Microencapsulation of water soluble polypeptides

Claim 2

A pharmaceutical composition designed for sustained release of an effective amount of drug over an extended period of time prepared in microcapsule form wherein the composition comprises: at least one hormonally active polypeptide in an effective amount greater then a conventional single dose; optionally, at least one polymer hydrolysis modifying agent; and a biocompatable, biodegradable encapsulating polymer.

Claim 3

A composition of Claim 1 wherein said polypeptide is a luteinizing hormone-releasing hormone or an analogue thereof; said hydrolysis modifying agent, if present, is an organic acid, acid salt, neutral salt or basic salt; and said polymer is a polylactide polymer, polyacetal polymer, polyorthoester polymer or polyorthocarbonate polymer.

Claim 4

A composition of Claim 1 wherein said polypeptide is a nonapeptide or a decapeptide analogue of LH-RH having the formula and the pharmaceutically acceptable salts thereof wherein: V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-alanyl; W is tyrosyl, phenylalanyl or 3-(l-pentafluoro- phen yl ) -L-alanyl; X is a D-amino acid residue wherein R is (a) a carbocyclic aryl-containing radical selected from naphthyl, anthryl, fluorenyl, phenylanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain C 1-4 alkyl groups; or (b) a saturated carbocyclic radical selected f.rom cyclohexyl substituted with three or more straight chain C l-4 alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl; Y is leucyl, isoleucyl, nor-leucyl or N-methyl-leucyl; Z is glycinamide or -NH-R l , wherein R 1 is C l-4 alkyl, C 3-6 cycloalkyl, fluoro C l-4 alkyl or R 2 is hydrogen or C 1-4 alkyl.

Claim 5

A composition of Claim 3 having a polymer which is a poly(lactide-co-glycolide) copolymer wherein the copolymer comprises lactide-glycolide in a molar ratio of between 100:0 and 40:60 ; and wherein the copolymer has an average molecular weight between about 20,000 and 100,000.

Claim 6

A composition of Claim 4 wherein said polypeptide is present in an amount of between 0.01 and 40.0 weight % of the polymer; and said hydrolysis modifying agent is present in an amount of between 1 and 15 weight % of the polymer.

Claim 7

A composition of Claim 4 or Claim 5 having a polypeptide 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 NHEt: said hydrolysis modifying agent is citric acid, ammonium chloride sodium chloride or sodium carbonate; and said polymer comprises lactide-co-glycolide in a molar ratio of between 75:25 and 50:50.

Claim 8

A composition of Claim 6 wherein said polypeptide is present in an amount of 0.1 to 10.0 weight %; said hydrolysis modifying agent is present an an amount of 5 to 10 weight %; and said polymer is present in the molar ratio of 50:50.

Claim 9

A composition of Claim 7 wherein said peptide is (pyro)Glu-His-Trp-Ser-Tyr-3-(naphthyl)-D-alanyl-leu-Arg-Pro-Gly-NH 2 or a pharmaceutically acceptable acid salt thereof.

Claim 10

A composition of any one of the preceding Claims in the form of injectable particles ranging in size from about 0.1 to 500 microns.

Claim 11

A composition of any of Claims 1 to 9 which are dispersed in a pharmaceutically acceptable carrier suitable for parenteral administration.

Claim 12

A process for preparing a composition of Claim 1 comprising: dispersing an aqueous solution containing the polypeptide, an optionally a polymer hydrolysis modifying agent, in a halogenated organic solvent containing said encapsulating polymer; adding to the dispersion a coacervation agent; hardening the microcapsules; collecting the microcapcules from this solution; washing the microcapsules; and drying the microcapsules.

Claim 13

A process for preparing a pharmaceutical composition designed for sustained release of an effective amount of drug over an extended period of time prepared in microcapsule form; characterised in that the process comprises: dispersing an aqueous solution containing a hormonally active polypeptide, and optionally a polymer hydrolysis modifying agent, in a halogenated organic solvent containing a biocompatable, biodegradable encapsulating polymer; adding to the dispersion a coacervation agent; hardening the microcapsules; collecting the microcapsules from this solution; washing the microcapsules; and drying the microcapsules.

Claim 14

A process for preparing a pharmaceutical composition designed for sustained release of an effective amount of drug over an extended period of time prepared in microcapsule form; characterised in that the process comprises: dispersing an aqueous solution containing a hormonally active polypeptide, and optionally a polymer hydrolysis modifying agent, in a halogenated organic solvent containing a biocompatable, biodegradable encapsulating polymer; adding to the dispersion a coacervation agent; hardening the microcapsules; collecting the microcapsules from this solution; washing the microcapsules; and drying the microcapsules.

Claim 15

A process of Claim 1 wherein said polypeptide is a luteinizing hormone-releasing hormone or an analogue thereof; said hydrolysis modifying agent, if present, is an organic acid, acid salt,neutral salt or basic salt; and said polymer is a polylactide polymer, polyacetal polymer, polyorthoester polymer or polyorthocarbonate polymer.

Claim 16

A process of Claim 1 wherein said polypeptide is a nonapeptide or a decapeptide analogue of LH-RH having the formula and the pharmaceutically acceptable salts thereof wherein; V is tryptophyl, phenylalanyl or 3-(l-naphthyl)-L-alanyl; W is tyrosyl, phenylalanyl or 3-(l-pentafluorophenyl)-L-alanyl; X is a D-amino acid residue wherein R is (a) a carbocyclic aryl-containing radical selected from naphthyl, anthryl, fluorenyi, phenylanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain C 1-4 alkyl groups; or (b) a saturated carbocyclic radical selected from cyclohexyl substituted with three or more straight chain C l-4 alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl; Y is leucyl, isoleucyl, nor-leucyl or N-methyl-leucyl; Z is glycinamide or -NH-R 1 , wherein R 1 is C 1-4 alkyl, C 3-6 cycloalkyl, fluoro C 1-4 alkyl or R 2 is hydrogen or C 1-4 alkyl.

Claim 17

A process of Claim 3 using a polymer which is a poly(lactide-co-glycolide) copolymer wherein the copolymer comprises lactide-glycolide in a molar ratio of between 100:0 and 40:60 ; and wherein the copolymer has an average molecular weight between about 20,000 and 100,000.

Claim 18

A process of Claim 4 wherein said polypeptide is present in an amount of between 0.01 and 40.0 weight % of the polymer; and said hydrolysis modifying agent is present in an amount of between 1 and 15 weight % of the polymer.

Claim 19

A process of Claim 4 or Claim 5 using a polypeptide wherein: V is tryptophyl or phenylaianyl; 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 NHEt; said hydrolysis modifying agent is citric acid, ammonium chloride sodium chloride or sodium carbonate; and said polymer comprises lactide-co-glycolide in a molar ratio of between 75:25 and 50:50.

Claim 20

A process of Claim 6 wherein said polypeptide is present in an amount of 0.1 to 10.0 weight %; said hydrolysis modifying agent is present an an amount of 5 to 10 weight %; and said polymer is present in the molar ratio of 50:50.

Claim 21

A process of Claim 7 wherein said peptide is (pyro)Glu-His-Trp-Ser-Tyr-3-(naphthyl)-D-alanyl-leu-Arg-Pro-Gly-NH 2 or a pharmaceutically acceptable acid salt thereof.

Claim 22

A process of any one of the preceding claims wherein the product is in the form of injectable particles ranging in size from about 0.1 to 500 microns.

Claim 23

A process of any one of the preceding claims wherein the product composition is dispersed in a pharmaceutically acceptable carrier suitable for parenteral administration.