Polypeptides/chelating agent nasal compositions having enhanced peptide absorption

Claim 2

A nasal spray composition having enhanced polypeptide absorption which comprises 0.00005 to 10% weight/weight (w/w) of a pharmaceutically active polypeptide; 0.005 to 10% w/w of a pharmaceutically acceptable chelating agent; and a pharmaceutically acceptable excipient in a quantity sufficient to make weight.

Claim 3

The composition of claim 1 wherein said polypeptide is a nona- or decapeptide having LHRH agonist or antagonist activity.

Claim 4

The composition of claim 2 comprising 0.0005 to 5% w/w of said polypeptide; 0.05 to 5% w/w of said chelating agent; and aqueous buffered solution in a quantity to make weight.

Claim 5

The composition of claim 3 wherein said polypeptide is an LHRH agonist represented by Formula (I) (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) and the pharmaceutically acceptable salts thereof wherein: V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-ala-nyl; W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl; X is a D-amino acid residue ##STR11## wherein R is (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain lower alkyl groups; or (b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl; Y is leucyl, isoleucyl, nor-leucyl or N-methyl-leucyl; Z is glycinamide or --NR--R 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR12## wherein R 2 is hydrogen or lower alkyl and the chelating agent is an alkali metal salt of ethylenediaminetetraacetic acid (EDTA).

Claim 6

The composition of claim 4 wherein said polypeptide is present in an amount of 0.0005 to 5% w/w and said chelating agent is present in an amount of 0.05 to 5% w/w.

Claim 7

The composition of claim 5 wherein said compound is (pyro)Glu-His-Trp-Ser-Tyr-3-(2-naphthyl)-D-alanyl-Leu-Arg-Pro-Gly-NH 2 and its pharmaceutically acceptable salts which is present in an amount of 0.01% w/w and the chelating agent is disodium EDTA present in an amount of 0.1% w/w.

Claim 8

The composition of claim 3 wherein said polypeptide is an LHRH antagonist of Formula (II) ##STR13## and the pharmaceutically acceptable salts thereof, wherein: X is N,N'-guanido-disubstituted-D-argininyl or D-homoargininyl, D-argininyl, D-lysyl, or D-alanyl residue wherein one hydrogen on C-3 of the D-alanyl is replaced by: (a) a carbocyclic aryl-containing radical selected from the group consisting of phenyl substituted with three or more straight chain lower alkyl or alkoxy groups, trifluoromethyl, naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl and benzhydryl; or (b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl, and adamantyl; or (c) a heterocyclic aryl containing radical selected from the group consisting of radicals represented by the following structural formulas: ##STR14## wherein A" and A' are independently selected from the group consisting of hydrogen, lower alkyl, chlorine, and bromine, and G is selected from the group consisting of oxygen, nitrogen, and sulfur; A is an amino acyl residue selected from the group consisting of L-pyroglutamyl, D-pyroglutamyl, N-acyl-L-prolyl, N-acyl-D-prolyl, N-acyl-D-tryptophanyl, N-acyl-D-phenylalanyl, N-acyl-D-p-halophenylalanyl, N-acyl-D,L-seryl, N-acyl-D,L-threonyl, N-acyl-glycyl, N-acyl-D,L-alanyl, N-acyl-L-alkylprolyl, and N-acyl-X wherein X is as defined previously; B is an amino acyl residue selected from the group consisting of D-phenylalanyl, D-p-halophenylalanyl, 2,2-diphenylglycyl, and X wherein X is as defined previously; C is an amino acyl residue selected from the group consisting of L-tryptophanyl, D-tryptophanyl, D-phenylalanyl, D-phenylalanyl and X wherein X is as defined above; D is an amino acyl residue selected from the group consisting of L-seryl, and D-alanyl; Y is an amino acyl residue selected from the group consisting of L-leucyl, L-norleucyl and L-norvalyl; E is D-alanyl, glycinamide or --NH--R 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or --NH--CO--NH--R 2 wherein R 2 is hydrogen or lower alkyl; are disclosed.

Claim 11

The method of claim 8 wherein said polypeptide is a nona- or decapeptide having LHRH agonist or antagonist activity.

Claim 12

The method of claim 9 which is a nasal spray composition comprising 0.0005 to 5% w/w said polypeptide; 0.05 to 5% w/w of said chelating agent; and buffer solution in a quantity sufficient to make weight.

Claim 13

The method of claim 10 wherein the polypeptide is an agonist represented by Formula (I) (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) and the pharmaceutically acceptable salts thereof wherein: V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-ala-nyl; W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl; X is a D-amino acid residue ##STR15## wherein R is (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain lower alkyl groups; or (b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl; Y is leucyl, isoleucyl, nor-leucyl or N-methyl-leucyl; Z is glycinamide or --NR--R 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR16## wherein R 2 is hydrogen or lower alkyl and the chelating agent is an alkali metal salt of ethylenidiaminetetraacetic acid (EDTA).

Claim 14

The composition of claim 11 wherein said polypeptide is present in an amount of 0.005 to 5% w/w and said chelating agent is present in an amount of 0.05 to 5% w/w.

Claim 15

The method of claim 12 wherein said polypeptide is (pyro)Glu-His-Trp-Ser-Tyr-3-(2-naphthyl)-D-alanyl-Leu-Arg-Pro-Gly-NH 2 and its pharmaceutically acceptable salts which is present in an amount of 0.01% w/w and the chelating agent is disodium EDTA present in an amount of 0.1% w/w.

Claim 16

The method of claim 9 wherein said polypeptide is an antagonist of Formula (II) ##STR17## and the pharmaceutically acceptable salts thereof, wherein: X is N,N'-guanido-disubstituted-D-argininyl or D-homoargininyl, D-argininyl, D-lysyl, or D-alanyl residue wherein one hydrogen on C-3 of the D-alanyl is replaced by: (a) a carbocyclic aryl-containing radical selected from the group consisting of phenyl substituted with three or more straight chain lower alkyl or alkoxy groups, trifluoromethyl, naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl and benzhydryl; or (b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl, and adamantyl; or (c) a heterocyclic aryl containing radical selected from the group consisting of radicals represented by the following structural formulas: ##STR18## wherein A" and A' are independently selected from the group consisting of hydrogen, lower alkyl, chlorine, and bromine, and G is selected from the group consisting of oxygen, nitrogen, and sulfur; A is an amino acyl residue selected from the group consisting of L-pyroglutamyl, D-pyroglutamyl, N-acyl-L-prolyl, N-acyl-D-prolyl, N-acyl-D-tryptophanyl, N-acyl-D-phenylalanyl, N-acyl-D-p-halophenylalanyl, N-acyl-D,L-seryl, N-acyl-D,L-threonyl, N-acyl-glycyl, N-acyl-D,L-alanyl, N-acyl-L-alkylprolyl, and N-acyl-X wherein X is as defined previously; B is an amino acyl residue selected from the group consisting of D-phenylalanyl, D-p-halophenylalanyl, 2,2-diphenylglycyl, and X wherein X is as defined previously; C is an amino acyl residue selected from the group consisting of L-tryptophanyl, D-tryptophanyl, D-phenylalanyl, D-phenylalanyl and X wherein X is as defined above; D is an amino acyl residue selected from the group consisting of L-seryl, and D-alanyl; Y is an amino acyl residue selected from the group consisting of L-leucyl, L-norleucyl and L-norvalyl; E is D-alanyl, glycinamide or --NH--R 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or --NH--CO--NH--R 2 wherein R 2 is hydrogen or lower alkyl.