Water-Soluble Phenicol Prodrugs in a Lipophilic Vehicle System

1 . A pharmaceutical composition comprising a therapeutically effective amount of a water-soluble prodrug of a phenicol, wherein the composition comprises a suspension of the phenicol prodrug in a lipophilic vehicle system.

2 . The pharmaceutical composition of claim 1 wherein the water-soluble phenicol prodrug is a florfenicol prodrug.

3 . The pharmaceutical composition of claim 1 wherein the prodrug has the formula (II):

in which:

R is selected from the group consisting of

A is oxygen and a is zero or 1;

L is (a) CH 2 and l is an integer from 1 to 6; (b) CHR 1 where R 1 is an amino acid side chain and l is 1; or (c) CHR 1 NHC(O)CH(NH 2 )R 2 where R 1 and R 2 are amino acid side chains and l is 1;

M is (a) oxygen or sulfur and m is zero or one; (b) CH 2 and m is zero or an integer from 1 to 4; or (c) and m is 1;

X is (a) CH 2 and x is zero or an integer from 1 to 4; or (b) C(O) and x is 1; and Y is (a) NH 2 ; (b) NHR x where R x is methyl, ethyl, n-propyl or isopropyl; (c) NR y R z , where R y and R z are independently hydrogen, methyl, ethyl, n-propyl or isopropyl, or R y and R z taken together from a C 2 -C 5 alkylene chain, or a C 2 -C 4 alkylene chain further including a nitrogen or oxygen heteroatom in said chain; (d) C(═NH)NH 2 ; (e) N + R 4 R 5 R 6 where R 4 , R 5 and R 6 are independently hydrogen, methyl or ethyl, or R 4 and R 5 taken together form a C 2 -C 5 , alkylene chain, or a C 2 -C 4 alkylene chain further including a nitrogen or oxygen heteroatom in said chain; (f) pyridinium; (g) N-methyl or N-ethyl pyridinium; (h) N′-3-methyl-N-1-imidazolium; (i) a phenyl group substituted by a group having the formula NR 4 R 5 or N + R 4 R 5 R 6 where R 4 , R 5 and R 6 are as defined above; or (j) NH—CR 3 (═NH) where R 3 is hydrogen, methyl or amino;

and R 7 is selected from the group consisting of dichloromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, azidomethyl, and aminomethyl;

provided that the group A a L l M m X x Y is other than an alpha-N-unfunctionalized glycine, ornithine or lysine residue;

and pharmaceutically acceptable salts thereof.

4 . The pharmaceutical composition of claim 1 wherein the prodrug has the formula (III):

in which:

A is oxygen and a is zero or 1:

L is (a) CH 2 and l is an integer from 1 to 5 or (b) CHR 1 where R 1 is an amino acid side chain and l is 1; or (c) CHR 1 NHC(O)CH(NH 2 )R 2 where R 2 is an amino acid side chain and l is 1;

M is (a) oxygen and m is zero or one, (b) CH 2 and m is zero or an integer from 1 to 4; or (c) NH and m is 1;

X is (a) CH 2 and x is zero or an integer from 1 to 4; or (b) C(O) and x is 1; and

Y is (a) NH 2 ; (b) NHR x where R x is methyl, ethyl, n-propyl or isopropyl; (c) NR y R z where R y and R z are independently hydrogen, methyl, ethyl, n-propyl or isopropyl (d) C(═NH)NH 2 ; (e) N + R 4 R 5 R 6 where R 4 , R 5 and R 6 are independently hydrogen, methyl or ethyl; (N-pyridinium; (g) N′-3-methyl-N-1-imidazolium; or (h) NH—CR 3 (═NH) where R 3 is hydrogen, methyl or amino;

and R 7 is selected from the group consisting of dichloromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, azidomethyl, and aminomethyl; (with R 7 preferably being dichloromethyl)

provided that the sum of a+l+m+x is from 2 to 6 and preferably from 3 to 6;

provided that if a is 1, then M is (CH 2 ) m ;

and provided that the group A a L l M m X x Y is other than an alpha-N-unfunctionalized glycine, ornithine or lysine residue;

and pharmaceutically acceptable salts thereof.

5 . The pharmaceutical composition of claim 1 wherein the prodrug has the formula (IV):

in which:

R is selected from the group consisting of

A is oxygen and a is zero or 1;

L is (a) CH 2 and l is an integer from 1 to 6; (b) CHR 1 where R 1 is an amino acid side chain and l is 1; or (c) CHR 1 NHC(O)CH(NH 2 )R 2 where R 1 and R 2 are amino acid side chains and l is 1;

M is (a) oxygen or sulfur and m is zero or one; (b) CH 2 and m is zero or an integer from 1 to 4; or (c) NH and nm is 1;

X is (a) CH 2 and x is zero or an integer from 1 to 4; or (b) C(O) and x is 1; and

Y is (a) NH 2 : (b) NHR x where R x is methyl, ethyl, n-propyl or isopropyl; (c) NR y R z where R y and R z are independently hydrogen, methyl, ethyl, n-propyl or isopropyl, or R y and R z taken together form a C 2 -C 5 alkylene chain, or a C 2 -C 4 alkylene chain further including a nitrogen or oxygen heteroatom in said chain; (d) C(═NH)NH 2 ; (e) N + R 4 R 5 R 6 where R 4 , R 5 and R 6 are independently hydrogen, methyl or ethyl or R 4 and R 5 taken together form a C 2 -C 5 alkylene chain, or a C 2 -C 4 alkylene chain further including a nitrogen or oxygen heteroatom in said chain; (f) (pyridinium: (g) N-methyl or N-ethyl pyridinium; (h) N′-3-methyl-N-1-imidazolium; (i) a phenyl group substituted by a group having the formula NR 4 R 5 or N + R 4 R 5 R 6 where R 4 , R 5 and R 6 are as defined above; or (j) NH—CR 8 (═NH) where R 8 is hydrogen, methyl or amino; and

R 3 is selected from the group consisting of dichloromethyl, difluoromethyl, chlorofluoromethyl, chloromethyl, methyl, cyanomethyl, azidomethyl, and aminomethyl;

and pharmaceutically acceptable salts thereof.

6 . The pharmaceutical composition of claim 1 wherein the lipophilic vehicle system is selected from the group consisting of sesame oil, soybean oil, lanolin, oleic acid, lauric acid, ethyl oleate, sorbitan laurate, triethyl citrate, ethyl tartrate, benzyl alcohol, butanol, stearyl alcohol, a glyceryl ethers, a phospholipid, a terpene, a wax, and any combination thereof.

7 . The pharmaceutical composition of claim 6 wherein the lipophilic vehicle system is ethyl oleate.

8 . A method of treating or preventing a disease or disorder in a subject comprising administering to said subject a therapeutically effective amount of the pharmaceutical composition of claim 1 .