Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
View Patent ↗Compositions and methods for the treatment of pain in a mammal are described. More specifically, a dosage form designed for release of acetaminophen and an opioid is described, wherein the dosage form provides delivery of the drugs to the upper gastrointestinal tract (“GI”) of a mammal for an extended period of time.
1. A dosage form for extended release of an opioid and acetaminophen, comprising:
an extended release (ER) portion comprising a polymer matrix with a first dose of acetaminophen and a first dose of an opioid dispersed therein, said polymer matrix comprised of between about 20-60 weight percent poly(ethylene oxide) having a molecular weight of between about 900,000 Daltons to 4,000,000 Daltons, wherein the matrix swells upon imbibition of fluid to a size sufficient to promote gastric retention of the matrix in the gastrointestinal tract of a subject, said first dose of acetaminophen released from the dosage form through erosion of the polymer matrix, and said first doses of opioid and acetaminophen controllably-released from the dosage form such that substantially all of each of the first doses is released within about ten hours when measured in an in vitro disintegration test using a USP type II apparatus at 37° C. in 0.1N HCl.
2. The dosage form of claim 1 , wherein the first dose of acetaminophen is about 100 mg to about 600 mg.
3. The dosage form of claim 1 , wherein the opioid is selected from the group consisting of tramadol, oxycodone, hydromorphone, codeine and hydrocodone.
4. The dosage form of claim 1 , wherein the poly(ethylene oxide) has a molecular weight of about 900,000 Daltons.
5. The dosage form of claim 1 , wherein the poly(ethylene oxide) is present in an amount ranging from about 35 wt % to about 50 wt % of the extended release portion.
6. The dosage form of claim 1 , wherein the extended release portion comprises particles of acetaminophen admixed with the opioid.
7. The dosage form of claim 6 , wherein the particles have an average particle size greater than about 20 microns and less than about 500 microns.
8. The dosage form of claim 1 , further comprising an immediate release portion comprising a second dose of acetaminophen and a second dose of the opioid, both of the second doses dispersed in the immediate release portion, said immediate release portion in contact with said extended release portion.
9. The dosage form of claim 8 , wherein the second dose of acetaminophen is approximately 100 mg to 600 mg.
10. The dosage form of claim 8 , wherein the immediate release portion of the dosage form and the extended release portion of the dosage form comprise a bilayer tablet.
11. The dosage form of claim 10 , wherein said tablet has a hardness of about 12 Kp to about 20 Kp.
12. The dosage form of claim 10 , wherein said tablet has a friability of about 0.3% to about 1.0%.
13. The dosage form of claim 10 , wherein upon administration of the tablet to the subject, the ER portion imbibes fluid and swells to a size between about 120% to 140% of the size of the dosage form prior to administration within 1 hour after administration.
14. The dosage form of claim 10 , wherein between about 40% to about 60% of the acetaminophen and between about 50% to about 70% of the opioid are released within about 1 hour in an in vitro disintegration test.
15. A method for preparing a dosage form for extended release of an opioid and acetaminophen, comprising,
wet-granulating a first mixture that comprises acetaminophen, an opioid, and a binder to form a first granulation mixture, and
blending the first granulation mixture with between about 20-60 weight percent poly(ethylene oxide) having a molecular weight of between about 900,000 Daltons to 4,000,000 Daltons and one or more excipients to form a polymer matrix that comprises an extended release portion of the dosage form, wherein said extended release matrix swells upon imbibition of fluid to a size sufficient to promote gastric retention of the matrix in a gastrointestinal tract of a subject, said first dose of acetaminophen released from the dosage form through erosion of the polymer matrix, and said first doses of opioid and acetaminophen controllably-released from the dosage form such that substantially all of each of the first doses is released within about ten hours, when measured in an in vitro disintegration test using a USP type II apparatus at 37° C. in 0.1N HCl.
16. The method of claim 15 , further comprising compressing the extended release portion of the dosage form to form a monolithic tablet.
17. The method of claim 15 , further comprising wet granulating a second mixture comprising acetaminophen, an opioid, and a binder to form a second granulation mixture,
blending the second granulation mixture with one or more excipients to form an immediate release portion; and
compressing the extended release portion and the immediate release portion to form a bilayer tablet.
18. The method of claim 17 , wherein the wet-granulating comprises wet-granulating by fluid-bed granulation.
19. The method of claim 17 , wherein the wet granulating of the first or second granulation mixtures comprises spraying a solution comprised of the binder and the opioid onto a mixture comprising acetaminophen.
20. A method for treating a subject suffering from pain, comprising orally administering to said subject the dosage form of claim 1 .
21. The method of claim 20 , wherein said administering comprises administering twice in a 24-hour period, and wherein said administering is with a meal.
22. The dosage form of claim 1 , wherein the first dose of opioid is approximately about 5 mg to about 60 mg.
23. The dosage form of claim 1 , wherein the first dose of opioid ranges from about 5 mg to about 40 mg.
24. The dosage form of claim 8 , wherein the total dose of opioid ranges from about 5 mg to about 40 mg.
25. The dosage form of claim 1 , wherein the poly(ethylene oxide) is present in the ER portion in an amount ranging from about 25 wt % to about 55 wt %.
26. The dosage form of claim 1 , wherein the poly(ethylene oxide) has a molecular weight of about 900,000 daltons or about 1,000,000 daltons and wherein the polymer is present in the ER portion in an amount ranging from about 30 wt % to about 50 wt %.
27. The dosage form of claim 1 , wherein release approaching zero-order of the opioid is observed over a period of approximately six hours.
28. The dosage form of claim 1 , wherein the polymer matrix is a monolithic polymer matrix in which said first doses are dispersed, and wherein said first doses are therapeutically effective doses.
29. The dosage form of claim 1 , wherein the poly(ethylene oxide) has a molecular weight of between about 900,000 daltons to about 2,000,000 daltons.