TRANSPORTER-ENHANCED CORTICOSTEROID ACTIVITY AND METHODS AND COMPOSITIONS FOR TREATING DRY EYE

• US 20080194468A1
• Filed: 11/20/2007
• Published: 08/14/2008
• Est. Priority Date: 05/25/2006
• Status: Active Grant

• Current Assignee: Bodor Laboratories, Inc.
• Original Assignee: Nicholas S. Bodor
• Inventors: Bodor, Nicholas S.
• Granted Patent: US 7,691,811 B2
• Time in Patent Office: Days
• US Class Current: 514/1.1
• 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 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

Methods and compositions for enhancing the activity and/or duration of action of loteprednol etabonate and other soft anti-inflammatory steroids of the haloalkyl 17α-alkoxycarbonyloxy-11β-hydroxyandrost-4-cn-3-one-17β-carboxylate type and the corresponding Δ^1,4-compounds are described. The enhancing agents have the formula:

• • wherein Z₁ is carbonyl, β-hydroxymethylene or methylene; R₂ is H, —OH or —OCOR₃ wherein R₃ is C_1-5 alkyl; Y is —OH, —SH or —OCOR₄ wherein R₄ is C_1-5 alkyl, cyclopentylethyl or diethylaminoethyl; and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated. Ophthalmic administration in the treatment of dry eye is specifically targeted.

Claims

1. A method for enhancing the anti-inflammatory activity or duration of action, or both, of a compound having the formula:

2. A method according to Claim 1, wherein the compound of formula (I) is:

(a) chloromethyl 17α

-ethoxycarbonyloxy-11β

-hydroxyandrosta-1,4-dien-3-one-17β

-carboxylate;

(b) chloromethyl 11β

-hydroxy-17α

-methoxycarbonyloxyandrost-4-en-3-one-17β

-carboxylate;

(c) chloromethyl 17α

-ethoxycarbonyloxy-11β

-hydroxyandrost-4-en-3-one-17β

-carboxylate;

(d) chloromethyl 17α

-butoxycarbonyloxy-11β

-hydroxyandrost-4-en-3-one-17β

-carboxylate;

(e) chloromethyl 11β

-hydroxy-17α

-isopropoxycarbonyloxyandrost-4-en-3-one-17β

-car carboxylate;

(f) chloromethyl 11β

-hydroxy-17α

-isopropoxycarbonyloxyandrosta-1,4-dien-3-one-17β

-carboxylate;

(g) chloromethyl-11β

-hydroxy-17α

-isobutoxycarbonyloxyandrost-4-en-3-one-17β

-carboxylate;

(h) chloromethyl 11β

-hydroxy-17α

-propoxycarbonyloxyandrost-4-en-3-one-17β

-carboxylate;

(i) fluoromethyl 11β

-hydroxy-17α

-isopropoxycarbonyloxyandrost-4-en-3-one-17β

-car carboxylate;

(j) chloromethyl 11β

-hydroxy-17α

-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β

-carboxylate;

or

(k) chloromethyl 11β

-hydroxy-17α

-methoxycarbonyloxyandrosta-1,4-dien-3-one-17β

-carboxylate.

3. A method according to Claim 1, wherein the compound of formula (I) is loteprednol etabonate.

4. A method according to Claim 1, wherein the compound of formula (II) is cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone butyrate, cortisone 21-cyclopentanepropionate, hydrocortisone 21-cypionate, hydrocortisone valerate, prednisolone, prednisolone acetate, prednisolone tebutate, prednisolone 21-pivalate, prednisolamate, prednival, prednisone, prednisone 21-acetate, corticosterone, tixocortol, corticosterone 21-acetate, hydrocortamate, 11-deoxycorticosterone, 11-deoxyhydrocortisone, prednicarbate or hydrocortisone tebutate.

5. A method according to Claim 1, wherein the molar ratio of compound of formula (II) to compound of formula (I) is from about 2:

1 to about 0.05;

1.

6. A method for enhancing the anti-inflammatory activity or duration of action, or both, of loteprednol etabonate following ophthalmic administration thereof to a warm-blooded animal in need of treatment to alleviate dry eye, said method comprising ophthalmically co-administering loteprednol etabonate to said animal with a synergistically effective amount, of a compound having the formula:

7. A method according to Claim 6, wherein the compound of formula (II) is cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone butyrate, hydrocortisone valerate, prednisolone, prednisolone acetate, prednisolone tebutate, prednisolone 21-pivalate, prednival, prednisone, prednisone 21-acetate, corticosterone, tixocortol, corticosterone 21-acetate, 11-deoxycorticosterone, 11-deoxyhydrocortisone, prednicarbate or hydrocortisone tebutate.

8. A method according to Claim 7, wherein the molar ratio of compound of formula (II) to loteprednol etabonate is from about 2:

1 to about 0.05;

1.

9. A method according to Claim 7, wherein the animal is in need of treatment to alleviate moderate to severe dry eye.

10. A method, for alleviating dry eye in a warm-blooded animal exhibiting same, said method comprising administering to the eye or eyes of said animal a combination comprising:

(a) a compound having the formula;

11. A method according to Claim 10, wherein the compound of formula (I) is loteprednol etabonate.

12. A method according to claim 11, wherein the compound of formula (II) is cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone butylate, cortisone 21-cyclopentanepropionate, hydrocortisone 21-cypionate, hydrocortisone valerate, prednisolone, prednisolone acetate, prednisolone tebutate, prednisolone 21-pivalate, prednisolamate, prednival, prednisone, prednisone 21-acetate, corticosteroid, tixocortol, corticosteroid 21-acetate, hydrocortamate, 11-deoxycorticosterone, 11-deoxyhydrocortisone, prednicarbate or hydrocortisone tebutate.

13. A method according to Claim 10, wherein the animal is in need of treatment to alleviate moderate to severe dry eye.

14. A method for alleviating dry eye in a warm-blooded animal exhibiting same, said method comprising administering to the eye or eyes of said animal a pharmaceutical composition comprising:

(1) a combined synergistic anti-inflammatory effective amount of;

(a) a compound having the formula;

15. A method according to Claim 14, wherein the compound of formula (I) is loteprednol etabonate.

16. A method according to Claim 15, wherein the compound of formula (II) is cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone butyrate, cortisone 21-cyclopentanepropionate, hydrocortisone 21-cypionate, hydrocortisone valerate, prednisolone, prednisolone acetate, prednisolone tebutate, prednisolone 21-pivalate, prednisolamate, prednival, prednisone, prednisone 21-acetate, corticosteroid, tixocortol, corticosterone 21-acetate, hydrocortamate, 11-deoxycorticosterone, 11-deoxyhydrocortisone, prednicarbate or hydrocortisone tebutate.

17. A method to Claim 16, wherein the compound of formula (II) is hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisolone, prednisolone acetate, prednisone, corticosteroid, 11-deoxycorticosterone or 11-deoxyhydrocortisone.

23. A method according to Claim 14, wherein the composition further comprises cyclosporin.

18. A method for alleviating dry eye in a warm-blooded animal exhibiting same, said method comprising administering to the eye or eyes of said animal a pharmaceutical composition comprising:

(1) a combined synergistic anti-inflammatory effective amount of;

(a) loteprednol etabonate; and

(b) a compound having the formula;

19. A method according to Claim 18, wherein the molar ratio of compound of formula (II) to loteprednol etabonate is from about 2:

1 to about 0.05;

1

20. A method according to Claim 18, wherein the animal has moderate to severe dry eye.

21. A method according to Claim 18, wherein the animal is treated for a period of greater than one month

22. A method according to Claim 21 wherein the treatment is for a period of greater than three years.

24. A method according to Claim 18, wherein the composition further comprises cyclosporin

25. A method according to Claim 18, wherein the composition further comprises a MUC-1 secretagogue or a non-steroidal immunophilin-dependent immunosuppressant.

30. A composition according to Claim 22, wherein the molar ratio of compound of formula (II) to loteprednol etabonate is from about 2:

1 to about 0.05;

1.

26. A pharmaceutical composition comprising:

(1) a combined synergistic anti-inflammatory effective amount of;

(a) a compound having the formula;

27. A composition according to Claim 26, wherein the compound of formula (I) is loteprednol etabonate.

28. A composition according to Claim 26, wherein the compound of formula (II) is cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone butyrate, cortisone 21-cyclopentanepropionate, hydrocortisone 21-cypionate, hydrocortisone valerate, prednisolone, prednisolone acetate, prednisolone tebutate, prednisolone 21-pivalate, prednisolamate, prednival, prednisone, prednisone 21-acetate, corticosteroid, tixocortol, corticosterone 21-acetate, hydrocortamate, 11-deoxycorticosterone, 11-deoxyhydrocortisone, prednicarbate or hydrocortisone tebutate.

29. A pharmaceutical composition comprising:

(1) a combined synergistic anti-inflammatory effective amount of;

(a) loteprednol etabonate; and

(b) a compound having the formula;