# US 9,517,209 B2 · Fumarate ester pharmaceutical compositions

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 9,517,209 B2
- Document ID: US9517209B2
- Status: Granted
- Kind: B2
- Application number: 15/073,720
- Filed: 2016-03-18
- Published: 2016-07-14
- Granted: 2016-12-13
- Earliest claimed: 2014-02-28
- Assignees: Banner Life Sciences LLC
- Applicants: Banner Life Sciences LLC
- Inventors: Tatyana Dyakonov; Sunil Agnihotri; Aqeel A. Fatmi
- Web page: https://patentgrep.com/patent/US9517209B2

## CPC

- A61K 31/225: Polycarboxylic acids
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- 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 9/4825: {Proteins, e.g. gelatin (gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816)}
- A61K 9/4833: {Encapsulating processes; Filling of capsules (mechanical aspects A61J3/07)}
- A61K 9/4858: {Organic compounds}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 9/4875: {Compounds of unknown constitution, e.g. material from plants or animals (oils, fats, waxes, shellac A61K9/4858)}
- A61K 9/4891: {Coated capsules; Multilayered drug free capsule shells (with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004)}
- A61K 31/22: of acyclic acids, e.g. pravastatin
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone}
- A61K 47/44: Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin (synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14)
- A61K 47/46: Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
- 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)

## Abstract

Described herein are pharmaceutical compositions comprising fumarate esters, methods for making the same, and methods for treating subjects in need thereof. In particular, oral pharmaceutical compositions comprising fumarate esters are described.

## Claims

### Claim 1

An oral immediate release pharmaceutical composition comprising solid particles of one or more fumarate esters suspended in a single phase liquid matrix comprising a lipid liquid or lipophilic liquid vehicle at a weight ratio of fumarate ester to matrix from about 1:1 to about 1:9.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the composition comprises about 80 mg to about 480 mg of fumarate ester.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the composition comprises about 100 mg to about 230 mg of fumarate ester.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the composition comprises about 200 mg to about 230 mg of fumarate ester.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the fumarate ester comprises dimethyl fumarate, monomethyl fumarate, or a combination thereof.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the lipid liquid or lipophilic liquid vehicle comprises a vegetable oil, fatty acid, fatty acid ester, or a combination thereof.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the lipid liquid or lipophilic liquid vehicle consists of soybean oil.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the lipid liquid or lipophilic liquid vehicle comprises a mixture of mono- and di-glycerides, polyvinylpyrrolidone, and polyoxyl 40 hydrogenated castor oil.

### Claim 9 (depends on 1)

The method of claim 1, wherein the matrix further comprises lactic acid.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the pharmaceutical composition comprises:
about 10% to about 50% of one or more fumarate esters comprising dimethyl fumarate, monomethyl fumarate, or a combination thereof; and
about 50% to about 90% of a lipid liquid or lipophilic liquid vehicle.

### Claim 11 (depends on 1)

The composition of claim 1, wherein the fumarate ester comprises milled or micronized particles having a particle size distribution with a d90 of less than 200 μm (PSD d90<200 μm).

### Claim 12 (depends on 1)

The composition of claim 1, wherein the fumarate ester comprises dimethyl fumarate.

### Claim 13 (depends on 1)

The composition of claim 1, wherein the fumarate ester comprises monomethyl fumarate.

### Claim 14 (depends on 1)

The composition of claim 1, wherein the composition prevents sublimation of the fumarate ester during manufacturing or storage.

### Claim 15 (depends on 1)

The composition of claim 1, wherein upon administration to a subject, the subject experiences one or more of flushing, abdominal pain, diarrhea, or nausea at a rate of less than about 20%.

### Claim 16 (depends on 1)

The composition of claim 1, wherein the composition comprises a liquid that is stable for at least 1 year at 25° C.

### Claim 17 (depends on 1)

The composition of claim 1, wherein the composition is encapsulated in a soft capsule or an enteric soft capsule.

### Claim 18 (depends on 1)

The composition of claim 1, wherein the composition comprises about 90 mg to about 110 mg of fumarate ester.

### Claim 19

An oral immediate release pharmaceutical composition comprising:
about 10% to about 50% of one or more fumarate esters comprising solid particles of dimethyl fumarate, monomethyl fumarate, or a combination thereof; and
about 50% to about 90% of a single phase lipid liquid or lipophilic liquid vehicle.

### Claim 20 (depends on 19)

The composition of claim 19, wherein the composition comprises about 100 mg to about 230 mg of fumarate ester.

### Claim 21 (depends on 19)

The composition of claim 19, wherein the composition comprises about 200 mg to about 230 mg of fumarate ester.

### Claim 22 (depends on 19)

The composition of claim 19, wherein the single phase lipid liquid or lipophilic liquid vehicle comprises a mixture of mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lactic acid.

### Claim 23 (depends on 19)

The composition of claim 19, wherein the single phase lipid liquid or lipophilic liquid vehicle consists of soybean oil.

### Claim 24 (depends on 19)

The composition of claim 19, wherein the composition comprises about 80 mg to about 480 mg of fumarate ester.

### Claim 25 (depends on 19)

The composition of claim 19, wherein the composition comprises about 90 mg to about 110 mg of fumarate ester.

### Claim 26

A method for manufacturing an oral immediate release pharmaceutical composition comprising:
(i) providing a single phase liquid matrix comprising a lipid liquid or lipophilic liquid vehicle and a suspension of one or more fumarate esters at a weight ratio of fumarate ester to matrix from about 1:1 to about 1:9;
(ii) providing a soft capsule shell composition;
(iii) casting the soft capsule shell composition into films using heat-controlled drums or surfaces; and
(iv) forming a soft capsule comprising the matrix using rotary die encapsulation technology.

### Claim 27 (depends on 26)

An oral immediate release pharmaceutical composition comprising a soft capsule shell encapsulating a single phase liquid matrix comprising a lipid liquid or lipophilic liquid vehicle and one or more fumarate esters produced by the method of claim 26.

### Claim 28 (depends on 27)

The composition of claim 27, wherein the fumarate ester comprises dimethyl fumarate, monomethyl fumarate, or a combination thereof.

### Claim 29

A pharmaceutical dosage form comprising a soft capsule encapsulating an immediate release composition comprising about 10% to about 50% of one or more fumarate esters comprising dimethyl fumarate, monomethyl fumarate, or a combination thereof and about 50% to about 90% of a single phase liquid vehicle comprising a lipid liquid or lipophilic liquid.

### Claim 30 (depends on 29)

The dosage form of claim 29, wherein the soft capsule comprises an enteric soft capsule that provides delayed release of the fumarate ester.