Gastric retentive extended release pharmaceutical compositions
View Patent ↗The present disclosure provides extended release pharmaceutical compositions comprising an opioid and an additional active pharmaceutical ingredient, wherein the composition exhibits gastric retentive properties which are achieved by a combination of a physical property of the composition and release of the opioid, wherein upon administration to a subject, the composition has at least one pharmacokinetic parameter that differs by less than about 30% when the subject is in a fasted state as compared to a fed state.
1. A pharmaceutical composition comprising:
(a) at least one immediate release portion comprising about 125 mg to about 325 mg of acetaminophen and about 1.5 mg to about 4.0 mg hydrocodone or a pharmaceutically acceptable salt thereof; and
(b) at least one extended release portion comprising about 125 mg to about 325 mg of acetaminophen and about 4.5 mg to about 6.5 mg hydrocodone or a pharmaceutically acceptable salt thereof, and an extended release-component;
wherein the total amount of acetaminophen in the composition is about 325 mg to about 650 mg, and the total amount of hydrocodone or a pharmaceutically acceptable salt thereof in the composition is about 7.5 mg to about 10 mg, wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at a paddle speed of about 100 rpm in 900 mL of 0.1N HCl using a USP type II apparatus at a constant temperature of about 37° C., about 20% to about 40% of the total amount of hydrocodone or a pharmaceutically acceptable salt thereof in the composition is released at about 15 minutes in the test and about 50% to about 55% of the total amount of acetaminophen in the composition is released at about 15 minutes in the test.
2. The pharmaceutical composition of claim 1 , wherein upon oral administration of a single dose of the composition to a subject, the composition provides a C max for hydrocodone from about 0.9 ng/mL/mg to about 2.0 ng/mL/mg, a C max for acetaminophen from about 4.0 ng/mL/mg to about 11.0 ng/mL/mg, a T max for hydrocodone from about 2 hours to about 8 hours, and a T max for acetaminophen from about 0.5 hour to about 6 hours.
3. The pharmaceutical composition of claim 1 , wherein from about 45% to about 65%, by weight, of the hydrocodone or a pharmaceutically acceptable salt thereof is released from the composition at about 2 hours in the test, from about 60% to about 85%, by weight, of the hydrocodone or a pharmaceutically acceptable salt thereof is released from the composition at about 4 hours in the test, from about 80% to about 100%, by weight, of the hydrocodone or a pharmaceutically acceptable salt thereof is released from the composition at about 8 hours in the test, from about 60% to about 75%, by weight, of the acetaminophen is released from the composition at about 2 hours in the test, and from about 75% to about 85%, by weight, of the acetaminophen is released from the composition at about 4 hours in the test.
4. The pharmaceutical composition of claim 1 , wherein upon oral administration of multiple doses to a subject in need of analgesia, the composition produces a blood plasma profile characterized by a mean AUC for hydrocodone from about 10.0 ng·hr/mL/mg to about 22.0 ng·hr/mL/mg, a steady state AUC for hydrocodone from about 13.0 ng·hr/mL/mg to about 18.0 ng·hr/mL/mg, a mean AUC for acetaminophen from about 35.0 ng·hr/mL/mg to about 80.0 ng·hr/mL/mg, and a steady state AUC for acetaminophen from about 37.0 ng·hr/mL/mg to about 42.0 ng·hr/mL/mg.
5. The pharmaceutical composition of claim 1 , wherein upon oral administration of multiple doses to a subject in need of analgesia, the composition produces a blood plasma profile characterized by a median T max for hydrocodone from about 3.0 hours to about 6.0 hours, a steady state T max for hydrocodone from about 2.0 hours to about 4.0 hours, a median T max for acetaminophen from about 1.0 hour to about 5.0 hours, and a steady state T max for acetaminophen from about 0.5 hour to about 1.0 hours.
6. The pharmaceutical composition of claim 1 , wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at a paddle speed of about 100 rpm in 900 mL of 0.1N HCl using a USP type II apparatus at a constant temperature of about 37° C, about 35% to about 40% of the hydrocodone or a pharmaceutically acceptable salt thereof is released at about 30 minutes in the test and about 51% to about 58% of the acetaminophen is released at about 30 minutes in the test.
7. The pharmaceutical composition of claim 1 , Wherein the extended release component comprises polyethylene oxide.
8. The pharmaceutical composition of claim 7 , wherein the polyethylene oxide has a molecular weight from about 500,000 Daltons to about 10,000,000 Daltons.
9. The pharmaceutical composition of claim 1 , wherein the at least one immediate release portion comprises from about 20% to about 30% of the total amount of hydrocodone or a pharmaceutically acceptable salt thereof in the composition and from about 40% to about 60% of the total amount of acetaminophen in the composition, and the at least one extended release portion comprises the balance of each of the hydrocodone or a pharmaceutically acceptable salt thereof and the acetaminophen.
10. The pharmaceutical composition of claim 1 , wherein the immediate release portion comprises, by weight of the immediate release portion, from about 70% to about 80% acetaminophen and from about 0.5% to about 1% of hydrocodone or a pharmaceutically acceptable salt thereof;and the extended release portion comprises, by weight of the extended release portion, from about 30% to about 50% of the extended release component, from about 20% to about 40% of acetaminophen, and from about 0.5% to about 2% of hydrocodone or a pharmaceutically acceptable salt thereof.
11. The pharmaceutical composition of claim 1 , wherein the extended release component comprises a polymer selected from the group consisting of linear, branched, dendrimeric, or star polymers, hydrophilic polymers, and mixtures thereof.
12. The pharmaceutical composition of claim 1 , wherein the extended release component comprises a polymer selected from the group consisting of a polyalkylene oxide, poly(ethylene oxide), polyethylene glycol and poly(ethylene oxide) poly(propylene oxide), methylcetlulose, hydroxymethylcellulose, laydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylceliulose, carboxymethylcellulose, microcrystalline cellulose, acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, aminoethyl acrylate, maleic anhydride copolymer, polymaleic acid, poly(acrylamide), poly(methacrylanaide), poly(dimethylacrylamide), poly(N-isopropyl-acrylamide), poly(oiefinic alcohol), poly(vinyi alcohol), poly(N-vinyl lactam), poly(vinyl pyrrolidone), poly(N-vinyl caprolactam), polyol, glycerol, polyglycerol, propylene glycol, trimethylene glycol, mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, mono- and di-polyoxyethylated trirnethylene glycol, polyoxyethylated sorbitol, polyoxyethylated glucose, polyoxazolines, poly(methyloxazoline), poly(ethyloxazoline), polyvinylamine, polyvinylacetate, ethylene-vinyl acetate copolymer, polyvinyl acetate phthalate, polyimines, polyethyleneimine, starch, starch-based polymer, polyurethane hydrogel, chitosan, polysaccharide gums, xanthan gum, zein, shellac, ammoniated shellac, shellac-acetyl alcohol, shellac n-butyl, stearate, and mixtures thereof.
13. A pharmaceutical composition comprising:
(a) at least one immediate release portion comprising about 125 mg to about 325 mg of acetaminophen and about 1.5 mg to about 4.0 mg hydrocodone or a pharmaceutically acceptable salt thereof; and
(b) at least one extended release portion comprising about 125 mg to about 32.5 mg of acetaminophen and about 4.5 mg to about 6.5 mg hydrocodone or a pharmaceutically acceptable salt thereof, and an extended release component;
wherein the total amount of acetaminophen in the composition is about 325 mg to about 650 mg, and the total amount of hydrocodone or a pharmaceutically acceptable salt thereof in the composition is about 7.5 mg to about 10 mg; and
wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at a paddle speed of about 150 rpm in 900 mL of 0.1N HCl using a USP type II apparatus at a constant temperature of about 37° C, the drug release profile substantially corresponds to the following:
after 15 minutes, no more than about 35%, by weight, of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof is released and no more than about 55%, by weight, of the total amount of the acetaminophen is released;
after 1 hour, no more than about 50%, by weight, of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof is released and no more than about 63%, by weight, of the total amount of the acetaminophen is released;
after 2 hours, no more than about 65%, by weight, of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof is released and no more than about 75%, by weight, of the total amount of the acetaminophen is released;
after 4 hours, from about 65% to about 85%, by weight, of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof is released and from about 70% to about 90%, by weight, of the total amount of the acetaminophen is released;
after 8 hours, from about 85% to about 100%, by weight, of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof is released and from about 85% to about 100%, by weight, of the total amount of the acetaminophen is released; and
after 12 hours, from about 95% to about 100%, by weight, of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof is released and from about 90% to about 100%, by weight, of the total amount of the acetaminophen is released.
14. The pharmaceutical composition of claim 13 , wherein the composition comprises about 325 mg of acetaminophen and about 7.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof.
15. The pharmaceutical composition of claim 13 , wherein when orally administered to a subject, the composition produces a blood plasma concentration profile characterized by a biphasic increase in blood plasma concentrations of hydrocodone and acetaminophen.
16. The pharmaceutical composition of claim 15 , wherein the biphasic increase in blood plasma concentrations of hydrocodone is characterized by a plasma concentration-time profile for hydrocodone in which the slope of a line drawn between 0 hour and about 2 hours is greater than the slope of a line drawn between about 2 hours and about 5 hours.
17. A pharmaceutical composition as a solid oral dosage form comprising:
(a) at least one immediate release portion comprising about 125 mg to about 325 mg of acetaminophen and about 1.5 mg to about 4.0 mg hydrocodone or a pharmaceutically acceptable salt thereof; and
(b) at least one extended release portion comprising about 125 mg to about 325 mg of acetaminophen and about 4.5 mg to about 6.5 mg hydrocodone or a pharmaceutically acceptable salt thereof, and an extended release component;
wherein the total amount of acetaminophen in the composition is about 325 mg and the total amount of hydrocodone or a pharmaceutically acceptable salt thereof in the composition is about 7.5 mg; and
wherein upon oral administration of two solid oral dosage forms of the composition wherein upon oral administration of two solid oral dosage forms of the composition, the composition provides the composition provides an AUC 0-1.7h for acetaminophen of about 5.0 ng·h/mL/mg to about 13.0 ng·h/mL/mg; an AUC 1.7-48h for acetaminophen of about 25.0 ng·h/mL/mg to about 75.0 ng·h/mL/mg, an AUC 0-2.44h for hydrocodone or a pharmaceutically acceptable salt thereof of about 1.0 ng·h/mL/mg to about 4.25 ng·h/mL/mg; and AUC 2.44-36h of about 10 ng·h/mL/mg to about 20.0 ng·h/mL/mg.
18. The pharmaceutical composition of claim 17 wherein the AUC 0-1hr for acetaminophen is from about 1.25 ng·hr/mL/mg to about 3.25 ng·hr/mL/mg.
19. The pharmaceutical composition of claim 17 wherein the AUC 0-2hr for acetaminophen is from about 4.25 ng·hr/mL/mg to about 8.75 ng·hr/mL/mg.
20. The pharmaceutical composition of claim 17 wherein the AUC 0-4hr for acetaminophen is from about 10.0 ng·hr/mL/mg to about 20.0 ng·hr/mL/mg.
21. The pharmaceutical composition of claim 17 wherein the AUC 0-3hr for hydrocodone is from about 1.0 ng·hr/mL/mg to about 5.0 ng·h/mL/mg.
22. The pharmaceutical composition of claim 21 wherein the AUC 3-36hr for hydrocodone is from about 5.0 ng·h/mL/mg to about 25.0 ng·hr/mL/mg.
23. A pharmaceutical composition as a solid oral dosage form comprising:
(a) at least one immediate release portion comprising about 125 mg to about 325 mg of acetaminophen and about 1.5 mg to about 4.0 mg hydrocodone or a pharmaceutically acceptable salt thereof; and
(b) at least one extended release portion comprising about 125 mg to about 325 mg of acetaminophen and about 4.5 mg to about 6.5 mg hydrocodone or a pharmaceutically acceptable salt thereof thereof, and an extended release component;
wherein the total amount of acetaminophen in the composition is about 325 mg to about 650 mg, and the total amount of hydrocodone or a pharmaceutically acceptable salt thereof in the composition is about 7.5 mg to about 10 mg; and
wherein upon oral administration of two solid oral dosage forms of the composition wherein upon oral administration of two solid oral dosage forms of the composition, the composition maintains the composition maintains a therapeutic blood plasma concentration of hydrocodone of at least about 5 ng/mL from about 0.75 hours to about 10 hours after administration of the composition, and wherein at least about 90% of the acetaminophen is released from the composition by about 8 hours after administration of the composition such that, by about 10 hours after administration of the composition, acetaminophen has a blood plasma concentration that is less than about 30% of acetaminophen's maximum plasma concentration.
24. The pharmaceutical composition of claim 23 , wherein the AUC Tmax-t for acetaminophen is from about 20.0 ng·hr/mL/mg to about 40.0 ng·hr/mL/mg.
25. The pharmaceutical composition of claim 23 , wherein the AUC (1.7-48hr) for acetaminophen is from about 25.0 ng·hr/mL/mg to about 75.0 ng·hr/mL/mg.
26. The pharmaceutical composition of claim 23 , wherein the composition is administered to a subject as a bilayer tablet.
27. The pharmaceutical composition of claim 26 , wherein the bilayer tablet comprises about 325 mg of acetaminophen and about 7.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof.
28. The pharmaceutical composition of claim 27 , wherein a single dose comprises two bilayer tablets.
29. The solid oral dosage form of claim 23 , wherein the solid oral dosage form is a tablet or capsule.
30. The solid oral dosage form of claim 23 , wherein the solid oral dosage form is used in the treatment of acute pain.