MEDICAL TREATMENT COMPRISING ENTERAL ADMINISTRATION OF EDARAVONE

• US 20190328711A1
• Filed: 07/12/2019
• Published: 10/31/2019
• Est. Priority Date: 01/17/2017
• Status: Active Grant

• Current Assignee: Treeway Tw001 B.V.
• Original Assignee: Treeway Tw001 B.V.
• Inventors: MOOLENAAR, Sytske Hyke
• Granted Patent: US 10,966,960 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/4152 having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

A solid water-dispersible pharmaceutical composition for use in the treatment of a disease is disclosed. The treatment comprises dispersing the pharmaceutical composition into an aqueous liquid to produce an enterally administrable liquid containing at least 0.5 grams of the pharmaceutical composition and at least 0.3 g/l of edaravone, followed by enterally administering the enterally administrable liquid to a human patient in an amount providing a dose of 30-300 mg edaravone. The pharmaceutical composition comprises 2-50 wt. % of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) and 3-50 wt. % of a water soluble alkalizing agent. This solid edaravone containing composition can easily be dispersed in aqueous liquid to prepare an aqueous edaravone solution that can be ingested by a patient. The solid composition of the present invention offers the advantage that edaravone dissolves very rapidly when the composition is introduced into water and that the enterally administrable liquid so obtained has high oral bioavailability.

Claims

1. A method of treating a disease, comprising:

(a) dispersing a pharmaceutical composition comprising edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) into an aqueous liquid to produce a pharmaceutical liquid comprising at least 0.5 grams of the pharmaceutical composition and at least 0.3 g/l of edaravone, followed by

(b) enterally administering the pharmaceutical liquid to a human patient in an amount providing a dose of 30-300 mg edaravone, the pharmaceutical composition comprising;

(i) 2-50 wt. % of edaravone; and

(ii) 3-50 wt. % of water soluble alkalizing agent;

wherein the edaravone in the pharmaceutical composition fully dissolves in a solution when the composition is added to demineralized water of 25°

C. in a concentration equivalent to an edaravone concentration of 1.4 g/l, and wherein the pH of the solution at 25°

C. is at least 0.5 pH units higher than the pH of a solution having the same edaravone concentration and consisting exclusively of edaravone and demineralized water.

2. The method according to claim 1, wherein the pharmaceutical composition is a powder or a tablet.

3. The method according to claim 1, wherein the composition further contains 25-95 wt. % of excipients selected from filler, disintegrant, effervescent, binder and combinations thereof.

4. The method according to claim 3, wherein the composition comprises at least 30 wt. % of one or more polyols selected from mannitol, sorbitol, xylitol, maltitol, lactitol and combinations thereof.

5. The method according to claim 1, wherein the composition further comprises 0.5-15 wt. % of surfactant.

6. The method according to claim 5, wherein the composition comprises at least 0.5 wt. % nonionic surfactant.

7. The method according to claim 1, wherein at least 90 vol. % of the edaravone is present in the form of micronized particles having a particle size of less than 100 micrometer.

8. The method according to claim 1, wherein the composition comprises less than 1 wt. % water-insoluble material.

9. The method according to claim 1, wherein the water-soluble alkalizing agent is selected from oxides and hydroxides of alkaline metals;

oxides and hydroxides of alkali-earth metals;

Al(OH)₃;

Fe₂O₃;

salts of weak organic and weak inorganic acids, alkaline amines;

alkaline amino acids; and

combinations thereof.

10. The method according to claim 1, wherein the water-soluble alkalizing agent has a pKa of at least 7.

11. The method according to claim 1, wherein the edaravone present in the pharmaceutical liquid is not contained in a clathrate.

12. The method according to claim 1, wherein the pharmaceutical liquid comprises less than 3 wt. % of water-soluble organic solvent selected from polyethylene glycol, propylene glycol, diethylene glycol monoethyl ether, polyoxyl castor oils, polyoxylglycerides, polyoxyethylene sorbitan fatty acid esters, water-soluble forms of vitamin E and ethanol.

13. The method according to claim 1, wherein the pharmaceutical liquid is a monophasic solution.

14. The method according to claim 1, wherein 1 part by weight of the pharmaceutical composition is dispersed into 20 to 200 parts by weight of the aqueous liquid.

15. The method according to claim 1, wherein the pharmaceutical liquid comprises at least 500 mg/l of edaravone.

16. The method according to claim 15, wherein the pharmaceutical liquid comprises 800-3,000 mg/l of edaravone.

17. The method according to claim 1, wherein the disease is selected from neurodegenerative diseases;

cerebral amyloid angiopathy (CAA);

auto-immune diseases;

myocardial infarction and cerebrovascular diseases.