Composition for treating dry eye diseases and sjögren's syndrome

Patent metadata

Field	Value
Publication number	US-2018280348-A1
Application number	US-201615753707-A
Country	US
Kind code	A1
Filing date	Aug 24, 2016
Priority date	Aug 24, 2015
Publication date	Oct 4, 2018
Grant date	—

Abstract

Disclosed are compositions and methods for treatment of a disease or disorder of the eye and adnexa of the eye, including dry eye disease and Sjögren's syndrome, by administering a composition comprising an indole and a flavonoid either as an admixture or as a synthetic heterodimer thereof.

First claim

1 . A method of treating an ocular disease characterized by inflammation of the eye or adnexa of the eye in a patient suffering therefrom, the method comprising administering a composition comprising a therapeutically effective amount of a combination of an indole and a flavonoid to said patient.

2 . The method according to claim 1 wherein the ocular disease is dry eye disease or Sjögren's disease.

3 . The method according to claim 1 , wherein the indole has a chemical formula according to Formula 1 or Formula 2:

wherein
Y is selected from NH and NOH;
Z, Z′ and Z″ are independently selected from H, Cl, Br and I; and
Aryl′ is a phenyl group substituted by one or more substituents selected from the group consisting of: hydrogen, halogens, hydroxyl, C 1-3 alkyl groups, C 1-3 ester groups, amines, C 1-3 alkyl substituted amines, aryl substituted amines, carboxylate groups, C 1-3 alkyl carboxylate esters, C 1-3 alkyl amides, sulfonates and C 1-3 alkyl sulfonates.

4 . The method according to claim 1 , wherein the indole is selected from the group consisting of indigo, isoindigo, indirubin E804, indirubin-3′-oxime (I3O), indirubin-3′-(2,3 dihydroxypropyl)-oximether (E804), 6-bromo-indirubin-3′-oxime, 5-iodo-indirubin-3′-oxime, 5-5′-dibromo-indirubin 5-sulfonic acid-indirubin-3′-oxime, sunitinib, SU4312, SU5416 and combinations thereof.

5 . The method according to claim 1 , wherein the flavonoid has a chemical formula according to Formula 3:

wherein:
R 3 , R 5 , R 6 and R 8 are independently selected from H, OH, OCH 3 , and OP wherein P is a protecting group;
R 7 is selected from H and P wherein P is a protecting group; and
Aryl is a phenyl group or a substituted phenyl group.

6 . The method according to claim 1 , wherein the flavonoid is one or more selected from the group consisting of: quercetin, baicalein, chrysin, kaempferol, wogonin, apigenin, luteolin, fisetin, galangin, myricetin, scutellarein, morin; azaleatin, gossypetin, kaempferide, isorhamnetin, natsudaidain, pachypodol, rhamnazin and rhamnetin.

7 . The method according to claim 1 where the indole is indirubin-3′-oxime (I3O).

8 . The method according to claim 1 where the flavonoid is quercetin or baicalein.

9 . The method according to claim 1 , wherein the composition comprises:
a) from about 0.1 ng/ml to about 100 mg/ml of the indole; and b) from about 0.1 ng/ml to about 100 mg/ml of the flavonoid.

10 . The method according to claim 1 , wherein the composition comprises the indole and the flavonoid in a molar ratio from about 1000:1 to 1:1000.

11 . The method according to claim 1 , wherein the composition comprises a therapeutically effective amount of a synthetic heterodimer selected from compounds having a chemical formula according to Formula 4 and Formula 5:

wherein
Y is selected from NH and NOH;
Z, Z′ and Z″ are independently selected from H, Cl, Br and I;
R 3 , R 5 , R 6 and R 8 are independently selected from H, OH, OCH 3 , and OP, wherein P is a protecting group;
R 7 is selected from H and P wherein P is a protecting group; and
Aryl and Aryl′ are independently a phenyl group or a substituted phenyl group.

12 . The method according to claim 11 , wherein the composition comprises from about 0.1 ng/ml to about 100 mg/ml of the synthetic heterodimer.

13 . The method according to claim 1 , wherein the composition is formulated as an ophthalmic composition.

14 . A synthetic heterodimer that has a chemical formula according to Formula 4 or Formula 5:

wherein:
Y is selected from NH and NOH;
Z, Z′ and Z″ are independently selected from H, Cl, Br and I;
R 3 , R 5 , R 6 and R 8 are independently selected from H, OH, OCH 3 , and OP wherein P is a protecting group; and
Aryl and Aryl′ are independently a phenyl group or a substituted phenyl group.

15 . A composition comprising a combination of an indole and a flavonoid in an amount that is therapeutically effective for treating an ocular disease characterized by inflammation of the eye or adnexa of the eye in a patient suffering therefrom.

16 . The composition of claim 15 , wherein the indole has a chemical formula according to Formula 1 or Formula 2:

wherein
Y is selected from NH and NOH;
Z, Z′ and Z″ are independently selected from H, Cl, Br and I; and
Aryl′ is a phenyl group substituted by one or more substituents selected from the group consisting of: hydrogen, halogens, hydroxyl, C 1-3 alkyl groups, C 1-3 ester groups, amines, C 1-3 alkyl substituted amines, aryl substituted amines, carboxylate groups, C 1-3 alkyl carboxylate esters, C 1-3 alkyl amides, sulfonates and C 1-3 alkyl sulfonates.

17 . The composition according to claim 15 , wherein the indole is selected from the group consisting of indigo, isoindigo, indirubin E804, indirubin-3′-oxime (I3O), indirubin-3′-(2,3 dihydroxypropyl)-oximether (E804), 6-bromo-indirubin-3′-oxime, 5-iodo-indirubin-3′-oxime, 5-5′-dibromo-indirubin 5-sulfonic acid-indirubin-3′-oxime, sunitinib, SU4312, SU5416 and combinations thereof.

18 . The composition according to claim 15 , wherein the flavonoid has a chemical formula according to Formula 3:

wherein:
R 3 , R 5 , R 6 and R 8 are independently selected from H, OH, OCH 3 , and OP wherein P is a protecting group;
R 7 is selected from H and P wherein P is a protecting group; and
Aryl is a phenyl group or a substituted phenyl group.

19 . The composition according to claim 15 , wherein the flavonoid is one or more selected from the group consisting of: quercetin, baicalein, chrysin, kaempferol, wogonin, apigenin, luteolin, fisetin, galangin, myricetin, scutellarein, morin; azaleatin, gossypetin, kaempferide, isorhamnetin, natsudaidain, pachypodol, rhamnazin and rhamnetin.

20 . The composition according to claim 15 where the indole is indirubin-3′-oxime (I3O).

21 . The composition according to claim 15 where the flavonoid is quercetin or baicalein.

22 . The composition according to claim 15 , wherein the composition comprises:
a) from about 0.1 ng/ml to about 100 mg/ml of the indole; and b) from about 0.1 ng/ml to about 100 mg/ml of the flavonoid.

23 . The composition according to claim 15 , wherein the composition comprises the indole and the flavonoid in a molar ratio from about 1000:1 to 1:1000.

24 . The composition according to claim 15 which comprises a therapeutically effective amount of a synthetic heterodimer selected from compounds having a chemical formula according to Formula 4 and Formula 5:

wherein
Y is selected from NH and NOH;
Z, Z′ and Z″ are independently selected from H, Cl, Br and I;
R 3 , R 5 , R 6 and R 8 are independently selected from H, OH, OCH 3 , and OP

Assignees

• Univ Macau

Inventors

• Lee Ming Yuen
• Ng Tatfong

Classifications

• A61P27/02

  Ophthalmic agents · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K47/02

  Inorganic compounds · CPC title

• A61K9/0048

  Eye, e.g. artificial tears · CPC title

• A61K9/08

  Solutions {(composition of solutions A61K47/00)} · CPC title