EP0341745A1
Expired / Lapsed
EP
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Crosslinked carboxy polysaccharides
Assignee: Fidia Farmaceutici SpA
•
Filing: 1989-05-12
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Granted: —
•
Expires: 2009-05-12
Abstract
Abstract Inter and/or intramolecular cross-linked esters of acid polysaccharides are disclosed in which a part or all of the carboxy groups are esterified with hydroxyl groups of the same molecule and/or of different molecules of the acid polysaccharide. These inner cross-linked esters of polysaccharide acids are useful in the field of biodegradable plastic materials, to manufacture sanitary and surgical articles, in the cosmetic and pharmaceutical fields, in the food industry and in many other industrial fields.
Inventors
- 👤 Francesco Dr. Della Valle
- 👤 Aurelio Prof. Romeo
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-24 06:29
CPC Classifications
C; C08; C08B; C08B15/00; A; A61; A61K; A61K9/00; A61K9/0012; A61K9/0014; A61K47/00; A61K47/30; A61K47/36; A61K47/38; A61K8/00; A61K8/02; A61K8/0208; A61K8/18; A61K8/72; A61K8/73; A61K8/731; A61K8/733; A61K8/735; A61K8/736; A61L; A61L15/00; A61L15/16; A61L15/22; A61L15/28; A61L15/42; A61L15/425; A61L17/00; A61L17/06; A61L17/10; A61L27/00; A61L27/14; A61L27/20; A61L27/50; A61L27/58; A61L31/00; A61L31/04; A61L31/042; A61Q; A61Q19/00; C08B11/00; C08B11/20; C08B15/005; C08B37/00; C08B37/0006; C08B37/0024; C08B37/0027; C08B37/003; C08B37/006; C08B37/0063; C08B37/0072; C08B37/0084; A61K2800/00; A61K2800/40; A61K2800/57
Claims Analysis
Total Claims: 74
Claim 1
Independent Claim
41 words
Cross-linked carboxy acidic polysaccharides wherein at least a first portion of the carboxyl groups of said polysaccharide are cross-linked by ester bonding or lactonic bonding to hydroxyl groups of the same polysaccharide molecule and/or to hydroxyl groups of different polysaccharide molecules.
Claim 2
Dependent Claim
41 words
Cross-linked carboxy acidic polysaccharides wherein at least a first portion of the carboxyl groups of said polysaccharide are cross-linked by ester bonding or lactonic bonding to hydroxyl groups of the same polysaccharide molecule and/or to hydroxyl groups of different polysaccharide molecules.
Claim 3
Dependent Claim
24 words
Cross-linked acidic polysaccharides according to claim 1, wherein said polysaccharides are selected from the group consisting of hyaluronic acid, alginic acid, carboxymethylcellulose, and carboxymethylchitin.
Claim 4
Dependent Claim
27 words
Cross-linked acidic polysaccharides according to one of claims 1 and 2, wherein all of the carboxyl functions of said polysaccharides are ester bonded to a hydroxyl group.
Claim 5
Dependent Claim
38 words
Cross-linked acidic polysaccharides according to any one of claims 1-3, wherein the percentage of said first portion of carboxyl groups involved in cross-linking to the total number of carboxyl groups in said polysaccharide ranges between 1% and 60%.
Claim 6
Dependent Claim
17 words
Cross-linked acidic polysaccharides according to claim 4, wherein the percentage of cross-linking ranges between 15% and 30%.
Claim 7
Dependent Claim
48 words
Cross-linked acidic polysaccharides according to any one of claims 1-2 and 4-5, wherein only a portion of the carboxyl groups of said polysaccharides are cross-linked to hydroxyl groups and in which a second portion of carboxyl groups of said polysaccharide are esterified with a mono- or polyvalent alcohol.
Claim 8
Dependent Claim
25 words
Cross-linked acidic polysaccharides according to claim 6, wherein said alcohol is a member selected from the group consisting of aliphatic, araliphatic, cycloaliphatic and heterocyclic alcohols.
Claim 9
Dependent Claim
107 words
Cross-linked acidic polysaccharides according to claim 7, wherein said alcohols of the aliphatic series have a maximum of 34 carbon atoms and may be substituted by one or two functional groups chosen from the group formed by amino, hydroxy, mercapto, aldehydo, ketal, carboxy, hydrocarbyl, and dihydrocarbylamino, ether, ester, thioester, acetal, ketal, carbamidic groups or carbamidic groups substituted by one or more alkyl groups, the hycrocarbyl radicals in these groups having a maximum of 6 functionally modified 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 10
Dependent Claim
101 words
Cross-linked acidic polysaccharides according to claim 8, wherein said alcohol is an alcohol with a maximum of 32 carbon atoms and, in the case of alcohols substituted by functional groups, the hydrocarbyl radicals of the amine groups, ether, ester, thioether, thioester, acetal, ketal, represent alkyl groups with a maximum of 4 carbon atoms and in the esterified carboxy groups and in the substituted carbamidic groups the hydrocarbyl groups are alkyl groups with the same number of carbon atoms, and in which the substituted amino or carbamidic groups may also be alkyleneamino or alkylenecarbamidic groups with a maximum of 8 carbon atoms.
Claim 11
Dependent Claim
25 words
Cross-linked acidic polysaccharides according to claim 9, wherein said alcohol is ethyl, propyl, isopropyl, N-butyl, isobutyl, tert-butyl alcohols, an amyl, pentyl, hexyl or octyl alcohol.
Claim 12
Dependent Claim
18 words
Cross-linked acidic polysaccharides according to claim 9, wherein said alcohol component derives from ethyleneglycol, propyleneglycol, butyleneglycol or glycerin.
Claim 13
Dependent Claim
25 words
Cross-linked acidic polysaccharides according to claim 9, wherein said alcohol is tartronic alcohol, lactic acids, glycolic acid, malic acid, a tartaric acid or citric acid.
Claim 14
Dependent Claim
84 words
Cross-linked acidic polysaccharides according to claim 7, wherein said alcohols of the araliphatic series have only one benzene residue and have an aliphatic chain with a maximum of 4 carbon atoms and wherein the benzene residue may be substituted by between 1 and 3 methyl or hydroxy groups, by halogen atoms, and wherein the aliphatic chain may be substituted by one or two functions chosen from the group consisting of free amino groups or mono- or diethyl groups or by pyrrolidine or piperidine groups.
Claim 15
Dependent Claim
28 words
Cross-linked acidic polysaccharides according to claim 7, wherein said alcohols of the cycloaliphatic or aliphatic-cycloaliphatic series are mono- or polycyclic hydrocarbons with a maximum of 34 carbon atoms.
Claim 16
Dependent Claim
43 words
Cross-linked acidic polysaccharides according to claim 7, wherein said heterocyclic alcohols are mono- or polycyclic cycloaliphatic or aliphatic cycloaliphatic alcohols interrupted in their carbon atom chain or ring by one or more heteroatoms chosen from the group formed by nitrogen, oxygen and sulfur.
Claim 17
Dependent Claim
51 words
Cross-linked acidic polysaccharides according to claim 7, wherein said heterocyclic alcohols are selected from the group consisting of alkaloids, phenylethylamines, phenothiazine drugs, thioxanthene drugs, anticonvulsivants, antipsychotics, antiemetics, analgesics, hypnotics, anorexics, tranquillizers, muscle relaxants, coronary vasodilators, adrenergic blockers, narcotic blockers, antineoplastics, antibiotics, antivirals, peripheral vasodilators, carbonic anhydrase inhibitors, antiasthmatics, antiinflammatories and sulfamidics.
Claim 18
Dependent Claim
27 words
A salt of a cross-linked polysaccharide according to any one of claims 1-2 and 4-16 with an alkaline or alkaline earth metal, magnesium, aluminum or an amine.
Claim 19
Dependent Claim
10 words
A salt according to claim 17, with sodium or ammonium.
Claim 20
Dependent Claim
17 words
A salt according to claim 17, wherein said amine is an aliphatic, araliphatic, cycloaliphatic or heterocyclic amine.
Claim 21
Dependent Claim
14 words
A salt according to claim 19, wherein said amine is a therapeutically acceptable base.
Claim 22
Dependent Claim
14 words
A salt according to claim 19, wherein said amine is a therapeutically active base.
Claim 23
Dependent Claim
56 words
A salt according to claim 21, wherein said amine is selected from the group consisting of: alkaloids, peptides, phenothiazine, benzodiazepine, thioxanthene, hormones, vitamins, anticonvulsivants, antipsychotics, antiemetics, anesthetics, hypnotics, anorexics, tranquilizers, muscle relaxants, coronary vasodilators, antineoplastics, antibiotics, antibacterials, antivirals, antimalarials, carbonic anhydrase inhibitors, nonsteroid antiinflammatories, vasoconstrictors, cholinergic agonists, cholinergic blockers, adrenergic agonists, adrenergic blockers, and narcotic blockers.
Claim 24
Dependent Claim
104 words
A salt according to claim 17, wherein said amine is pharmacologically inactive and is selected from the group consisting of mono-, di-and tri-alkylamines with a maximum of 18 carbon atoms, arylalkylamines with a maximum of 18 carbon atoms in the aliphatic part and with a benzene group as an aromatic part, optionally substituted by between 1 and 3 methyl groups or halogen atoms or hydroxyl groups, alkyleneamines with cycles of between 4 and 6 carbon atoms optionally interrupted in the cycle by heteroatoms chosen from the group consisting of O and S, and amines of all these types substituted by amino or hydroxy functions.
Claim 25
Dependent Claim
20 words
Cross-linked acidic polysaccharides or a salt thereof according to any one of claims 1-23, wherein said polysaccharide is hyaluronic acid.
Claim 26
Dependent Claim
20 words
Cross-linked acidic polysaccharides or a salt thereof according to any one of claims 1-23, wherein said polysaccharide is alginic acid.
Claim 27
Dependent Claim
19 words
Cross-linked acidic polysaccharides or a salt thereof according to any one of claims 1-23, wherein said polysaccharide is carboxymethylchitin.
Claim 28
Dependent Claim
47 words
A cross-linked polysaccharide according to claim 24 which is a totally or partially cross-linked hyaluronic acid, wherein said partially cross-linked hyaluronic acid includes a portion of carboxyl groups esterified with a lower aliphatic alcohol, and optionally includes a portion of carboxyl groups salified with an alkaline metal.
Claim 29
Dependent Claim
240 words
A compound according to claim 27, selected from the group consisting of: - hyaluronic acid cross-linked to an extent of 1% of the carboxy groups and salified with sodium to an extent of 99%; - hyaluronic acid cross-linked to an extent of 5% of the carboxy groups and salified with sodium to an extent of 95%; - hyaluronic acid cross-linked to an extent of 10% of the carboxy groups and salified with sodium to an extent of 90%; - hyaluronic acid cross-linked to an extent of 25% of the carboxy groups and salified with sodium to an extent of 75%; - hyaluronic acid cross-linked to an extent of 50% of the carboxy groups and salified with sodium to an extent of 50%; - hyaluronic acid cross-linked to an extent of 75% of the carboxy groups and salified with sodium to an extent of 25%; - hyaluronic acid cross-linked to an extent of 100% of the carboxy groups; - hyaluronic acid cross-linked to an extent of 25% of the carboxy groups, esterified to an extent of 25% with ethanol and salified with sodium to an extent of 50%; - hyaluronic acid cross-linked to an extent of 25% of the carboxy groups, esterified to an extent of 50% with ethanol and salified with sodium to an extent of 25%; and - hyaluronic acid cross-linked to an extent of 25% of the carboxy groups and esterified with ethanol to an extent of 75%.
Claim 30
Dependent Claim
47 words
A cross-linked polysaccharide according to claim 25, which is a totally or partially cross-linked alginic acid, wherein said partially cross-linked alginic acid includes a portion of carboxy groups esterified with a lower aliphatic alcohol, and optionally includes a portion of carboxy groups salified with an alkaline metal.
Claim 31
Dependent Claim
240 words
A compound according to claim 29, selected from the group consisting of: - alginic acid cross-linked to an extent of 1% of the carboxy groups and salified with sodium to an extent of 99%; - alginic acid cross-linked to an extent of 5% of the carboxy groups and salified with sodium to an extent of 95%; - alginic acid cross-linked to an extent of 10% of the carboxy groups and salified with sodium to an extent of 90%; - alginic acid cross-linked to an extent of 25% of the carboxy groups and salified with sodium to an extent of 75%; - alginic acid cross-linked to an extent of 50% of the carboxy groups and salified with sodium to an extent of 50%; - alginic acid cross-linked to an extent of 75% of the carboxy groups and salified with sodium to an extent of 25%; - alginic acid cross-linked to an extent of 100% of the carboxy groups; - alginic acid cross-linked to an extent of 25% of the carboxy groups, esterified with ethanol to an extent of 25% and salified with sodium to an extent of 50%; - alginic acid cross-linked to an extent of 25% of the carboxy groups, esterified with ethanol to an extent of 50% and salified with sodium to an extent of 25%; and - alginic acid cross-linked to an extent of 25% of the carboxy groups ed esterified to an extent of 75% with ethanol.
Claim 32
Dependent Claim
44 words
A compound according to claim 26 which is a totally or partially cross-linked carboxymethylchitin, wherein said partially cross-linked carboxymethylchitin includes a portion of carboxy groups esterified with a lower aliphatic alcohol, and optionally includes a portion of carboxy groups salified with an alkaline metal.
Claim 33
Dependent Claim
168 words
A compound according to claim 31 selected from the group consisting of: - carboxymethylchitin cross-linked to an extent of 1% of the carboxy groups and salified with sodium to an extent of 99%; - carboxymethylchitin cross-linked to an extent of 5% of the carboxy groups salified with sodium to an extent of 95%; - carboxymethylchitin cross-linked to an extent of 10% of the carboxy groups and salified with sodium to an extent of 90%; - carboxymethylchitin cross-linked to an extent of 10% of the carboxy groups and salified with sodium to an extent of 90%; - carboxymethylchitin cross-linked to an extent of 25% of the carboxy groups and salified with sodium to an extent of 75%; - carboxymethylchitin cross-linked to an extent of 50% of the carboxy groups and salified with sodium to an extent of 50%; - carboxymethylchitin cross-linked to an extent of 75% of the carboxy groups and salified to an extent of 25%; and carboxymethylchitin cross-linked to an extent of 100% of the carboxy groups.
Claim 34
Dependent Claim
90 words
A compound according to claim 31 selected from the group consisting of: - carboxymethylchitin cross-linked to an extent of 25% of the carboxy groups, esterified to an extent of 25% with ethanol and salified to an extent of 50%; - carboxymethylchitin cross-linked to an extent of 25% of the carboxy groups, esterified with ethanol to an extent of 50% and salified with sodium to an extent of 25%; and - carboxymethylchitin cross-linked to an extent of 25% of the carboxy groups and esterified with ethanol to an extent of 75%.
Claim 35
Dependent Claim
176 words
A compound according to claim 24 selected from the group consisting of: - hyaluronic acid cross-linked to an extent of 25% of the carboxy groups, esterified to an extent of 20% with cortisone and salified with sodium to an extent of 55%; - hyaluronic acid cross-linked to an extent of 25% of the carboxy groups, esterified with cortisone to an extent of 20% and with ethanol to an extent of 25% and salified with sodium to an extent of 30%; - hyaluronic acid cross-linked to an extent of 10% of the carboxy groups, esterified with cortisone to an extent of 20% and with ethanol to an extent of 70%; - hyaluronic acid cross-linked to an extent of 25% of the carboxy groups and salified with carteololo to an extent of 75%; - hyaluronic acid cross-linked to an extent of 25% of the carboxy groups and salified to an extent of 75% with kanamycin; and - hyaluronic acid cross-linked to an extent of 25% of the carboxy groups and salified with amikacin to an extent of 75%.
Claim 36
Dependent Claim
18 words
A pharmaceutical composition comprising as an active ingredient a compound according to claim 21 together with an excipient.
Claim 37
Dependent Claim
31 words
A medicament comprising: (1) a pharmacologically active substance or a mixture of pharmacologically active substances; and (2) a vehicle comprised of a cross-linked polysaccharide according to any one of claims 1-34.
Claim 38
Dependent Claim
19 words
A medicament according to claim 36, in which component (1) is a substance for oral, parenteral or topical use.
Claim 39
Dependent Claim
16 words
A medicament according to claim 37, in which the polysaccharide of component (2) is hyaluronic acid.
Claim 40
Dependent Claim
23 words
A medicament according to any one of claims 36-38, wherein the component (1) is an anesthetic, analgesic, antiinflammatory, vasocontrictory antibiotic/antibacterial or antiviral agent.
Claim 41
Dependent Claim
15 words
A cosmetic article containing a cross-linked acidic polysaccharide according to any one of claims 1-34.
Claim 42
Dependent Claim
17 words
A sanitary or surgical article containing a cross-linked acidic polysaccharide according to any one of claims 1-34.
Claim 43
Dependent Claim
22 words
A sanitary or surgical article according to claim 41, comprised of threads or films of a cross-linked product of an acidic polysaccharide.
Claim 44
Dependent Claim
18 words
A sanitary or surgical article according to claim 41, comprised of capsules for the subcutaneous implantation of medicaments.
Claim 45
Dependent Claim
18 words
A sanitary or surgical article according to claim 41, comprised of microcapsules for subcutaneous, intramuscular or intravenous injection.
Claim 46
Dependent Claim
23 words
A sanitary or surgical article according to claim 41, comprised of solid inserts adapted to be removed after a certain length of time.
Claim 47
Dependent Claim
19 words
A sanitary or surgical article according to claim 41, comprised of sponges for the medication of wounds and lesions.
Claim 48
Dependent Claim
18 words
A sanitary or surgical article according to any one of claims 41-46, wherein the polysaccharide is hyaluronic acid.
Claim 49
Dependent Claim
18 words
A sanitary or surgical article according to any one of claims 41-46, wherein the polysaccharide is alginic acid.
Claim 50
Dependent Claim
15 words
Use in therapy of a cross-linked acidic polysaccharide according to any one of claims 1-34.
Claim 51
Dependent Claim
17 words
Use of a cross-linked acidic polysaccharide according to any one of claims 1-34 in the industrial field.
Claim 52
Dependent Claim
31 words
Use of a cross-linked acidic polysaccharide according to any one of claims 1-34 in the alimentary, cosmetic, sanitary and surgical fields, in the production of paper, resin, dye and household goods.
Claim 53
Dependent Claim
17 words
Use of a cross-linked polysaccharide according tc any one of claims 1-34 in dermatology as artificial skin.
Claim 54
Dependent Claim
21 words
Use of a cross-linked product according to any one of claims 1-34 wherein the polysaccharide is hyaluronic acid or alginic acid.
Claim 55
Dependent Claim
18 words
Use of a cross-linked polysaccharide according to any one of claims 1-34 as suture thread in surgical operations.
Claim 56
Dependent Claim
63 words
A process for the preparation of threads or films of a cross-linked acidic polysaccharide which comprises: (a) dissolving a cross-linked acidic polysaccharide in a first organic solvent; (b) forming said solution of a cross-linked acidic polysaccharide into a sheet or thread form; (c) eliminating said solvent by treatment with a second organic or aqueous solvent which is soluble in said first organic solvent.
Claim 57
Dependent Claim
63 words
A process for the preparation of threads or films of a cross-linked acidic polysaccharide which comprises: (a) dissolving a cross-linked acidic polysaccharide in a first organic solvent; (b) forming said solution of a cross-linked acidic polysaccharide into a sheet or thread form; (c) eliminating said solvent by treatment with a second organic or aqueous solvent which is soluble in said first organic solvent.
Claim 58
Dependent Claim
15 words
A process according to claim 55, wherein dimethylsulfoxide is used as said first organic solvent.
Claim 59
Dependent Claim
27 words
A process according to claim 55, wherein hexafluoroisopropanol is used as said first organic solvent and is eliminated by treatment with a flow of heated inert gas.
Claim 60
Dependent Claim
52 words
A process for the preparation of cross-linked carboxy acidic polysaccharides which comprises: (a) treating an acidic polysaccharide with an activating agent to activate carboxy groups in said polysaccharide to form intermediate activated polysaccharide derivatives; and (b) subjecting said intermediate activated polysaccharide derivatives to heat or irradiation to produce cross-linked carboxy acidic polysaccharides.
Claim 61
Dependent Claim
52 words
A process for the preparation of cross-linked carboxy acidic polysaccharides which comprises: (a) treating an acidic polysaccharide with an activating agent to activate carboxy groups in said polysaccharide to form intermediate activated polysaccharide derivatives; and (b) subjecting said intermediate activated polysaccharide derivatives to heat or irradiation to produce cross-linked carboxy acidic polysaccharides.
Claim 62
Dependent Claim
21 words
A process according to claim 58, wherein at least a portion of the carboxy groups in said acidic polysaccharides are salified.
Claim 63
Dependent Claim
29 words
A process according to claim 59, wherein said at least a portion of carboxy groups are salified with an alkaline or alkaline earth metal, or with a quaternary ammonium.
Claim 64
Dependent Claim
21 words
A process according to claim 58, wherein said treatment with an activating agent is performed in the presence of a catalyst.
Claim 65
Dependent Claim
25 words
A process according to claim 58, wherein a portion of the carboxy groups in said acidic polysaccharide are esterified with a mono- or polyvalent alcohol.
Claim 66
Dependent Claim
21 words
A process according to any one of claims 58-62, wherein said activating agent is a carbodiimide, ethoxyacetylene, Woodward's reagent, or chloroacetonitryl.
Claim 67
Dependent Claim
41 words
A process according to any one of claims 58-62, wherein said activating agent is a 2-halogen-N-alkylpyridinium salt, in which the halogen is selected from the group consisting of chlorine and bromine and the alkyl has a maximum of 6 carbon atoms.
Claim 68
Dependent Claim
32 words
A process according to claim 64, wherein said activating agent is a chloride of 2-chloro-N-methyl-pyridine and reacts with a tetrabutylammonium salt of the polysaccharide in the presence of a tertiary amine base.
Claim 69
Dependent Claim
20 words
A process according to any one of claims 58-65, wherein the reaction is carried out in an organic aprotic solvent.
Claim 70
Dependent Claim
34 words
A process according to claim 66, wherein said organic involving the aprotic solvent is a dialkylsulfoxide or a dialkylamide of a lower aliphatic alcohol with an alkyl having a maximum of 6 carbon atoms.
Claim 71
Dependent Claim
13 words
A process according to claim 67, wherein dimethylsulfoxide is used as said solvent.
Claim 72
Dependent Claim
26 words
A process according to any one of claims 58-68, wherein the reaction is carried out within a temperature range of between 0 o and 150 o
Claim 73
Dependent Claim
16 words
A process according to claim 69 in which the reaction is carried out at room temperature.
Claim 74
Dependent Claim
40 words
A process according to any one of claims 58-70, wherein subsequent to said cross-linking reaction, at least a portion of any remaining free carboxyl groups in said cross-linked acidic polysaccharide are salified or esterified with a mono- or polyvalent alcohol.
References Cited (Backward Citations)
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