Claims for Patent: 10,098,845

Summary for Patent: 10,098,845

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):	Hsu Ann, Dong Liang C., Ding Amy, Gupta Suneel
Assignee:	IMPAX LABORATORIES, LLC
Application Number:	US15027654
Patent Claims:	1. A controlled release oral solid formulation comprising(a) a controlled release component comprising a core comprising levodopa and/or an ester of levodopa or salts thereof, wherein the core is coated with a first layer comprising a rate-controlling polymer; the first layer is coated with a muco-adhesive layer comprising a dimethylaminoethyl methacrylate copolymer and the muco-adhesive layer is coated with a layer of an enteric coating polymer; and(b) an immediate release component comprising levodopa and/or an ester of levodopa or salts thereof; and [{'sub': 'max', '(a) a levodopa plasma concentration corresponding to maximum levodopa plasma concentration (C) occurring within 6 hours after administration of the dosage form;'}, {'sub': 'max', '(b) a time to reach 50% Cof less than one hour; and'}, {'sub': 'max', '(c) wherein the in vivo plasma level of levodopa is maintained at 50% Cor above for at least 5.0 hours.'}], 'wherein the controlled release component is formulated as a mini-tablet, bead, or granule and produces an in vivo levodopa plasma profile following oral administration of the controlled release oral solid formulation to a subject under fasting conditions comprising2. The controlled release oral solid formulation of wherein the immediate release component (b) is formulated as a mini-tablet claim 1 , bead claim 1 , or granule.3. The controlled release oral solid formulation of further comprising a decarboxylase inhibitor.4. The controlled release oral solid formulation of claim 1 , wherein the formulation is encapsulated in a capsule.5. The controlled release oral solid formulation of claim 1 , wherein the muco-adhesive layer comprising a dimethylaminoethyl methacrylate copolymer further comprises a polymer selected from the group consisting of polycarbophil claim 1 , carbomer claim 1 , cellulosics claim 1 , chitosan claim 1 , diethylaminodextran claim 1 , diethyl aminoethyldextran claim 1 , polygalactosamine claim 1 , polylysine claim 1 , polyomithine claim 1 , prolamine claim 1 , polyimine claim 1 , hyaluronic acid claim 1 , sodium alginate claim 1 , sodium carboxymethylcellulose (sodium CMC) claim 1 , and alginate claim 1 , or a combination thereof.6. The controlled release oral solid formulation of claim 1 , wherein the rate-controlling polymer comprises cellulose acetate or ethylcellulose.7. The controlled release oral solid formulation of claim 6 , wherein the rate-controlling polymer comprises cellulose acetate and copovidone.8. The controlled release oral solid formulation of claim 1 , wherein the enteric coating polymer comprises one or more methacrylic acid copolymers.9. The controlled release oral solid formulation of claim 1 , wherein the ester of levodopa is selected from the group consisting of ethyl (2S)-2-amino-3-(3 claim 1 ,4-dihydroxyphenyl)propanoate (levodopa ethyl ester) claim 1 , levodopa butyl ester claim 1 , and levodopa methyl ester.10. The controlled release oral solid formulation of claim 9 , wherein the ester of levodopa is a salt selected from the group consisting of an octanoate salt claim 9 , myristate salt claim 9 , succinate salt claim 9 , succinate dihydrate salt claim 9 , fumarate salt claim 9 , or fumarate dihydrate salt.11. The controlled release oral solid formulation of claim 1 , wherein the controlled release component (a) has an in vitro dissolution profile with less than 20% release of the levodopa or ester of levodopa at about pH 1.0 within two hours using a USP I dissolution method at a speed of 75 and after two hours of testing in the dissolution fluid of about pH 1.0 changing the dissolution to a fluid with a pH of about 7.0 claim 1 , the controlled release component will exhibit an extended release over at least 4 to 8 hours.12. The controlled release formulation of claim 11 , wherein the controlled release component (a) has an in vitro dissolution profile with less than 10% release of the levodopa or ester of levodopa at about pH 1.0 within two hours.13. The controlled release formulation of claim 1 , wherein the in vivo plasma level of levodopa is maintained at 50% Cor above for at least 5.5 hours.14. The controlled release formulation of claim 1 , wherein the in vivo plasma level of levodopa is maintained at 50% Cor above for at least 6.0 hours.15. The controlled release formulation of claim 1 , wherein the in vivo plasma level of levodopa is maintained at 50% Cor above for at least 6.5 hours.16. The controlled release formulation of claim 1 , wherein the in vivo plasma level of levodopa is maintained at 50% Cor above for at least 7.0 hours.17. A method of treating Parkinson's disease or primary parkinsonism comprising claim 1 , administering to the subject an effective amount of the controlled release oral solid formulation of .18. The controlled release oral solid formulation of wherein the controlled release component is a bead exhibiting a size between 0.8 to 1.2 mm.19. The controlled release oral solid formulation of wherein the controlled release component is a bead that passes through a 12 mesh screen but may be retained on a 18 claim 1 , 24 claim 1 , or 25 mesh screen.20. The controlled release oral solid formulation of wherein the controlled release component is a bead that passes through a 14 mesh screen but may be retained on a 18 claim 1 , 24 claim 1 , or 25 mesh screen.21. The controlled release oral solid formulation of wherein the controlled release component is a bead that passes through a 16 mesh screen but may be retained on a 18 claim 1 , 24 claim 1 , or 25 mesh screen.22. The controlled release oral solid formulation of wherein the levodopa claim 1 , and/or ester of levodopa claim 1 , and/or salts thereof are dispersed throughout the core or layered on a sugar sphere.