Flumazenil complexes, compositions comprising same and uses thereof

• US 9,585,893 B2
• Filed: 08/23/2013
• Issued: 03/07/2017
• Est. Priority Date: 02/23/2011
• Status: Active Grant

• Current Assignee: Coeruleus Ltd.
• Original Assignee: Coeruleus Ltd.
• Inventors: Amselem, Shimon
• Primary Examiner(s): Tran, My-Chau T
• Application Number:
  US13/974,760
• Publication Number:
  US 20130345202A1
• Time in Patent Office: 1,292 Days
• Field of Search: 514/220, 540/498
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/455 Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• CPC Class Codes: A61K 31/5517 condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/26 Androgens
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Soluble complexes of flumazenil, methods for the preparation thereof, pharmaceutical compositions including same and use of the compositions for alleviating or counteracting the various types of hypersomnia, drowsiness, residual effects associated with the administration of sleep/hypnotic drugs, alcohol intoxication or hepatic encephalopathy.

Claims

1. A pharmaceutically acceptable complex of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (flumanzenil) or a salt thereof and a complexation agent or a derivative thereof, wherein the complexation agent is selected from the group consisting of:

nicotinamide, sodium nicotinate, sodium benzoate, sodium hydroxybenzoates, sodium salicylate, sodium gentisate, gentisic acid ethanolamide, sodium toluates, sodium aminobenzoate, sodium anthranilate, sodium butylmonoglycolsulfate and resorcinol.

2. The pharmaceutically acceptable complex of claim 1, wherein the complexation agent is nicotinamide or a derivative thereof.

3. The pharmaceutically acceptable complex of claim 1, wherein the complexation agent:

flumazenil ratio is in the range of 1;

1 to 2;

1.

4. The pharmaceutically acceptable complex of claim 1, wherein the pharmaceutically acceptable complex is a flumazenil nicotinamide complex.

5. A pharmaceutical composition comprising the flumazenil complex of claim 4 and a pharmaceutical acceptable carrier.

6. The pharmaceutical composition of claim 5, wherein the composition is in a form selected from the group consisting of:

a pill, tablet, lozenge, coated tablet, granule, capsule, hard or soft gelatin capsule, aqueous solution, alcoholic solution, oily solution, syrup, emulsion suspension pastille suppository, solution for injection or infusion, ointment, tincture, cream, lotion, powder, spray, transdermal therapeutic systems, nasal spray, aerosol mixture, microcapsule, implant, rod and plaster.

7. The pharmaceutical composition of claim 5, wherein the composition is in a form selected from the group consisting of:

immediate release, delayed release, pulsatile release, continuous release and repetitive release.

8. The pharmaceutical composition of claim 5, wherein the concentration of flumazenil is within the range of about 0.4 to 2% w/w.

9. The pharmaceutical composition of claim 8, wherein the concentration of flumazenil is within the range of about 0.5 to 1.8% w/w.

10. The pharmaceutical composition of claim 5, further comprising a solubilizing agent selected from an alcohol, a glycol and a combination thereof.

11. The pharmaceutical composition of claim 10, wherein the solubilizing agent comprises a combination of an alcohol and a glycol and wherein the alcohol:

glycol ratio is at least 1.5;

1.

12. The pharmaceutical composition of claim 11, wherein the alcohol:

glycol ratio is in the range of 1.5;

1 to 5;

1.

13. The pharmaceutical composition of claim 10, wherein the solubilizing agent comprises a combination of an alcohol and a glycol and wherein the concentration of the solubilizing agent is at least 40%.

14. The pharmaceutical composition of claim 13, wherein the concentration of the solubilizing agent is in the range of 40% to 60%.

15. The pharmaceutical composition of claim 10, further comprising a buffering agent.

16. The pharmaceutical composition of claim 10, further comprising at least one agent selected from the group consisting of:

a penetration enhancer, a surfactant and cyclodextrin.

17. The pharmaceutical composition of claim 10, further comprising a preservative selected from the group consisting of:

benzyl alcohol, propylparaben, methylparaben and combinations thereof.

18. The pharmaceutical composition of claim 16, wherein the penetration enhancer is menthol.

19. The pharmaceutical composition of claim 15, wherein the buffering agent is selected from the group consisting of:

citric buffer, sodium chloride and combination thereof.

20. The pharmaceutical composition of claim 16, wherein the surfactant is benzalkonium chloride.