Compositions containing hydroxyeicosatetraenoic acid derivatives and methods of use in treating dry eye disorders

• US 6,353,022 B1
• Filed: 10/23/2000
• Issued: 03/05/2002
• Est. Priority Date: 11/09/1999
• Status: Expired due to Fees

• Current Assignee: Alcon Universal Ltd. (Novartis Ag)
• Original Assignee: Alcon Universal Ltd. (Novartis Ag)
• Inventors: Schneider, L. Wayne, Weimer, Lori K., Kessler, Timothy L., Wei, Zhongyou, Pasquine, Terri, Yanni, John M., Gamache, Daniel A., Bhagat, Haresh G.
• Primary Examiner(s): FAY, ZOHREH A
• Application Number:
  US09/694,796
• Time in Patent Office: 498 Days
• Field of Search: 514/530, 514/573, 514/76, 514/75, 514/912
• US Class Current: 514/530
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: C07C 51/42 Separation; Purification; Stabilisation; Use of additives
• CPC Class Codes: C07C 59/42 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 59/58 containing ether groups, groups, groups, or groups

Abstract

Compositions containing one or more HETE derivative(s) and an effective concentration of ethanol and methods of use for treating dry eye are disclosed.

Claims

1. A composition for the treatment of dry eye and other disorders requiring the wetting of the eye comprising a pharmaceutically acceptable carrier, a pharmaceutically effective amount of one or more HETE derivatives according to formulas (I), (II) or (III), and ethanol in an amount sufficient to enhance the efficacy of the HETE derivative(s):

wherein;

X is OR or NHR;

R is H, substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, wherein the substitution is made with a moiety selected from the group consisting of;

alkyl, halogen, hydroxy and functionally modified hydroxy; and

Y is

wherein R″

is H or OR″

is a functionally modified hydroxy group.

2. The composition of claim 1, wherein the HETE derivative is selected from the group consisting of:

5(S)-HETE, 5(R)-HETE, 12(S)-HETE, 12(R)-HETE, 15(S)-HETE, 15(R)-HETE and racemic and non-racemic mixtures thereof.

3. The composition of claim 1, wherein the HETE derivative is 15(S)-HETE.

4. The composition of claim 3, wherein the HETE derivative is contained in the composition in a concentration of between 0.00001 to 0.01% w/v.

5. The composition of claim 1, wherein the composition further comprises a surfactant.

6. The composition of claim 1, wherein the ethanol concentration is between 0.001-2% w/v.

7. The composition of claim 4, wherein the ethanol concentration is between 0.005-0.20% w/v.

8. The composition of claim 1 further comprising one or more artificial tear or phospholipid components.

9. The composition of claim 8 wherein the composition comprises a phospholipid selected from the group consisting of are selected from the group consisting of phosphatidylethanolamines, phosphatidylcholines, phosphatidylserines, phospatidylinositols and sphingomyelins.

10. The composition of claim 8 wherein the composition comprises a phospholipid of the formula:

wherein, X²¹ and X²² are the same or different and are O, NH(C═

O), O(C═

O), or a direct bond;

R²² is H or CH═

CH(CH₂)₁₂CH₃;

X²¹—

R¹ is OH, or R¹ is C_12-26 substituted or unsubstituted alkyl or alkenyl;

R² is C_12-26 substituted or unsubstituted alkyl or alkenyl; and

R³ is OH, OCH₂CH(NH₃⁺)COO⁻

, OCH₂CH₂NH₃⁺, OCH₂CH₂N⁺(CH₃)₃, OCH₂CH(OH)CH₂OH and O-inositol.

11. The composition of claim 10, wherein the phospholipid is selected from the group consisting of:

DPPC, DPPG, DSPI, SPPC, DPPE, DOPS, DSPE, SPPE, DOPE, DPPS, N-stearyl sphingomyelin, N-palmityl sphingomyelin and N-oleyl sphingomyelin.

12. The composition of claim 8 wherein the composition comprises an artificial tear component selected from the group consisting of monomeric polyols;

polymeric polyols;

hyaluronic acid;

chondroitin sulfate;

dextrans;

water-soluble proteins; and

vinyl polymers.

13. The composition of claim 12 wherein the artificial tear component is selected from the group consisting of glycerol;

propylene glycol;

ethylene glycol;

polyethylene glycol;

hydroxypropylmethyl cellulose;

carboxy methylcellulose sodium;

hydroxy propylcellulose;

hyaluronic acid;

chondroitin sulfate;

dextran 70;

gelatin;

polyvinyl alcohol;

polyvinylpyrrolidone;

povidone;

carbomer 934P;

carbomer 941;

carbomer 940; and

carbomer 974P.

14. The composition of claim 1, wherein the composition further comprises one or more ingredients selected from the group consisting of surfactants, tonicity agents, buffers, preservatives, co-solvents and anti-oxidants.

15. A method for the treatment of dry eye and other disorders requiring the wetting of the eye comprising administering to a mammal a composition comprising a pharmaceutically effective amount of one or more HETE derivatives according to formulas (I), (II) or (III), and ethanol in an amount sufficient to enhance the efficacy of the HETE derivative(s):

wherein;

X is OR or NHR;

R is H, substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, wherein the substitution is made with a moiety selected from the group consisting of;

alkyl, halogen, hydroxy and functionally modified hydroxy; and

Y is

wherein R″

is H or OR″

is a functionally modified hydroxy group.

16. The method of claim 15, wherein the HETE derivative is selected from the group consisting of:

5(S)-HETE, 5(R)-HETE, 12(S)-HETE, 12(R)-HETE, 15(S)-HETE, 15(R)- HETE and racemic and non-racemic mixtures thereof.

17. The method of claim 16, wherein the HETE derivative is 15(S)-HETE.

18. The method of claim 15, wherein the HETE derivative is contained in the composition in a concentration of between 0.00001 to 0.01% w/v.

19. The method of claim 15, wherein the composition further comprises a surfactant.

20. The method of claim 15, wherein the ethanol concentration in the composition is between 0.001-2% w/v.

21. The method of claim 20, wherein the ethanol concentration in the composition is between 0.005-0.20% w/v.

22. The method of claim 15 wherein the dry eye and other disorders requiring wetting of the eye is symptoms of dry eye associated with refractive surgery.