Once daily formulations of tetracyclines

• US 20040228912A1
• Filed: 04/07/2004
• Published: 11/18/2004
• Est. Priority Date: 04/07/2003
• Status: Active Grant

• Current Assignee: TCD Royalty Sub LLC
• Original Assignee: Supernus Pharmaceuticals Incorporated
• Inventors: Chang, Rong-Kun, Shah, Niraj, Raoufinia, Arash
• Granted Patent: US 7,749,532 B2
• Time in Patent Office: Days
• US Class Current: 424/464
• 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 containing a tetracycline, which at a once-daily dosage will give steady state blood levels of the tetracycline of a minimum of about 0.1 μ

g/ml and a maximum of about 1.0 μ

g/ml.

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

g/ml to about 0.8 μ

g/ml.

3. The composition of claim 1, wherein the tetracycline is doxycycline.

4. The composition of claim 3, wherein between 50 mg. and 25 mg. doxycycline is present.

5. The composition of claim 3, wherein about 40 mg. doxycycline is present.

6. The composition of claim 4, which is an immediate release formulation.

7. The composition of claim 5, which is an immediate release formulation.

8. The composition of claim 1, which is a combination of a component containing a tetracycline in an immediate release (IR) formulation and a second component containing a tetracycline in a delayed release (DR) formulation, wherein the ratio of IR to DR is from about 99:

1 to about 70;

30.

9. The composition of claim 8, wherein the tetracycline is doxycycline.

10. The composition of claim 9, wherein the ratio of immediate release component to delayed release component is from about 80:

20 to about 70;

30.

11. The composition of claim 9, wherein the ratio of immediate release component to delayed release component is 75:

25.

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

13. The composition of claim 12, which is in a dosage form of a combination of pellets, wherein a portion of the pellets are of an immediate release formulation and the remaining pellets are of a delayed release formulation.

14. The composition of claim 13, wherein the pellets are contained in a capsule.

15. The composition of claim 9, wherein the IR and DR components are compressed into a tablet.

16. The composition of claim 15, which is a layered tablet, wherein one layer contains the DR component and another layer contains the IR component.

17. The composition of claim 12, which is a layered pellet, wherein the DR portion comprises the core of the pellet, and the IR portion surrounds the core.

26. A method for treating a collagenase dependent disease or condition, and/or acute or chronic inflammatory condition in a mammal, comprising administering a daily dose of a tetracycline composition according to claim 1 to the mammal, for at least a time sufficient to ameliorate the disease or condition.

27. The method of claim 26, wherein the mammal is a human.

28. The method of claim 26, wherein the disease or condition is selected from periodontal disease, rosacea, acne, dry eye, rheumatoid arthritis, hyperparathyroidism, and diabetes.

29. The method of claim 28, wherein the disease is periodontal disease.

30. The method of claim 29, wherein the tetracycline is doxycycline.

31. The method of claim 28, wherein the condition is rosacea.

32. The method of claim 31, wherein the tetracycline is doxycycline.

33. The method of claim 28, wherein the condition is dry eye.

34. The method of claim 33, wherein the tetracycline is doxycycline.

35. The method of claim 30, wherein between 50 mg. and 25 mg. doxycycline is present in the composition.

36. The method of claim 35, wherein about 40 mg. doxycycline is present in the composition.

37. The method of claim 30, which is an immediate release composition.

38. The method of claim 30, wherein the composition is in the form of a dosage unit that contains an immediate release portion and a delayed release portion.

39. The method of claim 32, wherein between 50 mg. and 25 mg. doxycycline is present in the composition.

40. The method of claim 39, wherein about 40 mg. doxycycline is present in the composition.

41. The method of claim 32, which is an immediate release composition.

42. The method of claim 32, wherein the composition is in the form of a dosage unit that contains an immediate release portion and a delayed release portion.

43. The method of claim 34, wherein between 50 mg. and 25 mg. doxycycline is present in the composition.

44. The method of claim 43, wherein about 40 mg. doxycycline is present in the composition.

45. The method of claim 34, which is an immediate release composition.

46. The method of claim 34, wherein the composition is in the form of a dosage unit that contains an immediate release portion and a delayed release portion

48. The process of claim 41, wherein the tetracycline is doxycycline.

18. An oral pharmaceutical dosage form containing between 25 and 50 mg. of a tetracycline.

19. The dosage form of claim 18, wherein the tetracycline is doxycycline.

20. The dosage form of claim 19, which contains about 40 mg. of doxycycline.

21. The dosage form of claim 18, which is in an immediate release formulation.

22. The dosage form of claim 18, which is a granule, tablet, pellet, powder, sachet, capsule, gel, dispersion or suspension.

23. The dosage form of claim 19, which is a tablet containing the doxycycline with pharmaceutically acceptable excipient(s).

24. The dosage form of claim 19, which is a capsule containing pellets of doxycycline with pharmaceutically acceptable excipient(s).

25. The dosage form of claim 19, wherein a portion thereof is of a delayed release formulation, and another portion is of an immediate release formulation.

47. A process for preparing a once-daily oral pharmaceutical composition containing a tetracycline, which will give steady state blood levels of the tetracycline of a minimum of about 0.1 μ

g/ml and a maximum of about 1.0 μ

g/ml, comprising combining between 50 mg. and 25 mg. doxycycline with orally pharmaceutically acceptable excipients.