Claims for Patent: 10,973,769

Summary for Patent: 10,973,769

Title:	Muco-adhesive, controlled release formulations of levodopa and/or esters of levodopa and uses thereof
Abstract:	The invention provides a controlled release oral solid formulation comprising (a) a controlled release component comprising core comprising levodopa and/or an ester of levodopa or salts thereof, wherein the core is coated with a layer of a muco-adhesive polymer and externally coated with a layer of an enteric coated polymer; and a method of using the controlled release oral solid formulation to treat Parkinson's disease or primary parkinsonism.
Inventor(s):	Ann Hsu, Liang Dong, Amy Ding, Suneel Gupta
Assignee:	Impax Laboratories LLC
Application Number:	US16/864,323
Patent Claims:	1. A method for treating Parkinson's disease or primary parkinsonism comprising orally administering a multiparticulate formulation to a human patient three or four times a day wherein the multiparticulate formulation comprises: (a) a plurality of controlled release particles wherein the controlled release particles are mini-tablets, beads or granules and comprise: i) a core comprising levodopa, optionally carbidopa, and at least one pharmaceutically acceptable excipient; ii) a muco-adhesive layer or coating surrounding the core wherein the muco-adhesive layer comprises an amino methacrylate copolymer; and iii) an enteric layer or coating surrounding the muco-adhesive layer or coating wherein the enteric layer or coating comprises at least one enteric polymer; (b) an immediate release component comprising levodopa and optionally carbidopa and wherein the immediate release component is a powder, mini-tablet, bead, pellet, granule, a coating applied to the controlled release particles, or a combination thereof. 2. The method of claim 1 wherein the controlled release particles release: 0-60% of the levodopa after 2 hours; 25-90% of the levodopa after 4 hours; and 35-100% of the levodopa after 6 hours when the controlled release particles are tested using a United States Pharmacopeia (USP) Type I or USP Type II dissolution apparatus at 37° C., with a rotational speed of 75 rpms and 900 mL of an aqueous media with a pH of 7. 3. The method of claim 1 wherein the multiparticulate formulation releases at least 90% of the levodopa in approximately 5 to 7 hours when tested in a United States Pharmacopeia (USP) Type I dissolution apparatus at 37° C. with a rotational speed of 75 rpms and 900 mL of simulated gastric fluid with a pH of 1.0 for 2 hours followed by simulated intestinal fluid with a pH of 7.0. 4. The method of claim 1 wherein the muco-adhesive layer further comprise a polymer selected from the group consisting of polycarbophil, carbomer, cellulosics, chitosan, diethylaminodextran, diethylaminoethyldextran, polygalactosamine, polylysine, polyomithine, prolamine, polyimine, hyaluronic acid, sodium alginate, sodium carboxymethylcellulose and alginate or a combination thereof. 5. The method of claim 1, wherein the amino methacrylate copolymer is a dimethylaminoethyl methacrylate copolymer. 6. The method of claim 1, wherein the enteric polymer is selected from the group consisting of shellac, cellulose acetate phthalate, methacrylic acid copolymers, cellulose acetate trimellitate, poly(vinyl acetate phthalate), hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate. 7. The method of claim 6 wherein the enteric polymer is a methacrylic acid copolymer. 8. The method of claim 1 wherein the controlled release particles have a size that passes through a 12 mesh screen but are retained on a 25 mesh screen. 9. The method of claim 1 wherein the controlled release particles comprises: (i) the core comprising levodopa and at least one pharmaceutically acceptable excipient; (ii) a first layer surrounding the core comprising at least one rate-controlling polymer; (iii) the muco-adhesive layer surrounding the first layer; and (iv) the enteric layer surrounding the muco-adhesive layer comprising at least one enteric polymer. 10. A method for treating Parkinson's disease or primary parkinsonism comprising orally administering a multiparticulate formulation to a human patient three or four times a day wherein the multiparticulate formulation comprises: (a) a plurality of controlled release particles wherein the controlled release particles are mini-tablets, beads or granules and comprise: (i) a core comprising levodopa, optionally carbidopa, and at least one pharmaceutically acceptable excipient; (ii) a first layer surrounding the core comprising at least one rate-controlling polymer; (iii) a second layer surrounding the first layer comprising an amino methacrylate copolymer and optionally one or more additional muco-adhesive polymers selected from the group consisting of polycarbophil, carbomer, cellulosic, chitosan, diethylaminodextran, diethylaminoethyldextran, polygalactosamine, polylysine, polyomithine, prolamine, polyimine, hyaluronic acid, sodium alginate, sodium carboxymethylcellulose and alginate or a combination thereof; and (iv) a third layer surrounding the second layer comprising at least one enteric polymer selected from the group consisting of shellac, cellulose acetate phthalate, methacrylic acid copolymers, cellulose acetate trimellitate, poly(vinyl acetate phthalate), hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; and (b) an immediate release component comprising levodopa and optionally carbidopa wherein the immediate release component is a powder, mini-tablet, bead, pellet, granule, a coating applied to the controlled release particles, or a combination thereof. 11. The method of claim 10 wherein the controlled release particles pass through a 14 mesh screen but are retained on a 24 mesh screen. 12. The method of claim 10 wherein the controlled release particles release: 10-55% of the levodopa after 2 hours; 30-85% of the levodopa after 4 hours; and 40-100% of the levodopa after 6 hours when the controlled release particles are tested using a United States Pharmacopeia (USP) Type I or USP Type II dissolution apparatus at 37° C., with a rotational speed of 75 rpms and 900 mL of an aqueous media with a pH of 7. 13. The method of claim 10 wherein the multiparticulate formulation releases at least 90% of the levodopa in approximately 5 to 7 hours when tested in a USP Type I dissolution apparatus at 37° C. with a rotational speed of 75 rpms and 900 mL of simulated gastric fluid with a pH of 1.0 for 2 hours followed by simulated intestinal fluid with a pH of 7.0. 14. A multiparticulate formulation comprising: (a) a plurality of controlled release particles wherein the controlled release particles are mini-tablets, beads, or granules comprising: i) a core comprising levodopa, optionally carbidopa, and at least one pharmaceutically acceptable excipient; ii) a muco-adhesive layer or coating surrounding the core wherein the muco-adhesive layer comprises an amino methacrylate copolymer; and iii) an enteric layer or coating surrounding the muco-adhesive layer or coating wherein the enteric layer or coating comprises at least one enteric polymer; (b) an immediate release component comprising levodopa and optionally carbidopa wherein the immediate release component is a powder, mini-tablet, bead, pellet, granule, a coating applied to the controlled release particles, or a combination thereof. 15. The formulation of claim 14 wherein the controlled release particles release: 0-60% of the levodopa after 2 hours; 25-90% of the levodopa after 4 hours; and 35-100% of the levodopa after 6 hours when the controlled release particles are tested using a United States Pharmacopeia (USP) Type I or USP Type II dissolution apparatus at 37° C., with a rotational speed of 75 rpms and 900 mL of an aqueous media with a pH of 7. 16. The formulation of claim 14 wherein the formulation releases at least 90% of the levodopa in approximately 5 to 7 hours when tested in a United States Pharmacopeia (USP) Type I dissolution apparatus at 37° C. with a rotational speed of 75 rpms and 900 mL of simulated gastric fluid with a pH of 1.0 for 2 hours followed by simulated intestinal fluid with a pH of 7.0. 17. The formulation of claim 14 wherein the muco-adhesive layer further comprise a polymer selected from the group consisting of polycarbophil, carbomer, cellulosics, chitosan, diethylaminodextran, diethylaminoethyldextran, polygalactosamine, polylysine, polyomithine, prolamine, polyimine, hyaluronic acid, sodium alginate, sodium carboxymethylcellulose and alginate or a combination thereof. 18. The formulation of claim 14, wherein the amino methacrylate copolymer is a dimethylaminoethyl methacrylate copolymer. 19. The formulation of claim 14, wherein the enteric polymer is selected from the group consisting of shellac, cellulose acetate phthalate, methacrylic acid copolymers, cellulose acetate trimellitate, poly(vinyl acetate phthalate), hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate. 20. The formulation of claim 19 wherein the enteric polymer is a methacrylic acid copolymer. 21. The formulation of claim 14 wherein the controlled release particles have a size that passes through a 12 mesh screen but are retained on a 25 mesh screen. 22. The formulation of claim 14 wherein the controlled release particles comprises: (i) the core comprising levodopa and at least one pharmaceutically acceptable excipient; (ii) a first layer surrounding the core comprising at least one rate-controlling polymer; (iii) the muco-adhesive layer surrounding the first layer; and (iv) the enteric layer surrounding the muco-adhesive layer comprising at least one enteric polymer. 23. The formulation of claim 14 wherein the formulation produces an in vivo levodopa plasma profile following oral administration of the formulation to a human subject under fasting conditions comprising: (a) a levodopa plasma concentration corresponding to maximum levodopa plasma concentration (Cmax) occurring within 6 hours after administration of the formulation; (b) a time to reach 50% Cmax of less than one hour after administration of the formulation; and (c) wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 5.0 hours after administration of the formulation. 24. The formulation of claim 14 wherein the controlled release particles comprise: (i) a core comprising levodopa, optionally carbidopa, and at least one pharmaceutically acceptable excipient; (ii) a first layer surrounding the core comprising at least one rate-controlling polymer; (iii) a second layer surrounding the first layer comprising an amino methacrylate copolymer and optionally one or more additional muco-adhesive polymers selected from the group consisting of polycarbophil, carbomer, cellulosic, chitosan, diethylaminodextran, diethylaminoethyldextran, polygalactosamine, polylysine, polyomithine, prolamine, polyimine, hyaluronic acid, sodium alginate, sodium carboxymethylcellulose and alginate or a combination thereof; and (iv) a third layer surrounding the second layer comprising at least one enteric polymer selected from the group consisting of shellac, cellulose acetate phthalate, methacrylic acid copolymers, cellulose acetate trimellitate, poly(vinyl acetate phthalate), hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate. 25. The formulation of claim 24 wherein the controlled release particles pass through a 14 mesh screen but are retained on a 24 mesh screen. 26. The formulation of claim 24 wherein the controlled release particles release: 10-55% of the levodopa after 2 hours; 30-85% of the levodopa after 4 hours; and 40-100% of the levodopa after 6 hours when the controlled release particles are tested using a United States Pharmacopeia (USP) Type I or USP Type II dissolution apparatus at 37° C., with a rotational speed of 75 rpms and 900 mL of an aqueous media with a pH of 7. 27. The formulation of claim 24 wherein the formulation releases at least 90% of the levodopa in approximately 5 to 7 hours when tested in a USP Type I dissolution apparatus at 37° C. with a rotational speed of 75 rpms and 900 mL of simulated gastric fluid with a pH of 1.0 for 2 hours followed by simulated intestinal fluid with a pH of 7.0.