylcellulose succinate; cellulose acetate succinate; cellulose acetate hexahydrophthalate; cellulose propionate phthalate; a copolymer of methylmethacrylic acid and methyl methacrylate; a copolymer of methyl acrylate, methylmethacrylate and methacrylic acid; a copolymer of methylvinyl ether and maleic anhydride; ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer; zein; shellac; poly(methacrylic acid-co-ethyl acrylate) 1:1, and combinations thereof.
19. The method of claim 1 , wherein the DR formulation is in the form of granules, pellets, or a tablet.
20. A method for treating rosacea in a mammal in need thereof, comprising administering an oral pharmaceutical composition consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline; (ii) a delayed release formulation (DR) comprising about 10 mg doxycycline and an enteric polymer; and, optionally, (iii) a pharmaceutically acceptable excipient selected from the group consisting of binder, disintegration agent, filling agent, surfactant, solubilizer, stabilizer, lubricant, plasticizer, and combinations thereof; and (iv) optionally, a protective coating, a color coating, a core, and combinations thereof, wherein doxycycline is the sole active ingredient and the total amount of doxycyline in the composition is about 40 mg.
21. The method of claim 20 , wherein the mammal is a human.
22. The method of claim 20 , which at a once-daily dosage, administration of the composition will give blood levels of the doxycycline of between 0.1 μg/ml to 1.0 μg/ml.
23. The method of claim 22 , which at a once-daily dosage, administration of the composition will give blood levels of the doxycycline of between 0.3 μg/ml to 0.8 μg/ml.
24. The method of claim 20 , wherein the pharmaceutically acceptable excipient is incorporated in the IR formulation, the DR formulation, or both.
25. The method of claim 20 , wherein the binder is selected from the group consisting of methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyvinylpyrrolidone/vinyl acetate copolymer.
26. The method of claim 20 , wherein the disintegration agent is selected from the group consisting of cornstarch, pregelatinized starch, cross-linked carboxymethylcellulose, sodium starch glycolate, and cross-linked polyvinylpyrrolidone.
27. The method of claim 20 , wherein the filling agent is selected from the group consisting of lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, and polyethylene glycol.
28. The method of claim 20 , wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts, and glyceryl monostearate.
29. The method of claim 20 , wherein the solubilizer is selected from the group consisting of citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate, and sodium carbonate.
30. The method of claim 20 , wherein the stabilizer is selected from the group consisting of antioxidation agents, buffers, and acids.
31. The method of claim 20 , wherein the plasticizer is selected from the group consisting of acetyltriethyl citrate, triethyl citrate, acetyltributyl citrate, dibutylsebacate, triacetin, polyethylene glycols, and propylene glycol.
32. The method of claim 20 , wherein the lubricant is selected from the group consisting of talc, colloidal silica dioxide, magnesium stearate, calcium stearate, titanium dioxide, magnesium silicate, stearic acid, polyethylene glycol, leucine, glyceryl behenate, and hydrogenated vegetable oil.
33. The method of claim 20 , wherein the core comprises sugar spheres or microcrystalline spheres.
34. The method of claim 20 , wherein the composition is in the form of a granule, tablet, pellet, powder, sachet, capsule, gel, dispersion or suspension.
35. The method of claim 20 , wherein the DR formulation comprises at least one enteric polymer.
36. The method of claim 20 , wherein the enteric polymer is selected from the group consisting of cellulose acetate phthalate; hydroxypropyl methylcellulose phthalate; polyvinyl acetate phthalate; hydroxypropyl methylcellulose acetate succinate; cellulose acetate trimellitate; hydroxypropyl methylcellulose succinate; cellulose acetate succinate; cellulose acetate hexahydrophthalate; cellulose propionate phthalate; a copolymer of methylmethacrylic acid and methyl methacrylate; a copolymer of methyl acrylate, methylmethacrylate and methacrylic acid; a copolymer of methylvinyl ether and maleic anhydride; ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer; zein; shellac; poly(methacrylic acid-co-ethyl acrylate) 1:1, and combinations thereof.
37. The method of claim 20 , wherein the DR formulation is in the form of granules, pellets, or a tablet.