A method for preparing ganglioside derivatives and use thereof in pharmaceutical compositions

Claim 2

- A method for preparing inner ester ganglioside derivatives which comprises: (a) dissolving a ganglioside or a mixture of gangliosides obtained from a mammal in a non-aqueous organic solvent; (b) converting the carboxylate groups in the gangliosides to carboxyl groups or a salt thereof by means of ion exchange; and (c) reacting the resultant ganglioside or mixture of gangliosides with a lactonization reagent to form at least one lactonic bond in said inner ester ganglioside derivatives.

Claim 3

- The method of claim 1, wherein the ganglioside or mixture of gangliosides of step (a) is extracted from bovine brains.

Claim 4

- The method of claim 1, wherein said organic solvent is selected from the group consisting of dimethyl sulfoxide, dimethylformamide, sulfolane, tetrahydrofuran, dimenthoxyethane and pyridine.

Claim 5

- The method of claim 1, wherein said lactonization reagent is selected from the group consisting of carbodiimides soluble in organic solvents, 2-chloro-l-methyl-pyridinium salts, ethoxyacetylene and N-ethyl-5-phenylisoxazolium-3'-sulfonate.

Claim 6

- The method of claim 4, wherein the carbodiimide is dicyclohexylcarbodiimide, benzylisopropylcarbodiimide or benzylethylcarbodiimide.

Claim 7

- The method of claim 1, wherein said inner ester ganglioside derivative obtained in step (c) is precipated with acetone.

Claim 8

- A composition for treating peripheral nervous system disorders due to traumatic, compressive degenerative or toxic-infectious causes for the stimulation of nerve regeneration and recovery of neuromuscular function or for treating central nervous system disorders due to traumatic, anoxic, degenerative or toxic-infectious causes where the stimulation of - neuronal sprouting is necessary for functional recovery which comprises an effective amount of at least one inner ester ganglioside derivative comprising: (a) a carbohydrate portion, at least one ceramide and at least one acid moiety; (b) said carbohydrate portion including at least one N-acetylgalactosamine or N-acetylglucosamine moiety and at least one glucose or galactose moiety; (c) said acid moiety including at least one N-acetyl-neuraminic acid or N-glycolylneuraminic acid; and (d) the carboxyl group of at least one of said acid moieties being ester bonded to a hydroxy group of one of said carbohydrates or one of said acid moieties to form a lactonic ring.

Claim 9

- A composition for treating peripheral nervous system disorders due to traumatic, compressive degenerative or toxic-infectious causes for the stimulation of nerve regeneration and recovery of neuromuscular function or for treating central nervous system disorders due to traumatic, anoxic, degenerative or toxic-infectious causes where the stimulation of - neuronal sprouting is necessary for functional recovery which comprises an effective amount of at least one inner ester ganglioside derivative comprising: (a) a carbohydrate portion, at least one ceramide and at least one acid moiety; (b) said carbohydrate portion including at least one N-acetylgalactosamine or N-acetylglucosamine moiety and at least one glucose or galactose moiety; (c) said acid moiety including at least one N-acetyl-neuraminic acid or N-glycolylneuraminic acid; and (d) the carboxyl group of at least one of said acid moieties being ester bonded to a hydroxy group of one of said carbohydrates or one of said acid moieties to form a lactonic ring.

Claim 10

- The composition of claim 7, wherein: (a) the carbohydrate portion of said ganglioside derivatives has the structure: (Gal) (GalNAC) (Gal) (Glc) (Ceramide) where: Gal is a galactose moiety, GalNAC is an N-acetylgalactosamine moiety, and Glc is a glucose moiety.

Claim 11

- The composition of claim 7 or 8, wherein: (a) said ganglioside derivative has at least one N-acetyl-neuraminic acid bonded to at least one of said Gal moieties.

Claim 12

- The composition of claim 7, wherein: (a) at least one of said ganglioside derivatives has the structure: (Gal)CGalNAC)(GaC)(Glc)(Ceramide) I NANA wherein: Gal is a galactose moiety, GaINAC is an N-acetylgalactosamine moiety, Glc is a glucose moiety, and NANA is an N-acetyl-neuraminic acid moiety, and wherein: (b) said NANA is ester bonded to said Gal.

Claim 13

- The composition of claim 7 or 10, wherein said acid moiety consists of N-acetyl-neuraminic acid.

Claim 14

- The composition of claim 7, wherein the carbohydrate portion consists of galactose, glucose and N-acetylgalactosamine moieties.

Claim 15

- The composition of claim 7, wherein said ganglioside derivative comprises a mixture of: and wherein: Gal represents a galactose moiety, GaLNAC represents an N-acetylgalactosamine moiety, GLc represents a glucose moiety, and NANA represents an N-acetyl-neuraminic moiety, and wherein at least one of said NANA moieties is ester bonded to a hydroxy group of a galactose moiety and/or an adjoining NANA moiety to form a lactonic ring.

Claim 16

- The composition according to any of claims 7 to 13, in the form of an injectable solution.

Claim 17

- The composition according to any of claims 7 to 14, wherein said carrier or diluent is a mixture of sodium chloride and a citrate buffer.

Claim 18

- The composition according to any of claims 7 to 15, wherein said ganglioside derivative is present in an amount of from about 2% to about 50% by weight.

Claim 19

- A pharmaceutical composition system for treating peripheral nervous system disorders due to traumatic, compressive degenerative or toxic-infectious causes for the stimulation of nerve regeneration and recovery of neuromuscular fonction or for treating central nervous system disorders due to traumatic, anoxic, degenerative or toxic-infectious causes where the stimulation of neuronal sprouting is necessary for functional recovery, which comprises a first container containing a solid excipient and a lyophilized power of an effective nervous system treating amount of at least one inner ester ganglioside derivative, said ganglioside derivative comprising: (a) a carbohydrate portion, at least one ceramide and at least one acid moiety; (b) said carbohydrate portion including at least one N-acetylgalactosamine or N-acetylglucosamine moiety and at least one glucose or galactose moiety; (c) said acid moiety including at least one N-acetyl-neuraminic acid or N-glycolylneuraminic acid; and (d) the carboxyl group of at least one of said acid moieties being ester bonded to a hydroxy group of one of said carbohydrates or one of said acid moieties to form a lactonic ring, whereby the contents of said containers are mixed to form a treatment solution.

Claim 20

- A pharmaceutical composition system for treating peripheral nervous system disorders due to traumatic, compressive degenerative or toxic-infectious causes for the stimulation of nerve regeneration and recovery of neuromuscular fonction or for treating central nervous system disorders due to traumatic, anoxic, degenerative or toxic-infectious causes where the stimulation of neuronal sprouting is necessary for functional recovery, which comprises a first container containing a solid excipient and a lyophilized power of an effective nervous system treating amount of at least one inner ester ganglioside derivative, said ganglioside derivative comprising: (a) a carbohydrate portion, at least one ceramide and at least one acid moiety; (b) said carbohydrate portion including at least one N-acetylgalactosamine or N-acetylglucosamine moiety and at least one glucose or galactose moiety; (c) said acid moiety including at least one N-acetyl-neuraminic acid or N-glycolylneuraminic acid; and (d) the carboxyl group of at least one of said acid moieties being ester bonded to a hydroxy group of one of said carbohydrates or one of said acid moieties to form a lactonic ring, whereby the contents of said containers are mixed to form a treatment solution.

Claim 21

- The pharmaceutical composition system of claim 17, wherein said first container contains sodium chloride and a citrate buffer.

Claim 22

- The pharmaceutical composition system of claim 17, wherein said solid excipient is glycine.

Claim 23

- The pharmaceutical composition system of claim 17 or 19,wherein said solid excipient is mannitol.

Claim 24

- The pharmaceutical composition system of claim 17, wherein said second container contains said ganglioside derivative in an amount of from about 10% to about 90% by weight.

Claim 25

- Pharmaceutical composition system according to any of claims 17 to 21, wherein: (a) the carbohydrate portion of said ganglioside derivatives as the structure: (GaL)(GaLNAC)(GaL)(GLc)(Ceramide) where: Gal is a galactose moiety, GaINAC is an N-acetylgalactosamine moiety, and Glc is a glucose moiety.

Claim 26

- Pharmaceutical composition system according to claim 22, wherein (a) said ganglioside derivative has at least one N-acetyl-neuraminic acid bonded to at least one of said G al moieties.

Claim 27

- The parmaceutical composition system according to any of claims 17 to 21, wherein: (10) at least one of said ganglioside derivatives has the structure: wherein: Gal is a galactose moiety, GalNAC is an N-acetylgalactosamine moiety; Glc is a glucose moiety, and NANA is an N-acetyl-neuraminic acid moiety, and wherein: (b) said NANA es ester bonded to said G al.

Claim 28

- The pharmaceutical composition system according to claim 24, wherein said acid moiety consists of N-acetyl-neuraminic acid.

Claim 29

- The pharmaceutical composition system according to any of claims 17 to 21, wherein the carbohydrate portion consists of galactose, glucose and N-acetylgalactosamine moieties.

Claim 30

- The pharmaceutical composition system according to any of claims 17 to 21, wherein said ganglioside derivative comprises of mixture of: and wherein: Gal represents a galactose moiety, GelNAC represents an N-acetylgalactosamine moiety, Glc represents a glucose moiety, and NANA represents an N-acetyl-neuraminic moiety, and wherein at least one of said NANA moieties is ester bonded to a hydroxy group of a galactose moiety and/or an adjoining NANA moiety to form a lactonic ring.