Once daily formulations of tetracyclines

• US 8,206,740 B2
• Filed: 06/06/2008
• Issued: 06/26/2012
• Est. Priority Date: 04/07/2003
• Status: Active Grant

• Current Assignee: TCD Royalty Sub LLC
• Original Assignee: Supernus Pharmaceuticals Incorporated
• Inventors: Shah, Niraj, Chang, Rong-Kun, Raoufinia, Arash
• Primary Examiner(s): DICKINSON, PAUL W
• Application Number:
  US12/155,676
• Publication Number:
  US 20090011006A1
• Time in Patent Office: 1,481 Days
• Field of Search: None
• US Class Current: 424/458
• 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. An oral pharmaceutical composition of doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum of 0.1 μ

g/ml and a maximum of 1.0 μ

g/ml, the composition consisting of (i) an immediate release (IR) portion comprising 30 mg doxycycline;

(ii) a delayed release (DR) portion comprising 10 mg doxycycline; and

optionally, (iii) one or more pharmaceutically acceptable excipients.

2. The composition of claim 1, which at a once-daily dosage will give steady state blood levels of the doxycycline of between 0.3 μ

g/ml to 0.8 μ

g/ml.

3. The composition of claim 1, wherein the ratio of IR to DR is from 99:

1 to 70;

30.

4. The composition of claim 3, wherein the ratio of IR to DR is from 80:

20 to 70;

30.

5. The composition of claim 4, wherein the ratio of IR to DR is 75:

25.

6. The composition of claim 1, which is in the form of a granule, tablet, pellet, powder, sachet, capsule, gel, dispersion or suspension.

7. The composition of claim 1, which is in a dosage form of a combination of pellets.

8. The composition according to claim 1, wherein the DR portion comprises at least one enteric polymer.

9. The composition of claim 8, wherein the enteric polymer is 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(methacylic acid-co-ethyl acrylate) 1;

1, or combinations thereof.

10. The composition according to claim 1, wherein the DR formulation is in the form of granules, pellets, or tablet.

11. The composition according to claim 1, wherein the one or more pharmaceutically acceptable excipients is incorporated in the IR portion, the DR portion, or both.

12. The composition of claim 11, wherein the one or more pharmaceutically acceptable excipients is a binder, a disintegration agent, a filling agent, a surfactant, a solubilizer, a stabilizer, and combinations thereof.

13. The composition of claim 12, wherein the binder is selected from the group consisting of methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyvinylpyrrolidone/vinyl acetate copolymer.

14. The composition of claim 12, wherein the disintegration agent is selected from the group consisting of cornstarch, pregelatinized starch, cross-linked carboxymethylcellulose, sodium starch glycolate, and cross-linked polyvinylpyrrolidone.

15. The composition of claim 12, wherein the filling agents are 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.

16. The composition of claim 12, wherein the surfactants are selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts, and glyceryl monostearate.

17. The composition of claim 12, wherein the solubilizers are 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.

18. The composition of claim 12, wherein the stabilizers are selected from the group consisting of antioxidation agents, buffers, and acids.

22. A process for preparing a once-daily oral pharmaceutical composition according to claim 1, which will give steady state blood levels of the tetracycline of a minimum of 0.1 μ

g/ml and a maximum of 1.0 μ

g/ml, comprising combining (i) an immediate release (IR) portion comprising 30 mg doxycycline;

(ii) a delayed release (DR) portion comprising 10 mg doxycycline; and

optionally, (iii) one or more pharmaceutically acceptable excipients.

19. A method for treating rosacea in a mammal in need thereof, comprising administering an oral pharmaceutical composition of doxycycline comprising, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum of 0.1 μ

g/ml and a maximum of 1.0 μ

g/ml, the composition consisting of (i) an immediate release (IR) portion comprising 30 mg doxycycline;

(ii) a delayed release (DR) portion comprising 10 mg doxycycline; and

optionally, (iii) one or more pharmaceutically acceptable excipients.

20. The method of claim 19, wherein the mammal is a human.

21. The method of claim 19, which at a once-daily dosage, administration of the composition will give steady state blood levels of the doxycycline of between 0.3 μ

g/ml to 0.8 μ

g/ml.

23. A delayed-release tablet of doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum of 0.1 μ

g/ml and a maximum of 1.0 μ

g/ml, the tablet consisting of (i) an immediate release (IR) portion comprising 30 mg doxycycline in the form of tablet;

(ii) a delayed release (DR) portion comprising 10 mg doxycycline; and

, optionally, (iii) one or more pharmaceutically acceptable excipients.

24. The delayed-release tablet of claim 23, wherein the delayed release (DR) portion is present as a core and the immediate-release (IR) portion as an outer layer atop the core.

25. The delayed-release tablet of claim 23, which at a once-daily dosage will give steady state blood levels of the doxycycline of between 0.3 μ

g/ml to 0.8 μ

g/ml.

26. The delayed-release tablet of claim 23, wherein the one or more pharmaceutically acceptable excipients is incorporated in the IR portion, the DR portion, or both.

27. The delayed-release tablet of claim 23, wherein the one or more pharmaceutically acceptable excipients is a binder, a disintegration agent, a filling agent, a surfactant, a solubilizer, a stabilizer, and combinations thereof.

28. A method for treating rosacea in a mammal in need thereof, comprising administering to the mammal a delayed-release tablet of doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum of 0.1 μ

g/ml and a maximum of 1.0 μ

g/ml, wherein the tablet consisting of (i) an immediate release (IR) portion comprising 30 mg doxycycline in the form of tablet;

(ii) a delayed release (DR) portion comprising 10 mg doxycycline; and

optionally, (iii) one or more pharmaceutically acceptable excipients.

29. The method of claim 28, wherein the mammal is a human.