Esters of hyaluronic acid

• US 4,851,521 A
• Filed: 07/02/1986
• Issued: 07/25/1989
• Est. Priority Date: 07/08/1985
• Status: Expired due to Term

• Current Assignee: Fidia Farmaceutici s.p.a (P.&R. S.p.A)
• Original Assignee: Fidia S.P.A.
• Inventors: Romeo, Aurelio, della Valle, Francesco
• Primary Examiner(s): Griffin, Ronald W.
• Application Number:
  US06/881,454
• Time in Patent Office: 1,119 Days
• Field of Search: 536/55.1, 514/54, 424/423, 424/443, 424/489
• US Class Current: 536/55.1
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 8/735 Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61L 15/28 Polysaccharides or their derivatives A61L15/225 takes precedence
• CPC Class Codes: A61L 17/06 At least partially resorbable materials
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• CPC Class Codes: A61Q 19/08 Anti-ageing preparations
• CPC Class Codes: C08B 37/0072 Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

The invention concerns the esters of hyaluronic acid in which all or only a portion of the carboxylic groups of the acid are esterfied, and the salts of the partial esters with metals or with pharmacologically acceptable organic bases.

The compounds possess interesting and precious bioplastic and pharmaceutical properties and may be used in innumerable fields, including cosmetics, surgery and medicine. The invention also includes pharmaceutical preparations containing, as an active ingredient, one or more hyaluronic acid esters, or a salt thereof as described above, as well as medicaments containing:

(1) a pharmacologically active substance or an association of pharmacologically active substances and

(2) a carrying vehicle containing a total or partial ester of hyaluronic acid. The invention includes also various uses of the hyaluronic esters or of the above mentioned medicaments, such as in medicine, surgery or cosmetics.

The invention also relates to a new procedure for the preparation of polysaccharide esters containing carboxylic groups, such as in particular the above mentioned hyaluronic acid esters.

Claims

1. 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.

2. 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.

3. 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.

4. 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 groups, 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. A salt of a hyaluronic ester according to claim 1 with an alkaline or alkaline earth metals, magnesium or aluminum.

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

11. A salt of a partial ester according to claim 1 with a therapeutically acceptable ammonium, aliphatic, araliphatic, cycloaliphatic or heterocyclic bases.

12. 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 25% of the carboxy groups salified with sodium;

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 is 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.

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

14. A pharmaceutical preparation containing as an active ingredient a hyaluronic acid ester according to claim 1, together with a pharmaceutically acceptable excipient or carrier.

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

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

26. Cosmetic articles including a hyaluronic ester or one of its salts according to claim 1, or the total methyl ester of hyaluronic acid.

27. Sanitary and surgical articles including a hyaluronic ester or one of its salts according to claim 1, or the total methyl ester of hyaluronic acid.

28. Sanitary and surgical articles according to claim 27 in the form of films and threads.

29. Films and threads according to claim 27 in the form of artificial skin for use in surgical dermatology and in this respect as suture threads in surgical operations.

30. Gauzes made of threads according to claim 27 for the medication of wounds and in surgery.

31. Sanitary and surgical articles according to claim 27 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.

42. Esters, according to claim 1, 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.

43. Esters, according to claim 1, in which the hyaluronic ester derives from hyaluronic acid obtained by first dehydrating the cocks'"'"' combs with acetone and then exposing them to enzymatic digestion with papain, followed by, as desired, molecular ultrafiltration, and further purification of the hyaluronic acid fraction obtained.

44. Esters, according to claim 1, 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.

45. Esters, according to claim 1, 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.

46. Esters, according to claim 1, 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.

47. An ester of hyaluronic acid according to claim 1, comprising a mixed ethanol hydrocortisone ester of hyaluronic acid wherein 80% of the carboxyl groups are esterified with ethanol and 20% of the carboxyl groups are esterified with hydrocortisone.

15. A medicament comprising:

(a) one or more pharmacologically active substances and

(b) a carrying vehicle comprising a total or partial ester of hyaluronic acid wth alcohols of the aliphatic, araliphatic, cycloaliphatic and heterocyclic series or salts of these partial esters with inorganic or organic bases.

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

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

18. 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.

19. A medicament according to claim 15 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, and an antiviral.

20. A medicament according to claim 15 in which the active substance (a) is topically active.

21. A medicament according to claim 15, wherein said pharmacologically active substance is hydrocortisone and said alcohol is ethanol.

22. A medicament according to claim 15, which further comprises, as a vehicle, hyaluronic acid or a salt thereof with an inorganic of organic base.

23. A medicament according to claim 15, which further comprises an additional pharmaceutically acceptable excipient.

32. 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, as desired, free carboxy groups are salified in the partial esters obtained, or salified groups are released in them.

33. A process according to claim 32 in which acidic polysaccharides of animal origin are used.

34. A process according to claim 32 in which acidic polysaccharides of vegetable origin are used.

35. A process according to claim 32 in which acidic polysaccharides containing also sulfonic groups are used.

36. A process according to claim 32 in which hyaluronic acid or one of its molecular fractions is used.

37. A process according to claim 32 in which demethylsulfoxide is used as the aprotic solvent.

38. A process according to claim 32 in which an lower tetraalkylammonium salt is used as the starting salt.

39. A process according to claim 32 in which the tetrabutylammonium salt of acidic polysaccharide is used.

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

41. The salts according to claim 40 in which the acidic polysaccharide is hyaluronic acid or one of its molecular fractions.

48. Acidic polysaccharide esters containing carboxy groups deriving from alkyls with between one and six carbon atoms, with the exception of the total methyl ester of hyaluronic acid.