Once daily formulations of tetracyclines

• US 8,709,478 B2
• Filed: 06/18/2013
• Issued: 04/29/2014
• Est. Priority Date: 04/07/2003
• Status: Expired due to Term

• Current Assignee: TCD Royalty Sub LLC
• Original Assignee: Supernus Pharmaceuticals Incorporated
• Inventors: Chang, Rong-Kun, Raoufinia, Arash, Shah, Niraj
• Primary Examiner(s): Dickenson, Paul
• Application Number:
  US13/920,538
• Publication Number:
  US 20140072626A1
• Time in Patent Office: 315 Days
• Field of Search: None
• US Class Current: 424/468
• CPC Class Codes: A61K 31/65 Tetracyclines
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/08 Antiseborrheics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/18 : of the parathyroid hormones

Abstract

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.

Claims

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 μ

g/ml to 1.0 μ

g/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 μ

g/ml to 0.8 μ

g/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 μ

g/ml to 1.0 μ

g/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 μ

g/ml to 0.8 μ

g/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.