Claims for Patent: 10,111,839

Summary for Patent: 10,111,839

Title:	Methods and compositions particularly for treatment of attention deficit disorder
Abstract:	There is described, inter alia, a coated bead comprising: (a) a granule; (b) a first layer coated over the granule, the first layer comprising a first amount of an active pharmaceutical ingredient comprising a central nervous system stimulant; and (c) a second layer coated over the first layer, the second layer being present in an amount sufficient to substantially delay release of the active pharmaceutical ingredient in the first layer until after the coated bead reaches a distal intestine portion of a subject to whom the coated bead is administered; and (d) the third layer coated over the second layer, the third layer comprising a second amount of the active pharmaceutical ingredient, the third layer being configured to permit substantially immediate release of the active pharmaceutical ingredient comprised therein. Embodiments related to a solid oral pharmaceutical composition are also described.
Inventor(s):	Vargas Rincon; Ricardo Alberto (Mississauga, CA), Reiz; Joseph (Markham, CA)
Assignee:	Purdue Pharma (Pickering, Ontario, CA)
Application Number:	15/958,413
Patent Claims:	1. A method of treating Attention Deficit Hyperactivity Disorder (ADHD) in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of an oral solid pharmaceutical composition comprising a plurality of coated beads, wherein each coated bead comprises: a) a granule; b) a first layer coated over the granule, the first layer comprising a first amount of methylphenidate or a pharmaceutically acceptable salt thereof; c) an inner controlled release coating coated over the first layer and an outer delayed release coating coated over the inner controlled release coating; and d) an immediate release layer comprising a second amount of methylphenidate or a pharmaceutically acceptable salt thereof, coated over the outer delayed release coating, the immediate release layer providing immediate release of the second amount of methylphenidate or pharmaceutically acceptable salt thereof, wherein: the plurality of coated beads has the following in vitro methylphenidate dissolution profile: TABLE-US-00017 Time (hours) Methylphenidate (% dissolved) 1 NLT 15% 4 18-38% 8 35-55% 12 68-98 16 NLT 68 when tested according to the USP paddle method, 100 rpm, at 37.degree. C.; (i) starting with 900 ml simulated gastric fluid for 2 hours, (ii) followed by 900 ml phosphate buffer pH 6.0 for 4 hours, and (iii) for the 7th hour onwards, 900 mL of phosphate buffer pH 7.4; USP <711> Acceptance Table 2; and wherein the oral solid pharmaceutical composition provides, in a fed state, an in vivo methylphenidate T.sub.max0-4 of about 3 hours and a methylphenidate T.sub.max8-16 of about 13.5 hours. 2. The method of claim 1, wherein the oral solid pharmaceutical composition is in the form of a capsule comprising the plurality of coated beads. 3. The method of claim 1, wherein the inner controlled release coating is selected from the group consisting of an ethylcellulose polymer, a cellulose ether, a polyethylene oxide, a polyvinyl alcohol derivate, a methacrylic acid copolymer, polyethylene glycol, a polyglycolic acid, a polylactic acid, a polycaprolactone, a poly(n-hydroxybutyrate), a polyamino acid, a poly(amide-enamine), a polyester, an ethylene-vinyl acetate (EVA), a polyvinyl pyrrolidone (PVP), a poly (acrylic acid) (PAA), a poly (methacrylic acid) (PMAA), and mixtures of any two or more thereof. 4. The method of claim 1, wherein the inner controlled release coating comprises ammonio methacrylate copolymer, Type B USP/NF. 5. The method of claim 1, wherein the inner controlled release coating is present in an amount of about 3% to about 16% by weight, of each coated bead. 6. The method of claim 5, wherein the inner controlled release coating is present in an amount of about 10.0% to about 10.7% by weight, of each coated bead. 7. The method of claim 1, wherein the outer delayed release coating comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1. 8. The method of claim 1, wherein the outer delayed release coating is present in an amount of from about 3% to about 20% by weight, of each coated bead. 9. The method of claim 8, wherein the outer delayed release coating is present in an amount of from about 15.0% to about 16.0% by weight, of each coated bead. 10. The method of claim 1, wherein the first amount of methylphenidate or pharmaceutically acceptable salt thereof and the second amount of methylphenidate or pharmaceutically acceptable salt thereof, together, provide a total amount of methylphenidate or pharmaceutically acceptable salt thereof in each coated bead, and wherein the first amount of methylphenidate or pharmaceutically acceptable salt thereof comprises from about 70% to about 99% by weight of the total amount of the methylphenidate or pharmaceutically acceptable salt thereof in each coated bead. 11. The method of claim 10, wherein the first amount of methylphenidate or pharmaceutically acceptable salt thereof comprises from about 78% to about 82% by weight of the total amount of methylphenidate or pharmaceutically acceptable salt thereof. 12. The method of claim 11, wherein the first amount of methylphenidate or pharmaceutically acceptable salt thereof comprises about 80% by weight of the total amount of the methylphenidate or pharmaceutically acceptable salt thereof and the second amount of methylphenidate or pharmaceutically acceptable salt thereof comprises about 20% by weight of the total amount of the methylphenidate or pharmaceutically acceptable salt thereof. 13. The method of claim 1, wherein the inner controlled release coating is present in an amount of about 3% to about 16% by weight, of each coated bead, and wherein the outer delayed release coating is present in an amount of from about 3% to about 20% by weight, of each coated bead. 14. The method of claim 1, wherein the inner controlled release coating is present in an amount of about 10.0% to about 10.7% by weight of each coated bead, and wherein the outer delayed release coating is present in an amount of from about 15.0% to about 16.0% by weight, of each coated bead. 15. The method of claim 1, wherein the granule is selected from the group consisting of: a sugar sphere, a microcrystalline cellulose granule, a silica granule, a starch granule, a lactose granule, a calcium carbonate granule, and a mannitol-polyvinylpyrrolidone granule. 16. The method of claim 1, wherein the oral solid pharmaceutical composition comprises 25 mg, 30 mg, 35 mg, 45 mg, 55 mg, 70 mg, 85 mg, or 100 mg of methylphenidate HCl. 17. A method of treating ADHD in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of an oral solid pharmaceutical composition comprising a plurality of coated beads, wherein each coated bead comprises: a) a core comprising a first amount of methylphenidate or a pharmaceutically acceptable salt thereof; b) an inner controlled release coating coated over the core and an outer delayed release coating coated over the inner controlled release coating; and c) an immediate release layer comprising a second amount of methylphenidate or a pharmaceutically acceptable salt thereof, coated over the outer delayed release coating, the immediate release layer providing immediate release of the second amount of the methylphenidate or pharmaceutically acceptable salt thereof, wherein the plurality of coated beads has the following in vitro methylphenidate dissolution profile: TABLE-US-00018 Time (hours) Methylphenidate (% dissolved) 1 NLT 15% 4 18-38% 8 35-55% 12 68-98 16 NLT 68 when tested according to the USP paddle method, 100 rpm, at 37.degree. C.; (i) starting with 900 ml simulated gastric fluid for 2 hours, (ii) followed by 900 ml phosphate buffer pH 6.0 for 4 hours, and (iii) for the 7th hour onwards, 900 mL of phosphate buffer pH 7.4; USP<711> Acceptance Table 2; and wherein the oral solid pharmaceutical composition provides, in a fed state, an in vivo methylphenidate T.sub.max0-4 of about 3 hours and a methylphenidate T.sub.max8-16 of about 13.5 hours. 18. The method of claim 17, wherein the inner controlled release coating comprises ammonio methacrylate copolymer, Type B USP/NF. 19. The method of claim 17, wherein the inner controlled release coating is present in an amount of about 3% to about 16% by weight, of each coated bead. 20. The method of claim 17, wherein the outer delayed release coating is present in an amount of from about 3% to about 20% by weight, of each coated bead. 21. The method of claim 17, wherein the first amount of methylphenidate or pharmaceutically acceptable salt thereof and the second amount of methylphenidate or pharmaceutically acceptable salt thereof, together, provide a total amount of methylphenidate or pharmaceutically acceptable salt thereof in each coated bead, and wherein the first amount of methylphenidate or pharmaceutically acceptable salt thereof comprises from about 70% to about 99% by weight of the total amount of the methylphenidate or pharmaceutically acceptable salt thereof in each coated bead. 22. The method of claim 21, wherein the first amount of methylphenidate or pharmaceutically acceptable salt thereof comprises from about 78% to about 82% by weight of the total amount of methylphenidate or pharmaceutically acceptable salt thereof. 23. The method of claim 22, wherein the first amount of methylphenidate or pharmaceutically acceptable salt thereof comprises about 80% by weight of the total amount of methylphenidate or pharmaceutically acceptable salt thereof and the second amount of methylphenidate or pharmaceutically acceptable salt thereof comprises about 20% by weight of the total amount of methylphenidate or pharmaceutically acceptable salt thereof. 24. A method of treating ADHD in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of an oral solid pharmaceutical composition comprising a plurality of coated beads, wherein each coated bead comprises: (a) a granule; (b) a first layer coated over the granule, the first layer comprising a first amount of methylphenidate or a pharmaceutically acceptable salt thereof; (c) an inner controlled release coating coated over the first layer and an outer delayed release coating coated over the inner controlled release coating, wherein the inner controlled release coating is present in an amount of about 3% to about 16% by weight of each coated bead and wherein the outer delayed release coating is present in an amount of from about 3% to about 20% by weight of each coated bead; and (d) an immediate release layer comprising a second amount of methylphenidate or a pharmaceutically acceptable salt thereof, coated over the outer delayed release coating, the immediate release layer providing immediate release of the second amount of the methylphenidate or pharmaceutically acceptable salt thereof, wherein the first amount of methylphenidate or pharmaceutically acceptable salt thereof and the second amount of methylphenidate or pharmaceutically acceptable salt thereof, together, provide a total amount of methylphenidate or pharmaceutically acceptable salt thereof in each coated bead, and wherein the first amount of methylphenidate or pharmaceutically acceptable salt thereof comprises about 80% by weight of the total amount of the methylphenidate or pharmaceutically acceptable salt thereof, and the second amount of methylphenidate or pharmaceutically acceptable salt thereof comprises about 20% by weight of the total amount of methylphenidate or pharmaceutically acceptable salt thereof in each bead; wherein the plurality of coated beads has the following in vitro methylphenidate dissolution profile: TABLE-US-00019 Time (hours) Methylphenidate (% dissolved) 1 NLT 15% 4 18-38% 8 35-55% 12 68-98 16 NLT 68 when tested according to the USP paddle method, 100 rpm, at 37.degree. C.; (i) starting with 900 ml simulated gastric fluid for 2 hours, (ii) followed by 900 ml phosphate buffer pH 6.0 for 4 hours, and (iii) for the 7th hour onwards, 900 mL of phosphate buffer pH 7.4; USP<711> Acceptance Table 2; and wherein the oral solid pharmaceutical composition provides, in a fed state, an in vivo methylphenidate T.sub.max0-4 of about 3 hours and a methylphenidate T.sub.max8-16 of about 13.5 hours. 25. The method of claim 24, wherein the inner controlled release coating comprises ammonio methacrylate copolymer, Type B USP/NF. 26. The method of claim 24, wherein the outer delayed release coating is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 and the inner controlled release coating is ammonio methacrylate copolymer, Type B USP/NF. 27. The method of claim 24, wherein the granule is selected from the group consisting of: a sugar sphere, a microcrystalline cellulose granule, a silica granule, a starch granule, a lactose granule, a calcium carbonate granule, and a mannitol-polyvinylpyrrolidone granule. 28. The method of claim 24, wherein the plurality of coated beads provide 25 mg, 30 mg, 35 mg, 45 mg, 55 mg, 70 mg, 85 mg, or 100 mg of methylphenidate HCl.