Claims for Patent: 10,463,624

Summary for Patent: 10,463,624

Title:	Controlled release formulations
Abstract:	The invention is directed to oral modified/controlled release drug formulations which provide a rapid initial onset of effect and a prolonged duration of effect. Preferably, the peak concentration is lower than that provided by the reference standard for immediate release formulations of the drug, and the duration of effect falls rapidly at the end of the dosing interval.
Inventor(s):	Krishnamurthy; Thinnayam N. (Scarborough, CA), Darke; Andrew (Newmarket, CA)
Assignee:	RHODES PHARMACEUTICALS L.P. (Coventry, RI)
Application Number:	15/714,542
Patent Claims:	1. An oral controlled release formulation, comprising a plurality of substrates in the form of matrix spheroids or inert pharmaceutically acceptable beads, wherein said plurality of substrates comprise a portion of an effective dose of methylphenidate or a pharmaceutically acceptable salt thereof in immediate release form incorporated into the matrix spheroids or coated over the inert pharmaceutically acceptable beads, a hydrophobic material comprising an acrylic polymer coated onto the surface of said substrates in an amount sufficient to retard the release of said portion of the methylphenidate or pharmaceutically acceptable salt thereof, and an enteric coating applied over said hydrophobic material to obtain enteric coated substrates, wherein said enteric coating is in an amount sufficient to substantially delay the release of said methylphenidate or pharmaceutically acceptable salt thereof from said substrates until after said formulation passes through the stomach, wherein said enteric coating is derived from an aqueous dispersion comprising an acrylic/methacrylic copolymer, a plasticizer and a glidant, the formulation further comprising the remaining portion of the effective dose of the methylphenidate or pharmaceutically acceptable salt thereof in immediate release form, and wherein the formulation provides a maximum plasma concentration of methylphenidate at about 0.5 to about 2 hours after oral administration, and the duration of effect provided by the methylphenidate or pharmaceutically acceptable salt thereof contained in the formulation falls below effective plasma concentrations at about 10 to about 12 hours after the oral administration. 2. The oral controlled release formulation of claim 1, wherein said formulation comprises methylphenidate hydrochloride. 3. The oral controlled release formulation of claim 2, wherein said remaining portion of the effective dose of methylphenidate hydrochloride is applied as a topcoat over the enteric coated substrates. 4. The oral controlled release formulation of claim 3, wherein said topcoat of methylphenidate hydrochloride is obtained through spraying a solution of methylphenidate hydrochloride in water over the enteric coated substrates. 5. The oral controlled release formulation of claim 2, wherein the enteric coated substrates are contained within a capsule. 6. The oral controlled release formulation of claim 5, wherein the capsule is coated with the remaining portion the effective dose of methylphenidate hydrochloride in the immediate release form. 7. The oral controlled release formulation of claim 5, wherein said remaining portion of methylphenidate hydrochloride is incorporated into the capsule in the form of an immediate release powder within the capsule. 8. The oral controlled release formulation of claim 5, wherein said remaining portion of the effective dose of methylphenidate hydrochloride is incorporated into the capsule in the form of an immediate release granulate within the capsule. 9. The oral controlled release formulation of claim 2, wherein the enteric coated substrates are contained within a tablet. 10. The oral controlled release formulation of claim 9, wherein the tablet is coated with the remaining portion of the effective dose of methylphenidate hydrochloride in the immediate release form. 11. The oral controlled release formulation of claim 2, wherein said remaining portion of the effective dose of methylphenidate hydrochloride is incorporated into the formulation in the form of immediate release substrates, wherein the enteric coated substrates are mixed with the immediate release substrates within the oral controlled release formulation. 12. The oral controlled release formulation of claim 11, wherein said immediate release substrates are obtained through spraying an aqueous solution comprising methylphenidate hydrochloride onto a second plurality of substrates. 13. The oral controlled release formulation of claim 11, wherein the immediate release substrates are selected from the group of immediate release beads, immediate release ion exchange resins, immediate release pellets, immediate release spheroids, and immediate release spheres. 14. The oral controlled release formulation of claim 2, wherein the maximum plasma concentration occurs at about 0.5 to about 1 hour after the oral administration. 15. The oral controlled release formulation of claim 14, wherein the maximum plasma concentration occurs at about 1 hour after the oral administration. 16. The oral controlled release formulation of claim 15, wherein the maximum plasma concentration occurs under fasting conditions. 17. The oral controlled release formulation of claim 2, wherein the maximum plasma concentration occurs at about 1 to about 2 hours after the oral administration. 18. The oral controlled release formulation of claim 2, wherein the remaining portion of the effective dose contains from about 30% to about 40% of the effective dose of the methylphenidate or pharmaceutically acceptable salt thereof. 19. The oral controlled release formulation of claim 2, wherein the duration of effect provided by the methylphenidate or pharmaceutically acceptable salt thereof contained in the formulation falls below effective plasma concentrations at about 12 hours after the oral administration. 20. The oral controlled release formulation of claim 19, wherein the remaining portion of the effective dose contains from about 30% to about 40% of the effective dose of the methylphenidate or pharmaceutically acceptable salt thereof. 21. An oral controlled release formulation, comprising a plurality of substrates in the form of matrix spheroids or inert pharmaceutically acceptable beads, wherein said plurality of substrates comprise a portion of an effective dose of methylphenidate or a pharmaceutically acceptable salt thereof incorporated into the matrix spheroids or coated over the inert pharmaceutically acceptable beads, a controlled release coating comprising an acrylic polymer coated onto the surface of said substrates, and an enteric coating applied over said controlled release coating to obtain enteric coated substrates, wherein said enteric coating is derived from an aqueous dispersion comprising an acrylic/methacrylic copolymer, a plasticizer and a glidant, and is in an amount sufficient to delay the release of said portion of the effective dose of the methylphenidate or pharmaceutically acceptable salt thereof from said enteric coated substrates until after said formulation passes through the stomach, the formulation further comprising the remaining portion of the effective dose in an immediate release form, and providing a time to maximum plasma concentration of methylphenidate at about 0.5 to about 2 hours after oral administration, and a duration of effect for a time period of from about 10 to about 12 hours. 22. The oral controlled release formulation of claim 21, wherein said formulation comprises methylphenidate hydrochloride. 23. The oral controlled release formulation of claim 22, wherein said remaining portion of the effective dose is applied as a topcoat over the enteric coated substrates. 24. The oral controlled release formulation of claim 22, wherein the enteric coated substrates are contained within a capsule. 25. The oral controlled release formulation of claim 22, wherein the enteric coated substrates are contained within a tablet. 26. The oral controlled release formulation of claim 22, wherein said remaining portion of the effective dose is incorporated into the formulation in the form of immediate release substrates, and the oral controlled release formulation comprises a mixture of the enteric coated substrates and the immediate release substrates. 27. The oral controlled release formulation of claim 21, wherein the oral administration is under fasting conditions. 28. The oral controlled release formulation of claim 21, wherein said remaining portion of the effective dose comprises from about 30% to about 40% of the effective dose. 29. The oral controlled release formulation of claim 21, wherein the portion of the effective dose is coated over said inert pharmaceutically acceptable beads, and the plasticizer comprises from about 1 to about 50 percent of the acrylic/methacrylic acid copolymer by weight. 30. The oral controlled release formulation of claim 1, wherein the portion of the effective dose is coated over said inert pharmaceutically acceptable beads, and the plasticizer comprises from about 1 to about 50 percent of the acrylic/methacrylic acid copolymer by weight. 31. An oral controlled release formulation, comprising a plurality of substrates in the form of inert pharmaceutically acceptable beads, comprising a portion of an effective dose of methylphenidate or a pharmaceutically acceptable salt thereof coated over said inert pharmaceutically acceptable beads, a controlled release coating comprising an acrylic polymer coated onto the surface of said substrates, and an enteric coating applied over said controlled release coating to obtain enteric coated substrates, wherein said enteric coating is derived from an aqueous dispersion comprising an acrylic/methacrylic copolymer, a plasticizer and a glidant, and is in an amount sufficient to delay the release of said portion of the effective dose of the methylphenidate or pharmaceutically acceptable salt thereof from said enteric coated substrates until after said formulation passes through the stomach, the formulation further comprising the remaining portion of the effective dose in an immediate release form, wherein the acrylic polymer is a copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters of 1:40, the acrylic/methacrylic acid copolymer is a methacrylic acid copolymer which does not swell at about pH<5.7 and is soluble at about pH>6, and the plasticizer comprises from about 1 to about 50 percent of the methacrylic acid copolymer by weight. 32. An oral controlled release formulation, comprising a plurality of substrates comprising a portion of an effective dose of methylphenidate or a pharmaceutically acceptable salt thereof is coated over inert pharmaceutically acceptable beads, a controlled release coating comprising an acrylic polymer coated onto the surface of said substrates, and an enteric coating applied over said controlled release coating to obtain enteric coated substrates, wherein said enteric coating is derived from an aqueous dispersion comprising an acrylic/methacrylic copolymer, a plasticizer and a glidant, and is in an amount sufficient to delay the release of said portion of the effective dose of the methylphenidate or pharmaceutically acceptable salt thereof from said enteric coated substrates until after said formulation passes through the stomach, the formulation further comprising the remaining portion of the effective dose in an immediate release form, wherein the formulation provides a mean AUC.sub.0-t of 54686.38+15118.66 pg.times.h/ml, a mean AUC.sub.0-inf of 57931.47+16762.54 pg.times.h/ml, a mean C.sub.max of 4879.37 +1027.85 pg/ml, a mean T.sub.max of 7.29+1.29 hours, a mean K.sub.el of 0.1812+0.0392h.sup.-, and a mean T.sub.1/2el of 4.06 +1.25 hours, based on a fed administration of a formulation comprising 20 mg of said methylphenidate or pharmaceutically acceptable salt thereof.