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 polypeptide which is a naturally occurring luteinizing hormone-releasing hormone (LH-RH), a synthetically prepared material of the same type or synthetically prepared analogues of naturally occurring LH-RH which act in some manner on the anterior pituitary gland to affect the release of luteinizing hormone (LH) and follicular stimulating hormone (FSH); optionally, at least one polymer hydrolysis modifying agent selected from organic acids, acid salts, neutral salts and basic salts; and a biocompatible, biodegradable encapsulating polymer which is a polylactide polymer, polyacetal polymer, polyorthoester polymer or polyorthocarbonate polymer.

Claim 3

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-(1-pentafluorophenyl)-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 l - 4 alkyl groups; or (b) a saturated carbocyclic radical selected from cyclohexyl substituted with three or more straight chain C 1-4 alkyl groups, perhydronaphthyl, perhydro- biphenylyl, perhydro-2,2-diphenylmethyl and adamantyl; Y is leucyl, isoleucyl, nor-leucyl or N-methylleucyl; Z is glycinamide or ―NH―R 1 , wherein R, is C 1-4 alkyl, C 3 - 6 cycloalkyl, fluoro C l - 4 alkyl or R 2 is hydrogen or C 1 - 4 alkyl.

Claim 4

A composition of claim 2 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 5

A composition of claim 3 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 6

A composition of claim 3 or claim 4 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 7

A composition of claim 5 wherein said polypeptide is present in an amount of 0.1 to 10.0 weight %; said hydrolysis modifying agent is present in an amount of 5 to 10 weight %; and said polymer comprises lactide-co-glycolide in a molar ratio of 50:50.

Claim 8

A composition of any one of claims 1 to 6 wherein said polypeptide is or a pharmaceutically acceptable acid salt thereof.

Claim 9

A composition according to claim 1, wherein the polypeptide is an analogue of natural LH-RH, in which modification comprises the 6-position residue changed from Gly to a D-amino acid.

Claim 10

A composition according to claim 8, wherein the D-amino acid is D-Ala, D-Leu, D-Phe, or D-Trp.

Claim 11

A composition according to claim 9, wherein the D-amino acid is D-Leu.

Claim 12

A composition according to claim 9, wherein the D-amino acid is D-Trp.

Claim 13

A composition according to any one of claims 8 to 11, wherein the 10-position is modified to afford a nonapeptide as an alkyl-, cycloalkyl- or fluoroalkyl-amine.

Claim 14

A composition according to any one of claims 8 to 11, wherein the Gly-NH z is replaced by an a-azaglycine amide.

Claim 15

A composition according to any one of claims 8 to 11, wherein N-methyl-leucine is substituted for leucine in position 7.

Claim 16

A composition of any one of claims 7 to 14 wherein the polymer is a poly(lactide-co-glycolide) copolymer.

Claim 17

A composition of claim 15 wherein the copolymer comprises lactide-glycolide in a molar ratio of between 100:0 and 40:60.

Claim 18

A composition of any one of claims 7 to 16 wherein said polypeptide is present in an amount of between 0.01 and 40.0 weight % of the polymer.

Claim 19

A composition of any one of claims 7 to 17 wherein said hydrolysis modifying agent is present in an amount of between 0.1 and 20 weight %.

Claim 20

A composition of any one of claims 7 to 18 wherein said polypeptide is present in an amount of 0.1 to 10.0 weight %.

Claim 21

A composition of any one of claims 7 to 19 wherein said polymer comprises lactide-glycolide in a molar ratio of from 75:25 to 40:60.

Claim 22

A composition of any one of the preceding claims in the form of injectable particles ranging in size from about 1 to 500 pm.

Claim 23

A composition of any of claims 1 to 21 which are dispersed in a pharmaceutically acceptable carrier suitable for parenteral administration.

Claim 24

A process for preparing a composition of any one of the preceding claims comprising: dispersing an aqueous solution containing the polypeptide, and optionally a polymer hydrolysis modifying agent, in a halogenated organic solvent containing said encapsulating polymer; adding to the dispersion a coacervation agent; and collecting the microcapsules from this solution.