Cross-linked esters of hyaluronic acid

Claim 2

Total or partial cross-linked esters of hyaluronic acid with an aliphatic polyhydric alcohol, and salts of such partial esters with inorganic or organic bases, with the proviso that said cross-linked ester is not the cross-linked ester of hyaluronic acid with an alomethyloxirane or a bisepoxy compound.

Claim 3

Cross-linked esters according to claim 1, wherein said aliphatic polyhydric alcohol is a dihydric alcohol.

Claim 4

Cross-linked esters according to claim 1, wherein said aliphatic polyhydric alcohol has between 2 and 16 carbon atoms.

Claim 5

Cross-linked esters according to claim 2, wherein said dihydric alcohol is a member selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol, glycols derived from pentane, hexane, heptane and octane, and positional isomers thereof.

Claim 6

Cross-linked esters according to claim 1, wherein said aliphatic polyhydric alcohol is a member selected from the group consisting of glycerine, erythrite and pentaerythrite.

Claim 7

Cross-linked esters according to any one of claims 1-5, wherein at least one non-cross-linked carboxy group in said hyaluronic acid is esterified with an aliphatic alcohol having a maximum of 34 carbon atoms and wherein said aliphatic alcohol may be unsubstituted or substituted by one or two functional groups selected from the group consisting of amino, hydroxy, mercapto, aldehyde, keto, carboxy, hydrocarbyl and dihydrocarbyl amino groups, ether, ester, thioether, thioester, acetal, ketal, carbalkoxy, carbamidic and substituted carbamidic groups substituted by one or two alkyl groups, the hydrocarbyl radicals in these functionally modified groups having a maximum of 6 carbon atoms, and in which such aliphatic alcohols may be interrupted in the carbon atom chain by heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen.

Claim 8

Cross-linked esters according to claim 6, wherein said aliphatic alcohol is ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl alcohols, an amyl, pentyl, hexyl or octyl alcohol.

Claim 9

Cross-linked esters according to any one of claims 1-5, wherein at least one non-cross-linked carboxy group in said hyaluronic acid is esterified with an araliphatic alcohol having only one benzene residue and in which the aliphatic chain has a maximum of 4 carbon atoms and in which the benzene residue may be substituted with between 1 and 3 methyl or hydroxy groups or with halogen atoms, and in which the aliphatic chain may be substituted with one or two functional groups selected from the group consisting of free- or mono- or diethyl amino groups, pyrrolidine and piperidine groups.

Claim 10

Cross-linked esters according to any one of claims 1-5, wherein at least one non-cross-linked carboxy group in said hyaluronic acid is esterified with a cycloaliphatic alcohol or aliphatic-cycloaliphatic alcohol or heterocyclic alcohol which derives from a mono- or polycyclic carbohydrate with a maximum of 34 carbon atoms and is unsubstituted or substituted by one or more functional groups selected from the group consisting of amino, hydroxy, mercapto, aldehyde, keto, carboxy, hydrocarbyl- and dihydrocarbylamino groups, ether, ester, thioether, thioester, acetal, ketal, carbalkoxy, carbamidic and substituted carbamidic groups, by one or two alkyl groups, the hydrocarbyl radicals in these functionally modified groups having a maximum of 6 carbon atoms, and may be interrupted in the carbon atom chain by heteroatoms chosen from the group formed by oxygen, nitrogen and sulfur, and may have one or more aromatic bonds.

Claim 11

Cross-linked esters according to claim 9, wherein at least one of said non-cross-linked carboxy groups is esterified with an alcohol selected from the group consisting of cortisone, hydrocortisone, prednisone, prednisolone, fluorocortisone, dexamethasone, betamethasone, corticosterone, deoxysicorticosterone, paramethasone, flumethasone, flucinolone and its acetonide, fluprednylidene, clobetasol and beclomethasone.

Claim 12

Salts of partial esters according to any one of claims 1-10, wherein said salt is a salt of said cross-linked ester with an alkaline or alkaline earth metal, magnesium or aluminum.

Claim 13

A sodium or ammonium salt of a cross-linked ester according to claim 11.

Claim 14

Salts of partial esters according to one of claims 1-10 deriving from ammonium, araliphatic, cycloaliphatic or heterocyclic groups.

Claim 15

A pharmaceutical composition comprising a cross-linked ester according to any one of claims 1-13 together with a pharmaceutically acceptable carrier, excipient or diluent.

Claim 16

A pharmaceutical composition comprising a cross-linked ester according to any one of claims 1-13 as a vehicle, in admixture with a pharmacologically active agent.

Claim 17

A pharmaceutical composition comprising a cross-linked ester according to any one of claims 8-13, wherein said alcohol esterified with said non-cross-linked carboxy group is a pharmacologically active alcohol.

Claim 18

A cosmetic article comprising as an active ingredient a cross-linked ester or a salt thereof according to any one of claims 1-13.

Claim 19

A cosmetic article comprising as a cosmetic vehicle a cross-linked ester or a salt thereof according to any one of claims 1-13.

Claim 20

A sanitary, medical or surgical article comprising a cross-linked ester or a salt thereof according to any one of claims 1-13.

Claim 21

A sanitary, medical or surgical article according to claim 19, comprising a film of a cross-linked ester deriving from a therapeutically inert alcohol.

Claim 22

A sanitary, medical or surgical article according to claim 19 comprising threads of a cross-linked ester deriving from a therapeutically inert alcohol.

Claim 23

A capsule or microcapsule for medicaments comprising a cross-linked ester or a salt thereof according to any one of claims 1-13.

Claim 24

The use of a cross-linked ester or a salt thereof according to any one of claims 1-13 for the manufacture of a film for use in dermatology as artificial skin.

Claim 25

The use of a cross-linked ester or a salt thereof according to any one of claims 1-13 for the manufacture of suture threads for use in surgical operations.

Claim 26

A process for the preparation of total or partial cross-linked esters of hyaluronic acid comprising reacting a potassium or sodium or quaternary ammonium salt of hyaluronic acid with an etherifying agent in an aprotic solvent.

Claim 27

A process for the preparation of total or partial cross-linked esters of hyaluronic acid comprising reacting a potassium or sodium or quaternary ammonium salt of hyaluronic acid with an etherifying agent in an aprotic solvent.

Claim 28

A process according to claim 25, wherein said salt of hyaluronic acid is a potassium or sodium salt and said reaction is conducted in the presence of a catalyzing quantity of a quaternary ammonium salt.

Claim 29

A process according to claim 26, wherein said quaternary ammonium salt is tetrabutyl ammonium iodide.

Claim 30

A process according to any one of claims 25-27, wherein said aprotic solvent is a dialkylsulfoxide, a dialkylcarboxylamide, a lower alkyl dialkylamide of lower aliphatic acids.

Claim 31

A process according to any one of claims 25-28, wherein said polyhydric alcohol is an aliphatic polyhydric alcohol and said etherifying agent is an alkyl halogenide of an aliphatic polyhydric alcohol.

Claim 32

A process according to claim 29, wherein said aliphatic polyvalent alcohol is a bivalent alcohol.

Claim 33

A process according to claim 29, wherein said aliphatic polyvalent alcohol is a member selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol, glycols derived from pentane, hexane, heptane and octane, and positional isomers thereof, glycerine, erythrite and pentaerythrite.

Claim 34

A process according to any one of claims 25-31, wherein said hyaluronic acid or the non-cross-linked carboxy groups of said partial cross-linked ester of hyaluronic acid are esterified with an aliphatic, araliphatic or cycloaliphatic alcohol.

Claim 35

A process according to claim 32, wherein said alcohol esterified with said non-cross-limited carboxy groups is a pharmacologically active alcohol.

Claim 36

A process according to any one of claims 25-33, wherein said partial cross-linked ester having at least one free carboxy group is salified with an alkaline or alkaline earth metal, magnesium or ammonium.

Claim 37

A process according to any one of claims 25-34, wherein said hyaluronic acid is a hyaluronic acid fraction having an average molecular weight of between 50,000 to 730,000 and is substantially free of hyaluronic acid having an average molecular weight of less than 30,000.

Claim 38

A process according to claim 35, wherein said hyaluronic acid fraction has an average molecular weight of 50,000 to 100,000, 250,000 to 350,000 or 500,000 to 730,000.