High drug load formulations and dosage forms

• US 20070042034A1
• Filed: 07/24/2006
• Published: 02/22/2007
• Est. Priority Date: 07/22/2005
• Status: Abandoned Application

• Current Assignee: Myrexis, Inc.
• Original Assignee: Myriad Genetics
• Inventors: Williams, Mark, Oehrtman, Gregory, Zentner, Gaylen, McRea, James, Powers, Tracy
• Application Number:
  US11/491,771
• Publication Number:
  US 20070042034A1
• Time in Patent Office: Days
• US Class Current: 424/451
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The invention relates to high drug load formulations containing (R)-2-(2-fluoro-4-biphenylyl)propionic acid as an active pharmaceutical ingredient.

Claims

1. A unit dosage form comprising from 55-90% by weight (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from 10-45% by weight excipient, wherein said unit dosage form has 200 mg or more of (R)-2-(2-fluoro-4-biphenylyl)propionic acid.

2. The unit dosage form of claim 1 having from 200-800 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid.

3. The unit dosage form of claim 1 having from 300-500 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid.

4. The unit dosage form of claim 3 wherein the total weight of said dosage form is no more than 800 mg.

5. The unit dosage form of claim 3 wherein the total weight of said dosage form is no more than 700 mg.

6. The unit dosage form of claim 1 wherein said excipient comprises microcrystalline cellulose.

7. The unit dosage form of claim 1 wherein said (R)-2-(2-fluoro-4-biphenylyl)propionic acid is the free acid form of (R)-2-(2-fluoro-4-biphenylyl)propionic acid.

8. The unit dosage form of claim 1 wherein said dosage form is a tablet or a capsule.

9. The unit dosage form of claim 1 wherein said dosage form is a tablet.

40. A method of using the unit dosage form of claim 1 comprising identifying and individual in need of treatment and administering to said individual a therapeutically effective amount the unit dosage form of claim 1.

41. The method of claim 40 wherein said individual in need of treatment has a neurodegenerative disorder.

42. The method of claim 41 wherein said neurodegenerative disorder is chosen from Alzheimer'"'"'s disease, dementia, mild cognitive impairment, Parkinson'"'"'s disease, Huntington'"'"'s disease and symptoms thereof

43. The method of claim 42 wherein said Alzheimer'"'"'s disease is chosen from prodromal Alzheimer'"'"'s disease, mild Alzheimer'"'"'s disease, mild-to-moderate Alzheimer'"'"'s disease, moderate Alzheimer'"'"'s disease, moderate-to-severe Alzheimer'"'"'s disease, and severe Alzheimer'"'"'s disease.

44. The method of claim 42 wherein said Alzheimer'"'"'s disease is mild Alzheimer'"'"'s disease.

45. The method of claim 41 wherein said unit dosage form is administered twice daily.

46. The method of claim 41 wherein said unit dosage form comprises from about 320 to 480 mg of (R)-2-(2-fluoro-4-biphenylyl)propionic acid or molar equivalent of a pharmaceutically acceptable salt thereof and said individual is administered two unit dosage forms twice daily.

47. The method of claim 46 wherein said individual has Alzheimer'"'"'s disease or is desiring prophylaxis against the development of symptoms of Alzheimer'"'"'s disease.

48. The method of claim 40 wherein said individual in need of treatment has cancer.

49. The method of claim 48 where in said cancer is chosen from brain, lung, liver, spleen, kidney, lymph node, small intestine, pancreas, blood cell, colon, stomach, breast, endometrial, prostate, testicle, ovary, skin, and head and neck, esophagus, and bone marrow cancer.

50. The method of claim 48 wherein said cancer is prostate cancer.

10. A unit dosage form comprising from 380-420 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid and from 200-260 mg excipient.

11. A unit dosage form comprising from 200-600 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid that is more than 55% by weight (R)-2-(2-fluoro-4-biphenylyl)propionic acid.

12. The unit dosage form of claim 11 having from 350-450 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid and less than 300 mg excipient.

13. The unit dosage form of claim 12 wherein when orally administered to a fasting subject provides a C_max of from about 30 to about 95 μ

g/ml.

14. The unit dosage form of claim 13 which is suitable for oral administration.

15. The unit dosage form of claim 14 which is a tablet or a capsule.

16. The unit dosage form of claim 15 which is a tablet.

17. A unit dosage form comprising from 55-80% by weight (R)-2-(2-fluoro-4-biphenylyl)propionic acid and from about 20-45% by weight excipient that has a total weight of less than 800 mg.

18. The unit dosage form of claim 17, having from 380-420 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid.

19. The unit dosage form of claim 17, wherein said excipient comprises microcrystalline cellulose.

20. The unit dosage form of claim 19 further comprising hydroxypropyl methylcellulose.

21. The unit dosage form of claim 17 further comprising lactose, colloidal silicon dioxide, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate.

22. The unit dosage form of claim 21 which is a coated tablet.

23. The unit dosage form of claim 21 having from about 380 mg to 420 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from about 50 mg to 70 mg lactose, from about 3 mg to 7 mg colloidal silicon dioxide, from about 30 mg to 50 mg hydroxypropyl methylcellulose, from about 70 mg to 105 mg microcrystalline cellulose, from about 1 mg to 5 mg croscarmellose sodium, from about 4 mg to 8 mg magnesium stearate, and optional ingredients as desired.

24. The unit dosage form of claim 21 having from about 385 mg to 415 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from about 55 mg to 65 mg lactose, from about 3.5 mg to 6.5 mg colloidal silicon dioxide, from about 32 mg to 48 mg hydroxypropyl methylcellulose, from about 75 mg to 100 mg microcrystalline cellulose, from about 1.5 mg to 4.5 mg croscarmellose sodium, from about 4.5 mg to 7.5 mg magnesium stearate, and optional ingredients as desired.

25. The unit dosage form of claim 21 having from about 390 mg to 410 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from about 56 mg to 64 mg lactose, from about 4.0 mg to 6.5 mg colloidal silicon dioxide, from about 34 mg to 46 mg hydroxypropyl methylcellulose, from about 80 mg to 95 mg microcrystalline cellulose, from about 2.0 mg to 4.0 mg croscarmellose sodium, from about 5.0 mg to 7.0 mg magnesium stearate, and optional ingredients as desired.

26. The unit dosage form of claim 21 having from about 395 mg to 405 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from about 56 mg to 64 mg lactose, from about 4.0 mg to 6.0 mg colloidal silicon dioxide, from about 34 mg to 46 mg hydroxypropyl methylcellulose, from about 82 mg to 93 mg microcrystalline cellulose, from about 2.0 mg to 4.0 mg croscarmellose sodium, from about 5.0 mg to 7.0 mg magnesium stearate, and optional ingredients as desired.

27. A method of manufacturing a tablet unit dosage form having (R)-2-(2-fluoro-4-biphenylyl)propionic acid as an active pharmaceutical ingredient comprising:

(a) charging the lactose, (R)-2-(2-fluoro-4-biphenylyl)propionic acid drug substance, and colloidal silicon dioxide into a drum-type blender;

(b) blending components together for a sufficient amount of time and discharge into a mill;

(c) milling through a sufficient size screen to decrease the particle size of the large particles in the drug substance and discharging into a high shear granulator;

(d) charging the hydroxypropyl methylcellulose into the high shear granulator and dry blending;

(e) granulating the material using purified water;

(f) milling the wet granulation through an appropriate size screen;

(g) drying the milled granulation;

(h) milling the dried granulation through an appropriate size screen;

(i) charging dried granulation along with microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide into a diffusion blender and blending the material for an appropriate amount of time;

(j) charging the magnesium stearate into the diffusion blender and blending for an appropriate amount of time;

(k) compressing the blended powders on a high-speed rotary press; and

(l) film coating the tablets.

28. A composition having (R)-2-(2-fluoro-4-biphenylyl)propionic acid, one or more diluents, and one or more glidants as ingredients.

29. The composition of claim 28 having 50-95% of the total weight as (R)-2-(2-fluoro-4-biphenylyl)propionic acid;

1-30% of the total weight as one or more diluents present; and

0.01-5% of the total weight as one or more glidants.

30. The composition of claim 28 having 60-95% of the total weight as (R)-2-(2-fluoro-4-biphenylyl)propionic acid;

3-25% of the total weight as one or more diluents present; and

0.1-5% of the total weight as one or more glidants.

31. The composition of claim 28 having 70-95% of the total weight as (R)-2-(2-fluoro-4-biphenylyl)propionic acid;

5-20% of the total weight as one or more diluents present; and

0.1-3% of the total weight as one or more glidants.

32. A composition having (R)-2-(2-fluoro-4-biphenylyl)propionic acid, one or more diluents, one or more glidants, one or more binders, one or more wetting agents and optionally, one or more additional ingredients.

33. A composition having from 40-95% (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from 1-30% of one or more diluents, from 0.01-10% of one or more glidants, from 1-30% of one or more binders, from 1-40% of one or more wetting agents and from 0-20% of one or more optional ingredients.

34. A composition having from 45-95% (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from 1-20% one or more diluents, from 0.01-5% of one or more glidants, from 1-20% of one or more binders, from 1-25% of one or more wetting agents and from 1-20% of one or more optional ingredients.

35. A composition having from 50-90% (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from 5-15% of one or more diluents, from 0.1-5% of one or more glidants, from 1-15% of one or more binders, from 5-25% of one or more wetting agents and from 1-10% of one or more optional ingredients.

36. A composition having a dried granulation component and one or more disintegrants wherein the dried granulation has (R)-2-(2-fluoro-4-biphenylyl)propionic acid, one or more diluents, one or more binders, and one or more glidants.

37. The composition of claim 36 wherein the one or more disintegrants is 1-40% of the total weight of the composition.

38. The composition of claim 36 wherein the one or more disintegrants is 5-25% of the total weight of the composition.

39. The composition of claim 36 wherein the one or more disintegrants is 5-20% of the total weight of the composition.

51. A method of manufacturing a tablet unit dosage form having (R)-2-(2-fluoro-4-biphenylyl)propionic acid as an active pharmaceutical ingredient comprising:

(a) charging the lactose, (R)-2-(2-fluoro-4-biphenylyl)propionic acid drug substance, colloidal silicon dioxide, and hydroxypropyl methylcellulose into the high shear granulator;

(b) dry blending the lactose, (R)-2-(2-fluoro-4-biphenylyl)propionic acid drug substance, colloidal silicon dioxide, and hydroxypropyl methylcellulose in the high shear granulator;

(c) granulating the material using purified water;

(d) milling the wet granulation through an appropriate size screen;

(e) drying the milled granulation;

(f) milling the dried granulation through an appropriate size screen;

(g) charging dried granulation along with microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide into a diffusion blender and blending the material for an appropriate amount of time;

(h) charging the magnesium stearate into the diffusion blender and blending for an appropriate amount of time;

(i) compressing the blended powders on a high-speed rotary press; and

(j) film coating the tablets.