Claims for Patent: 10,688,058

Summary for Patent: 10,688,058

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 (b) a decarboxylase inhibitor component.
Inventor(s):	Ann Hsu, Liang Dong, Amy Ding, Suneel Gupta
Assignee:	Impax Laboratories LLC
Application Number:	US16/360,936
Patent Claims:	1. A method for treating Parkinson's disease or primary parkinsonism comprising orally administering a multiparticulate formulation to a human patient two, three or four times a day wherein the multiparticulate formulation comprises: (a) a plurality of controlled release particles 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 at least one muco-adhesive polymer; 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 controlled release particles are formulated as a mini-tablet, bead, or granule and the multiparticulate formulation produces an in vivo levodopa plasma profile following oral administration of the multiparticulate 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 multiparticulate formulation; (b) a time to reach 50% Cmax of less than one hour after administration of the multiparticulate 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 multiparticulate formulation. 2. The method of claim 1 wherein the time to reach 50% Cmax is within 30 minutes after administration of the multiparticulate formulation. 3. 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. 4. The method of claim 3 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. 5. The method of claim 3 wherein the controlled release particles release: 15-50% of the levodopa after 2 hours; 35-80% of the levodopa after 4 hours; and 50-100% of the levodopa after 6 hours. 6. 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. 7. The method of claim 1 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. 8. The method of claim 1 wherein the controlled release particles do not comprise an organic acid in the core other than levodopa and carbidopa. 9. The method of claim 1 wherein the muco-adhesive polymer is selected from the group consisting of amino methacrylate copolymer, polycarbophil, carbomer, cellulosics, chitosan, diethylaminodextran, diethylaminoethyldextran, polygalactosamine, polylysine, polyomithine, prolamine, polyimine, hyaluronic acid, sodium alginate, sodium carboxymethylcellulose and alginate or a combination thereof. 10. The method of claim 9, wherein the muco-adhesive polymer is an amino methacrylate copolymer. 11. The method of claim 10, wherein the amino methacrylate copolymer is a dimethylaminoethyl methacrylate copolymer. 12. The method of claim 1, wherein the enteric polymer is selected form 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. 13. The method of claim 12 wherein the enteric polymer is a methacrylic acid copolymer. 14. The method of claim 1, wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 5.5 hours. 15. The method of claim 1, wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 6.0 hours. 16. The method of claim 1, wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 6.5 hours. 17. The method of claim 1, wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 7.0 hours. 18. 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. 19. 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 comprising at least one muco-adhesive polymer; and (iv) the enteric layer surrounding the muco-adhesive layer comprising at least one enteric polymer. 20. A method for treating Parkinson's disease or primary parkinsonism comprising orally administering a multiparticulate formulation to a human patient two, three or four times a day wherein the multiparticulate formulation comprises: (a) a plurality of controlled release particles 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 at least one muco-adhesive polymer selected from the group consisting of amino methacrylate copolymer, 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 form 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 and wherein the controlled release particles are mini-tablets, beads, or granules that pass through a 14 mesh screen but are retained on a 24 mesh screen and 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; 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 and produces an in vivo levodopa plasma profile following oral administration of the multiparticulate formulation to a human subject under fasting conditions comprising: (a) a levodopa plasma concentration corresponding to maximum levodopa plasma concentration (Cmax) occurring within 30 minutes to 7 hours after administration of the multiparticulate formulation; (b) reaches 50% Cmax within 30 minutes after administration of the multiparticulate 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 multiparticulate formulation. 21. The method of claim 20 wherein: (i) the first layer comprises at least one rate controlling polymer selected from the group consisting of cellulose acetate, ethylcellulose, an ammonio methacrylate copolymer, a neutral copolymer of polymethacrylic acid esters or mixtures thereof; (ii) the second layer comprises at least one amino methacrylate copolymer; and (iii) the third layer comprises at least one methacrylic acid copolymer. 22. The method of claim 21 wherein the multiparticulate formulation does not comprise a controlled release organic acid other than levodopa and carbidopa.