Sustained release formulations of guaifenesin and additional drug ingredients

• US 20030049318A1
• Filed: 04/15/2002
• Published: 03/13/2003
• Est. Priority Date: 04/28/2000
• Status: Active Grant

• Current Assignee: RB Health (US) LLC (Reckitt Benckiser Group PLC)
• Original Assignee: Adams Respiratory Therapeutics Incorporated (Reckitt Benckiser Group PLC)
• Inventors: Blume, Ralph W., Keyser, Donald Jeffrey, Davis, Robert D.
• Granted Patent: US 6,955,821 B2
• Time in Patent Office: Days
• US Class Current: 424/468
• 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 31/09 having two or more such linkages
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• 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 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 11/10 Expectorants

Abstract

The invention relates to a novel pharmaceutical sustained release formulation of guaifenesin and at least one additional drug ingredient. The formulation may comprise a hydrophilic polymer, preferably a hydroxypropyl methylcellulose, and a water-insoluble polymer, preferably an acrylic resin, in a ratio range of about one-to-one (1:1) to about nine-to-one (9:1), more preferably a range of about three-to-two (3:2) to about six-to-one (6:1), and most preferably in a range of about two-to-one (2:1) to about four-to-one (4:1) by weight. This formulation capable of providing therapeutically effective bioavailability of guaifenesin for at least twelve hours after dosing in a human subject. The invention also relates to a modified release product which has two portions: a first portion having an immediate release formulation of guaifenesin and a second portion having a sustained release formulation of guaifenesin, wherein one or both portions has at least one additional drug ingredient. The modified release product has a maximum guaifenesin serum concentration equivalent to that of an immediate release guaifenesin tablet, and is capable of providing therapeutically effective bioavailability of guaifenesin for at least twelve hours after dosing in a human subject.

Claims

1. A modified release drug product comprising two portions, a first portion comprising a first quantity of guaifenesin in an immediate release formulation wherein the guaifenesin becomes bioavailable in the subject'"'"'s stomach;

and a second portion comprising a second quantity of guaifenesin, a first quantity of at least one additional drug ingredient, and a release-delaying matrix,

wherein the release-delaying matrix comprises a hydrophilic polymer and a water-insoluble polymer in a weight ratio of hydrophilic polymer to water-insoluble polymer from about 1;

1 to about 9;

1,

wherein the guaifenesin has a C_max in a human subject equivalent to the C_max obtained when the first of three doses of a standard immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period, and releases therapeutically effective bioavailable guaifenesin dose for at least twelve hours after a single dose in a human subject according to serum analysis.

2. The modified release drug product according to claim 1, wherein the hydrophilic polymer is acacia, gum tragacanth, locust bean gum, guar gum, karaya gum, modified cellulosic, methylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose, agar, pectin, carrageen, alginate, carboxypolymethylene, gelatin, casein, zein, bentonite, magnesium aluminum silicate, polysaccharide, modified starch derivatives, or a combination thereof.

3. The modified release drug product according to claim 1, wherein the water-insoluble polymer is polyacrylic acid, acrylic resin, acrylic latex dispersion, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, or a combination thereof.

4. The modified release drug product according to claim 1, wherein the hydrophilic polymer is hydroxypropyl methylcellulose and the water-insoluble polymer is an acrylic resin.

5. The modified release drug product according to claim 1, wherein the first portion further comprises at least one additional drug ingredient.

6. The modified release drug product according to claim 1, wherein the additional drug ingredient is an antitussive, a decongestant, an antihistamine, an analgesic, or combinations thereof.

7. The modified release drug product according to claim 6, wherein the additional drug ingredient is dextromethorphan hydrobromide, codeine, hydrocodone, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, chlorpheniramine maleate, brompheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, clemastine fumerate, aspirin, ibuprofen, acetaminophen, naprosin, or combinations thereof.

8. The modified release drug product according to claim 6, wherein the additional drug ingredient is dextromethorphan hydrobromide, pseudoephedrine hydrochloride, or a combination thereof.

9. The modified release drug product according to claim 1, further comprising binders, colorants, excipients, glidants, lubricants, preservatives, stabilizers, surface active ingredients, or combinations thereof.

10. The modified release drug product according to claim 9, wherein the lubricant is magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oil, talc, polyethylene glycol, mineral oil, or a combination thereof.

11. The modified release drug product according to claim 9, wherein the binder is sucrose, lactose, gelatin, starch paste, acacia, tragacanth, povidone, polyethylene glycol, Pullulan, corn syrup, or a combination thereof.

12. The modified release drug product according to claim 9, wherein the glidant is colloidal silicon dioxide, talc, or a combination thereof.

13. The modified release drug product according to claim 9, wherein the surface active agent is sodium lauryl sulfate, dioctyl sodium sulfosuccinate, triethanolamine, polyoxyethylene sorbitan, poloxalkol, quaternary ammonium salts, or a combination thereof.

14. The modified release drug product according to claim 9, wherein the excipient is mannitol, glucose, fructose, xylose, galactose, maltose, xylitol, sorbitol, potassium chloride, potassium sulfate, potassium phosphate, sodium chloride, sodium sulfate, sodium phosphate, magnesium chloride, magnesium sulfate, magnesium phosphate, microcrystalline cellulose, sodium starch glycolate, or a combination thereof.

15. The modified release drug product according to claim 9, wherein colorant is Emerald Green Lake, FD&

C Red #40, FD&

C Yellow #6, FD&

C Yellow #10, FD&

C Blue #1, or a combination thereof.

16. The modified release drug product according to claim 1, wherein the first portion further comprises microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.

17. The modified release drug product according to claim 1, wherein the total quantity of guaifenesin is from about 600 mg to about 1200 mg.

18. The modified release drug product according to claim 1, wherein the ratio of the total quantity of guaifenesin to the additional drug is from about 1:

1 to about 4;

1 by weight.

19. The modified release drug product according to claim 1, wherein the ratio of the total quantity of guaifenesin to the additional drug is from about 3:

2 to about 9;

1 by weight.

20. The modified release drug product according to claim 1 or 17, wherein the ratio of the first quantity of guaifenesin to the second quantity of guaifenesin is about 1:

1 to about 1;

49 by weight.

21. The modified release drug product according to claim 1 or 17, wherein the ratio of the first quantity of guaifenesin to the second quantity of guaifenesin is from about 2:

3 to about 1;

19.

22. The modified release drug product according to claim 17, wherein guaifenesin within the tablet has a C_max of at least about 1900 μ

g/ml and an AUC_inf of at least 7000 hr*μ

g/ml.

23. The modified release drug product according to claim 17, wherein guaifenesin within the tablet has a C_max of at least 1000 μ

g/ml and an AUC_inf of at least 3500 hr*μ

g/ml.

24. The modified release drug product according to claim 1, wherein the tablet has a half life of at least 3 hours as determined by serum analysis.

25. The modified release drug product according to claim 1, wherein the second portion comprises about 75% to about 95% by weight of guaifenesin, from about 1% to about 15% of the additional drug ingredient, from about 1% to about 10% of the hydrophilic polymer, and about 0.5% to about 2.5% water-insoluble polymer by weight.

26. The modified release drug product according to claim 1, wherein the first and second portions each comprise abutting substantially planar layers which form a bilayer tablet.

27. The modified release drug product according to claim 1, wherein the second portion is coated by a layer of the first portion.

28. The modified release drug product according to claim 17, wherein the second portion comprises from about 80% to about 90% by weight of guaifenesin, from about 3% to about 10% by weight of a additional drug ingredient, from about 2% to about 5% of the hydroxypropyl cellulose, and from about 1% to about 1.5% by weight of an acrylic resin.

66. A method of treating or preventing coughing and symptoms or diseases associated with coughing which comprises administering to a subject in need of such treatment or prevention a therapeutically or prophylactically effective amount of a drug release product according to claim 1 effective to treat or prevent coughing and symptoms or diseases associated with coughing in the subject.

67. The method according to claim 66, wherein the drug release product is administered orally.

68. The method according to claim 66, wherein the hydrophilic polymer is acacia, gum tragacanth, locust bean gum, guar gum, karaya gum, modified cellulosic, methylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose, agar, pectin, carrageen, alginate, carboxypolymethylene, gelatin, casein, zein, bentonite, magnesium aluminum silicate, polysaccharide, modified starch derivatives, or a combination thereof.

69. The method according to claim 66, wherein the water-insoluble polymer is polyacrylic acid, acrylic resin, acrylic latex dispersion, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, or a combination thereof.

70. The method according to claim 66, wherein the hydrophilic polymer is hydroxypropyl methylcellulose and the water-insoluble polymer is an acrylic resin.

71. The method according to claim 66, wherein the first portion further comprises at least one additional drug ingredient.

72. The method according to claim 66, wherein the additional drug ingredient is an antitussive, a decongestant, an antihistamine, an analgesic, or combinations thereof.

73. The method according to claim 72, wherein the additional drug ingredient is dextromethorphan hydrobromide, codeine, hydrocodone, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, chlorpheniramine maleate, brompheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, clemastine fumerate, aspirin, ibuprofen, acetaminophen, naprosin, or combinations thereof.

74. The method according to claim 72, wherein the additional drug ingredient is dextromethorphan hydrobromide, pseudoephedrine hydrochloride, or a combination thereof.

75. The method according to claim 66, wherein the total quantity of guaifenesin is from about 600 mg to about 1200 mg.

76. The method according to claim 66, wherein the ratio of the total quantity of guaifenesin to the additional drug is from about 1:

1 to about 4;

1 by weight.

77. The method according to claim 66, wherein the ratio of the first quantity of guaifenesin to the second quantity of guaifenesin is about 1:

1 to about 1;

49 by weight.

78. The method according to claim 66, wherein guaifenesin within the tablet has a C_max of at least about 1900 μ

g/ml and an AUC_inf of at least 7000 hr*μ

g/ml.

79. The method according to claim 66, wherein the second portion comprises about 75% to about 95% by weight of guaifenesin, from about 1% to about 15% of the additional drug ingredient, from about 1% to about 10% of the hydrophilic polymer, and about 0.5% to about 2.5% water-insoluble polymer by weight.

29. A modified release drug product comprising two portions, a first portion comprising a first quantity of guaifenesin in an immediate release formulation wherein the guaifenesin becomes bioavailable in the subject'"'"'s stomach;

and a second portion comprising a second quantity of guaifenesin and at least one additional drug ingredient in a sustained release form

wherein the guaifenesin has a C_max in a human subject equivalent to the C_max obtained when the first of three doses of a standard immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period and wherein the product provides a therapeutically effective bioavailable guaifenesin dose for at least twelve hours after a single dose in a human subject according to serum analysis and a therapeutically effective bioavailable dose of the additional drug ingredient.

30. The modified release drug product according to claim 29, wherein the total quantity of guaifenesin is from about 600 mg to about 1200 mg.

31. The modified release drug product according to claim 29, wherein the additional drug ingredient is an antitussive, a decongestant, an antihistamine, an analgesic, or combinations thereof.

32. The modified release drug product according to claim 31, wherein the additional drug ingredient is dextromethorphan hydrobromide, codeine, hydrocodone, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, chlorpheniramine maleate, brompheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, clemastine fumerate, acetaminophen, aspirin, ibuprofen, naprosin, or combinations thereof.

33. The modified release drug product according to claim 29, wherein the additional drug ingredient is dextromethorphan hydrobromide, pseudoephedrine hydrochloride, or a combination thereof.

34. The modified release drug product according to claim 29, wherein the ratio of the total quantity of guaifenesin to the additional drug is from about 1:

1 to about 4;

1 by weight.

35. The modified release drug product according to claim 29, wherein the ratio of the total quantity of guaifenesin to the additional drug is from about 3:

2 to about 9;

1 by weight.

36. The modified release drug product of claim 29, wherein the ratio of the first quantity of guaifenesin to the second quantity of guaifenesin is about 1:

1 to about 1;

49.

37. The modified release drug product to claim 29, wherein the ratio of the first quantity of guaifenesin to the second quantity of guaifenesin is about 2:

3 to about 1;

19.

38. The modified release drug product according to claim 30, wherein guaifenesin has a C_max from about 1600 to 2500 μ

g/ml and an AUC_inf of about 5600 to 8750 hr*μ

g/ml.

39. The modified release drug product according to claim 30, wherein the guaifenesin has a C_max of at least 1900 μ

g/ml and an AUC_inf of at least 7000 hr*μ

g/ml.

40. The modified release drug product according to claim 30, wherein the guaifenesin has a C_max of about 800 to 1250 μ

g/ml and an AUC_inf of about 2800 to 4375 hr*μ

g/ml.

41. The modified release drug product according to claim 30, wherein the guaifenesin has a C_max of at least 1000 μ

g/ml and an AUC_inf of at least 3500 hr*μ

g/ml.

42. The modified release drug product according to claim 29, wherein the guaifenesin has a half life of at least three hours as determined by serum analysis.

43. The modified release drug product according to claim 29, wherein the first and second portions each comprise abutting substantially planar layers which form a bilayer tablet.

44. The modified release drug product according to claim 29, wherein the second portion is coated by a layer of the first portion.

45. The modified release drug product according to claim 29, wherein the product is shaped as a capsule and contains the first and second portions.

46. The modified release drug product according to claim 29, which is approximately equally effective when administered to a patient on an empty or full stomach.

47. The modified release drug product according to claim 30, wherein the product has a guaifenesin serum concentration profile of FIG. 10.

48. A drug release product comprising two portions, a first portion comprising a first quantity of guaifenesin in an immediate release formulation wherein guaifenesin becomes bioavailable in the subject'"'"'s stomach;

and a second portion comprising a second quantity of guaifenesin and a first quantity of at least one additional drug ingredient in a sustained release formulation

wherein the ratio of the first quantity to the second quantity of guaifenesin is about 1;

1 to about 1;

49, the product provides a guaifenesin C_max in a human subject equivalent to the C_max obtained when the first of three doses of a standard immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period, and the product provides a therapeutically effective bioavailable guaifenesin for at least twelve hours after a single dose in a human subject according to serum analysis and a therapeutically effective amount of the additional drug ingredient.

49. The drug release product according to claim 48, wherein the total quantity of guaifenesin is from about 600 mg to about 1200 mg.

50. The drug release product according to claim 48, wherein the additional drug ingredient is an antitussive, decongestant, antihistamine, analgesic, or combinations thereof.

51. The drug release product according to claim 50, wherein the additional drug ingredient is dextromethorphan hydrobromide, codeine, hydrocodone, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, chlorpheniramine maleate, brompheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, clemastine fumerate, acetaminophen, aspirin, ibuprofen, naprosin, or combinations thereof.

52. The drug release product according to claim 50, wherein the additional drug ingredient is dextromethorphan hydrobromide, pseudoephedrine hydrochloride, or a combination thereof.

53. The drug release product according to claim 48, wherein the ratio of the total quantity of guaifenesin to the additional drug is from about 1:

1 to about 4;

1 by weight.

54. The drug release product according to claim 48, wherein the ratio of the total quantity of guaifenesin to the additional drug is from about 3:

2 to about 9;

1 by weight.

55. The drug release product according to claim 48, wherein the ratio of the first quantity of guaifenesin to the quantity of second quantity of guaifenesin is from about 2:

3 to about 1;

19.

56. The drug release product according to claim 48, wherein the guaifenesin C_max of the product is from about 1600 to 2500 μ

g/ml and the AUC_inf is from about 5600 to 8750 hr*μ

g/ml.

57. The drug release product according to claim 48, wherein the guaifenesin C_max is at least 1900 μ

g/ml and the AUC_inf is at least 7000 hr*μ

g/ml.

58. The drug release product according to claim 48, wherein the guaifenesin C_max is about 800 to 1250 μ

g/ml and the AUC_inf is from about 2800 to 4375 hr*μ

g/ml.

59. The drug release product according to claim 48, wherein the guaifenesin C_max is at least 1000 μ

g/ml and the AUC_inf is at least 3500 hr*μ

g/ml.

60. The drug release product according to claim 48, wherein the guaifenesin has a half life of at least three hours as determined by serum analysis.

61. The drug release product according to claim 48, wherein the first and second portions each comprise abutting substantially planar layers which form a bilayer tablet.

62. The drug release product according to claim 48, wherein the second portion is coated by a layer of the first portion.

63. The drug release product according to claim 48, wherein the product is shaped as a capsule containing the first and second portions.

64. The drug release product according to claim 48, which is approximately equally effective when administered to a patient on an empty or full stomach.

65. The drug release product according to claim 48, which has the serum guaifenesin concentration profile of FIG. 10.

80. A method of treating or preventing coughing and symptoms or diseases associated with coughing which comprises administering to a subject in need of such treatment or prevention a therapeutically or prophylactically effective amount of a modified release drug product comprising two portions, a first portion comprising a first quantity of guaifenesin in an immediate release formulation wherein the guaifenesin becomes bioavailable in the subject'"'"'s stomach;

and a second portion comprising a second quantity of guaifenesin, a first quantity of at least one additional drug ingredient, and a release-delaying matrix,

wherein the release-delaying matrix comprises a hydrophilic polymer and a water-insoluble polymer in a weight ratio of hydrophilic polymer to water-insoluble polymer from about 1;

1 to about 9;

1,

wherein the guaifenesin has a C_max in a human subject equivalent to the C_max obtained when the first of three doses of a standard immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period, and releases therapeutically effective bioavailable guaifenesin dose for at least twelve hours after a single dose in a human subject according to serum analysis.

81. A method of treating or preventing coughing and symptoms or diseases associated with coughing which comprises administering to a subject in need of such treatment or prevention a therapeutically or prophylactically effective amount of a drug release product having two portions, wherein a first portion comprises a first quantity of guaifenesin in an immediate release form which becomes fully bioavailable in the subject'"'"'s stomach and a second portion comprises a second quantity of guaifenesin and a release-delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer wherein the weight ratio of said hydrophilic polymer to said water-insoluble polymer is in the range of from about 1:

1 to about 6.8;

1, wherein said tablet demonstrates a C_max in a human subject equivalent to the C_max obtained when the first of three doses of a standard immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period, and wherein said tablet also provides therapeutically effective bioavailability for at least twelve hours after a single dose in a human subject according to serum analysis.

82. The method according to claim 81, wherein the drug release product is administered orally.

83. The method according to claim 81, wherein the hydrophilic polymer is acacia, gum tragacanth, locust bean gum, guar gum, karaya gum, modified cellulosic, methylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose, agar, pectin, carrageen, alginate, carboxypolymethylene, gelatin, casein, zein, bentonite, magnesium aluminum silicate, polysaccharide, modified starch derivatives, or a combination thereof.

84. The method according to claim 81, wherein the water-insoluble polymer is polyacrylic acid, acrylic resin, acrylic latex dispersion, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, or a combination thereof.

85. The method according to claim 81, wherein the hydrophilic polymer is hydroxypropyl methylcellulose and the water-insoluble polymer is an acrylic resin.

86. The method according to claim 81, wherein the ratio of the first quantity of guaifenesin to the second quantity of guaifenesin is about 1:

1 to about 1;

49 by weight.

87. The method according to claim 81, wherein guaifenesin within the tablet has a C_max of at least about 1900 μ

g/ml and an AUC_inf of at least 7000 hr*μ

g/ml.