Claims
- 1. A drug delivery system in which a unit dose form comprises a sustained release portion comprising guaifenesin and a release-delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer; an immediate release portion comprising guaifenesin; wherein the guaifenesin is bioavailable at a therapeutically effective level for at least twelve hours following a single dose.
- 2. The system of claim 1, wherein the release-delaying matrix comprises hydrophilic polymer and water-insoluble polymer in a weight ratio selected from 1:1 to about 9:1, 3:2 to about 6:1, and 2:1 to about 4:1.
- 3. The system of claim 2, wherein the total amount of guaifenesin is between 500 mg and 1300 mg.
- 4. The drug delivery system of claim 1, wherein the total quantity of guaifenesin in said unit dose form is from about 600 mg to about 1200 mg.
- 5. The system of claim 4, wherein said unit dose form has a Cmax for guaifenesin that is bioequivalent to the FDA-specified Cmax for an immediate guaifenesin release tablet of one-third the dose strength.
- 6. The system of claim 5, wherein said unit dose form contains 1200 mg of guaifenesin.
- 7. The system of claim 6, wherein the Cmax for guaifenesin is selected from between 1,000 ng/mL and 3,750 ng/mL, 1,200 ng/mL and 3,500 ng/mL, 1,350 ng/mL and 3,000 ng/mL, and 1450 ng/mL and 2,750 ng/mL.
- 8. The system of claim 5, wherein said unit dose form contains 600 mg of guaifenesin.
- 9. The system of claim 8, wherein the Cmax for guaifenesin is selected from between 320 ng/mL and 1875 ng/mL, 400 ng/mL and 1500 ng/mL, 500 ng/mL and 1375 ng/mL, and 625 ng/mL and 1250 ng/mL.
- 10. The system of claim 4, wherein said therapeutically effective level is measured according to Cmin.
- 11. The system of claim 10, wherein the unit dose form has a Cmin for guaifenesin that is bioequivalent to the FDA-specified Cmin for an immediate release guaifenesin tablet containing 400 mg of guaifenesin.
- 12. The system of claim 11, wherein the Cmin for guaifenesin is selected from between 35 ng/mL and 75 ng/mL, 40 ng/mL and 70 ng/mL, 45 ng/mL and 65 ng/mL, and 50 ng/mL and 60 ng/mL.
- 13. The system of claim 11, wherein the Cmin for guaifenesin is select from between 50 ng/mL and 150 ng/mL, 50 ng/mL and 125 ng/mL, 60 ng/mL, 125 ng/mL, 70 ng/mL and 125 ng/mL, and 80 ng/mL and 125 ng/mL.
- 14. The system of claim 4, wherein said therapeutically effective level is measured according to AUCinf.
- 15. The system of claim 14, wherein said unit dose form contains 1200 mg of guaifenesin.
- 16. The system of claim 15, wherein the AUCinf for guaifenesin is selected from between 4,000 hr-ng/mL and 12,500 hr-ng/mL, 5,000 hr-ng/mL and 10,000 hr-ng/mL, 5,500 hr-ng/mL and 9,500 hr-ng/mL, and 6,000 hr-ng/mL and 9,000 hr-ng/mL.
- 17. The system of claim 4, where said unit dose form contains 600 mg of guaifenesin.
- 18. The system of claim 17, wherein the AUCinf for guaifenesin is selected from between 2,000 hr-ng/mL and 6,250 hr-ng/mL, 2,500 hr-ng/mL and 5,000 hr-ng/mL, 2,250 hr-ng/mL and 4,750 hr-ng/mL, and 3,000 hr-ng/mL and 4,500 hr-ng/mL.
- 19. The system of claim 4, wherein said therapeutically effective level is measured according to AUC0-t.
- 20. The system of claim 19, wherein said unit dose form contains 1200 mg of guaifenesin.
- 21. The system of claim 20, wherein the AUC0-t for guaifenesin is selected from between 3,200 hr-ng/mL and 11,250 hr-ng/mL, 3,700 hr-ng/mL and 10,500 hr-ng/mL, 4,000 hr-ng/mL and 9,500 hr-ng/mL, 4,250 hr-ng/mL and 9,000 hr-ng/mL, and 4,500 hr-ng/mL and 8,500 hr-ng/mL.
- 22. The system of claim 19, where said unit dose form contains 600 mg of guaifenesin.
- 23. The system of claim 22, wherein the AUC0-t for guaifenesin is selected from between 1,600 hr-ng/mL and 5,625 hr-ng/mL, 1,850 hr-ng/mL and 5,250 hr-ng/mL, 2,000 hr-ng/mL and 4,750 hr-ng/mL, 2,125 hr-ng/mL and 4,500 hr-ng/mL, and 2,250 hr-ng/mL and 4,250 hr-ng/mL.
- 24. The system of claim 4, wherein said therapeutically effective level is measured according to AUCss.
- 25. The system of claim 24, wherein said unit dose form contains 1200 mg of guaifenesin.
- 26. The system of claim 25, wherein the AUCss for guaifenesin is selected from between 5000 hr-ng/mL and 9000 hr-ng/mL, 5600 hr-ng/mL and 8750 hr-ng/mL, 6000 hr-ng/mL and 8000 hr-ng/mL, and 6500 hr-ng/mL and 8250 hr-ng/mL.
- 27. The system of claim 24, where said unit dose form contains 600 mg of guaifenesin.
- 28. The system of claim 27, wherein the AUCss for guaifenesin is selected from between 2,500 hr-ng/mL and 4,500 hr-ng/mL, 2,800 hr-ng/mL and 4,375 hr-ng/mL, 3,000 hr-ng/mL and 4,000 hr-ng/mL, and 3,250 hr-ng/mL and 4,125 hr-ng/mL.
- 29. The system of claim 4, wherein said therapeutically effective level is measured according to Tmax.
- 30. The system of claim 29, wherein said unit dose form contains 1200 mg of guaifenesin.
- 31. The system of claim 30, wherein the Tmax for guaifenesin is selected from between 0.6 hours and 3.0 hours, 0.8 hours and 2.5 hours, 0.9 hours and 2.25 hours, 1.0 hours and 2 hours, and 1.1 hours and 2 hours.
- 32. The system of claim 29, where said unit dose form contains 600 mg of guaifenesin.
- 33. The system of claim 32, wherein the Tmax for guaifenesin is selected from between 0.3 hours and 1.5 hours, 0.4 hours and 1.25 hours, 0.45 hours and 1.13 hours, 0.50 hours and 1 hour, and 0.55 hours and 1 hours.
- 34. The system of claim 33, wherein said therapeutically effective level is measured according to T1/2.
- 35. The system of claim 34, wherein said unit dose form contains 1200 mg of guaifenesin.
- 36. The system of claim 35, wherein the T1/2 for guaifenesin is selected from between 0.7 hours and 7.25 hours, 0.9 hours and 6.0 hours, 1.1 hours and 5.0 hours, 1.3 hours and 3.5 hours, and 1.4 hours and 3.5 hours.
- 37. The system of claim 34, where said unit dose form contains 600 mg of guaifenesin.
- 38. The system of claim 37, wherein the T1/2 for guaifenesin is selected from between 0.35 hours and 3.63 hours, 0.45 hours and 3.0 hours, 0.55 hours and 2.5 hours, 0.65 hours and 1.75 hours, and 0.70 hours and 1.75 hours.
- 39. The drug delivery system of claim 3, 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.
- 40. The drug delivery system of claim 3, 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.
- 41. The drug delivery system of claim 3, wherein the hydrophilic polymer is hydroxypropyl methylcellulose and the water-insoluble polymer is an acrylic resin.
- 42. The drug delivery system of claim 68, comprising binders, colorants, excipients, glidants, lubricants, preservatives, stabilizers, surface active ingredients, or combinations thereof.
- 43. The drug delivery system of claim 42, 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.
- 44. The drug delivery system of claim 42, wherein the binder is sucrose, lactose, gelatin, starch paste, acacia, tragacanth, povidone, polyethylene glycol, Pullulan, corn syrup, or a combination thereof.
- 45. The drug delivery system of claim 42, wherein the glidant is colloidal silicon dioxide, talc, or a combination thereof.
- 46. The drug delivery system of claim 41, wherein the surface active agent is sodium lauryl sulfate, dioctyl sodium sulfosuccinate, triethanolamine, polyoxyethylene sorbitan, poloxalkol, quaternary ammonium salts, or a combination thereof.
- 47. The drug delivery system of claim 41, 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.
- 48. The drug delivery system of claim 41, wherein colorant is Emerald Green Lake, FD&C Red No. 40, FD&C Yellow No. 6, D&C Yellow No. 10, FD&C Blue No. 1, or a combination thereof.
- 49. The drug delivery system of claim 1, wherein the immediate release portion further comprises microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.
- 50. The drug delivery system of claim 1, wherein the ratio of the immediate release quantity of guaifenesin to the sustained release quantity of guaifenesin is about 1:1 to about 1:15 by weight.
- 51. The drug delivery system of claim 1, wherein the ratio of the immediate release quantity of guaifenesin to the sustained release quantity of guaifenesin is from about 2:3 to about 1:11.
- 52. The drug delivery system of claim 1, wherein at least about 60% of the guaifenesin particles used to make the unit dose form have a particle size in the range of from about 150 μm to 2.0 mm.
- 53. The drug delivery system of claim 1, wherein a unit dose form has a Cmax for guaifenesin of at least about 1900 ng/ml and an AUCinf for guaifenesin of at least 7000 hr-ng/ml.
- 54. The drug delivery system of claim 1, wherein a unit dose form has a Cmax for guaifenesin of at least 1000 ng/ml and an AUCinf for guaifenesin of at least 3500 hr-ng/ml.
- 55. The drug delivery system of claim 1, wherein a unit dose form has a half life of at least 3 hours as determined by serum analysis.
- 56. The drug delivery system of claim 1, wherein the unit dose form comprises immediate release and sustained release portions each comprise abutting substantially planar layers which form a bi-layer tablet.
- 57. The drug delivery system of claim 1, wherein a unit dose form has a Cmax for guaifenesin from about 1600 to 2500 ng/ml and an AUCinf for guaifenesin of about 5600 to 8750 hr-ng/ml.
- 58. The drug delivery system of claim 1, wherein a unit dose form has a Cmax for guaifenesin of about 800 to 1250 ng/ml and an AUCinf for guaifenesin of about 2800 to 4375 hr-ng/ml.
- 59. The drug delivery system of claim 1, wherein the unit dose form comprises a capsule that contains discrete or associated immediate release and sustained release portions.
- 60. The drug delivery system of claim 58, which is approximately equally effective when administered to a patient on an empty or full stomach.
- 61. The drug delivery system of claim 1, wherein said unit dose form has the guaifenesin serum concentration profile of FIG. 10.
- 62. A drug product comprising an immediate release portion comprising a guaifenesin wherein guaifenesin becomes bioavailable in the subject's stomach; and a sustained release portion comprising guaifenesin
wherein the ratio of the immediate release guaifenesin to the sustained release guaifenesin is about 1:1 to about 1:15, the product provides a guaifenesin Cmax in a human subject equivalent to the Cmax obtained when the first of three doses of a FDA-specified 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.
- 63. The drug product according to claim 62, wherein the immediate release and sustained release portions each comprise abutting substantially planar layers which form a bi-layer tablet.
- 64. The drug product according to claim 62, wherein the sustained release portion is coated by a layer of the immediate release portion.
- 65. The drug product according to claim 62, wherein the product comprises a capsule containing immediate release and sustained release portions.
- 66. A method of treating a subject in need of temporary relief from bronchial mucus accumulation comprising administering to said subject a therapeutically effective amount of one drug delivery system according to claim 1.
- 67. The method according to claim 66, wherein the drug delivery system is administered orally.
- 68. A method of treating a subject in need of temporary relief from bronchial mucus accumulation comprising administering to said subject a therapeutically effective amount of a modified release drug product comprising guaifenesin in an immediate release formulation wherein the guaifenesin becomes bioavailable in the subject's stomach; and a sustained release portion comprising a guaifenesin 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 Cmax in a human subject equivalent to the Cmax obtained when the first of three doses of a FDA-specified 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.
- 69. A drug delivery system comprising a sustained release portion comprising guaifenesin and a release-delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer; and an immediate release portion comprising guaifenesin; wherein the guaifenesin is bioavailable at a therapeutically effective level for at least twelve hours according to serum analysis following a single dose and wherein a unit dose form demonstrates a Cmax in a human subject above 640 ng/ml with a Tmax within 0.8 hours and maintains a Cmin above 80 ng/ml for a period of 12 or more hours.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent application Ser. No. 10/121,706 which was filed on Apr. 15, 2002 (pending) which is a continuation-in-part of U.S. Pat. No. 6,372,252 which was filed on Apr. 28, 2000 as application Ser. No. 09/559,542 and issued on Apr. 16, 2002 both of which are hereby incorporated in their entirety by reference.
Continuation in Parts (2)
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Number |
Date |
Country |
Parent |
10121706 |
Apr 2002 |
US |
Child |
10406557 |
Apr 2003 |
US |
Parent |
09559542 |
Apr 2000 |
US |
Child |
10121706 |
Apr 2002 |
US |