Solid dosage form comprising a fibrate

• US 7,658,944 B2
• Filed: 10/01/2004
• Issued: 02/09/2010
• Est. Priority Date: 10/10/2003
• Status: Active Grant

• Current Assignee: Veloxis Pharmaceuticals, Inc. (Asahi Kasei Corporation)
• Original Assignee: LifeCycle Pharma AS
• Inventors: Holm, Per, Norling, Tomas
• Primary Examiner(s): Wax; Robert A
• Assistant Examiner(s): Mercier; Melissa S
• Application Number:
  US10/513,807
• Publication Number:
  US 20060110444A1
• Time in Patent Office: 1,957 Days
• Field of Search: None
• US Class Current: 424/464
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 31/195 having an amino group
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid

Abstract

The invention provides stable, solid dosage forms and pharmaceutical compositions in particulate form comprising a fibrate, for example fenofibrate, dissolved in an non-aqueous vehicle in order to ensure improved bioavailability of the active ingredient upon oral administration relative to known fibrate formulations.

Claims

1. A tablet comprising fenofibrate in a vehicle, wherein (i) the vehicle comprises polyethylene glycol having an average molecular weight of 3000 daltons to 35000 daltons and a poloxamer in a weight proportion of between 1:

3 and 10;

1, and (ii) the tablet comprises 10 to 35% by weight of fenofibrate, based upon 100% total weight of the tablet.

2. The tablet according to claim 1, wherein the vehicle further comprises a water-miscible polar lipid, higher alcohol, glyceryl monooleate, substituted and/or unsubstituted monoglyceride, substituted and/or unsubstituted diglyceride, or a mixture thereof.

3. The tablet according to claim 1, wherein the vehicle further comprises polyoxyethylene oxides, polyoxyethylene stearates, poly-epsiloncaprolactone or any mixture thereof.

4. The tablet according to claim 1, wherein the poloxamer is poloxamer 188.

5. The tablet according to claim 1, wherein the polyethylene glycol has an average molecular weight of about 6000 daltons.

6. The tablet according to claim 1, wherein the vehicle is non-aqueous.

7. The tablet according to claim 1, wherein the concentration of fenofibrate in the vehicle is in the range of 10% w/w to 90% w/w, based on the total weight of the fenofibrate and the vehicle.

8. The tablet according to claim 1, wherein the concentration of fenofibrate in the vehicle is in the range of 15% w/w to 90% w/w, based on the total weight of the fenofibrate and the vehicle.

9. The tablet according to claim 1, wherein the concentration of fenofibrate in the vehicle is in the range of 15% w/w to 80% w/w, based on the total weight of the fenofibrate and the vehicle.

10. The tablet according to claim 1, wherein the concentration of fenofibrate in the vehicle is in the range of 20% to 75% w/w, based on the total weight of the fenofibrate and the vehicle.

11. The tablet according to claim 1, wherein at least 75% of the fenofibrate is released within about 45 minutes when tested in an in vitro dissolution test according to Ph. Eur. dissolution test (paddle) employing water with 0.75% sodium lauryl sulfate as dissolution medium, 50 rpm and a temperature of about 37°

C.

12. The tablet according to claim 11, wherein the dosage form, after 3 months of storage at a temperature of about 40°

C. and a relative humidity of about 75%, releases at least 75% of the fenofibrate within about 45 minutes when tested in an in vitro dissolution test according to Ph. Eur. dissolution test (paddle) employing water with 0.75% sodium lauryl sulfate as dissolution medium, 50 rpm and a temperature of about 37°

C.

13. The tablet according to claim 1 which further comprises one or more pharmaceutically acceptable excipients.

14. The tablet according to claim 13, wherein the pharmaceutical acceptable excipients are selected from the group consisting of fillers, diluents, disintegrants, binders, glidants and lubricants.

15. The tablet according to claim 13, wherein at least one pharmaceutical acceptable excipient is a silica acid or a derivative or salt thereof.

16. The tablet according to claim 13, wherein at least one pharmaceutical acceptable excipient is a silica acid or a derivative or salt thereof selected from the group consisting of silicates, silicon dioxide;

magnesium aluminosilicate, magnesium aluminometasilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and/or saponite.

17. The tablet according to claim 13, wherein at least one pharmaceutical acceptable excipient is selected from silicon dioxide, magnesium aluminosilicate, and magnesium aluminometasilicate.

18. The tablet according to claim 1, which further comprises a pharmaceutical acceptable additive selected from the group consisting of flavoring agents, coloring agents, taste-masking agents, pH-adjusting agents, buffering agents, preservatives, stabilizing agents, anti-oxidants, wetting agents, humidity-adjusting agents, surface-active agents, suspending agents and absorption enhancing agents.

19. The tablet according to claim 1, which is a unit dosage form.

20. The tablet according to claim 1, wherein the individual units of the solid dosage form are coated with a coating selected from the group consisting of film coatings, modified release coatings, enteric coatings, protective coatings and anti-adhesive coatings.

21. The tablet according to claim 1, wherein the fenofibrate is embedded in a matrix that releases the fenofibrate by diffusion.

22. The tablet according to claim 21, wherein the matrix remains substantially intact during the period of drug release.

23. The tablet according to claim 1, wherein the fenofibrate is embedded in a matrix that releases the fenofibrate by eroding.

24. The tablet according to claim 1, wherein the fenofibrate is released from the dosage form by diffusion through a substantially water-insoluble coating.

25. The tablet according to claim 1, wherein the fenofibrate is stable.

26. The tablet according to claim 25, wherein the fenofibrate is present in an amount of at least 90%, relative to the amount prior to storage, when assayed after 3 months of storage at a temperature of about 40°

C. and a relative humidity of about 75%.

27. A method of manufacturing the tablet of claim 1 comprising the steps of:

i) Bringing the vehicle in liquid form, if applicable, ii) Maintaining the liquid vehicle at a temperature below the melting point of the fenofibrate, iii) Dissolving the desired amount of fenofibrate in the vehicle, iv) Spraying the resulting solution onto a solid carrier having a temperature below the melting point of the vehicle, v) Mechanically working the resulting composition to obtain particles, and vi) Optionally subjecting the particulate material to conventional methods for preparing tablets.

29. The tablet of claim 1, wherein

i) the vehicle comprises a mixture of poloxamer 188 and polyethylene glycol having an average molecular weight of about 6000 daltons, and

ii) at least 75% of the fenofibrate is released from the tablet within about 45 minutes when tested in an in vitro dissolution test according to Ph. Eur. dissolution test (paddle) employing water with 0.75% sodium lauryl sulfate as dissolution medium, 50 rpm and a temperature of about 37°

C.

36. The tablet of claim 1, wherein the tablet further comprises a solid earner.

40. The tablet of claim 36, wherein the solid carrier is lactose.

28. A tablet comprising fenofibrate in a vehicle, wherein (i) the vehicle comprises polyethylene glycol having an average molecular weight of 3000 daltons to 35000 daltons and a poloxamer in a weight proportion of between 1:

3 and 10;

1, and (ii) the tablet comprises 10 to 35% by weight of fenofibrate, based upon 100% total weight of the tablet, and wherein the tablet is prepared by (a) forming a mixture comprising poloxamer and polyethylene glycol having an average molecular weight of 3000 daltons to 35000 daltons in which fenofibrate is dissolved (b) spraying the mixture formed in step (a) onto a solid carrier, and (c) forming a tablet from the product of step (b).

30. A tablet comprising fenofibrate in a vehicle, wherein (i) the vehicle comprises polyethylene glycol having an average molecular weight of 3000 daltons to 35000 daltons and a poloxamer in a weight proportion of between 2:

1 and 3;

1, and (ii) the tablet comprises at least 25% by weight of fenofibrate, based upon the total weight of fenofibrate and vehicle in the tablet.

32. The tablet of claim 30, wherein the tablet comprises at least 30% by weight of fenofibrate, based upon the total weight of fenofibrate and vehicle in the tablet.

37. The tablet of claim 30, wherein the tablet further comprises a solid carrier.

41. The tablet of claim 37, wherein the solid carrier is lactose.

31. A tablet comprising fenofibrate in a vehicle, wherein (i) the vehicle comprises polyethylene glycol having an average molecular weight of 3000 daltons to 35000 daltons and a poloxamer in a weight proportion of between 2:

1 and 3;

1, and (ii) the tablet comprises at least 25% by weight of fenofibrate, based upon the total weight of fenofibrate and vehicle in the tablet, and wherein the tablet is prepared by (a) forming a mixture comprising poloxamer and polyethylene glycol having an average molecular weight of 3000 daltons to 35000 daltons in which fenofibrate is dissolved, (b) spraying the mixture formed in step (a) onto a solid carrier, and (c) forming a tablet from the product of step (b).

33. The tablet of claim 31, wherein the tablet comprises at least 30% by weight of fenofibrate, based upon the total weight of fenofibrate and vehicle in the tablet.

34. A tablet comprising crystalline fenofibrate in a vehicle, wherein (i) the vehicle comprises polyethylene glycol having an average molecular weight of 3000 daltons to 35000 daltons and a poloxamer in a weight proportion of between 1:

3 and 10;

1, and (ii) the tablet comprises 10 to 35% by weight of fenofibrate, based upon 100% total weight of the tablet.

38. The tablet of claim 34, wherein the tablet further comprises a solid carrier.

42. The tablet of claim 38, wherein the solid carrier is lactose.

35. A tablet comprising crystalline fenofibrate in a vehicle, wherein (i) the vehicle comprises polyethylene glycol having an average molecular weight of 3000 daltons to 35000 daltons and a poloxamer in a weight proportion of between 2:

1 and 3;

1, and (ii) the tablet comprises at least 25% by weight of fenofibrate, based upon the total weight of fenofibrate and vehicle in the tablet.

39. The tablet of claim 35, wherein the tablet further comprises a solid carrier.

43. The tablet of claim 39, wherein the solid carrier is lactose.