Claims for Patent: 10,512,613

Summary for Patent: 10,512,613

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 L.P. (Stamford, CT)
Application Number:	16/399,580
Patent Claims:	1. A method of treating Attention Deficit Hyperactivity Disorder (ADHD) in a subject in need thereof, the method comprising administering to the subject an oral solid pharmaceutical composition comprising an immediate release methylphenidate hydrochloride component and a controlled/delayed release methylphenidate hydrochloride component, wherein the immediate release methylphenidate component and the controlled/delayed release methylphenidate component, together, provide 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidate hydrochloride; and wherein the oral solid pharmaceutical composition, when administered to a subject in a fed state, provides at least two pharmacokinetic parameters selected from the group consisting of: an average.+-.standard deviation methylphenidate AUC.sub.0-4 of 21160.21.+-.6420.56 pghr/mL; an average.+-.standard deviation methylphenidate AUC.sub.8-12 of 29392.15.+-.8453.72 pghr/mL; an average.+-.standard deviation methylphenidate AUC.sub.12-16 of 36653.88.+-.11521.14 pghr/mL; an average.+-.standard deviation methylphenidate AUC.sub.0-16 of 113468.45.+-.26835.93 pghr/mL; an average.+-.standard deviation methylphenidate AUC.sub.0-12 of 76814.57.+-.16722.84 pghr/mL; an average.+-.standard deviation methylphenidate AUC.sub.12-t of 84456.90.+-.26718.88 pghr/mL; an average.+-.standard deviation methylphenidate C.sub.max0-4 of 9248.95.+-.1886.65 pg/mL; and an average.+-.standard deviation methylphenidate C.sub.max8-16 of 10667.64.+-.3017.29 pg/mL; when the oral solid pharmaceutical composition provides 100 mg of methylphenidate hydrochloride, or dose proportional AUC or C.sub.max values thereof, when the oral solid pharmaceutical composition provides 25, 35, 45, 55, 70, or 85 mg methylphenidate hydrochloride; wherein the oral solid pharmaceutical composition provides efficacious treatment of ADHD for 16 hours after a single oral administration; and further wherein the oral solid pharmaceutical composition 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.sup. 16 NLT 68 when tested according to the USP paddle oral solid pharmaceutical composition, 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. 2. The method of claim 1, wherein the controlled/delayed release methylphenidate hydrochloride component and the immediate release methylphenidate component are provided via a plurality of coated beads. 3. The method of claim 2, wherein each bead comprises a portion of the controlled/delayed release methylphenidate hydrochloride component and a portion of the immediate release methylphenidate component. 4. The method of claim 3, wherein each bead in the plurality of beads comprises a core comprising a first amount of methylphenidate hydrochloride corresponding to the portion of the delayed/controlled release methylphenidate hydrochloride component. 5. The method of claim 4, wherein the core comprises a granule coated with the first amount of methylphenidate hydrochloride or wherein the core comprises a granule substrate in admixture with the first amount of methylphenidate hydrochloride. 6. The method of claim 5, wherein the core comprises the granule coated with the first amount of methylphenidate hydrochloride. 7. The method of claim 6, wherein the first amount of methylphenidate hydrochloride is coated with an inner controlled release coating and an outer delayed release coating coated over the inner controlled release coating. 8. The method of claim 7, wherein a second amount of methylphenidate hydrochloride, corresponding to the portion of the immediate release methylphenidate component, is coated over the outer delayed release coating. 9. The method of claim 8, wherein the delayed/controlled release methylphenidate hydrochloride component comprises about 78 weight percent to about 82 weight percent of the 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidate hydrochloride in the pharmaceutical composition. 10. The method of claim 9, wherein the delayed/controlled release methylphenidate hydrochloride component comprises about 80 weight percent of the 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidate hydrochloride in the pharmaceutical composition and wherein the immediate release methylphenidate component provides about 20 percent by weight of the 25, 35, 45, 55, 70, 85, or 100 mg methylphenidate hydrochloride in the pharmaceutical composition. 11. The method of claim 6, 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. 12. The method of claim 7, wherein the inner controlled release coating is present in an amount of about 3 percent to about 16 percent by weight of each bead in the plurality of coated beads, and wherein the outer delayed release coating is present in an amount of from about 3 percent to about 20 percent by weight of each bead in the plurality of coated beads. 13. The method of claim 12, wherein the inner controlled release coating is present in an amount of about 10.0 percent to about 10.7 percent by weight of each bead in the plurality of coated beads, and wherein the outer delayed release coating is present in an amount of from about 15 percent to about 16 percent by weight of each bead in the plurality of coated beads. 14. The method of claim 13, wherein the inner controlled release coating comprises ammonio methacrylate copolymer, Type B USP/NF. 15. The method of claim 14, wherein the outer delayed release coating comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1. 16. A method of treating Attention Deficit Hyperactivity Disorder (ADHD) in a subject in need thereof, the method comprising administering to the subject an oral solid pharmaceutical composition comprising an immediate release methylphenidate hydrochloride component and a controlled/delayed release methylphenidate hydrochloride component, wherein the immediate release methylphenidate component and the controlled/delayed release methylphenidate component, together, provide 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidate hydrochloride; and wherein the oral solid pharmaceutical composition, when administered to a subject in a fasted state, provides at least two pharmacokinetic parameters selected from the group consisting of: an average.+-.standard deviation methylphenidate AUC.sub.0-4 of 24818.34.+-.7976.76 pghr/mL; an average.+-.standard deviation methylphenidate AUC.sub.8-12 of 36457.19.+-.18489.84 pghr/mL; an average.+-.standard deviation methylphenidate AUC.sub.12-16 of 39322.95.+-.10236.29 pghr/mL; an average.+-.standard deviation methylphenidate AUC.sub.0-16 of 124407.07.+-.40902.66 pghr/mL; an average.+-.standard deviation methylphenidate AUC.sub.0-12 of 85084.12.+-.33395.48 pghr/mL; an average.+-.standard deviation methylphenidate AUC.sub.12-t of 82699.74.+-.21862.39 pghr/mL; an average.+-.standard deviation methylphenidate C.sub.max0-4 of 9365.42.+-.3213.96 pg/mL; and an average.+-.standard deviation methylphenidate C.sub.max8-16 of 12413.97.+-.4546.66 pg/mL; when the oral solid pharmaceutical composition provides 100 mg of methylphenidate hydrochloride, or dose proportional AUC values thereof, or dose proportional C.sub.max values thereof, when the oral solid pharmaceutical composition provides 25, 35, 45, 55, 70, or 85 mg methylphenidate hydrochloride; wherein the oral solid pharmaceutical composition provides efficacious treatment of ADHD for 16 hours after a single oral administration; and further wherein the oral solid pharmaceutical composition 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.sup. 16 NLT 68 when tested according to the USP paddle oral solid pharmaceutical composition, 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. 17. The method of claim 16, wherein the controlled/delayed release methylphenidate hydrochloride component and the immediate release methylphenidate component are provided via a plurality of coated beads. 18. The method of claim 17, wherein each bead comprises a portion of the controlled/delayed release methylphenidate hydrochloride component and a portion of the immediate release methylphenidate component. 19. The method of claim 18, wherein each bead in the plurality of beads comprises a core comprising a first amount of methylphenidate hydrochloride corresponding to the portion of the delayed/controlled release methylphenidate hydrochloride component. 20. The method of claim 19, wherein the core comprises a granule coated with the first amount of methylphenidate hydrochloride or wherein the core comprises a granule substrate in admixture with the first amount of methylphenidate hydrochloride. 21. The method of claim 20, wherein the core comprises the granule coated with the first amount of methylphenidate hydrochloride. 22. The method of claim 21, wherein the first amount of methylphenidate hydrochloride is coated with an inner controlled release coating and an outer delayed release coating coated over the inner controlled release coating. 23. The method of claim 22, wherein a second amount of methylphenidate hydrochloride, corresponding to the portion of the immediate release methylphenidate component, is coated over the outer delayed release coating. 24. The method of claim 23, wherein the delayed/controlled release methylphenidate hydrochloride component comprises about 78 weight percent to about 82 weight percent of the 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidate hydrochloride in the pharmaceutical composition. 25. The method of claim 24, wherein the delayed/controlled release methylphenidate hydrochloride component comprises about 80 weight percent of the 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidate hydrochloride in the pharmaceutical composition and wherein the immediate release methylphenidate component provides about 20 percent by weight of the 25, 35, 45, 55, 70, 85, or 100 mg methylphenidate hydrochloride in the pharmaceutical composition. 26. The method of claim 21, 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. 27. The method of claim 22, wherein the inner controlled release coating is present in an amount of about 3 percent to about 16 percent by weight of each bead in the plurality of coated beads, and wherein the outer delayed release coating is present in an amount of from about 3 percent to about 20 percent by weight of each bead in the plurality of coated beads. 28. The method of claim 27, wherein the inner controlled release coating is present in an amount of about 10.0 percent to about 10.7 percent by weight of each bead in the plurality of coated beads, and wherein the outer delayed release coating is present in an amount of from about 15 percent to about 16 percent by weight of each bead in the plurality of coated beads. 29. The method of claim 28, wherein the inner controlled release coating comprises ammonio methacrylate copolymer, Type B USP/NF. 30. The method of claim 29, wherein the outer delayed release coating comprises poly(methyl) acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1.