|Abstract:||Provided herein is a pharmaceutical composition comprising an antagonist, an agonist, a seal coat, and a sequestering polymer, wherein the antagonist, agonist, seal coat and at least one sequestering polymer are all components of a single unit, and wherein the seal coat forms a layer physically separating the antagonist from the agonist from one another. Methods for manufacturing such a pharmaceutical composition are also provided.|
|Inventor(s):||Matthews; Frank (Edison, NJ), Boehm; Garth (Westfield, NJ), Tang; Lijuan (Flemington, NJ), Liang; Alfred (Edison, NJ)|
|Assignee:||Alpharma Pharmaceuticals, LLC (Bridgewater, NJ)|
1. A method of treating moderate to severe pain in a human, the method comprising: the human orally taking an intact composition in an amount sufficient to treat the
moderate to severe pain, wherein the composition comprises a plurality of multi-layer pellets comprising: a. a water-soluble core; b. an antagonist containing layer comprising naltrexone HCl coating the core; c. a sequestering polymer layer coating the
antagonist containing layer; d. an agonist layer comprising morphine sulfate coating the sequestering polymer layer; e. a controlled release layer coating the agonist layer; and f. immediately beneath the agonist layer, an osmotic pressure regulating
agent layer comprising sodium chloride; wherein the sequestering polymer layer comprises copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, sodium lauryl sulfate in an amount from 1.6% to 6.3% of the copolymers of acrylic
and methacrylic acid esters with quaternary ammonium groups on a weight-to-weight basis, and talc in an amount of from 75% to 125% of the copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups on a weight-to-weight basis;
wherein the agonist layer comprises morphine sulfate and hydroxypropyl cellulose; wherein in the multi-layer pellets, the sodium lauryl sulfate is only contained in the sequestering polymer layer; and wherein the composition sequesters at least 80% of
the naltrexone HCl as determined at 73 hours by first placing the composition in 500 mL of a 0.1 N HCl solution for 1 hour at 37.degree. C. using USP paddle method, 100 rotations per minute, and then placing the composition in 500 mL of a pH 7.5, 0.05 M
phosphate buffer, for 72 hours at 37.degree. C. using USP paddle method, 100 rotations per minute, and then determining the amount of the naltrexone HCl sequestered.
2. The method of claim 1, wherein the human is in the fed state when orally taking the composition, and wherein the area under the plasma concentration versus time curve for 6-beta-naltrexol for the human, at 168 hours (AUC.sub.last) after administration of the composition, is 1057 pg*h/mL.
3. The method of claim 2, wherein the time to maximum concentration for 6-beta-naltrexol (T.sub.max) in the human's plasma, after orally taking the composition, is 57.29 hours.
4. The method of claim 2, wherein the maximum concentration of 6-beta-naltrexol (C.sub.max) in the human's plasma, after orally taking the composition, is 25 pg/mL.
5. The method of claim 1, wherein the controlled release layer comprises a cellulose; a polyalkylene glycol; an anionic copolymer based on methacrylic acid and ethylacrylate; and a plasticizer.
6. The method of claim 1, wherein the composition does not contain a bittering agent, a gelling agent, an irritant, or an emetic.
7. The method of claim 1, wherein in said multi-layer pellets, antagonist is contained only in the antagonist containing layer.
8. The method of claim 1, wherein in said multi-layer pellets, agonist is contained only in the agonist layer.
9. The method of claim 1, wherein in said multi-layer pellets, the only agonist is the morphine sulfate.
10. The method of claim 1, wherein in said multi-layer pellets, the only antagonist is the naltrexone HCl.