# US 10,945,984 B2 · Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects

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- Number: US 10,945,984 B2
- Document ID: US10945984B2
- Status: Granted
- Kind: B2
- Application number: 13/973,700
- Filed: 2013-08-22
- Published: 2014-02-27
- Granted: 2021-03-16
- Earliest claimed: 2012-08-22
- Assignees: Arbor Pharmaceuticals, LLC
- Applicants: Arbor Pharmaceuticals, LLC
- Inventors: Kenneth C. Cundy; Sami Karaborni; Peter A. Virsik
- Web page: https://patentgrep.com/patent/US10945984B2

## CPC

- A61K 31/225: Polycarboxylic acids
- A61K 9/2846: {Poly(meth)acrylates}
- A61K 9/2866: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2886: {having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer (of the type active core-drug layer-inactive layer A61K9/209)}
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61P 17/06: Antipsoriatics
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/02: Immunomodulators
- 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

Methods of reducing undesirable side effects during therapeutic treatment using monomethyl fumarate and prodrugs of monomethyl fumarate are disclosed.

## Claims

### Claim 1

A method of systemically administering a therapeutically effective amount of (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate to treat a disease in each patient of a population of patients in need of such treatment, comprising administering an oral sustained release tablet consisting of (i) a core comprising (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and hydroxypropyl methyl-cellulose, wherein hydroxypropyl methyl-cellulose is from 8% to 10% by weight of the core and (ii) a compression-coated mantle layer comprising a sustained release polymer layer of hydroxypropyl methylcellulose surrounding the core, wherein the hydroxypropyl methylcellulose is from 30% to 32.5% by weight of the mantle, wherein the tablet does not contain an enteric coating,
the disease is selected from multiple sclerosis and psoriasis; and
the tablet, when subjected to an in vitro dissolution test employing as a dissolution medium 750 mL of 0.1N hydrochloric acid, at pH 1.2, for a period of 2 hours, followed by addition of 250 mL of 200 mM tribasic sodium phosphate buffer resulting in an adjustment of the pH of the dissolution medium to 6.8, the dissolution medium being maintained at 37° C. and stirred at 100 rpm,
releases (i) less than 10 wt % of the dose over an initial 2 hours of the in vitro dissolution test; (ii) at least 90 wt % of the dose over not less than an initial 8 hours of the in vitro dissolution test; (iii) no more than 30 wt % of the dose in any one hour during the in vitro dissolution test; and (iv) no more than 40 wt % of the dose in any consecutive two hours during the in vitro dissolution test.

### Claim 2 (depends on 1)

The method of claim 1, wherein administration of the oral sustained release tablet to each patient achieves, across the patient population, a maximum average concentration of monomethyl fumarate in the blood plasma of the patients is less than 500 ng/ml.

### Claim 3

A method of systemically administering a therapeutically effective amount of (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate to treat a disease in each patient of a population of patients in need of such treatment, comprising administering an oral sustained release tablet consisting of (i) a core comprising (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and hydroxypropyl methylcellulose, wherein hydroxypropyl methylcellulose is from 8% to 10% by weight of the core and (ii) a compression-coated mantle layer comprising a sustained release polymer layer of hydroxypropyl methylcellulose surrounding the core, wherein the hydroxypropyl methylcellulose is from 30% to 32.5% by weight of the mantle, wherein the tablet does not contain an enteric coating, to each patient to achieve across the population an average maximum rate of rise in monomethyl fumarate concentration in the blood plasma of patients of less than 0.25% wt % ng-eq of monomethyl fumarate dosed/ml/hr,
wherein the disease is selected from multiple sclerosis and psoriasis; and
the tablet, when subjected to an in vitro dissolution test employing as a dissolution medium 750 mL of 0.1N hydrochloric acid, at pH 1.2, for a period of 2 hours, followed by addition of 250 mL of 200 mM tribasic sodium phosphate buffer resulting in an adjustment of the pH of the dissolution medium to 6.8, the dissolution medium being maintained at 37° C. and stirred at 100 rpm,
releases (i) less than 10 wt % of the dose over an initial 2 hours of the in vitro dissolution test; (ii) at least 90 wt % of the dose over not less than an initial 8 hours of the in vitro dissolution test; (iii) no more than 30 wt % of the dose in any one hour during the in vitro dissolution test; and (iv) no more than 40 wt % of the dose in any consecutive two hours during the in vitro dissolution test.

### Claim 4 (depends on 3)

The method of claim 3, wherein the average maximum rate of rise in monomethyl fumarate concentration in the blood plasma of the patients is less than 0.20 wt % ng-eq of monomethyl fumarate dosed/ml/hr or is less than 0.15 wt % ng-eq of monomethyl fumarate dosed/ml/hr.

### Claim 5 (depends on 3)

The method of claim 3, wherein the average maximum rate of rise in monomethyl fumarate concentration in the blood plasma of the patients is less than 0.10 wt % ng-eq of monomethyl fumarate dosed/mL/hr.

### Claim 6 (depends on 3)

The method of claim 3, wherein administration of the oral sustained release tablet achieves, across the patient population, an average maximum rate of rise in monomethyl fumarate concentration of less than 500 ng/mL/hr.

### Claim 7 (depends on 3)

The method of claim 3, wherein administration of the oral sustained release tablet achieves, across the patient population, an average maximum rate of rise in monomethyl fumarate concentration of less than 400 ng/mL/hr.

### Claim 8 (depends on 1)

The method of claim 1, wherein incidence of flushing in the population of patients is reduced.

### Claim 9 (depends on 1, 3)

The method of claim 1 or claim 3, where dosing occurs at a frequency of not more than twice per day.

### Claim 10 (depends on 9)

The method of claim 9, wherein the dosing frequency is twice per day.

### Claim 11 (depends on 9)

The method of claim 9, wherein the dosing frequency is once per day.

### Claim 12 (depends on 1)

The method of claim 1, wherein, administration of the tablet to each patient achieves, across the patient population, a maximum average concentration of monomethyl fumarate in the blood plasma of the patients is less than 400 ng/ml.