# US 12,178,918 B2 · Muco-adhesive, controlled release formulations of levodopa and/or esters of levodopa and uses thereof

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- Number: US 12,178,918 B2
- Document ID: US12178918B2
- Status: Granted
- Kind: B2
- Application number: 18/755,045
- Filed: 2024-06-26
- Published: 2024-10-24
- Granted: 2024-12-31
- Earliest claimed: 2013-10-07
- Assignees: Impax Laboratories, LLC
- Applicants: Impax Laboratories, LLC
- Inventors: Ann Hsu; Liang Dong; Amy Ding; Suneel Gupta
- Web page: https://patentgrep.com/patent/US12178918B2

## CPC

- A61K 9/4808: {characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release (capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/4891: {Coated capsules; Multilayered drug free capsule shells (with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004)}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5042: {Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose}
- A61K 9/5073: {having two or more different coatings optionally including drug-containing subcoatings}
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The invention provides an oral solid formulation comprising (a) a controlled release component comprising a core comprising levodopa, wherein the core is coated with a muco-adhesive coating and the muco-adhesive coating is externally coated with an enteric coating; and (b) an immediate release component comprising levodopa. The invention further provides a method for making and using the oral solid formulation.

## Claims

### Claim 1

A multiparticulate controlled release levodopa solid oral dosage form comprising:
(i) one or more immediate release levodopa granules; and
(ii) one or more controlled release levodopa particles comprising:
(a) a spheronized core comprising levodopa and at least one pharmaceutically acceptable excipient selected from the group consisting of a binder, a filler, a wetting agent, and mixtures thereof;
(b) a rate controlling coating surrounding the spheronized core wherein the rate controlling coating comprises a rate controlling material;
(c) a muco-adhesive coating surrounding the rate controlling coating wherein the muco-adhesive coating comprises a muco-adhesive material capable of forming a positive ionic charge at pHs present in a human gastro-intestinal tract; and
(d) an enteric coating surrounding the muco-adhesive coating wherein the enteric coating comprises an enteric material.

### Claim 2 (depends on 1)

The dosage form of claim 1, wherein the rate controlling material comprises a rate controlling polymer selected from the group consisting of cellulose acetate, ethyl cellulose, and a mixture thereof.

### Claim 3 (depends on 1)

The dosage form of claim 1, wherein the muco-adhesive material comprises a cationic muco-adhesive polymer.

### Claim 4 (depends on 3)

The dosage form of claim 3, wherein the cationic muco-adhesive polymer is an amino methacrylate copolymer.

### Claim 5 (depends on 4)

The dosage form of claim 4, wherein the amino methacrylate copolymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate).

### Claim 6 (depends on 1)

The dosage form of claim 1, wherein the spheronized core is a spheronized bead.

### Claim 7 (depends on 6)

The dosage form of claim 6, wherein the spheronized bead has a size of between 0.8 to 1.2 mm.

### Claim 8 (depends on 7)

The dosage form of claim 7, wherein the spheronized bead coated with the rate controlling coating, the muco-adhesive coating, and the enteric coating passes through a mesh screen size of 16 or less and is retained on a mesh screen size of at least 18.

### Claim 9 (depends on 1)

The dosage form of claim 1, wherein the controlled release levodopa particles do not include carbidopa.

### Claim 10 (depends on 1)

The dosage form of claim 1, wherein the immediate release levodopa granules comprise levodopa and carbidopa.

### Claim 11

A multiparticulate controlled release levodopa solid oral dosage form comprising:
one or more controlled release levodopa particles comprising:
(a) a core comprising levodopa and at least one pharmaceutically acceptable excipient selected from the group consisting of a binder, a filler, a wetting agent, and mixtures thereof;
(b) a rate controlling coating surrounding the core wherein the rate controlling coating comprises a rate controlling material;
(c) a muco-adhesive coating surrounding the rate controlling coating wherein the muco-adhesive coating comprises a muco-adhesive material capable of forming a positive ionic charge at pHs present in a human gastro-intestinal tract; and
(d) an enteric coating surrounding the muco-adhesive coating wherein the enteric coating comprises an enteric material.

### Claim 12 (depends on 11)

The dosage form of claim 11, wherein the rate controlling material is a rate controlling polymer selected from the group consisting of cellulose acetate, ethyl cellulose, and a mixture thereof.

### Claim 13 (depends on 11)

The dosage form of claim 11, wherein the muco-adhesive material comprises a cationic muco-adhesive polymer.

### Claim 14 (depends on 13)

The dosage form of claim 13, wherein the cationic muco-adhesive polymer is an amino methacrylate copolymer.

### Claim 15 (depends on 14)

The dosage form of claim 14, wherein the amino methacrylate copolymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate).

### Claim 16 (depends on 11)

The dosage form of claim 11, wherein the core is a bead.

### Claim 17 (depends on 16)

The dosage form of claim 16, wherein the bead has a size of between 0.8 to 1.2 mm.

### Claim 18 (depends on 17)

The dosage form of claim 17, wherein the bead coated with the rate controlling coating, the muco-adhesive coating and the enteric coating passes through a mesh screen size of 16 or less and is retained on a mesh screen size of at least 18.

### Claim 19 (depends on 11)

The dosage form of claim 11 further comprising an immediate release component comprising levodopa and carbidopa and the controlled release levodopa particles do not include carbidopa.

### Claim 20

A multiparticulate controlled release levodopa solid oral dosage form comprising:
(i) an immediate release component comprising one or more immediate release levodopa granules; and
(ii) a controlled release component comprising one or more controlled release levodopa particles comprising:
(a) a spheronized core comprising levodopa and (b) a muco-adhesive coating surrounding the spheronized core wherein the muco-adhesive coating comprises a muco-adhesive material capable of forming a positive ionic charge at pHs present in a human gastro-intestinal tract, and wherein ratio of levodopa in the controlled release component:levodopa in the immediate release component is about 3:1.

### Claim 21 (depends on 20)

The dosage form of claim 20, wherein the dosage form provides 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 a 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.