Diclofenac Formulations and Methods of Use

• US 20100204330A1
• Filed: 01/07/2010
• Published: 08/12/2010
• Est. Priority Date: 06/17/2005
• Status: Active Grant

• Current Assignee: APR Applied Pharma Research SA (RELIEF THERAPEUTICS Holding SA)
• Original Assignee: APR Applied Pharma Research SA (RELIEF THERAPEUTICS Holding SA)
• Inventors: Meyer, Andreas, Reiner, Giorgio, Reiner, Alberto
• Granted Patent: US 8,097,651 B2
• Time in Patent Office: Days
• US Class Current: 514/567
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

Methods and formulations are provided for treating migraine and other acute pain episodes using diclofenac, and formulations of diclofenac that provide both rapid and sustained relief from acute pain. Methods and formulations are also provided for treating symptoms that often accompany migraine and acute pain such as photophobia, phonophobia, nausea and vomiting.

Claims

1. ) A method of treating migraine associated with phonophobia or photophobia in a human patient comprising:

a) providing a liquid formulation comprising 50 mg. of diclofenac or a pharmaceutically acceptable salt thereof, wherein said formulation;

i) is provided as a powder formulation and dissolved or suspended in water immediately before administration, or as a liquid formulation that is ingested with or without further mixing;

ii) optionally achieves a C_max of from about 1500 to about 2500 ng/ml; and

iii) achieves t_max in from about 10 to about 25 minutes; and

b) orally administering said formulation to a patient suffering from migraine associated with photophobia or phonophobia.

2. ) The method of claim 1 further comprising diagnosing said patient suffering from migraine as requiring sustained migraine relief for at least 24 hours.

3. ) The method of claim 1 wherein said liquid formulation comprises about 50 mg. of diclofenac potassium.

4. ) The method of claim 1 wherein said formulation achieves t_max in from about 10 to about 20 minutes.

5. ) A method of treating recurrent migraine in a human patient suffering from migraine comprising:

a) providing a liquid formulation comprising about 50 mg. of diclofenac or a pharmaceutically acceptable salt thereof, wherein said formulation;

i) is provided as a powder formulation and dissolved or suspended in water immediately before administration, or as a liquid formulation that is ingested with or without further mixing;

ii) optionally achieves a C_max of from about 1500 to about 2500 ng/ml; and

iii) achieves t_max in from about 10 to about 25 minutes; and

b) diagnosing a patient suffering from migraine as requiring sustained migraine relief for at least 24 hours; and

c) orally administering said formulation to said patient.

6. ) The method of claim 5 wherein said patient suffers from headache pain and either photophobia or phonophobia or both.

7. ) The method of claim 5 wherein said liquid formulation comprises about 50 mg. of diclofenac potassium.

8. ) The method of claim 5 wherein said C_max has an inter-subject variability of less than about 70%.

9. ) The method of claim 5 wherein said t_max has an inter-subject variability of less than about 70%.

10. ) The method of claim 5 wherein said formulation achieves t_max in from about 10 to about 20 minutes.

11. ) A method of treating migraine in a human patient comprising:

a) providing a liquid formulation comprising about 50 mg. of diclofenac or a pharmaceutically acceptable salt thereof, wherein said formulation;

i) is provided as a powder formulation and dissolved or suspended in water immediately before administration, or as a liquid formulation that is ingested with or without further mixing;

ii) optionally achieves a C_max of from about 1500 to about 2500 ng/ml; and

iii) achieves t_max in from about 10 to about 20 minutes; and

b) orally administering said formulation to a patient suffering from migraine, wherein said migraine is defined as a disease manifested in a population of patients by periodic attacks of headache pain, nausea, photophobia and phonophobia.

12. ) The method of claim 11 wherein said patient suffers from headache pain and either photophobia or phonophobia or both.

13. ) The method of claim 11 further comprising diagnosing said patient suffering from migraine as requiring sustained migraine relief for at least 24 hours.

14. ) The method of claim 11 wherein said C_max has an inter-subject variability of less than about 70%.

15. ) The method of claim 11 wherein said t_max has an inter-subject variability of less than about 70%.

16. ) The method of claim 11 wherein said liquid formulation comprises about 50 mg. of diclofenac potassium.

17. ) The method of claim 11 wherein said formulation achieves t_max in from about 10 to about 20 minutes.

18. ) A method of treating acute pain in a human patient requiring pain relief for at least eight hours, comprising:

a) providing an oral formulation comprising about 50 mg. of diclofenac or a pharmaceutically acceptable salt thereof, wherein said formulation;

i) optionally achieves a C_max of from about 1400 to about 2500 ng/ml; and

ii) achieves t_max in from about 10 to about 35 minutes; and

b) orally administering said formulation to a patient suffering from acute pain, no more than 3 total times in a 24 hour period.

19. ) The method of claim 18 wherein said formulation achieves t_max in from about 10 to about 30 minutes.

20. ) The method of claim 18 wherein said acute pain is post-operative dental pain.

21. ) The method of claim 18 wherein said liquid formulation comprises about 50 mg. of diclofenac potassium.

22. ) A pharmaceutical formulation comprising comprises mannitol and diclofenac or a pharmaceutically acceptable salt thereof in a particulate form at a weight ratio of greater than about 1.5:

1.

23. ) The formulation of claim 22, in a unit dose pack, wherein said pack comprises 900 mg. of said formulation, and said formulation comprises 50 or 25 or 12.5 mg. of diclofenac potassium.

24. ) The formulation of claim 22, wherein:

a) said formulation comprises fine mannitol and diclofenac potassium at a weight ratio of from about 1;

2 to about 5;

1, and

b) said fine mannitol has an average particle size of from about 10 to about 180 micrometers.

25. ) The formulation of claim 22, wherein:

a) said formulation comprises fine mannitol and diclofenac potassium at a weight ratio of from about 1;

2 to about 5;

1, and

b) said fine mannitol has an average particle size of from about 20 to about 80 micrometers.

26. ) The formulation of claim 22 comprising:

a) about 50, 25 or 12.5 mg. of diclofenac potassium per 900 mg. of said formulation;

b) from about 50 to about 100 mg. of fine mannitol per 900 mg. of said formulation; and

c) from about 600 to about 700 mg. of coarse mannitol per 900 mg. of said formulation.

27. ) The formulation of claim 22 wherein said formulation comprises from about 50 to about 90 wt. % of said mannitol.

28. ) The formulation of claim 22 wherein said formulation is sugar-free.

29. ) The formulation of claim 22 wherein said formulation comprises glyceryl dibehenate.

30. ) The formulation of claim 22 wherein said formulation further comprises an alkali metal bicarbonate at a weight ratio to said diclofenac of greater than about 1:

5.

31. ) The formulation of claim 22 wherein said formulation further comprises an alkali metal bicarbonate at a weight ratio to said diclofenac of from about 1:

5 to about 5;

1.

32. ) The formulation of claim 22 wherein said formulation comprises less than 1.5% water.

33. ) The formulation of claim 22 wherein said diclofenac is present in a granulate.

34. ) The formulation of claim 22 wherein said formulation has an average pH of 7.5 when dissolved in 50 ml. of water.

35. ) The formulation of claim 22 wherein at least 75% of said formulation dissolves completely in 50 ml. of water at 25 degrees Celsius under continuous stirring for five minutes.

36. ) A method of making a wet granulated powder formulation of diclofenac or a pharmaceutically acceptable salt thereof comprising:

a) wet granulating in ethanol an admixture of diclofenac or a pharmaceutically acceptable salt thereof, a first portion of coarse mannitol, and a bicarbonate to form a wet granulate; and

b) admixing said wet granulate with a second portion of coarse mannitol and fine mannitol.

37. ) The method of claim 36, further comprising admixing said wet granulate with glyceryl dibehenate.

38. ) The method of claim 36 wherein said wet granulate comprises:

a) from about 8 to about 15 weight parts diclofenac potassium;

b) from about 12 to about 20 weight parts coarse mannitol; and

c) from about 3 to about 7 weight parts potassium bicarbonate.

39. ) The method of claim 36 wherein from about 30 to about 60 weight parts of wet granulate are admixed with:

a) from about 100 to about 160 weight parts coarse mannitol;

b) from about 12 to about 20 weight parts fine mannitol; and

c) from about 0.2 to about 0.7 weight parts glyceryl dibehenate.

40. ) The method of claim 36 wherein said formulation comprises:

a) fine mannitol and diclofenac potassium at a weight ratio of from about 1;

2 to about 5;

1,

b) coarse mannitol and diclofenac potassium at a weight ratio of from about 2;

1 to about 40;

1,

wherein;

i) said fine diluent has an average particle size of from about 10 to about 180 micrometers,

ii) said coarse diluent has an average particle size of from about 85 to about 250 micrometers, and

iii) said coarse diluent has an average particle size greater than the average particle size of said fine diluent.

41. ) The method of claim 36 wherein:

a) said mannitol comprises fine mannitol and coarse mannitol at a weight ratio of from about 1;

5 to about 1;

20;

b) said fine mannitol has the following particle size distribution;

i) 250 μ

m;

not more than 5%

ii) 100 μ

m;

not more than 25%

iii) 20 μ

m;

not less than 55%

c) said coarse diluent has the following particle size distribution;

i) 315 μ

m;

not more than 10%

ii) >

75 μ

m;

not less than 90%.

42. ) A method of making a wet granulated powder formulation of diclofenac comprising:

(a) wet granulating an admixture of diclofenac or a pharmaceutically acceptable salt thereof, a first portion of mannitol and optionally a bicarbonate to form a wet granulate; and

(b) admixing said wet granulate with a second portion of mannitol, wherein the weight ratio of mannitol and diclofenac in said final formulation is greater than about 1.5;

1.

43. ) A method of making a particulate flowable diclofenac composition comprising:

(a) mixing non-granulated diclofenac or a pharmaceutically acceptable salt thereof with a fine mannitol particulate to form a first mixture; and

(b) mixing said first mixture with a coarse mannitol particulate to form a second mixture, wherein;

a) said fine mannitol and said diclofenac are present in said composition at a weight ratio of from about 1;

2 to about 5;

1, and

b) said coarse mannitol and said diclofenac are present in said composition at a weight ratio of from about 2;

1 to about 40;

1.

44. ) The method of claim 43 wherein the second mixture is obtained by adding the first mixture to a predefined volume of the coarse diluent, which has been pre-loaded into a mixing machine.

45. ) The method of claim 43 further comprising:

a) mixing said second mixture with an alkali metal bicarbonate to form a third dry mixture;

b) mixing said third mixture with coarse diluent to form a fourth mixture;

c) mixing coarse diluent with a lubricant to form a fifth mixture; and

d) mixing said fourth and fifth mixtures.

46. ) A method of making a diclofenac solution comprising a concentration of diclofenac of from about 10 to about 100 mg/ml. comprising:

a) dissolving diclofenac in ethyl alcohol to form a solution,

b) mixing said solution with glycerol to form a second solution, and

c) mixing said second solution with water to form a third solution.

47. ) The method of claim 46 further comprising:

a) preparing a fourth solution by dissolving potassium bicarbonate in water, and

b) mixing said third and fourth solutions to provide a final solution.

48. ) The method of claim 46 wherein said diclofenac solution comprises from about 35 to about 45 wt. % water, from about 25 to about 35 wt. % ethyl alcohol, and from about 15 to about 25 wt. % glycerol.

49. ) The method of claim 46 wherein said solution comprises 12.5, 25 or 50 mg. of diclofenac per ml. of solution.

50. ) The method of claim 46 wherein said solution has a pH of from about 8.5 to about 9.5.