Esters of hyaluronic acid and their salts.

Claim 2

Total and partial esters of hyaluronic acid with alcohols of the aliphatic, araliphatic, cycloaliphatic and heterocyclic series and salts of such partial esters with inorganic or organic bases, with the exception of the total methyl ester of hyaluronic acid.

Claim 3

Esters of hyaluronic acid and their salts according to claim 1, in which alcohols of the aliphatic series have a maximum of 34 carbon atoms and are unsubstituted or substituted by one or two functional groups chosen from the group formed by amino, hydroxy, mercapto, aldehyde, keto, carboxy, hydrocarbyl, dihydrocarbylamino, ether, ester, thio-ether, 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 in which such alcohols of the aliphatic series may be interrupted in the carbon atom chain by heteroatoms chosen from the' group formed by oxygen, sulfur and nitrogen.

Claim 4

Esters of hyaluronic acid and their salts according to claim 2, in which the esterifying alcoholic component derives from ethyl alcohol, propyl alcohol, isopropyl alcohol, normal butyl alcohol, isobutyl alcohol, tert-butyl alcohol, amyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohol, ethyleneglycol, propyleneglycol, butyleneglycol or glycerin.

Claim 5

Esters of hyaluronic acid and their salts according to claim 1, in which alcohols of the araliphatic series are those with 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 by 1 to 3 methyl or hydroxy Jgroups, by halogen atoms, and in which the aliphatic chain may be substituted by one or two functions chosen from the group including free or mono or diethyl amino groups or by pyrrolidinyl or piperidinyl groups.

Claim 6

Esters of hyaluronic acid and their salts according to claim 4, wherein said alcohol is chosen from the group formed by benzyl alcohol, phenethyl alcohol, ephedrine and adrenalin.

Claim 7

Esters of hyaluronic acid and their salts according to claim 1, in which the alcohol is of the cycloaliphatic or aliphatic-cycloaliphatic series and derives from mono- or polycyclic hydrocarbides with a maximum of 34 carbon atoms.

Claim 8

Esters of hyaluronic acid and their salts according to claim 6, in which the polycyclic alcohols are sterols, cholic acids, steroid alcohols, groups of the estrane and pregnane series and their unsaturated derivatives.

Claim 9

Esters of hyaluronic acid and their salts according to claim 7, in which the alcohol is chosen from the group formed by cortisone, hydrocortisone, prednisone, prednisolone, fluorocortisone, dexamethasone, betamethasone, corticosterone, deoxycorticosterone, paramethasone, flumethasone, fluocinolone, flucinolone acetonide, fluprednylidene, clobetasol, and beclomethasone.

Claim 10

A salt of a hyaluronic ester according to any one of claims 1-8 with an alkaline or alkaline earth metals, magnesium or aluminum.

Claim 11

A salt of a hyaluronic ester according to claim 9, which is a sodium or ammonium salt.

Claim 12

A salt of a partial ester according to any one of the claims 1-8 with a therapeutically acceptable ammonium, aliphatic, araliphatic, cycloaliphatic or heterocyclic bases.

Claim 13

A compound according to claim 1 chosen from the group formed by: the partial propyl ester of hyaluronic acid with 50% of the carboxyl groups esterified and 50% of the carboxy groups salified with sodium; the partial isopropyl ester of hyaluronic acid with 50% of the carboxy groups esterified and 50% of the carboxy groups salified with sodium; the partial propyl ester of hyaluronic acid in which 85% of the carboxylic groups are esterified and 15% of the carboxylic groups are salified with sodium; the partial ethyl ester of hyaluronic acid with 75% of the carboxy groups esterified and 25% of the carboxy groups salified with sodium; the partial methyl ester of hyaluronic acid with 75% of the carboxy groups esterified and 2 5% of the carboxy groups salified with sodium; the total methyl ester of hyaluronic acid; the total ethyl ester of hyaluronic acid; the total propyl ester of hyaluronic acid; the partial butyl ester of hyaluronic acid with 50% of the carboxylic groups esterified and 50% of the carboxylic groups salified with sodium; the partial ethoxycarbonylmethyl ester of hyaluronic acid with 75% of the carboxy groups esterified and 25% of the carboxy groups salified with sodium; the partial cortisone ester of hyaluronic acid with 20% of the carboxy groups esterified and with 80% of the carboxy groups salified with sodium; the partial hydrocortisone ester of hyaluronic acid with 20% of the carboxy groups esterified and with 80% of the carboxy groups salified with sodium; the partial fluorocortisone ester of hyaluronic acid with 20% of the carboxy groups esterified and with 80% of the carboxy groups salified with sodium; the deoxycorticosterone ester of hyaluronic acid with 20% of the carboxy groups esterified and with 80% of the carboxy groups salified with sodium; a mixed ethanol and cortisone ester of hyaluronic acid with 80% of the carboxy groups esterified with ethanol and 20% of the carboxy groups esterified with cortisone; the mixed ethanol - hydrocortisone ester of hyaluronic acid with 80% of the carboxy groups esterified with ethanol and 20% of the carboxy groups esterified with hydrocortisone; the mixed ethanol - fluorocortisone ester of hyaluronic acid with 80% of the carboxy groups esterified with ethanol and 20% of the carboxy groups esterified with fluorocortisone; the mixed ethanol - deoxycorticosterone ester of hyaluronic acid with 80% of the carboxy groups esterified with ethanol and 20% of the carboxy groups esterified with deoxycorticosterone; the partial and mixed ethanol and deoxycorticosterone ester of hyaluronic acid with 40% of the carboxy groups esterified with ethanol, 20% of the carboxy groups esterified with deoxycorticosterone and the remaining 40% of the carboxy groups salified with sodium; the partial and mixed ethanol and cortisone ester of hyaluronic acid with 40% of the carboxy groups esterified with ethanol, 20% of the carboxy groups esterified with cortisone and the remaining 40% of the carboxy groups salified with sodium; the partial and mixed ethanol - hydrocortisone ester of hyaluronic acid with 40% of the carboxy groups esterified with ethanol, 20% of the carboxy groups esterified with hydrocortisone and the remaining 40% of the carboxy groups salified with sodium; the partial and mixed ethanol - fluorocortisone ester of hyaluronic acid with 40% of the carboxy groups esterified with ethanol, 20% of the carboxy groups esterified with fluorocortisone and the remaining 40% of the carboxy groups salified with sodium; the total pentyl ester of hyaluronic acid; the total isopentyl ester of hyaluronic acid; the total benzyl ester of hyaluronic acid; the total phenethyl ester of hyaluronic acid; salt with streptomycin of a hyaluronic acid partially esterified with ethanol (75%) and 25% of the carboxyls of the same salified with streptomycin; salt with erythromycin of a hyaluronic acid partially esterified with ethanol (75%) and 25% of the carboxyls of the same salified-with erythromycin; salt with neomycin of a hyaluronic acid partially esterified with ethanol (75%) and 25% of the carboxyls of the same salified with neomycin; salt with gentamycin of a hyaluronic acid partially esterified with ethanol (75%) and 25% of the carboxyls of the same salified with gentamycin; salt with amikacin of hyaluronic acid partially esterified with ethanol (75%) and 25% of the carboxyls of the same salified with amikacin; salt with kanamycin of hyaluronic acid partially esterified with ethanol (75%) and 25% of the carboxyls of the same salified with kanamycin; salt with pilocarpine of hyaluronic acid partially esterified with ethanol (75%) and 25% of the carboxyls of the same salified with pilocarpine; and salt with pilocarpine of hyaluronic acid partially esterified (85%) with ethanol and 15% of the carboxyls of the same salified with pilocarpine.

Claim 14

A pharmaceutical preparation containing as an active ingredient an ester or one of its salts defined in claim 1 or a total methyl ester of hyaluronic acid, together with a pharmaceutically acceptable excipient or carrier.

Claim 15

A pharmaceutical preparation containing as an active ingredient a hyaluronic acid ester according to any one of claims 1-12, together with a pharmaceutically acceptable excipient or carrier.

Claim 16

A medicament comprising: a) one or more pharmacologically active substances and b) a carrying vehicle comprising a total or partial ester of hyaluronic acid with alcohols of the aliphatic, araliphatic, cycloaliphatic and heterocyclic series or salts of these partial esters with inorganic or organic bases, with the addition, if desired, of hyaluronic acid or one of its salts with inorganic or organic bases, and possibly c) common excipients for pharmaceutical preparations.

Claim 17

A medicament comprising: a) one or more pharmacologically active substances and b) a carrying vehicle comprising a total or partial ester of hyaluronic acid with alcohols of the aliphatic, araliphatic, cycloaliphatic and heterocyclic series or salts of these partial esters with inorganic or organic bases, with the addition, if desired, of hyaluronic acid or one of its salts with inorganic or organic bases, and possibly c) common excipients for pharmaceutical preparations.

Claim 18

A medicament according to claim 15 in which the carrying vehicle b) contains an ester of hyaluronic acid with a pharmacologically inactive alcohol.

Claim 19

A medicament according to claim 15 in which the carrying vehicle b) contains an ester of hyaluronic acid with a pharmacologically active alcohol.

Claim 20

A medicament according to claim 15 in which the vehicled substance is of a basic nature and contains partial hyaluronic esters, the unesterified groups of which are salified with the pharmacologically active substance.

Claim 21

A medicament according to any one of the claims 15-18 in which the pharmacologically active substance is chosen from the group formed by an anesthetic, an analgesic, an anti-inflammatory, a vasoconstrictor, an antibiotic-antibacterial, an antiviral.

Claim 22

A medicament according to any one of the claims 15-18 in which the active substance 1) is topically active.

Claim 23

The use of an ester of hyaluronic acid or one of its salts according to claim 1 for the preparation of a medicament for use in ophthalmology.

Claim 24

The use of an ester of hyaluronic acid or one of its salts according to claim 1 for the preparation of a medicament for use in dermatology, in otorhinolaryngology, odontology, angiology, gynecology, neurology or any type of internal medical pathologies.

Claim 25

Cosmetic articles including a hyaluronic ester or one of its salts according to any one of claims 1-12, or the total methyl ester of hyaluronic acid.

Claim 26

Sanitary and surgical articles including a hyaluronic ester or one of its salts according to any one of claims 1-12, or the total methyl ester of hyaluronic acid.

Claim 27

Sanitary and surgical articles according to claim 24 in the form of films and threads.

Claim 28

Films and threads according to claim 24 or 25 in the form of artificial skin for use in surgical dermatology and in this respect as suture threads in surgical operations.

Claim 29

Gauzes made of threads according to one of claims 24-26 for the medication of wounds and in surgery.

Claim 30

A procedure for the preparation of films or threads of hyaluronic esters according to any one of claims 24-27 in which the hyaluronic ester is dissolved in an organic solvent, the solution is made into sheet or thread form respectively and the organic solvent is then eliminated by treatment with another suitable organic or aqueous solvent which is soluble in the first solvent.

Claim 31

A procedure for the preparation of films or threads of hyaluronic esters according to any one of claims 24-27 in which the hyaluronic ester is dissolved in an organic solvent, the solution is made into sheet or thread form respectively and then the organic solvent is eliminated by treatment with a current of suitably heated inert gas.

Claim 32

Sanitary and surgical articles according to claim 24 in the form of capsules for the subcutaneous implantation of medicaments; in the form of microcapsules for subcutaneous, intramuscular or intraveneous injection; in the form of solid inserts to be removed after a certain length of time; or in the form of sponges for the medication of wounds and various lesions.

Claim 33

A process for the preparation of acidic polysaccharide esters containing carboxy groups, in which a quaternary ammonium salt of the polysaccharide is treated with an esterifying agent in an aprotic solvent, and, if desired, free carboxy groups are salified in the partial esters obtained, or salified groups are released in them.

Claim 34

A process for the preparation of acidic polysaccharide esters containing carboxy groups, in which a quaternary ammonium salt of the polysaccharide is treated with an esterifying agent in an aprotic solvent, and, if desired, free carboxy groups are salified in the partial esters obtained, or salified groups are released in them.

Claim 35

A process according to claim 31 in which acidic polysaccharides of animal origin are used.

Claim 36

A process according to claim 31 in which acidic polysaccharides of vegetable origin are used.

Claim 37

A process according to claim 31 in which acidic polysaccharides containing also sulfonic groups are used.

Claim 38

A process according to claim 31 in which hyaluronic acid or one of its molecular fractions is used.

Claim 39

A process according to claim 31 in which demethylsulfoxide is used as the aprotic solvent.

Claim 40

A process according to claim 31 in which an lower tetraalkylammonium salt is used as the starting salt.

Claim 41

A process according to claim 31 in which the tetrabutylammonium salt of acidic polysaccharide is used.

Claim 42

The tetraalkylammonium salts of an acidic polysaccharide containing carboxy groups deriving from alkyls with between 1 and 6 carbon atoms.

Claim 43

The tetraalkylammonium salts of an acidic polysaccharide containing carboxy groups deriving from alkyls with between 1 and 6 carbon atoms.

Claim 44

The salts according to claim 39 in which the acidic polysaccharide is hyaluronic acid or one of its molecular fractions.

Claim 45

Esters, according to any one of claims 1-12, in which the hyaluronic ester derives from integral hyaluronic acid or from one of its salts obtained by extraction from cocks' combs and having a molecular weight of between about 8 and 13 million.

Claim 46

Esters, according to one of claims 1-12, in which the hyaluronic ester derives from hyaluronic acid abtained by first dehydrating the cocks' combs with acetone and then exposing them to enzymatic digestion with papain, followed by, if desired, molecular ultrafiltration, and further purification of the hyaluronic acid fraction obtained.

Claim 47

Esters, according to one of claims 1-12, in which the hyaluronic ester derives from a hyaluronic acid fraction with a molecular weight of between about 90-80% and 0.23% of the molecular weight of an integral hyaluronic acid with a M.W. of 13 million..

Claim 48

Esters, according to one of claims 1-12, in which the hyaluronic ester derives from a molecular fraction identified as Hyalastine in the previous text, having a molecular weight of between about 50,000 and 100,000 and being substantially free of hyaluronic acid having a molecular weight of less than 30,000.

Claim 49

Esters, according to one of claims 1-12, in which the hyaluronic ester derives from a molecular fraction identified as Hyalectin in the previous text having a molecular weight of between about 500,000 and 730,000 and being substantially free of hyaluronic acid having a molecular weight of less than 30,000.