NOVEL PHARMACEUTICAL FORMULATION

Abstract

The present invention is directed to a pharmaceutical composition comprising a pharmaceutically effective amount of guaifenesin, naproxen and at least one further active which is selected to be an antitussive, a decongestant or an antihistamine.

Claims

1. A pharmaceutical composition comprising a pharmaceutically effective amount of guaifenesin, naproxen and at least one further active which is selected to be an antitussive, a decongestant or an antihistamine.

2. A composition as claimed in claim 1, wherein the at least one other drug is selected from an antitussive such as dextromethorphan, codeine, codeine phosphate, codeine sulphate, diphenhydramine citrate, and diphenhydramine hydrochloride, a decongestant such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine or ephedrine, an antihistamine such as chlorpheniramine maleate, brompheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, and clemastine fumerate, or a combination thereof.

3. A composition as claimed in claim 2, wherein the at least one other drug is dextromethorphan or pseudoephedrine.

4. A composition as claimed in claim 3, wherein the expectorant is guaifenesin, the analgesic is naproxen and the antitussive is dextromethorphan.

5. A composition as claimed in claim 4, wherein the ratio of guaifenesin:naproxen:dextromethorphan is from about 40:8:1 to about 10:3:1.

6. A composition as claimed in claim 5, wherein the ratio of guaifenesin:naproxen:dextromethorphan is from 22:4:1 to 17:3:1.

7. A composition as claimed in claim 5, wherein the ratio of guaifenesin:naproxen:dextromethorphan is 20:3.67:1.

8. A composition as claimed in claim 1, wherein the ratio of guaifensin:naproxen is from about 1:1 to about 10:1.

9. A composition as claimed in claim 8, wherein the ratio of guaifensin:naproxen is from about 2:1 to about 7:1.

10. A composition as claimed in claim 8, wherein the ratio of guaifensin:naproxen is from about 4:1 to about 6:1.

11. A composition as claimed in claim 2, wherein the ratio of naproxen:dextromethorphan is from about 1:1 to about 10:1.

12. A composition as claimed in claim 11, wherein the ratio of naproxen:dextromethorphan is from about 2:1 to about 7:1.

13. A composition as claimed in claim 11, wherein the ratio of wherein the ratio of naproxen:dextromethorphan is from about 3:1 to about 5:1.

14. A composition as claimed in claim 1, wherein composition comprises immediate and sustained release portions.

15. A composition as claimed in claim 14, wherein the composition is provided with both sustained-release and immediate-release portions comprising the expectorant.

16. A composition as claimed in claim 14, wherein the naproxen is incorporated into the composition such that it is the sole active in the portion in which it is contained.

17. A composition as claimed in claim 14, wherein the composition is provided with both sustained-release and immediate-release portions comprising guaifenesin.

18. A composition as claimed in claim 14, wherein the composition comprises a first immediate release portion which comprises guaifenesin and a decongestant or an antitussive, a second immediate release portion which comprises naproxen, and a sustained release portion which comprises guaifenesin.

19. A composition as claimed in claim 1, wherein the composition comprises: (a) 50-85% Guaifenesin; (b) up to 5% Dextromethorphan or a pharmaceutically acceptable salt thereof; and (c) 5-30% Naproxen or a pharmaceutically acceptable salt thereof.

20. A composition as claimed in claim 1, wherein the composition comprises: (a) 55-65% Guaifenesin; (b) 1-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 5-15% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1-10% Controlled release polymers; (e) 0.1-10% Binders; (f) 0.1-5% Disintegrants; (g) 5-25% Diluents; and (h) up to 1% Lubricants.

21. A composition as claimed in claim 20, wherein the composition comprises: (a) 55-65% Guaifenesin; (b) 1-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 5-15% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1-8% Hypromellose; (e) 10-25% Microcrystalline cellulose; (f) 0.1-2.5% Povidone; (g) 0.1-4.0% Croscarmellose Sodium; (h) 0.1-2.0% Hydroxyethyl Cellulose; and (i) up to 1% Magnesium stearate.

22. A composition as claimed in claim 21, wherein the composition comprises: (a) 58-63% Guaifenesin; (b) 2-3.5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 10-12% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1-2% Hypromellose; (e) 15-25% Microcrystalline cellulose; (f) 1-2% Povidone; (g) 0.5-2.5% Croscarmellose sodium; (h) 0.5-1% Hydroxyethyl cellulose; and (i) up to 0.5% Magnesium stearate.

23. A composition as claimed in claim 20, wherein the composition comprises: (a) 55-65% Guaifenesin; (b) 1-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 5-15% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1-8% Hypromellose; (e) 10-25% Microcrystalline cellulose; (f) 0.1-2.5% Povidone; (g) 0.1-2.0% Carbomer; (h) 0.1-2.0% Sodium Starch Glycolate; (i) up to 1% Magnesium stearate; and

24. A composition as claimed in claim 23, wherein the composition comprises: (a) 59-65% Guaifenesin; (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 10-12% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1-6% Hypromellose; (e) 10-20% Microcrystalline cellulose; (f) 0.3-1% Povidone; (g) 0.5-1% Carbomer; (h) 0.1-0.5% Sodium Starch Glycolate; and (i) up to 1% Magnesium stearate.

25. A composition as claimed in claim 20, wherein the composition comprises: (a) 59-65% Guaifenesin; (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 10-12% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1-6% Hypromellose; (e) 10-20% Microcrystalline cellulose; (f) 0.3-1% Povidone; (g) 0.5-1% Carbomer; (h) 1-2% Croscarmellose sodium; (i) 0.1-0.5% Sodium Starch Glycolate; and (j) up to 1% Magnesium stearate.

26. A composition as claimed in claim 1, wherein the composition comprises: (a) 64-69% Guaifenesin; (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 12-15% Naproxen or a pharmaceutically acceptable salt thereof; (d) 3-5% Hypromellose; (e) 9-15% Microcrystalline cellulose; (f) 0.4-0.65% Povidone; (g) 0.75-1.3% Carbomer; (h) 0.5-1% Magnesium stearate; and (i) 0.25-0.5% Sodium starch glycolate.

27. A composition as claimed in claim 26, wherein the composition further comprises: (j) 0.5-1.5% Lactose; (k) 2.5-3.5% Sodium lauryl sulphate; and (l) 0.1-1.5% Croscarmellose sodium.

28. A composition as claimed in claim 1, wherein the composition comprises: (a) 64-69% Guaifenesin; (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 12-15% Naproxen or a pharmaceutically acceptable salt thereof; (d) 0.1-0.6% Hypromellose; (e) 9-15% Microcrystalline cellulose; (f) 0.4-0.65% Povidone; (g) 0.75-1.3% Carbomer; (h) 0.5-1% Magnesium stearate; and (i) 0.25-0.5% Sodium starch glycolate.

29. A composition as claimed in claim 28, wherein the composition further comprises one or more of: (j) 0.5-1.5% Lactose; (k) 2.5-3.5% Sodium lauryl sulphate; and (l) 0.1-1.5% Croscarmellose sodium.

30. A composition as claimed in claim 1, wherein the composition comprises: (a) 63-66% Guaifenesin; (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 10-12% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1.75-3.0% Hypromellose; (e) 11-13% Microcrystalline cellulose; (f) 1-2% Povidone; (g) 0.5-0.75% Croscarmellose Sodium; (h) 1-2% Carbomer; (i) 0.1-0.5% Magnesium stearate; and (j) 0.5-1.5% Lactose.

31. A composition as claimed in claim 30, wherein the composition further includes: (k) 2-3% Sodium Lauryl Sulphate.

32. A composition as claimed in claim 1, wherein the composition comprises: (a) 64-66% Guaifenesin; (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 11-13% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1.75-3.0% Hypromellose; (e) 6-8.5% Microcrystalline cellulose; (f) 1-2% Povidone; (g) 1-5% Croscarmellose Sodium; (h) 0.5-1% Carbomer; (i) 0.5-1% Magnesium stearate; and (j) 0.5-1% Crospovidone.

33. A composition as claimed in claim 32, wherein the composition further includes one or more of: (k) 2-3% Sodium Lauryl Sulphate; and (l) 6-7% Sodium Bicarbonate.

34. A composition as claimed in claim 1, wherein the composition comprises: (a) 64-66% Guaifenesin; (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 11-13% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1.75-3.0% Hypromellose; (e) 6-8.5% Microcrystalline cellulose; (f) 1-2% Povidone; (g) 1-5% Croscarmellose Sodium; (h) 0.5-1% Carbomer; and (i) 0.5-1% Magnesium stearate.

35. A composition as claimed in claim 1, wherein the composition comprises: (a) 62-65% Guaifenesin; (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 11-13% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1.75-3.0% Hypromellose; (e) 6-8.5% Microcrystalline cellulose; (f) 1-2% Povidone; (g) 1-5% Croscarmellose Sodium; (h) 0.5-1% Carbomer; and (i) 0.5-1% Magnesium stearate; (j) 2-3% Sodium Lauryl Sulphate; and (k) 5-8% Sodium Bicarbonate.

36. A composition as claimed in claim 1, wherein the composition comprises: (a) 58-60% Guaifenesin; (b) 2-3% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 10-11% Naproxen or a pharmaceutically acceptable salt thereof; (d) 2-3% Hypromellose; (e) 7-8% Microcrystalline cellulose; (f) 1-2% Povidone; (g) 2-3% Croscarmellose Sodium; (h) 0.1-0.2% Magnesium stearate; (i) 0.5-1% Crospovidone; (j) 1-3% Hydroxyethyl cellulose; (k) 2-3% Sodium Lauryl Sulphate; and (l) 9-10% Sodium bicarbonate.

37. A composition as claimed in claim 1, wherein the composition comprises: (a) 64-66% Guaifenesin; (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 11-13% Naproxen or a pharmaceutically acceptable salt thereof; (d) 2-3% Hypromellose; (e) 6-7% Microcrystalline cellulose; (f) 1-2% Povidone; (g) 0.1-0.5% Magnesium stearate; (h) 7-10% Crospovidone; and (i) 1-3% Hydroxyethyl cellulose.

38. A pharmaceutical dosage form which comprises at least three distinct portions wherein two of the portions have immediate release characteristics and a third portion has modified release characteristics, wherein one of the immediate release portions comprises an expectorant and a second active which is an antitussive or a decongestant and the second immediate release portion comprises an analgesic having a half-life of twelve hours and wherein the modified release portion comprises guaifenesin and a second active which is an antitussive or a decongestant.

39. A pharmaceutical dosage form as claimed in claim 38, wherein the dosage form comprises a first composition which comprises both immediate and modified release portions of the expectorant and the second active which is an antitussive or a decongestant and a second composition which comprises an analgesic having a therapeutic effect of twelve hours.

40. A pharmaceutical dosage form as claimed in claim 38, wherein the analgesic is the sole active in the portion in which it is contained.

41. A composition as claimed in claim 1, wherein an analgesic-containing immediate release portion comprises: (a) 50-52% Naproxen or a pharmaceutically acceptable salt thereof; (b) 35-40% Microcrystalline cellulose; (c) up to 5% Povidone; (d) 5-8% Croscarmellose sodium; and (e) up to 1% Magnesium stearate.

42. A composition as claimed in claim 1 wherein an analgesic-containing immediate release portion comprises: (a) 70-75% Naproxen or a pharmaceutically acceptable salt thereof; (b) 20-25% Microcrystalline cellulose; (c) up to 5% Povidone; and (d) up to 1% Magnesium stearate.

43. A composition as claimed in claim 1, wherein an analgesic-containing immediate release portion comprises: (a) 70-75% Naproxen or a pharmaceutically acceptable salt thereof; (b) 5-10% Microcrystalline cellulose; (c) up to 5% Povidone; (d) up to 1% Magnesium stearate; (e) 5-10% Lactose; and (f) up to 5% Croscarmellose sodium.

44. A composition as claimed in claim 1, wherein an analgesic-containing immediate release portion comprises: (a) 70-75% Naproxen or a pharmaceutically acceptable salt thereof; (b) 5-10% Microcrystalline cellulose; (c) up to 5% Povidone; (d) up to 1% Magnesium stearate; (e) 5-10% Lactose; and (f) 5-10% Croscarmellose sodium.

45. A composition as claimed in claim 1, wherein an analgesic-containing immediate release portion comprises: (a) 70-75% Naproxen or a pharmaceutically acceptable salt thereof; (b) 5-10% Microcrystalline cellulose; (c) up to 5% Povidone; (d) up to 1% Magnesium stearate; (e) up to 5% Lactose; and (f) 15-20% Sodium Lauryl Sulphate.

46. A composition as claimed in claim 1, wherein an analgesic-containing immediate release portion comprises: (a) 70-75% Naproxen or a pharmaceutically acceptable salt thereof; (b) 5-10% Microcrystalline cellulose; (c) up to 5% Povidone; (d) up to 1% Magnesium stearate; (e) up to 2% Croscarmellose sodium; and (f) 15-20% Sodium Lauryl Sulphate.

47. A composition as claimed in claim 1, wherein a guaifenesin-containing immediate release portion comprises: (a) 30-40% Guaifenesin; (b) up to 5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 50-60% Microcrystalline cellulose; (d) up to 7% Povidone; (e) up to 7% Croscarmellose sodium; and (f) up to 1% Magnesium stearate.

48. A composition as claimed in claim 1, wherein a guaifenesin-containing immediate release portion comprises: (a) 40-50% Guaifenesin; (b) up to 5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 40-50% Microcrystalline cellulose; (d) up to 5% Hypromellose; (e) up to 5% Sodium starch glycolate; and (f) up to 1% Magnesium stearate.

49. A composition as claimed in claim 1, wherein a guaifenesin-containing immediate release portion comprises: (a) 50-65% Guaifenesin; (b) up to 5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 25-40% Microcrystalline cellulose; (d) up to 5% Povidone; (e) up to 5% Croscarmellose sodium; and (f) up to 1% Magnesium stearate.

50. A composition as claimed in claim 1, wherein a modified release portion comprises: (a) 80-90% Guaifenesin; (b) up to 5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) up to 10% Hypromellose; (d) up to 5% Carbomer; and (e) up to 1.55% Magnesium stearate.

51. A composition as claimed in claim 1, wherein a modified release portion comprises: (a) 80-90% Guaifenesin; (b) 3-6% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) up to 5% Hypromellose; (d) up to 2% Hydroxy ethylcellulose; (e) up to 5% Microcrystalline cellulose; and (f) up to 1% Magnesium stearate.

52. A composition as claimed in claim 1, wherein a modified release portion comprises: (a) 80-90% Guaifenesin; (b) 3-6% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) up to 5% Hypromellose; (d) up to 5% Hydroxy ethylcellulose; (e) up to 5% Microcrystalline cellulose; and (f) up to 1% Magnesium stearate.

53. A composition as claimed in claim 1, wherein a modified release portion comprises: (a) 85-90% Guaifenesin; (b) 4-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 3-6% Hypromellose; (d) 1-3% Carbomer; and (e) 0.5-1% Magnesium stearate.

54. A composition as claimed in claim 1, wherein a modified release portion comprises: (a) 90-93% Guaifenesin; (b) 4-6% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) 1-3% Carbomer; and (d) 0.5-1% Magnesium stearate.

Description

EXAMPLE 1

[0727]

TABLE-US-00001 Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110.0 mg 73.33% Microcrystalline Cellulose 34.45 mg 22.96% Povidone 4.50 mg  3.0% Mg Stearate 1.05 mg  0.7% Total Tablet 150.0 mg 100.0%

TABLE-US-00002 Tablet 2: Immediate/Sustained Release Dextromethorphan and Guaifenesin Ingredient mg/tablet % Weight Guaifenesin 600.0 mg 76.41% Hypromellose 50.00 mg  6.37% MCC 87.52 mg 11.15% Dextromethorphan HBr 30.0 mg  3.82% Carbomer 7.50 mg  0.96% Sodium Starch Glycolate 3.98 mg  0.51% Colourant 0.20 mg 0.025% Mg Stearate 6.0 mg  0.76% Total Tablet 785.2 mg 100.0%

EXAMPLE 2

[0728]

TABLE-US-00003 Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110.0 mg 51.16% Microcrystalline Cellulose 81.00 mg 37.67% Crospovidone 7.50 mg  3.49% Croscarmellose sodium 15.00 mg  6.98% Mg Stearate 1.50 mg  0.7% Total Tablet 215.0 mg 100.0%

TABLE-US-00004 Tablet 2: Immediate/Sustained Release Dextromethorphan and Guaifenesin Ingredient mg/tablet % Weight Guaifenesin 600.0 mg 74.77% Hypromellose 19.00 mg  2.37% MCC 129.40 mg 16.12% Dextromethorphan HBr 30.0 mg  3.74% Povidone 7.00 mg  0.87% Croscarmellose Sodium 6.00 mg  0.74% Hydroxy ethyl cellulose 9.00 mg  1.12% Colourant 0.20 mg 0.025% Mg Stearate 1.9 mg  0.24% Total Layer 802.5 mg 100.0%

EXAMPLE 3

[0729]

TABLE-US-00005 Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110.0 mg 73.33% Microcrystalline Cellulose 14.55 mg  9.7% Lactose 12.65 mg  8.4% Povidone 4.65 mg  3.1% Croscarmellose sodium 7.15 mg  4.8% Mg Stearate 1 mg  0.7% Total Tablet 150.0 mg 100.0%

TABLE-US-00006 Tablet 2: Immediate/Modified Release Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 200 mg  63.77% Dextromethorphan HBr 10 mg  3.19% Microcrystalline Cellulose 85 mg  27.10% Povidone 10 mg  3.19% Croscarmellose Sodium 8.5 mg  2.71% Mg Stearate 0.15 mg  0.05% Total Layer 313.65 mg 100.00%

TABLE-US-00007 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 400 mg  84.54% Dextromethorphan HBr 20 mg  4.23% Hypromellose (K100M) 24.5 mg  5.18% Hydroxyethylcellulose 12.25 mg  2.59% Microcrystalline Cellulose 14.75 mg  3.12% Colourant 0.1 mg  0.02% Mg Stearate 1.55 mg  0.33% Total Layer 473.15 mg 100.00% Total Tablet 786.8 mg  100.0%

EXAMPLE 4

[0730]

TABLE-US-00008 Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg 73.33% Microcrystalline Cellulose 6 mg  4.00% Lactose 5 mg  3.33% Povidone 3 mg  2.00% Sodium lauryl sulfate 25 mg 16.67% Mg Stearate 1 mg  0.67% Total Tablet 150.0 mg 100.0%

TABLE-US-00009 Tablet 2: Immediate/Modified Release Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 200 mg  63.77% Dextromethorphan HBr 10 mg  3.19% Microcrystalline Cellulose 85 mg  27.10% Povidone 10 mg  3.19% Croscarmellose Sodium 8.5 mg  2.71% Mg Stearate 0.15 mg  0.05% Total Layer 313.65 mg 100.00%

TABLE-US-00010 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 400 mg 84.54% Dextromethorphan HBr 20 mg  4.23% Hypromellose (K100M) 24.5 mg  5.18% Hydroxyethylcellulose 12.25 mg  2.59% Microcrystalline Cellulose 14.75 mg  3.12% Colourant 0.1 mg  0.02% Mg Stearate 1.55 mg  0.33% Total Layer 473.15 mg 100.00%  Total Tablet 786.8 mg 100.0%

EXAMPLE 5

[0731]

TABLE-US-00011 Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110.0 mg 73.33%  Microcrystalline Cellulose 14.55 mg 9.7% Lactose 12.65 mg 8.4% Povidone 4.65 mg 3.1% Croscarmellose sodium 7.15 mg 4.8% Mg Stearate 1 mg 0.7% Total Tablet 150.0 mg 100.0% 

TABLE-US-00012 Tablet 2: Immediate/Modified Release Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 130 mg 54.83% Dextromethorphan HBr 7.00 mg  2.95% Microcrystalline Cellulose 85.00 mg 35.85% Povidone 8.00 mg  3.37% Croscarmellose Sodium 7.00 mg  2.95% Mg Stearate 0.10 mg  0.04% Total Layer 237.10 mg 100.00% 

TABLE-US-00013 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 470 mg 86.35%  Dextromethorphan HBr 23 mg 4.23% Hypromellose (K100M) 17 mg 3.12% Hydroxyethylcellulose 17 mg 3.12% Microcrystalline Cellulose 15.5 mg 2.85% Colourant 0.1 mg 0.02% Mg Stearate 1.7 mg 0.31% Total Layer 544.3 mg 100.00%  Total Tablet 781.40 mg 100.0% 

EXAMPLE 6

[0732]

TABLE-US-00014 Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg 73.33% Microcrystalline Cellulose 6 mg  4.00% Lactose 5 mg  3.33% Povidone 3 mg  2.00% Sodium lauryl sulfate 25 mg 16.67% Mg Stearate 1 mg  0.67% Total Tablet 150.0 mg 100.0%

TABLE-US-00015 Tablet 2: Immediate/Modified Release Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 130 mg 54.83% Dextromethorphan HBr 7.00 mg  2.95% Microcrystalline Cellulose 85.00 mg 35.85% Povidone 8.00 mg  3.37% Croscarmellose Sodium 7.0 mg  2.95% Mg Stearate 0.10 mg  0.04% Total Layer 237.10 mg 100.00% 

TABLE-US-00016 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 470 mg 86.35%  Dextromethorphan HBr 23 mg 4.23% Hypromellose (K100M) 17 mg 3.12% Hydroxyethylcellulose 17 mg 3.12% Microcrystalline Cellulose 15.5 mg 2.85% Colourant 0.1 mg 0.02% Mg Stearate 1.7 mg 0.31% Total Layer 544.3 mg 100.00%  Total Tablet 781.40 mg 100.0% 

EXAMPLE 7

[0733]

TABLE-US-00017 Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg 73.33% Microcrystalline Cellulose 34.45 mg 22.97% Povidone 4.5 mg  3.00% Mg Stearate 1.05 mg  0.7% Total Tablet 150.0 mg 100.0%

TABLE-US-00018 Tablet 2: Immediate/Modified Release Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 85.5 mg 47.50% Dextromethorphan HBr 6.75 mg 3.75% Microcrystalline Cellulose 78.77 mg 43.76% Hypromellose 4.50 mg 2.50% Sodium Starch Glycolate 3.58 mg 1.99% Mg Stearate 0.90 mg 0.50% Total Layer 180.00 mg 100.00%

TABLE-US-00019 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 514.50 mg 88.83%  Dextromethorphan HBr 23.25 mg 4.03% Hypromellose 27.50 mg 4.75% Carbomer 8.25 mg 1.42% Colourant 0.22 mg 0.04% Mg Stearate 5.50 mg 0.95% Total Layer 579.22 mg 100.00%  Total Tablet 759.22 mg 100.0% 

EXAMPLE 8

[0734]

TABLE-US-00020 Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg 73.33% Microcrystalline Cellulose 34.45 mg 22.97% Povidone 4.5 mg  3.00% Mg Stearate 1.05 mg  0.7% Total Tablet 150.0 mg 100.0%

TABLE-US-00021 Tablet 2: Immediate/Modified Release Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 76.00 mg 47.50% Dextromethorphan HBr 6.00 mg 3.75% Microcrystalline Cellulose 70.02 mg 43.76% Hypromellose 4.00 mg 2.50% Sodium Starch Glycolate 3.18 mg 1.99% Mg Stearate 0.80 mg 0.50% Total Layer 160.00 mg 100.00%

TABLE-US-00022 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 424.00 mg 91.74%  Dextromethorphan HBr 24.00 mg 5.19% Carbomer 9.90 mg 2.14% Colourant 0.26 mg 0.06% Mg Stearate 4.00 mg 0.87% Total Layer 462.16 mg 100.00%  Total Tablet 622.16 mg 100.0% 

EXAMPLE 9

[0735]

TABLE-US-00023 Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg 73.33%  Microcrystalline Cellulose 14.5 mg 9.67% Povidone 4.75 mg 3.17% Mg Stearate 0.75 mg  0.7% Lactose 10.00 mg 6.67% Croscarmellose Sodium 10.00 mg 6.67% Total Tablet 150.0 mg 100.0% 

TABLE-US-00024 Tablet 2: Immediate/Modified Release Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 85.5 mg 47.50% Dextromethorphan HBr 6.75 mg 3.75% Microcrystalline Cellulose 78.77 mg 43.76% Hypromellose 4.50 mg 2.50% Sodium Starch Glycolate 3.58 mg 1.99% Mg Stearate 0.90 mg 0.50% Total Layer 180.00 mg 100.00%

TABLE-US-00025 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 514.50 mg 88.83%  Dextromethorphan HBr 23.25 mg 4.03% Hypromellose 27.50 mg 4.75% Carbomer 8.25 mg 1.42% Colourant 0.22 mg 0.04% Mg Stearate 5.50 mg 0.95% Total Layer 579.22 mg 100.00%  Total Tablet 759.22 mg 100.0% 

EXAMPLE 10

[0736]

TABLE-US-00026 Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg 73.33%  Microcrystalline Cellulose 14.5 mg 9.67% Povidone 4.75 mg 3.17% Mg Stearate 0.75 mg  0.7% Lactose 10.00 mg 6.67% Croscarmellose Sodium 10.00 mg 6.67% Total Tablet 150.0 mg 100.0% 

TABLE-US-00027 Tablet 2: Immediate/Modified Release Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 76.00 mg 47.50% Dextromethorphan HBr 6.00 mg 3.75% Microcrystalline Cellulose 70.02 mg 43.76% Hypromellose 4.00 mg 2.50% Sodium Starch Glycolate 3.18 mg 1.99% Mg Stearate 0.80 mg 0.50% Total Layer 160.00 mg 100.00%

TABLE-US-00028 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 424.00 mg 91.74%  Dextromethorphan HBr 24.00 mg 5.19% Carbomer 9.90 mg 2.14% Colourant 0.26 mg 0.06% Mg Stearate 4.00 mg 0.87% Total Layer 462.16 mg 100.00%  Total Tablet 622.16 mg 100.0% 

EXAMPLE 11

[0737]

TABLE-US-00029 Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg 72.37%  Microcrystalline Cellulose 9.25 mg 6.09% Povidone 4.75 mg 3.13% Mg Stearate 1.00 mg 0.66% Sodium Lauryl Sulphate 25.00 mg 16.45%  Croscarmellose Sodium 2.00 mg 1.32% Total Tablet 150.0 mg 100.0% 

TABLE-US-00030 Tablet 2: Immediate/Modified Release Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 85.5 mg 47.50% Dextromethorphan HBr 6.75 mg 3.75% Microcrystalline Cellulose 78.77 mg 43.76% Hypromellose 4.50 mg 2.50% Sodium Starch Glycolate 3.58 mg 1.99% Mg Stearate 0.90 mg 0.50% Total Layer 180.00 mg 100.00%

TABLE-US-00031 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 514.50 mg 88.83%  Dextromethorphan HBr 23.25 mg 4.03% Hypromellose 27.50 mg 4.75% Carbomer 8.25 mg 1.42% Colourant 0.22 mg 0.04% Mg Stearate 5.50 mg 0.95% Total Layer 579.22 mg 100.00%  Total Tablet 759.22 mg 100.0% 

EXAMPLE 12

[0738]

TABLE-US-00032 Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg 72.37%  Microcrystalline Cellulose 9.25 mg 6.09% Povidone 4.75 mg 3.13% Mg Stearate 1.00 mg 0.66% Sodium Lauryl Sulphate 25.00 mg 16.45%  Croscarmellose Sodium 2.00 mg 1.32% Total Tablet 150.0 mg 100.0% 

TABLE-US-00033 Tablet 2: Immediate/Modified Release Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 76.00 mg 47.50% Dextromethorphan HBr 6.00 mg 3.75% Microcrystalline Cellulose 70.02 mg 43.76% Hypromellose 4.00 mg 2.50% Sodium Starch Glycolate 3.18 mg 1.99% Mg Stearate 0.80 mg 0.50% Total Layer 160.00 mg 100.00%

TABLE-US-00034 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 424.00 mg 91.74%  Dextromethorphan HBr 24.00 mg 5.19% Carbomer 9.90 mg 2.14% Colourant 0.26 mg 0.06% Mg Stearate 4.00 mg 0.87% Total Layer 462.16 mg 100.00%  Total Tablet 622.16 mg 100.0% 

EXAMPLE 13

Composite Tablet

[0739]

TABLE-US-00035 Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 140 mg 28.58%  Dextromethorphan HBr 8 mg 1.63% Naproxen Sodium 110 mg 22.45%  Microcrystalline Cellulose 60 mg 12.24%  Povidone 11 mg 2.25% Croscarmellose sodium 26 mg 5.31% Crospovidone 9.8 mg 2.00% Sodium lauryl sulfate 25 mg 5.10% Bicarbonate 100 mg 20.41%  Mg Stearate 0.1 mg 0.02% Total Tablet 489.9 mg 100.0% 

TABLE-US-00036 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 460 mg 84.73%  Dextromethorphan HBr 22 mg 4.05% Hypromellose 28 mg 5.16% Hydroxy ethyl cellulose 14 mg 2.58% Microcrystalline Cellulose 17 mg 3.13% Colourant 0.1 mg 0.02% Mg Stearate 1.8 mg 0.33% Total Layer 542.9 mg 100.0% 

EXAMPLE 14

Composite Tablet

[0740]

TABLE-US-00037 Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 200 mg 45.25% Dextromethorphan HBr 10 mg  2.26% Naproxen Sodium 110 mg 24.89% Microcrystalline Cellulose 45 mg 10.18% Povidone 11 mg  2.49% Crospovidone 65 mg 14.71% Mg Stearate 1 mg  0.23% Total Tablet 442 mg 100.0%

TABLE-US-00038 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 400 mg 84.54%  Dextromethorphan HBr 20 mg 4.23% Hypromellose 24.5 mg 5.18% Hydroxy ethyl cellulose 12.25 mg 2.59% Microcrystalline Cellulose 14.75 mg 3.12% Colourant 0.1 mg 0.02% Mg Stearate 1.55 mg 0.33% Total Layer 473.15 mg 100.0% 

EXAMPLE 15

Composite Tablet

[0741]

TABLE-US-00039 Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 95 mg 24.26%  Dextromethorphan HBr 7.5 mg 1.92% Naproxen Sodium 110 mg 28.09%  Microcrystalline Cellulose 60 mg 15.32%  Povidone 11 mg 2.81% Croscarmellose sodium 15 mg 3.83% Crospovidone 8.00 mg 2.00% Sodium Lauryl Sulfate 25 mg 5.10% Sodium Bicarbonate 60 mg 20.41%  Mg Stearate 0.1 mg 0.03% Total Layer 391.6 mg 100.0% 

TABLE-US-00040 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 505 mg 89.35%  Dextromethorphan HBr 22.5 mg 3.98% Hypromellose 25 mg 4.42% Carbomer 7.5 mg 1.33% Colourant 0.2 mg 0.04% Mg Stearate 5.0 mg 0.88% Total Layer 565.2 mg 100.0% 

EXAMPLE 16

Composite Tablet

[0742]

TABLE-US-00041 Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 95 mg 27.34% Dextromethorphan HBr 7.5 mg  2.16% Naproxen Sodium 110 mg 31.65% Microcrystalline Cellulose 75 mg 21.58% Povidone 11 mg  3.17% Croscarmellose sodium 40 mg 11.51% Crospovidone 8.00 mg  2.30% Mg Stearate 1 mg  0.29% Total 347.5 mg 100.0%

Modified Release Layer

[0743]

TABLE-US-00042 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 505 mg 89.35%  Dextromethorphan HBr 22.5 mg 3.98% Hypromellose 25 mg 4.42% Carbomer 7.5 mg 1.33% Colourant 0.2 mg 0.04% Mg Stearate 5.0 mg 0.88% Total Layer 565.2 mg 100.0% 

EXAMPLE 17

Composite Tablet

[0744]

TABLE-US-00043 Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 95 mg 24.32%  Dextromethorphan HBr 7.5 mg 1.92% Naproxen Sodium 110 mg 28.16%  Microcrystalline Cellulose 60 mg 15.36%  Povidone 11 mg 2.82% Croscarmellose sodium 22 mg 5.63% Sodium Lauryl Sulphate 25.00 mg 6.40% Sodium Bicarbonate 60.00 mg 15.36%  Mg Stearate 0.1 mg 0.03% Total 390.6 mg 100.0% 

TABLE-US-00044 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 505 mg 89.35%  Dextromethorphan HBr 22.5 mg 3.98% Hypromellose 25 mg 4.42% Carbomer 7.5 mg 1.33% Colourant 0.2 mg 0.04% Mg Stearate 5.0 mg 0.88% Total Layer 565.2 mg 100.0% 

EXAMPLE 18

Composite Tablet

[0745]

TABLE-US-00045 Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 95 mg 27.98% Dextromethorphan HBr 7.5 mg  2.21% Naproxen Sodium 110 mg 32.40% Microcrystalline Cellulose 75 mg 22.09% Povidone 11 mg  3.24% Croscarmellose sodium 40 mg 11.78% Mg Stearate 1 mg  0.29% Total 339.5 mg 100.0%

TABLE-US-00046 Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 505 mg  89.35%  Dextromethorphan HBr 22.5 mg  3.98% Hypromellose  25 mg 4.42% Carbomer 7.5 mg 1.33% Colourant 0.2 mg 0.04% Mg Stearate 5.0 mg 0.88% Total Layer 565.2 mg  100.0% 

[0746] The tablets of the example embodiments of the present invention can be made using standard tableting procedures well-known to the person skilled in the art.

[0747] The bi-layer tablet may be manufactured according to any method known to those of skill in the art. The resulting tablet may comprise the two portions compressed against one another so that the face of each portion is exposed as either the top or bottom of the tablet, or the resulting tablet may comprise the sustained release portion in the centre coated by the immediate release portion so that only the immediate release portion is exposed. In a preferred embodiment, a bi-layer tablet of the present invention comprises the two portions compressed against one another so that the face of each portion is exposed.

[0748] The final dosage form can be made by inserting both the immediate-release naproxen tablet and the immediate-release/sustained or modified release guaifenesin/dextromethorphan tablet into a gelatin capsule which is then sealed.

[0749] Furthermore, the composite tablets of Examples 3 and 4 are final dosage forms and need not, though they can, be inserted into a suitable capsule.

[0750] An advantage of the present invention is that there is provided a composition that provides multi-symptom cough/cold/flu relief for 12 hours. Currently, there are no other products that offer all of these significant benefits to consumers.

[0751] A further advantage is that there is provided a composition which comprises naproxen, guaifenesin and dextromethorphan in a single dose yet avoids any impact on the dissolution rate of either guaifenesin or dextromethorphan by naproxen.

[0752] The composition of the present invention also provides for more consistent release of both guaifenesin and dextromethorphan when compared to known products in various pH conditions and when exposed to various agitation speeds. For example purposes only, these novel formulations have been shown to improve the consistency of dextromethorphan release after 6 hours by 29% and guaifenesin release after 6 hours by 52% and 71%.

[0753] Further modifications and improvements can be made without departing from the scope of the invention described herein.