# US 2014/0193495 A1 · Controlled release pharmaceutical compositions comprising a fumaric acid ester

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- Number: US 2014/0193495 A1
- Document ID: US20140193495A1
- Status: Published application
- Kind: A1
- Application number: 14/209,480
- Filed: 2014-03-13
- Published: 2014-07-10
- Earliest claimed: 2004-10-08
- Assignees: Forward Pharma A/S
- Applicants: Forward Pharma A/S
- Inventors: Henrik NILSSON; Florian SCHOENHARTING; Bernd W. MUELLER; Joseph R. ROBINSON
- Web page: https://patentgrep.com/patent/US20140193495A1

## 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 9/167: {with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface (with further drug-free outer coating A61K9/5073)}
- A61K 9/20: Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2077: {Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets}
- A61K 9/2081: {with microcapsules or coated microparticles according to A61K9/50}
- A61K 9/28: Dragees; Coated pills or tablets {, e.g. with film or compression coating (A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209)}
- A61K 9/2846: {Poly(meth)acrylates}
- A61K 9/2853: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)}
- A61K 9/2866: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- 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 9/4891: {Coated capsules; Multilayered drug free capsule shells (with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004)}
- A61K 9/50: Microcapsules {having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals (A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167)}
- A61K 9/5042: {Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose}
- A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose}
- A61K 9/5084: {Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs (tablets containing such a mixture A61K9/2077)}
- A61K 31/215: of carboxylic acids
- A61K 31/22: of acyclic acids, e.g. pravastatin
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/06: Antianaemics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to controlled release pharmaceutical compositions comprising fumaric acid ester(s) as active substance(s). The compositions are suitable for use in the treatment of e.g. psoriasis or other hyperproliferative, inflammatory or autoimmune disorders and are designated to release the fumaric acid ester in a controlled manner so that local high concentrations of the active substance within the gastrointestinal tract upon oral administration can be avoided and, thereby, enabling a reduction in gastro-intestinal related side-effects.

## Claims

### Claim 1

A pharmaceutical composition comprising as an active substance one or more fumaric acid esters selected from di-(C1-C5)alkylesters of fumaric acid and mono-(C1-C5)alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, which—upon oral administration and in comparison to that obtained after oral administration of Fumaderm® tablets in an equivalent dosage—gives a reduction in GI related side effects.

### Claim 2 (depends on 1)

The pharmaceutical composition according to claim 1 in the form of a controlled release composition.

### Claim 3

A controlled release pharmaceutical composition for oral use comprising as an active substance one or more fumaric acid esters selected from di-(C1-C5)alkylesters of fumaric acid and mono-(C1-C5)alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, wherein the release of the fumaric acid ester—when subjected to an in vitro dissolution test employing 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.5 as dissolution medium—is as follows:
within the first 3 hours after start of the test at the most about 70% w/w of the total amount of the fumaric acid ester contained in the composition is released.

### Claim 4

A controlled release pharmaceutical composition for oral use comprising as an active substance one or more fumaric acid esters selected from di-(C1-C5)alkylesters of fumaric acid and mono-(C1-C5)alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, wherein the release of the fumaric acid ester—when subjected to an in vitro dissolution test employing 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.5 as dissolution medium—is as follows:
within the first 4 hours after start of the test at the most about 92% w/w of the total amount of the fumaric acid ester is released.

### Claim 5 (depends on 3)

The controlled release composition according to claim 3, wherein the release of the fumaric acid ester is as follows:
within the first 4 hours after start of the test at the most about 92% w/w of the total amount of the fumaric acid ester is released.

### Claim 6 (depends on 3, 4, 5)

The controlled release composition according to any one of the claims 3-5, wherein the release of the fumaric acid ester is as follows:
within the first 5 hours after start of the test at the most about 94% w/w of the total amount of the fumaric acid ester is released.

### Claim 7 (depends on 3, 4, 5, 6)

The controlled release composition according to any one of the claims 3-6, wherein the release of the fumaric acid ester is as follows:
within the first 6 hours after start of the test at the most about 95% w/w of the total amount of the fumaric acid ester contained in the composition is released.

### Claim 8 (depends on 3, 4, 5, 6, 7)

The controlled release composition according to any one of the claims 3-7, wherein the release of the fumaric acid ester is as follows:
within the first 7 hours after start of the test at the most about 98% w/w of the total amount of the fumaric acid ester contained in the composition is released.

### Claim 9 (depends on 3, 4, 5, 6, 7, 8)

The controlled release composition according to any one of the claims 3-8, wherein the release of the fumaric acid ester is as follows:
within the first 9 hours after start of the test at the most about 99% w/w of the total amount of the fumaric acid ester contained in the composition is released.

### Claim 10 (depends on 3, 4, 5, 6, 7, 8, 9)

The controlled release composition according to any one of the claims 3-9, wherein the release of the fumaric acid ester is as follows:
within the first 12 hours after start of the test at the most about 99% w/w of the total amount of the fumaric acid ester contained in the composition is released.

### Claim 11

The controlled release pharmaceutical composition according to any one of the preceding claims, wherein the release has zero-order, first-order or square-root (Higuchi's equation) kinetics release profile.

### Claim 12 (depends on 11)

The controlled release pharmaceutical composition according to claim 11, wherein the release has a square-root (Higuchi's equation) kinetics release profile.

### Claim 13 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)

The controlled release pharmaceutical composition according to any one of the claims 3-12, which—upon oral administration and in comparison to that obtained after oral administration of Fumaderm® tablets in an equivalent dosage—gives a reduction in GI related side effects.

### Claim 14

A controlled release pharmaceutical composition comprising as an active substance from 10% to 90% by weight of one or more fumaric acid esters selected from di-(C1-C5)alkylesters of fumaric acid and mono-(C1-C5)alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, from 2% to 40% by weight pharmaceutically acceptable polymer(s), and from 1% to 40% by weight hydrophilic excipient(s), and optionally pharmaceutically acceptable excipients or additives.

### Claim 15 (depends on 14)

A controlled release pharmaceutical composition according to claim 14 comprising as an active substance from 40% to 60% by weight of one or more fumaric acid esters selected from di-(C1-C5)alkylesters of fumaric acid and mono-(C1-C5)alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, from 15% to 25% by weight pharmaceutically acceptable polymer(s), and from 2% to 15% by weight hydrophilic excipient(s), and optionally pharmaceutically acceptable excipients or additives.

### Claim 16 (depends on 14)

A controlled release pharmaceutical composition according to claim 14 comprising as an active substance from 65% to 80% by weight of one or more fumaric acid esters selected from di-(C1-C5)alkylesters of fumaric acid and mono-(C1-C5)alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, from 10% to 25% by weight pharmaceutically acceptable polymer(s), and from 2% to 15% by weight hydrophilic excipient(s), and optionally pharmaceutically acceptable excipients or additives.

### Claim 17 (depends on 14, 15, 16)

The controlled release pharmaceutical composition according to any one of the claims 14-16, wherein the pharmaceutically acceptable polymer is ethyl cellulose.

### Claim 18 (depends on 14, 15, 16, 17)

The controlled release pharmaceutical composition according to any one of the claims 14-17, wherein the hydrophilic excipient is polyethylene glycol.

### Claim 19 (depends on 14, 15, 16, 17)

The controlled release pharmaceutical composition according to any one of the claims 14-17, wherein the hydrophilic excipient is hydroxylpropyl cellulose.

### Claim 20

The controlled release pharmaceutical composition comprising as an active substance from 10% to 90% by weight of one or more fumaric acid esters selected from di-(C1-C5)alkylesters of fumaric acid and mono-(C1-C5)alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, and 2% to 40% by weight methacrylic acid copolymer A and B in a weight ratio between 1:9 and 9:1, and optionally pharmaceutically acceptable excipients or additives.

### Claim 21 (depends on 14, 16, 17, 18, 19, 20)

The controlled release pharmaceutical composition according to any one of the claims 14 and 16-20 comprising from 50% to 90% of one or more fumaric acid esters selected from di-(C1-C5)alkylesters of fumaric acid and mono-(C1-C5)alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)

The controlled release pharmaceutical composition according to any one of the claims 14-21 having a dissolution profile according to any one of the claims 3-13.

### Claim 23

The controlled release pharmaceutical composition according to any one of the preceding claims, wherein the fumaric acid ester is selected from the group consisting of dimethylfumarate, diethylfumarate, dipropylfumarate, dibutylfumarate, dipentylfumarate, methyl-ethyl-fumarate, methyl-propylfumarat, methyl-butylfumarat, methyl-pentylfumarate, monomethylfumarate, monoethylfumarate, monopropylfumarate, monobutylfumarate, and monopentylfumarate, including pharmaceutically acceptable salts thereof.

### Claim 24

The controlled release pharmaceutical composition according to any one of the preceding claims, wherein the fumaric acid ester is a mono-(C1-C5)alkylester of fumaric acid that is present in the form of a pharmaceutically acceptable salt.

### Claim 25 (depends on 24)

The controlled release composition according to claim 24, wherein the salt is a metal salt such as a salt selected from alkali metal salts and alkaline earth metal salts.

### Claim 26 (depends on 24, 25)

The controlled release composition according to any one of the claim 24 or 25, wherein the salt is a sodium, potassium, calcium, magnesium or zinc salt.

### Claim 27

The controlled release pharmaceutical composition according to any one of the preceding claims comprising dimethylfumarate as the active substance.

### Claim 28

The controlled release pharmaceutical composition according to any one of the preceding claims comprising monomethylfumarate as the active substance.

### Claim 29 (depends on 28)

The controlled release pharmaceutical composition according to claim 28, wherein monomethylfumarate is present in the form of its sodium, potassium, calcium, magnesium and/or zinc salt.

### Claim 30

The controlled release composition according to any one of the preceding claims for administration once, twice or three times daily.

### Claim 31 (depends on 30)

The controlled release composition according to claim 30 for administration once daily.

### Claim 32 (depends on 30)

The controlled release composition according to claim 30 for administration twice daily.

### Claim 33

The controlled release pharmaceutical composition according to any one of the preceding claims, wherein the amount of one or more fumaric acid esters selected from di-(C1-C5)alkylesters of fumaric acid and mono-(C1-C5)alkylesters of fumaric acid or a pharmaceutically acceptable salt thereof, in a dosage form is from 90 mg to 360 mg active substance.

### Claim 34 (depends on 33)

The controlled release pharmaceutical composition according to claim 33, wherein the amount in a dosage form is 90, 120, 180, 240 or 360 mg active substance.

### Claim 35 (depends on 33)

The controlled release pharmaceutical composition according to claim 33, wherein the amount in a dosage form is 120 mg active substance.

### Claim 36 (depends on 33)

The controlled release pharmaceutical composition according to claim 33, wherein the amount in a dosage form is 180 mg active substance.

### Claim 37 (depends on 33)

The controlled release pharmaceutical composition according to claim 33, wherein the amount in a dosage form is 240 mg active substance.

### Claim 38 (depends on 33)

The controlled release pharmaceutical composition according to claim 33, wherein the amount in a dosage form is 360 mg active substance.

### Claim 39

The controlled release pharmaceutical composition according to any one of the preceding claims in the form of a tablet.

### Claim 40 (depends on 39)

The controlled release pharmaceutical composition according to claim 39, wherein the tablet has a shape that makes it easy and convenient for a patient to swallow.

### Claim 41 (depends on 39, 40)

The controlled release pharmaceutical composition according to any one of claims 39-40, wherein the tablet has a rounded or a rod-like shape without any sharp edges.

### Claim 42 (depends on 39, 40, 41)

The controlled release pharmaceutical composition according to any one of claims 39-41, wherein the tablet is designed to be divided into two or more parts.

### Claim 43 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38)

The controlled release pharmaceutical composition according to any one of claims 1-38 in the form of a capsule.

### Claim 44 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)

A method of treating psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, autoimmune diseases, such as polyarthritis, multiple sclerosis (MS), juvenile-onset diabetes mellitus, Hashimoto's thyroiditis, Grave's disease, SLE (systemic lupus erythematosus), Sjögren's syndrome, Pernicious anemia, Chronic active (lupoid) hepatitis, Rheumatoid arthritis (RA) and optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/sciatic pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or granuloma annulare, which method comprises administering orally to a patient in need thereof, an effective dosage of a pharmaceutical composition according to any one of claims 1-43.

### Claim 45 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)

Use of a pharmaceutical composition according to any one of claims 1-43 for the preparation of a medicament for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, autoimmune diseases, such as polyarthritis, multiple sclerosis (MS), juvenile-onset diabetes mellitus, Hashimoto's thyroiditis, Grave's disease, SLE (systemic lupus erythematosus), Sjögren's syndrome, Pernicious anemia, Chronic active (lupoid) hepatitis, Rheumatoid arthritis (RA) and optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/sciatic pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or granuloma annulare.