Controlled release hydrocodone formulations
A solid oral controlled-release oral dosage form of hydrocodone is disclosed. The dosage form comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and a sufficient amount of a controlled release material to render the dosage form suitable for twice-a-day administration to a human patient, the dosage form providing a C 12 /C max ratio of 0.55 to 0.85, said dosage form providing a therapeutic effect for at least about 12 hours.
1. A twice-a-day solid oral controlled-release dosage form of a bitartrate salt of hydrocodone consisting of
a pharmaceutically acceptable capsule,
immediate release multiparticulates consisting of a first portion of pharmaceutically acceptable inert beads, a first portion of the bitartrate salt of hydrocodone, hydroxypropylmethylcellulose, glidant(s), and optional plasticizer(s), and
controlled release multiparticulates consisting of the remaining portion of the pharmaceutically acceptable inert beads, the remaining portion of the bitartrate salt of hydrocodone, an ammonio methacrylate copolymer, glidant(s), and optional plasticizer(s),
wherein the total amount of the bitartrate salt of hydrocodone in the dosage form is from about 5 mg to about 60 mg,
said dosage form providing an in-vitro release of from 18% to about 42.5% by weight of hydrocodone from the dosage form at one hour, when measured by the USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) for 55 minutes at 37° C. and thereafter switching to 900 ml of Simulated Intestinal Fluid (SIF) at 37° C., and
after a first administration to a human patient, providing a C 12 /C max hydrocodone ratio of 0.55 to 0.85, a T max of hydrocodone at from about 2 to 8 hours and a therapeutic effect for about 12 hours.
2. The dosage form of claim 1 , which provides a C 12 /C max ratio of 0.65 to 0.75 after said first administration.
3. The dosage form of claim 1 , which provides a dissolution rate in-vitro of the hydrocodone from the dosage form when measured by the USP Basket method at 100 rpm in 900 ml aqueous buffer at a pH of 1.2 at 37° C. from about 25 to about 65% by weight hydrocodone released after 2 hours, from about 45 to about 85% by weight hydrocodone released after 4 hours, and greater than about 60% by weight hydrocodone released after 8 hours.
4. The dosage form of claim 1 , which provides a dissolution rate in-vitro of the hydrocodone from the dosage form when measured by the USP Basket method at 100 rpm in 900 ml aqueous buffer at a pH of 7.5 at 37° C. from about 25 to about 65% by weight hydrocodone released after 2 hours, from about 45 to about 85% by weight hydrocodone released after 4 hours, and greater than about 60% by weight hydrocodone released after 8 hours.
5. The dosage form of claim 1 , which provides a T max of hydrocodone in said patient at from about 3 to about 7 hours after said first administration of the dosage form.
6. The dosage form of claim 1 , which provides a T max of hydrocodone in said patient at from about 4 to about 6 hours after said first administration of the dosage form.
7. The dosage form of claim 1 , which provides a plasma concentration of hydrocodone of at least 8 ng/ml at from about 2 to about 8 hours after said first administration and provides a plasma concentration of hydrocodone of at least 6 ng/ml at about 12 hours after said first administration, based on oral administration of a dosage form containing 15 mg hydrocodone bitartrate.
8. The dosage form of claim 7 , which provides a plasma concentration of hydrocodone of at least 8 ng/ml at from about 3 to about 7 hours after said first administration.
9. The dosage form of claim 1 , which maintains a plasma concentration of hydrocodone within 80% of C max for about 1 to about 9 hours during the 12 hour dosing interval.
10. The dosage form of claim 1 , which maintains a plasma concentration of hydrocodone within 80% of C max for about 4 to about 8 hours during the 12 hour dosing interval.
11. The dosage form of claim 1 , which maintains a plasma concentration of hydrocodone within 90% of C max for about 1 to about 6.5 hours during the 12 hour dosing interval.
12. The dosage form of claim 1 , which maintains a plasma concentration of hydrocodone within 90% of C max for about 2 to about 5 hours during the 12 hour dosing interval.
13. A twice-a-day solid oral controlled-release dosage form of a bitartrate salt of hydrocodone consisting of
a pharmaceutically acceptable capsule,
immediate release multiparticulates consisting of a first portion of pharmaceutically acceptable inert beads, a first portion of the bitartrate salt of hydrocodone, hydroxypropylmethylcellulose, glidant(s), and optional plasticizer(s), and
controlled release multiparticulates consisting of the remaining portion of the pharmaceutically acceptable inert beads, the remaining portion of the bitartrate salt of hydrocodone, an ammonio methacrylate copolymer, glidant(s), and optional plasticizer(s),
wherein the total amount of the bitartrate salt of hydrocodone in the dosage form is from about 5 mg to about 60 mg,
the dosage form providing an in-vitro release of from 18% to about 42.5% by weight of the hydrocodone from the dosage form at one hour, when measured by the USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) for 55 minutes at 37° C. and thereafter switching to 900 ml of Simulated Intestinal Fluid (SIF) at 37° C., said dosage form, after a first administration to the patient population, providing a mean T max of hydrocodone in-vivo at from about 2 to about 8 hours, a mean C 12 /C max hydrocodone ratio of 0.55 to 0.85, and a therapeutic effect for about 12 hours.
14. A twice-a-day solid oral controlled-release dosage form of a bitartrate salt of hydrocodone, the dosage form consisting of
a capsule and
two different types of multiparticulates in the form of granules, spheroids, or pellets,
a first type of said multiparticulates consisting of a first portion of pharmaceutically acceptable inert beads, a first portion of the bitartrate salt of hydrocodone, hydroxypropylmethylcellulose, glidant(s), and optional plasticizer(s) and providing an immediate release of hydrocodone, and
a second type of said multiparticulates consisting of the remaining portion of the pharmaceutically acceptable inert beads coated with the remaining portion of the bitartrate salt of hydrocodone, an ammonio methacrylate copolymer, glidant(s), and optional plasticizer(s), and providing a controlled release of hydrocodone,
wherein the total amount of the bitartrate salt of hydrocodone in the dosage form is from about 5 mg to about 60 mg,
said dosage form providing
an in-vitro release of from at least 18% to about 42.5% by weight of hydrocodone from the dosage form at one hour when measured by the USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) for 55 minutes at 37° C. and thereafter switching to 900 ml of Simulated Intestinal Fluid (SIF) at 37° C., and
after a first administration to a human patient, a C 12 /C max hydrocodone ratio of 0.55 to 0.85 and a T max of hydrocodone at from about 2 to 8 hours.
15. A twice-a-day solid oral controlled-release dosage form of a bitartrate salt of hydrocodone, the dosage form comprising
two different types of multiparticulates in the form of granules, spheroids, or pellets, the multiparticulates collectively comprising from about 5 mg to about 60 mg of a bitartrate salt of hydrocodone,
a first type of said multiparticulates consisting of a first portion of pharmaceutically acceptable inert beads, a first portion of the bitartrate salt of hydrocodone, hydroxypropylmethylcellulose, glidant(s), and optional plasticizer(s), and providing an immediate release of hydrocodone,
a second type of said multiparticulates comprising the remaining portion of the pharmaceutically acceptable inert beads, the remaining portion of the bitartrate salt of hydrocodone, an ammonio methacrylate copolymer and glidant(s) and providing a controlled release of hydrocodone,
said dosage form providing a dissolution rate in-vitro of hydrocodone from the dosage form when measured by the USP Paddle or basket method at 100 rpm in 900 ml aqueous buffer at a pH of 7.5 at 37° C., such that from about 25 to about 65% by weight hydrocodone is released after 2 hours, from about 45 to about 85% by weight hydrocodone is released after 4 hours, and greater than about 60% by weight hydrocodone is released after 8 hours, wherein
after a first administration to said patient, the dosage form provides a C 12 /C max hydrocodone ratio of 0.55 to 0.85 and a T max of hydrocodone of from about 2 to about 6 hours.
16. The dosage form of claim 1 , wherein the remaining portion of the pharmaceutically acceptable inert beads is coated with the remaining portion of the bitartrate salt of hydrocodone, the ammonio methacrylate copolymer and glidant(s).
17. The dosage form of claim 1 , wherein the multiparticulates are in the form of spheroids.
18. The dosage form of claim 17 , wherein the spheroids are in a form of spherical granules having a diameter of between 0.1 mm and 2.5 mm.
19. The dosage form of claim 18 , wherein the spherical granules have a diameter of between 0.5 mm and 2 mm.
20. The dosage form of claim 1 , wherein the multiparticulates are in the form of granules.
21. The dosage form of claim 1 , wherein at least one of the glidants is talc.
22. The dosage form of claim 1 , wherein the ammonio methacrylate copolymer is a copolymer of acrylic and methacrylic ester with a molar ratio of ammonium groups to neutral (meth)acrylic esters of 1:40.
23. The dosage form of claim 15 , wherein the second type of said multiparticulates consists of the remaining portion of the pharmaceutically acceptable inert beads, the remaining portion of the bitartrate salt of hydrocodone, the ammonio methacrylate copolymer, glidant(s), and optional plasticizer(s).