Sustained release formulations of guaifenesin and additional drug ingredients

• US 6,955,821 B2
• Filed: 04/15/2002
• Issued: 10/18/2005
• Est. Priority Date: 04/28/2000
• Status: Expired due to Term

• Current Assignee: RB Health (US) LLC (Reckitt Benckiser Group PLC)
• Original Assignee: Adams Laboratories, Inc.
• Inventors: Blume, Ralph W., Keyser, Donald Jeffrey, Davis, Robert D.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): TRAN, SUSAN T
• Application Number:
  US10/121,706
• Publication Number:
  US 20030049318A1
• Time in Patent Office: 1,282 Days
• Field of Search: 424/451, 424/452, 424/457, 424/458, 424/464, 424/465, 424/468, 424/469, 424/400, 424/439, 424/453, 424/472, 424/474, 424/489, 424/490, 514/849, 514/850, 514/962, 514/963
• 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 a first quantity of guaifenesin in an immediate release formulation wherein the guaifenesin becomes bioavailable in a subject'"'"'s stomach;

a second quantity of guaifenesin in a release-delaying matrix; and

at least one additional drug,

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 immediate release formulation guaifenesin has a C_max in a human subject equivalent to the C_max obtained when a dose of a standard immediate release formulation having one third the amount of guaifenesin is dosed, and immediately after administration the serum concentration of guaifenesin peaks in about an hour, followed by a gradual serum concentration decrease over twenty-four hours but the serum concentration of guaifenesin never decreases below the minimum concentration of said standard immediate release formulation over twelve hours, and

wherein the drug product releases a therapeutically effective bioavailable guaifenesin dose for at least twelve hours after a single dose in the 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 immediate release formulation, release-delaying matrix, or both further comprises the at least one additional drug.

6. The modified release drug product according to claim 1, wherein the additional drug 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 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 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 agents, 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 the 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 immediate release formulation further comprises microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.

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

18. The modified release drug product according to claim 1, wherein a ratio of a 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 a ratio of a 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 a 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 a 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 has a C_max of at least about 1900 ng/ml and an AUC_inf of at least 7000 hr*ng/ml.

23. The modified release drug product according to claim 17, wherein guaifenesin has a C_max of at least 1000 ng/ml and an AUC_inf of at least 3500 hr*ng/ml.

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

26. The modified release drug product according to claim 1, wherein the immediate release formulation and the release-delaying matrix each comprise abutting substantially planar layers which form a bilayer tablet.

27. The modified release drug product according to claim 1, wherein the release-delaying matrix is coated by a layer of the immediate release formulation.

28. The modified release drug product according to claim 17, wherein the release-delaying matrix comprises from about 80% to about 90% by weight of guaifenesin, from about 3% to about 10% by weight of the additional drug, from about 2% to about 5% of the hydrophilic polymer, and from about 1% to about 1.5% by weight of the water-insoluble polymer.

61. A method of treating coughing and symptoms or diseases associated with coughing which comprises administering to a subject in need of such treatment a therapeutically effective amount of a modified release drug product according to claim 1, 43 or 29 effective to treat coughing and symptoms or diseases associated with coughing in the subject.

62. The method according to claim 61, wherein the drug product is administered orally.

63. The method according to claim 61, wherein the additional drug is an antitussive, a decongestant, an antihistamine, an analgesic, or combinations thereof.

64. The method according to claim 63, wherein the additional drug 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.

65. The method according to claim 63, wherein the additional drug is dextromethorphan hydrobromide, pseudoephedrine hydrochloride, or a combination thereof.

66. The method according to claim 61, wherein a total quantity of guaifenesin is from about 600 mg to about 1200 mg.

67. The method according to claim 61, wherein a ratio of a total quantity of guaifenesin to the additional drug is from about 1:

1 to about 4;

1 by weight.

68. The method according to claim 61, wherein a ratio of the first quantity of guaifenesin to the second quantity of guaifenesin is about 1:

1 to about 1;

49 by weight.

69. The method according to claim 61, wherein guaifenesin has a C_max of at least about 1900 ng/ml and an AUC_inf of at least 7000 hr*ng/ml.

74. The modified release drug product according to claim 1 or 43, wherein a ratio of a total quantity of guaifenesin to the additional drug is from about 3:

1 to about 20;

1 by weight.

75. The modified release drug product according to claim 1 or 43, wherein the guaifenesin has a half life of at least 1.3 hours as determined by serum analysis.

77. The method according to claim 61, wherein a ratio of a total quantity of guaifenesin to the additional drug is from about 3:

1 to about 20;

1 by weight.

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

a second quantity of guaifenesin in a sustained release form,

wherein the sustained release form 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 immediate release formulation guaifenesin has a C_max in a human subject equivalent to the C_max obtained when a dose of a standard immediate release formulation having one third the amount of guaifenesin is dosed, and immediately after administration the serum concentration of guaifenesin peaks in about an hour, followed by a gradual serum concentration decrease over twenty-four hours but the serum concentration of guaifenesin never decreases below the minimum concentration of said standard immediate release formulation over twelve hours, and

wherein the drug product releases a therapeutically effective bioavailable guaifenesin dose for at least twelve hours after a single dose in the human subject according to serum analysis.

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

31. The modified release drug product of claim 30, wherein a ratio of the first quantity of guaifenesin to the second quantity of guaifenesin is about 1:

1 to about 1;

49.

32. The modified release drug product of claim 30, wherein a ratio of the first quantity of guaifenesin to the second quantity of guaifenesin is about 2:

3 to about 1;

19.

33. The modified release drug product according to claim 30, wherein guaifenesin has a C_max from about 1600 to 2500 ng/ml and an AUC_inf of about 5600 to 8750 hr*ng/ml.

34. The modified release drug product according to claim 30, wherein the guaifenesin has a C_max of at least 1900 ng/ml and an AUC_inf of at least 7000 hr*ng/ml.

35. The modified release drug product according to claim 30, wherein the guaifenesin has a C_max of about 800 to 1250 ng/ml and an AUC_inf of about 2800 to 4375 hr*ng/ml.

36. The modified release drug product according to claim 30, wherein the guaifenesin has a C_max of at least 1000 ng/ml and an AUC_inf of at least 3500 hr*ng/ml.

37. 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.

38. The modified release drug product according to claim 29, wherein the immediate release formulation and the sustained release form each comprise abutting substantially planar layers which form at bilayer tablet.

39. The modified release drug product according to claim 29, wherein the sustained release form is coated by a layer of the immediate release formulation.

40. The modified release drug product according to claim 29, wherein the drug product is shaped as a capsule and contains the immediate release formulation and the sustained release form.

41. The modified release drug product according to claim 29, wherein the drug product is approximately equally effective when administered to the human subject with an empty or full stomach.

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

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

a second quantity of guaifenesin in a sustained release formulation; and

at least one additional drug,

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

1 to about 1;

49,

wherein the immediate release formulation guaifenesin has a C_max in a human subject equivalent to the C_max obtained when a dose of a standard immediate release formulation having one third the amount of guaifenesin is dosed, and immediately after administration the serum concentration of guaifenesin peaks in about an hour, followed by a gradual serum concentration decrease over twenty-four hours but the serum concentration of guaifenesin never decreases below the minimum concentration of said standard immediate release formulation over twelve hours, and

wherein the drug product provides a therapeutically effective bioavailable guaifenesin dose for at least twelve hours after a single dose in the human subject according to serum analysis.

44. The modified release drug product according to claim 43, wherein a total quantity of guaifenesin is from about 600 mg to about 1200 mg.

45. The modified release drug product according to claim 43, wherein the additional drug is an antitussive, decongestant, antihistamine, analgesic, or combinations thereof.

46. The modified release drug product according to claim 45, wherein the additional drug 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.

47. The modified release drug product according to claim 45, wherein the additional drug is dextromethorphan hydrobromide, pseudoephedrine hydrochloride, or a combination thereof.

48. The modified release drug product according to claim 43, wherein a ratio of a total quantity of guaifenesin to the additional drug is from about 1:

1 to about 4;

1 by weight.

49. The modified release drug product according to claim 43, wherein a ratio of a total quantity of guaifenesin to the additional drug is from about 3:

2 to about 9;

1 by weight.

50. The modified release drug product according to claim 43 or 49, wherein a ratio of the first quantity of guaifenesin to the second quantity of guaifenesin is from about 2:

3 to about 1;

19.

51. The modified release drug product according to claim 44, wherein a guaifenesin C_max of the drug product is from about 1600 to 2500 ng/ml and an AUC_inf is from about 5600 to 8750 hr*ng/ml.

52. The modified release drug product according to claim 44, wherein a guaifenesin C_max is at least 1900 ng/ml and an AUC_inf is at least 7000 hr*ng/ml.

53. The modified release drug product according to claim 44, wherein a guaifenesin C_max is about 800 to 1250 ng/ml and an AUC_inf is from about 2800 to 4375 hr*ng/ml.

54. The modified release drug product according to claim 44, wherein a guaifenesin C_max is at least 1000 ng/ml and an AUC_inf is at least 3500 hr*ng/ml.

55. The modified release drug product according to claim 43, wherein the guaifenesin has a half life of at least three hours as determined by serum analysis.

56. The modified release drug product according to claim 43, wherein the immediate release formulation and the sustained release formulation each comprise abutting substantially planar layers which form a bilayer tablet.

57. The modified release drug product according to claim 43, wherein the sustained release formulation is coated by a layer of the immediate release formulation.

58. The modified release drug product according to claim 43, wherein the drug product is shaped as a capsule containing the immediate release formulation and the sustained release formulation.

59. The modified release drug product according to claim 43, wherein the drug product is approximately equally effective when administered to the human subject with an empty or full stomach.

60. The modified release drug product according to claim 44, wherein the drug product has the serum guaifenesin concentration profile of FIG. 10.

76. The modified release drug product according to claim 43, wherein the immediate release formulation, sustained release formulation, or both comprises the at least one additional drug.

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

1 to about 6;

1, wherein said immediate release formulation guaifenesin demonstrates a C_max in a human subject equivalent to the C_max obtained when a dose of a standard immediate release formulation having one third the amount of guaifenesin is dosed, and immediately after administration the serum concentration of guaifenesin peaks in about an hour, followed by a gradual serum concentration decrease over twenty-four hours but the serum concentration of guaifenesin never decreases below the minimum concentration of said standard immediate release formulation over twelve hours, and wherein said drug product provides therapeutically effective bioavailability for at least twelve hours after a single dose in the human subject according to serum analysis.

71. The method according to claim 70, wherein the drug product is administered orally.

72. The method according to claim 70, wherein a ratio of the first quantity of guaifenesin to the second quantity of guaifenesin is about 1:

1 to about 1;

49 by weight.

73. The method according to claim 70, wherein guaifenesin has a C_max of at least about 1900 ng/ml and an AUC_inf of at least 7000 hr*ng/ml.