Delivery systems for the controlled administration of LHRH analogs

Claim 2

A polymeric delivery system for the controlled and sustained administration of an LHRH analog to an animal in need of such treatment, the system being sized and shaped for placement in the in situ environment of use and comprising a silicone elastomer matrix in which is dispersed about 30 to about 42 weight percent of a water-soluble particulate phase containing an LHRH analog or pharmaceutically acceptable salt thereof, wherein the delivery system provides essentially zero-order in vivo delivery of the LHRH analog at a therapeutically effective rate.

Claim 3

A system of claim 1 in which the LHRH analog is a particulate comprised substantially of agglomerates of primary particles, wherein the primary particles have diameters in the range of less than 0.1 micron to about 1 micron, and the agglomerates have diameters in the range of less than 1 to about 500 microns.

Claim 4

A system of claim 1 in which at least 5 percent of the system surface is cut and the remainder is uncut.

Claim 5

A system of claim 3 in which at least 50 percent of the system surface is cut and the remainder is uncut.

Claim 6

A system of claim 1 in which the water-soluble particulate phase comprises about 35 to about 42 weight percent of the matrix.

Claim 7

A system of claim 5 in which the water-soluble particulate phase comprises about 39 to about 42 weight percent of the matrix.

Claim 8

A system of claim 6 in which the water-soluble particulate phase consists essentially of an LHRH analog or a pharmaceutically acceptable salt thereof.

Claim 9

A system of claim 1 in which the LHRH analog is a compound of the formula: (pryo)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (1) or a pharmaceutically acceptable salt thereof wherein: V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-alanyl; W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl; X is a D-amino acid residue ##STR4## wherein R is (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluorenyl, phenylanthryl, 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, isoluecyl, nor-leucyl or N-methyl-leucyl; Z is glycinamide or --NH--R 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR5## R 2 is hydrogen or lower alkyl.

Claim 10

A system of claim 8 in which the water-soluble particulate phase comprises about 35 to about 42 weight percent of the matrix.

Claim 11

A system of claim 9 in which the water-soluble particulate phase comprises about 39 to about 42 weight percent of the matrix.

Claim 12

A system of claim 10 in which the water-soluble particulate phase consists essentially of an LHRH analog or a pharmaceutically acceptable salt thereof.

Claim 13

A system of claim 11 in which the LHRH analog is a particulate comprised substantially of agglomerates of primary particles, wherein the primary particles have diameters in the range of less than 0.1 micron to about 1 micron, and the agglomerates have diameters in the range of less than 1 to about 500 microns.

Claim 14

The system of claim 11 in which at least 5 percent of the system surface is cut and the remainder is uncut.

Claim 15

The system of claim 13 in which at least 50 percent of the system surface is cut.

Claim 16

The system of claim 14 in which the LHRH analog is a compound of the formula: (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (1) or a pharmaceutically acceptable salt thereof wherein: V is tryptophyl or phenylalanyl; W is tyrosyl; X is 3-(2-naphthyl)-D-alanyl or 3-(2,4,6-trimethylphenyl)-D-alanyl; Y is leucyl or N-methyl-leucyl; and Z is glycinamide or --NH--R 1 , wherein R 1 is lower alkyl or ##STR6## in which R 2 is hydrogen or lower alkyl.

Claim 17

A system of claim 15 in which the LHRH analog is (pyro)Glu-His-Trp-Ser-Tyr-D-3-(2-naphthyl)alanyl-leu-Arg-Pro-azaglycine amide or a pharmaceutically acceptable salt thereof.

Claim 18

A system of claim 16 in which the LHRH analog is the acetate salt, namely (pyro)Glu-His-Trp-Ser-Tyr-D-3-(2-naphthyl)alanyl-leu-Arg-Pro-azaglycine amide acetate.

Claim 19

A system of claim 17 in which the LHRH analog is a particulate comprised substantially of agglomerates of primary particles, wherein the primary particles have diameters in the range of less than 0.1 micron to about 1 micron, and the agglomerates have diameters in the range of less than 1 to about 500 microns.

Claim 20

A system of claim 17 in which about 60 to 80 percent of the system surface is cut.

Claim 21

A system of claim 8 in which the LHRH analog is (pyro)Glu-His-Trp-Ser-Tyr-D-3-(2-naphthyl)alanyl-leu-Arg-Pro-GlyNH 2 or a pharmaceutically acceptable salt thereof.

Claim 22

The system of claim 20 in which the LHRH analog is the acetate salt, namely (pyro)Glu-His-Trp-Ser-Tyr-D-3-(2-naphthyl)alanyl-leu-Arg-Pro-GlyNH 2 acetate.

Claim 23

A polymeric delivery system for the controlled and sustained administration of an LHRH analog to an animal in need of such treatment, the system being sized and shaped for placement in the in situ environment of use and consisting essentially of a polydimethylsiloxane elastomer matrix in which is dispersed about 39 to about 42 weight percent of agglomerates of primary particles of (pyro)Glu-His-Trp-Ser-Tyr-D-3-(2-naphthyl)alanyl-leu-Arg-Pro-azaglycide amide acetate, wherein the primary particles have diameters in the range of less than 0.1 micron to about 1 micron, the agglomerates have diameters in the range of less than 1 to about 500 microns, and about 60 to 80 percent of the system surface is cut.

Claim 24

A polymeric delivery system for the controlled and sustained administration of an LHRH analog to an animal in need of such treatment, the system being sized and shaped for placement in the in situ environment of use and consisting essentially of a polydimethylsiloxane elastomer matrix in which is dispersed about 39 to about 42 weight percent of agglomerates of primary particles of (pyro)Glu-His-Trp-Ser-Tyr-D-3-(2-naphthyl)alanyl-leu-Arg-Pro-azaglycide amide acetate, wherein the primary particles have diameters in the range of less than 0.1 micron to about 1 micron, the agglomerates have diameters in the range of less than 1 to about 500 microns, and about 60 to 80 percent of the system surface is cut.

Claim 27

A method of claim 23 in which the animal is a cat, dog, bovine, pig, horse or human.

Claim 30

A method of claim 25 in which the animal is a male dog.

Claim 31

A method of claim 25 in which the animal is a female dog.

Claim 32

A method of claim 25 in which the animal is a male cat.

Claim 33

A method of claim 25 in which the animal is female cat.

Claim 34

The method of claim 25 in which the animal is a bovine, pig or horse.