Claims for Patent: 6,372,252

Summary for Patent: 6,372,252

Title:	Guaifenesin sustained release formulation and tablets
Abstract:	The invention relates to a novel pharmaceutical sustained release formulation of guaifenesin. 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 six-to-one (6:1), more preferably a range of about three-to-two (3:2) to about four-to-one (4:1), and most preferably about two-to-one (2:1), 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 guaifenesin tablet which has two portion: the first portion comprises an immediate release formulation of guaifenesin and the second portion comprises a sustained release formulation of guaifenesin as described above. This two portion, or bi-layer, tablet has a maximum 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.
Inventor(s):	Blume; Ralph W. (Fort Worth, TX), Davis; Robert D. (Arlington, TX), Keyser; Donald Jeffrey (Southlake, TX)
Assignee:	Adams Laboratories, Inc. (Ft. Worth, TX)
Application Number:	09/559,542
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,372,252
Patent Claims:	1. A modified release tablet 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.sub.max in a human subject equivalent to the C.sub.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. 2. The modified release tablet of claim 1 wherein said hydrophilic polymer is selected from the group consisting of 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, and a combination thereof. 3. The modified release tablet of claim 1 wherein the water-insoluble polymer is selected from the group consisting of polyacrylic acids, acrylic resins, acrylic latex dispersions, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and a combination thereof. 4. The modified release tablet of claim 1 wherein said hydrophilic polymer is hydroxypropyl methylcellulose and said water-insoluble polymer is an acrylic resin. 5. The modified release tablet of claim 1 wherein said tablet additionally comprises an additive selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oils, talc, polyethylene glycol, mineral oil, EMERALD GREEN LAKE, an FD&C color, sucrose, lactose, gelatin, starch paste, acacia, tragacanth, povidone, polyethylene glycol, Pullulan, corn syrup, colloidal silicon dioxide, talc, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, triethanolamine, polyoxyethylene sorbitan, poloxalkol, quarternary ammonium salts, 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, and a combination thereof. 6. The modified release tablet of claim 1 wherein said first portion includes microcrystalline cellulose, sodium starch glycolate and magnesium stearate. 7. The modified release tablet of claim 1 wherein the total quantity of guaifenesin is from about 600 mg to about 1200 mg. 8. The modified release tablet of claim 1 wherein the total quantity of guaifenesin is 600 mg. 9. The modified release tablet of claim 1 wherein the total quantity of guaifenesin is 1200 mg. 10. The modified release tablet of claim 1 wherein the C.sub.max, AUC.sub.inf and AUC.sub.0-12 are approximately proportional to dosage strength. 11. The modified release tablet of claim 1 or 7 wherein the ratio of said first quantity of guaifenesin to said second quantity of guaifenesin is about 1:1 to about 1:5. 12. The modified release tablet of claim 1 or 7 wherein the ratio of said first quantity of guaifenesin to said quantity of second quantity of guaifenesin is about 1:5. 13. The modified release tablet of claim 9 wherein the C.sub.max of said tablet is from about 1600 to 2500 .mu.g/mL and said tablet has an AUC.sub.inf of from about 5600 to 8750 hr*.mu.g/mL. 14. The modified release tablet of claim 9 wherein the C.sub.max of said tablet is at least 1900 .mu.g/mL and said tablet has an AUC.sub.inf of at least 7000 hr*.mu.g/mL. 15. The modified release tablet of claim 8 wherein the C.sub.max of said tablet is from about 800 to 1250 .mu.g/mL and said tablet has an AUC.sub.inf of from about 2800 to 4375 hr*.mu.g/mL. 16. The modified release tablet of claim 8 wherein the C.sub.max of said tablet is at least 1000 .mu.g/mL and said tablet has an AUC.sub.inf of at least 3500 hr*.mu.g/mL. 17. The modified release tablet of claim 1 wherein said tablet has a half life, according to serum analysis, of at least 3 hours. 18. The modified release tablet of claim 1 wherein the second portion comprises about 95.5% by weight of guaifenesin DC, about 2.4% by weight of hydrophilic polymer and about 1.2% by weight of water-insoluble polymer. 19. The modified release tablet of claim 1 wherein said first and second portions each comprise abutting substantially planar layers which form a bilayer tablet. 20. The modified release tablet of claim 1 wherein said first portion is provided as a coating on said second portion. 21. The modified release tablet of claim 1 which is approximately equally effective when administered to a patient on an empty or full stomach. 22. The modified release tablet of claim 9 which has the serum guaifenesin concentration profile of FIG. 10. 23. The modified release tablet of claim 9 wherein the second portion comprises from about 85.5% to about 91.4% by weight of guaifenesin, from about 6.8% to about 10.1% by weight to hydroxypropyl methylccllulose, and from about 1.1% to about 2.9% by weight of an acrylic resin. 24. A modified 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 in a sustained release form wherein the ratio of said first quantity to said second quantity provides a C.sub.max in a human subject equivalent to the C.sub.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 product also provides therapeutically effective bioavailability for at least twelve hours after a single dose in a human subject according to serum analysis. 25. The modified release product of claim 24 wherein the total quantity of guaifenesin is from about 600 mg to about 1200 mg. 26. The modified release product of claim 24 wherein the total quantity of guaifenesin is 600 mg. 27. The modified release product of claim 24 wherein the total quantity of guaifenesin is 1200 mg. 28. The modified release product of claim 24 wherein the C.sub.max, AUC.sub.inf and AUC.sub.0-12 are approximately proportional to dosage strength. 29. The modified release product of claim 24 or 25 wherein the ratio of said first quantity of guaifenesin to said quantity of second quantity of guaifenesin is about 1:1 to about 1:5. 30. The modified release product of claim 29 wherein the ratio of said first quantity of guaifenesin to said quantity of second quantity of guaifenesin is about 1:5. 31. The modified release product of claim 27 wherein the C.sub.max of said product is from about 1600 to 2500 .mu.g/mL and said product has an AUC.sub.inf of from about 5600 to 8750 hr1.mu.g/mL. 32. The modified release product of claim 27 wherein the C.sub.max of said product is at least 1900 .mu.g/mL and said product has an AUC.sub.inf of at least 7000 hr*.mu.g/mL. 33. The modified release product of claim 26 wherein the C.sub.max of said product is from about 300 to 1250 .mu.g/mL and said product has an AUC.sub.inf of from about 2800 to 4375 hr*.mu.g/mL. 34. The modified release product of claim 26 wherein the C.sub.max of said product is at least 1000 .mu.g/mL and said product has an AUC.sub.inf of at least 3500 hr*.mu.g/mL. 35. The modified release product of claim 24 wherein said product has a half life, according to serum analysis, of at least three hours. 36. The modified release product of claim 24 wherein said first and second portions each comprise abutting substantially planar layers which form a bilayer tablet. 37. The modified release product of claim 24 wherein said first portion is provided as a coating on said second portion. 38. The modified release product of claim 24 which is a capsule containing said first and second portions. 39. The modified release product of claim 24 which is approximately equally effective when administered to a patient on an empty or full stomach. 40. The modified release product of claim 27 which has the serum guaifenesin concentration profile of FIG. 10. 41. A modified 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 in a sustained release form wherein the ratio of said first quantity to said second quantity is from about 1:1 to about 1:5 and the product provides a C.sub.max in a human subject equivalent to the C.sub.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 product also provides therapeutically effective bioavailability for at least twelve hours after a single dose in a human subject according to serum analysis. 42. The modified release product of claim 41 wherein the total quantity of guaifenesin is from about 600 mg to about 1200 mg. 43. The modified release product of claim 41 wherein the total quantity of guaifenesin is 600 mg. 44. The modified release product of claim 41 wherein the total quantity of guaifenesin is 1200 mg. 45. The modified release product of claim 41 wherein the C.sub.max, AUC.sub.inf and AUC.sub.0-12 are approximately proportional to dosage strength. 46. The modified release product of claim 41 wherein the ratio of said first quantity of guaifenesin to said quantity of second quantity of guaifenesin is about 1:5. 47. The modified release product of claim 44 wherein the C.sub.max of said product is from about 1600 to 2500 .mu.g/mL and said product has an AUC.sub.inf of from about 5600 to 8750 hr*.mu.g/mL. 48. The modified release product of claim 44 wherein the C.sub.max of said product is at least 1900 .mu.g/mL and said product has an AUC.sub.inf of at least 7000 hr*t.mu.g/mL. 49. The modified release product of claim 43 wherein the C.sub.max of said product is from about 800 to 1250 .mu.g/mL and said product has an AUC.sub.inf from about 2800 to 4375 hr*.mu.g/mL. 50. The modified release product of claim 43 wherein the C.sub.max of said product is at least 1000 .mu.g/mL and said product has an AUC.sub.inf of at least 3500 hr*.mu.g/mL. 51. The modified release product of claim 41 wherein said product has a half life, according to serum analysis, of at least three hours. 52. The modified release product of claim 41 wherein said first and second portions each comprise abutting substantially planar layers which form a bilayer tablet. 53. The modified release product of claim 41 wherein said first portion is provided as a coating on said second portion. 54. The modified release product of claim 41 which is a capsule containing said first and second portions. 55. The modified release product of claim 41 which is approximately equally effective when administered to a patient on an empty or full stomach. 56. The modified release product of claim 44 which has the serum guaifenesin concentration profile of FIG. 10.