Enhancement of activity and/or duration of action of soft anti-inflammatory steroids for topical or other local application

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

wherein:

R 1 is C 1 -C 7 alkyl;

Z is carbonyl or β-hydroxymethylene;

X is Cl or F;

and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated;

following topical or other local administration of said compound to a warm-blooded animal in need of treatment to alleviate a topical or other localized inflammatory response, said method comprising topically or otherwise locally co-administering said compound to said animal with a synergistically effective amount of a compound having the formula:

wherein:

R is H or C 1 -C 4 alkyl;

Z 1 is carbonyl or β-hydroxymethylene;

X 1 is —O— or —S—;

R 5 is —OH, —OR 6 , —OCOOR 6 or —OCOR 7 wherein R 6 is C 1 -C 4 alkyl and R 7 is C 1 -C 4 alkyl, fluoromethyl or chloromethyl;

and the dotted line is defined as above;

with the proviso that when R is C 1 -C 4 alkyl, then R 5 is —OH;

the amount of compound of formula (II) being sufficient to enhance the anti-inflammatory activity or duration of action, or both, of said compound of formula (I);

with the proviso that [3H]-triamcinolone acetonide is excluded.

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-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-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:

(a) 11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid;

(b) 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid;

(c) methyl 11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate;

(d) ethyl 11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate;

(e) methyl 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate; or

(f) ethyl 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate.

5. A method according to claim 1 , wherein the molar ratio of compound of formula (II) to compound of formula (I) is from about 5:1 to about 0.5:1.

6. A method for enhancing the anti-inflammatory activity or duration of action, or both, of loteprednol etabonate following topical or other local administration thereof to a warm blooded animal in need of treatment to alleviate a topical or other localized inflammatory response, said method comprising topically or otherwise locally co-administering loteprednol etabonate to said animal with a synergistically effective amount of a compound having the formula:

wherein R is H or C 1 -C 4 alkyl and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated, the amount of compound of formula (IIa) being sufficient to enhance the anti-inflammatory activity or duration of action, or both, of loteprednol etabonate, with the proviso that [3H]-triamcinolone acetonide is excluded.

7. A method according to claim 6 , wherein the compound of formula (IIa) is 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid or methyl 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate.

8. A method according to claim 7 , wherein the molar ratio of compound of formula (IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.

9. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a topical or other localized inflammatory response, which comprises topically or otherwise locally administering to said animal an anti-inflammatory effective amount of a combination comprising:

(a) a compound having the formula:

wherein:

R 1 is C 1 -C 7 alkyl;

Z is carbonyl or β-hydroxymethylene;

X is Cl or F;

and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated; and

(b) a compound having the formula:

wherein:

R is H or C 1 -C 4 alkyl;

Z 1 is carbonyl or β-hydroxymethylene;

X 1 is —O— or —S—;

R 5 is —OH, —OR 6 , —OCOOR 6 or —OCOR 7 wherein R 6 is C 1 -C 4 alkyl and R 7 is C 1 -C 4 alkyl, fluoromethyl or chloromethyl;

and the dotted line is defined as above;

with the proviso that when R is C 1 -C 4 alkyl, then R 5 is —OH;

in a combined synergistic anti-inflammatory effective amount;

the amount of compound of formula (II) being sufficient to enhance the anti-inflammatory activity or duration of action, or both, of said compound of formula (I);

with the proviso that [3H]-triamcinolone acetonide is excluded from the combination.

10. A method according to claim 9 , comprising administering said anti-inflammatory effective amount to the eye or eyes of a warm-blooded animal exhibiting an ophthalmic inflammatory response; to the nasal mucosa of a warm-blooded animal exhibiting a nasal inflammatory response; by oral inhalation to a warm-blooded animal exhibiting an asthmatic inflammatory response; to the rectal mucosa of a warm-blooded animal exhibiting inflammation of the upper or lower intestine or rectum; orally to a warm-blooded animal exhibiting an inflammatory response of the upper or lower intestines; to the ear or ears of a warm-blooded animal exhibiting an otic inflammatory response; by injection into the joint or joints of a warm-blooded animal exhibiting an arthritic response; to the skin of a warm-blooded animal exhibiting a dermal inflammatory response; or orally to a warm-blooded animal exhibiting an oral, gingival or throat inflammatory response.

11. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a topical or other localized inflammatory response, which comprises topically or otherwise locally administering to said animal an anti-inflammatory effective amount of a combination comprising loteprednol etabonate and a compound having the formula:

wherein R is H or C 1 -C 4 alkyl and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated, in a combined synergistic anti-inflammatory effective amount, the amount of the compound of formula (IIa) being sufficient to enhance the anti-inflammatory activity or duration of action, or both, of loteprednol etabonate, with the proviso that [3H]-triamcinolone acetonide is excluded from the combination.

12. A method according to claim 11 , wherein, in the compound of formula (IIa), R is H, methyl or ethyl.

13. A method according to claim 12 , wherein the compound of formula (IIa) is 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid or methyl 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate.

14. A method according to claim 11 , wherein the molar ratio of compound of formula (IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.

15. A method according to claim 12 , wherein the molar ratio of compound of formula (IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.

16. A method according to claim 13 , wherein the molar ratio of compound of formula (IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.

17. A method according to claim 11 , comprising administering said anti-inflammatory effective amount to the eye or eyes of a warm-blooded animal exhibiting an ophthalmic inflammatory response; to the nasal mucosa of a warm-blooded animal exhibiting a nasal inflammatory response; by oral inhalation to a warm-blooded animal exhibiting an asthmatic inflammatory response; to the rectal mucosa of a warm-blooded animal exhibiting inflammation of the upper or lower intestine or rectum; orally to a warm-blooded animal exhibiting an inflammatory response of the upper or lower intestines; to the ear or ears of a warm-blooded animal exhibiting an otic inflammatory response; by injection into the joint or joints of a warm-blooded animal exhibiting an arthritic response; to the skin of a warm-blooded animal exhibiting a dermal inflammatory response; or orally to a warm-blooded animal exhibiting an oral, gingival or throat inflammatory response.

18. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a topical or other localized inflammatory response, which comprises topically or otherwise locally administering to said animal an anti-inflammatory effective amount of a pharmaceutical composition comprising:

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

(a) a compound having the formula:

wherein:

R 1 is C 1 -C 7 alkyl;

Z is carbonyl or β-hydroxymethylene;

X is Cl or F;

and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated;

and

(b) a compound having the formula:

wherein:

R is H or C 1 -C 4 alkyl;

Z 1 is carbonyl or β-hydroxymethylene;

X 1 is —O— or —S—;

R 5 is —OH, —OR 6 , —OCOOR 6 or —OCOR 7 wherein R 6 is C 1 -C 4 alkyl and R 7 is

C 1 -C 4 alkyl, fluoromethyl or chloromethyl;

and the dotted line is defined as above;

with the proviso that when R is C 1 -C 4 alkyl, then R 5 is —OH;

the amount of compound of formula (II) being sufficient to enhance the anti-inflammatory activity or duration of action, or both, of said compound of formula (I); and

(2) a non-toxic, pharmaceutically acceptable carrier therefor suitable for topical or other local application;

with the proviso that [3H]-triamincolone acetonide is excluded from the composition.

19. A method according to claim 18 , comprising administering said anti-inflammatory effective amount to the eye or eyes of a warm-blooded animal exhibiting an ophthalmic inflammatory response; to the nasal mucosa of a warm-blooded animal exhibiting a nasal inflammatory response; by oral inhalation to a warm-blooded animal exhibiting an asthmatic inflammatory response; to the rectal mucosa of a warm-blooded animal exhibiting inflammation of the upper or lower intestine or rectum; orally to a warm-blooded animal exhibiting an inflammatory response of the upper or lower intestines; to the ear or ears of a warm-blooded animal exhibiting an otic inflammatory response; by injection into the joint or joints of a warm-blooded animal exhibiting an arthritic response; to the skin of a warm-blooded animal exhibiting a dermal inflammatory response; or orally to a warm-blooded animal exhibiting an oral, gingival or throat inflammatory response.

20. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a topical or other localized inflammatory response, which comprises topically or otherwise locally administering to said animal an anti-inflammatory effective amount of a pharmaceutical composition comprising:

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

(a) loteprednol etabonate; and

(b) a compound having the formula:

wherein R is H or C 1 -C 4 alkyl and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated, the amount of compound of formula (IIa) being sufficient to enhance the anti-inflammatory activity or duration of action, or both, of loteprednol etabonate; and

(2) a non-toxic, pharmaceutically acceptable carrier therefor suitable for topical or other local application;

with the proviso that [3H]-triamcinolone acetonide is excluded from the composition.

21. A method according to claim 20 , wherein, in the compound of formula (IIa), R is H, methyl or ethyl.

22. A method according to claim 21 , wherein the compound of formula (IIa) is 11β, 17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid or methyl 11β, 17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate.

23. A method according to claim 20 , wherein the molar ratio of compound of formula (IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.

24. A method according to claim 21 , wherein the molar ratio of compound of formula (IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.

25. A method according to claim 22 , wherein the molar ratio of compound of formula (IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.

26. A method according to claim 20 , comprising administering said anti-inflammatory effective amount to the eye or eyes of a warm-blooded animal exhibiting an ophthalmic inflammatory response; to the nasal mucosa of a warm-blooded animal exhibiting a nasal inflammatory response; by oral inhalation to a warm-blooded animal exhibiting an asthmatic inflammatory response; to the rectal mucosa of a warm-blooded animal exhibiting inflammation of the upper or lower intestine or rectum; orally to a warm-blooded animal exhibiting an inflammatory response of the upper or lower intestines; to the ear or ears of a warm-blooded animal exhibiting an otic inflammatory response; by injection into the joint or joints of a warm-blooded animal exhibiting an arthritic response; to the skin of a warm-blooded animal exhibiting a dermal inflammatory response; or orally to a warm-blooded animal exhibiting an oral, gingival or throat inflammatory response.