Oral paracetamol formulations

• US 8,216,610 B2
• Filed: 11/27/2006
• Issued: 07/10/2012
• Est. Priority Date: 05/28/2004
• Status: Active Grant

• Current Assignee: Johnson & Johnson Consumer Inc. (Johnson & Johnson)
• Original Assignee: Imaginot Pty., Ltd.
• Inventors: Roberts, Michael Stephen, Jiang, Ruoying, Bezanehtak, Keivan, Davidson, George Alexander, Elliott, Geraldine Ann, Chandler, Stephen Douglas, Sarkar, Mantu, Davey, Greg Andrew
• Primary Examiner(s): Lundgren, Jeffrey S.
• Assistant Examiner(s): FINN, MEGHAN R
• Application Number:
  US11/604,972
• Publication Number:
  US 20070141144A1
• Time in Patent Office: 2,052 Days
• Field of Search: 514/183
• US Class Current: 424/489
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• 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 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Abstract

The present invention relates generally to formulations comprising paracetamol. More particularly, the present invention provides a swallow formulation comprising paracetamol which facilitates the rapid delivery of paracetamol into the circulatory system following oral administration. The present invention further relates to methods for inducing efficient pain relief including an analgesic effect by the administration of the paracetamol formulation.

Claims

1. A swallow formulation comprising paracetamol particles having a volume median diameter (D₅₀) of less than 350 μ

m and a surface area of greater than 0.07 m²g<sup>−

1</sup>, a pH modulating agent in an amount sufficient to neutralize from about 0.6 mL to about 110 mL 0.1 N hydrochloric acid and/or to neutralize from about 0.06 mmol to about 11 mmol of acid; and

an agent which facilitates water uptake into the formulation;

wherein at least 70% of the paracetamol is dissolved from the swallow formulation within 180 seconds in USP dissolution apparatus 2 with 900 mL 0.05 N hydrochloric acid at 30 rpm and 37°

C., wherein the weight ratio of the paracetamol and the pH modulating agent is between 1.8;

1 and 2.5;

1 and the weight ratio of the agent which facilitates water uptake into the formulation and the pH modulating agent is between 0.5;

1 and 1.5;

1.

4. The swallow formulation of claim 1, wherein at least 80% of the paracetamol is dissolved from the swallow formulation within 180 seconds in USP dissolution apparatus 2 with 900 mL 0.05 N hydrochloric acid at 30 rpm and 37°

C.

6. The swallow formulation of claim 1, wherein at least 80% of the paracetamol is dissolved from the swallow formulation within 120 seconds in USP dissolution apparatus 2 with 900 mL 0.05 N hydrochloric acid at 30 rpm and 37°

C.

7. The swallow formulation of claim 1, wherein at least 70% of the paracetamol is dissolved from the swallow formulation within 90 seconds in USP dissolution apparatus 2 with 900 mL 0.05 N hydrochloric acid at 30 rpm and 37°

C.

8. The swallow formulation of claim 1, wherein at least 80% of the paracetamol is dissolved from the swallow formulation within 90 seconds in USP dissolution apparatus 2 with 900 mL 0.05 N hydrochloric acid at 30 rpm and 37°

C.

9. The swallow formulation of any one of claims 1 to 3 wherein a single dose administration of 1000 mg paracetamol with water in fasted healthy human subjects provides a mean AUC₂₀ of more than about 150 min·

mg·

L<sup>−

1</sup>.

10. The swallow formulation of claim 1, wherein a single dose administration of 1000 mg paracetamol with water in fasted healthy human subjects provides a mean AUC₂₀ of more than about 170 min·

mg·

L<sup>−

1</sup>.

11. The swallow formulation of claim 1, wherein the paracetamol in the formulation exhibits a dissolution rate in USP dissolution apparatus 2 using 900 mL of 0.05 N hydrochloric acid at 30 rpm and 37°

C. of at least 30% in 180 seconds.

12. The swallow formulation of any one of claims 1 to 3 wherein the pH modulating agent is soluble and/or dispersible.

13. The swallow formulation of claim 1, wherein at least one pH modulating agent is a base.

14. The swallow formulation of claim 13, wherein at least one pH modulating agent is a carbonate.

15. The swallow formulation of claim 14, wherein the carbonate is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, sodium carbonate, ammonium carbonate, disodium glycine carbonate, sodium glycine carbonate, lysine carbonate and arginine carbonate.

16. The swallow formulation of claim 15, wherein the carbonate is water soluble.

17. The swallow formulation of claim 16, wherein the carbonate is a sodium carbonate.

18. The swallow formulation of any one of claims 1, 2, or 3, wherein the amount of paracetamol dissolved from the swallow formulation is at least about 5 times greater than the amount of rapidly dissolving paracetamol dissolved from a swallow formulation without a carbonate pH modulating agent after 30 seconds in USP dissolution apparatus 2 with 900 mL 0.05 N hydrochloric acid at 30 rpm and 37°

C.

19. The swallow formulation of any one of claims 1, 2, or 3, wherein the paracetamol has a volume median diameter (D₅₀) less than about 300 μ

m.

20. The swallow formulation of any one of claims 1, 2, or 3, wherein the paracetamol has a surface area to mass ratio greater than about 0.08 m²g⁻

1.

21. The swallow formulation of any one of claims 1, 2, or 3, wherein the paracetamol is the product of paracetamol crystallized in the presence of one or more crystallization modifiers.

22. The swallow formulation of any one of claims 1, 2, or 3, wherein the paracetamol has been crystallized in the presence of a crystal modifier chosen from the group consisting of polymers, proteins or mixture thereof.

23. The swallow formulation of any one of claims 1, 2, or 3, wherein the paracetamol has been crystallized in the presence of polyvinylpyrrolidone.

24. The swallow formulation of claim 1, wherein the paracetamol is in the form of granules.

25. The swallow formulation of any one of claims 1, 2, or 3, wherein the paracetamol is in the form of granules including an agent chosen from the group consisting of pH modulating agents, water uptake agents and mixtures thereof.

26. The swallow formulation of any one of claims 1, 2, or 3, comprising at least one of extra granular paracetamol, pH modulating agent, or water uptake agent.

27. The swallow formulation of claim 24, wherein the granules further comprise a disintegrant.

28. The swallow formulation of claim 27, wherein the disintegrant is chosen from the group consisting of crospovidone, croscarmellose, sodium starch glycolate, starch, starch derivative and mixtures thereof.

29. The swallow formulation of claims 1, 2, or 3, wherein the agent which facilitates water uptake into the formulation is selected from the group consisting of cross-linked polyvinylpyrrolidone (crospovidone), croscarmellose sodium, sodium starch glycolate, povidone, starch, starch derivatives, low substituted hydroxypropylcellulose, hydroxypropylcellulose, alginic acid, sodium alginate, calcium sulfate, calcium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, colloidal silicon dioxide, docusate sodium, guar gum, magnesium aluminium silicate, methylcellulose, polacrilin potassium, silicified microcrystalline cellulose, magnesium oxide, tragacanth, mannitol, sorbitol, xylitol, sucrose, lactose, fructose, maltose, polyethylene glycol, aminoacids, cyclodextrin, urea and polyvinylpyrrolidone.

30. The swallow formulation of claims 1, 2, or 3, further comprising one or more other pharmaceutically active agents.

31. The swallow formulation of claim 1, wherein the swallow formulation comprises paracetamol in an amount ranging from 100 mg to 1000 mg, and pH modulating agent in an amount sufficient to neutralize from about 0.3 mL to about 55 mL 0.1N hydrochloric acid and/or to neutralize from about 0.03 mmol to about 5.5 mmol of acid.

32. A dosage form comprising the swallow formulation of claims 1, 2 or 3.

33. A dosage form comprising the swallow formulation of claims 1, 2, or 3, wherein the dosage form is a coated tablet, uncoated tablet, capsule or powder.

34. A dosage form comprising a swallow formulation claims 1, 2, or 3, and selected from the group consisting of coated tablets, uncoated tablets, capsules and powders which further comprises one or more pharmaceutically active agents.

35. A dosage form comprising the swallow formulation of claims 1, 2, or 3, and selected from the group consisting of coated tablets, uncoated tablets, capsules and powders which dosage form comprises a further pharmaceutically active agents comprising paracetamol and wherein the dosage form exhibits dissolution in USP dissolution apparatus 2 using 900 mL of 0.05 N HCl with the paddle spinning at 30 rpm at 37°

C. of less than 30% in 180 seconds.

36. A method for the treatment of symptoms chosen from the group consisting of pain, fever, discomfort or combinations thereof in a subject, said method comprising administering to said subject the swallow formulation of any one of claims 1, 2, or 3.

37. A method for the treatment of symptoms chosen from the group consisting of pain, fever, discomfort or combinations thereof and wherein the symptoms are exhibited by a human and the method comprises administering to the human the swallow formulation of any one of claims 1, 2, or 3.

38. The swallow formulation according to claim 30, wherein said one or more other pharmaceutically active agent is an analgesic.

39. The swallow formulation according to claim 38, wherein said analgesic is tramadol.

40. The swallow formulation of claim 15, wherein the carbonate is sodium bicarbonate.

2. A swallow formulation comprising paracetamol particles having a volume median diameter (D₅₀) of less than 350 μ

m and a surface area of greater than 0.07 m²g<sup>−

1</sup>, a pH modulating agent in an amount sufficient to neutralize from about 0.6 mL to about 110 mL 0.1 N hydrochloric acid and/or to neutralize from about 0.06 mmol to about 11 mmol of acid; and

an agent which facilitates water uptake into the formulation;

wherein at least one pH modulating agent is a carbonate in an amount that will neutralise 0.01 to 9.0 millimoles of hydrochloric acid and is present in an amount from about 1% to 50% by weight of the swallow formulation;

wherein at least about 5% of the paracetamol is dissolved from the swallow formulation within 300 seconds at 0 rpm when the dissolution is measured in United States Pharmacopoeia (USP) dissolution apparatus 2 with 900 mL 0.0033 N hydrochloric acid at 37°

C., wherein the weight ratio of the paracetamol and the pH modulating agent is between 1.8;

1 and 2.5;

1 and the weight ratio of the agent which facilitates water uptake into the formulation and the pH modulating agent is between 0.5;

1 and 1.5;

1.

5. The swallow formulation of claims 2 or 3 wherein the swallow formulation is a tablet and at least 20% of the paracetamol is dissolved from the swallow formulation within 300 seconds in USP dissolution apparatus 2 with 900 mL 0.05 N hydrochloric acid at 0 rpm and 37°

C.

3. A swallow formulation comprising paracetamol particles having a volume median diameter (D₅₀) of less than 350 μ

m and a surface area of greater than 0.07 m²·

g<sup>−

1</sup>, a pH modulating agent in an amount sufficient to neutralize from about 0.6 mL to about 110 mL 0.1 N hydrochloric acid and/or to neutralize from about 0.06 mmol to about 11 mmol of acid; and

an agent which facilitates water uptake into the formulation;

wherein

(a) at least about 5% of the paracetamol is dissolved from the swallow formulation within 300 seconds at 0 rpm, and

(b) at least about 70% of the paracetamol is dissolved from the swallow formulation within 180 seconds at 30 rpm,

when the dissolution is measured in United States Pharmacopoeia (USP) dissolution apparatus 2 with 900 mL 0.0033 N hydrochloric acid at 37°

C., wherein the weight ratio of the paracetamol and the pH modulating agent is between 1.8;

1 and 2.5;

1 and the weight ratio of the agent which facilitates water uptake into the formulation and the pH modulating agent is between 0.5;

1 and 1.5;

1.