Claims
- 1. Succinic acid hemiester of hyaluronic acid, or of a hyaluronic acid partial or total ester, said succinic hemiester having the following repeating unit (I): ##STR4## wherein R.sub.1, R.sub.2 and R.sub.3 have the same or different meanings selected from the group consisting of H and CO--(CH.sub.2).sub.2 --COOY, wherein Y is H, R is OH, or R is an alcoholic residue.
- 2. The succinic acid hemiester according to claim 1 wherein in the repeating unit (I) R.sub.1 .dbd.R.sub.2 .dbd.R.sub.3 .dbd.H.
- 3. The succinic acid hemiester according to claim 1 having at least one repeating unit (I) wherein R.sub.1 .dbd.R.sub.3 .dbd.H and R.sub.2 .dbd.CO--(CH.sub.2).sub.2 --COOY and at least one repeating unit (I), wherein R.sub.2 .dbd.R.sub.3 .dbd.H, and R.sub.1 .dbd.CO--(CH.sub.2).sub.2 --COOY.
- 4. Heavy metal salt of succinic acid hemiester with hyaluronic acid or with a hyaluronic acid total or partial ester, said salt having the following repeating unit (II): ##STR5## wherein R.sub.1, R.sub.2 and R.sub.3 have the same or different meanings selected from the group consisting of H and CO--(CH.sub.2).sub.2 --COO.sup.-, R is O.sup.- or R is an alcoholic residue, (X.sup.z+) is a cation of a heavy metal in which z is a number between 1 and 6, p is an integer or a decimal number between 0.1 and 5, provided that p(X.sup.z+) is equal to the number of anionic groups COO.sup.- present in said repeating unit.
- 5. A diagnostical composition for the diagnosis of tumours containing the heavy metal salt according to claim 4, either as a contrast medium or in association with a known non radioactive contrast medium.
- 6. An antitumoral composition containing the heavy metal salts according to claim 4, optionally in association with known radioactive or non radioactive antitumoral agents.
- 7. Cosmetic creams and ointments containing at least one heavy metal salt of succinic acid hemiester with hyaluronic acid or a hyaluronic acid total or partial ester according to claim 4.
- 8. Shave and after-shave lotions containing at least one heavy metal salt of succinic acid hemiester with hyaluronic acid or a hyaluronic acid total or partial ester according to claim 4.
- 9. Hair lotions containing at least one heavy metal salt of succinic acid hemiester with hyaluronic acid or a hyaluronic acid total or partial ester according to claim 4.
- 10. Membranes containing at least one heavy metal salt of succinic acid hemiester with hyaluronic acid or a hyaluronic acid total or partial ester according to claim 4.
- 11. Non-woven tissues containing at least one heavy metal salt of succinic acid hemiester with hyaluronic acid or a hyaluronic acid total or partial ester according to claim 4.
- 12. Gauze containing at least one heavy metal salt of succinic acid hemiester with hyaluronic acid or a hyaluronic acid total or partial ester according to claim 4.
- 13. The heavy metal salt according to claim 4 wherein X is selected from the group consisting of Ag, Cu, Zn, Au, Ce, W, Fe.
- 14. The heavy metal salt according to claim 4, wherein R.sub.1 .dbd.R.sub.2 .dbd.R.sub.3 .dbd.H and X is selected from the group consisting of Ag, Au, Cu, Zn and Fe, z is between 1 and 3 and p is between 0.3 and 2.
- 15. The heavy metal salt according to claim 4, having at least one repeating unit (II) wherein R.sub.1 .dbd.R.sub.3 .dbd.H and R.sub.2 .dbd.CO--(CH.sub.2).sub.2 --COO.sup.-, and at least one repeating unit (II) wherein R.sub.2 .dbd.R.sub.3 .dbd.H and R.sub.1 .dbd.CO--(CH.sub.2).sub.2 --COO.sup.-, X is selected from the group consisting of Ag, Au, Cu, Zn and Fe, z is between 1 and 3 and p is between 0.6 and 3.
- 16. A process for preparing the heavy metal salt of succinic acid hemiester with hyaluronic acid or with a partial ester of hyaluronic acid, said salt having the following repeating unit (II): ##STR6## wherein R.sub.1, R.sub.2 and R.sub.3 have the same or different meanings selected from the group consisting of H and CO--(CH.sub.2).sub.2--COO.sup.-, R is O.sup.- or R is an alcoholic residue, (X.sup.Z+) is a cation of a heavy metal in which z is a number between 1 and 6, p is an integer or a decimal number between 0.1 and 5, selected from the group consisting of Ag, Cu, Zn, Au, Ce, W and Fe, provided that p(X.sup.z+) is equal to the number of anionic groups COO.sup.- present in said repeating unit, and provided that at least in one repeating unit (II) R is OH, said process comprising the following steps:
- a) reacting the hyaluronic acid sodium salt into a hyaluronic acid salt with a compound selected from the group consisting of pyridine, a tetraalkylammonium salt, a tetraarylammonium salt, a tetraalkylphosphonium salt and a tetraarylphosphonium salt, in the presence of water and an aprotic solvent, thereby obtaining the corresponding pyridinium, tetraalkylammonium, tetraarylammonium, tetraalkylphosphonium and tetraarylphosphonium hyaluronate,
- b) treating the solution coming from step a) with succinic anhydride in the presence of an organic base, as a catalyst, removing the pyridinium, tetraalkylammonium, tetraarylammonium, tetraalkylphosphonium or tetraarylphosphonium cation by dialysis, thereby obtaining the succinic acid hemiester with hyaluronic acid or a partial ester thereof, said hemiester having at least one repeating unit (I): ##STR7## wherein R.sub.1, R.sub.2 and R.sub.3 have the same or different meanings selected from the group consisting of H and CO--(CH.sub.2).sub.2 --COOY, wherein Y is H, R is OH, or R is an alcoholic residue, provided that at least in one repeating unit (I) R is OH, and optionally recovering said succinic acid hemiester with hyaluronic acid or a partial ester thereof as a solid product by freeze-drying,
- c) treating the solution directly coming from step b), or an aqueous solution of said recovered solid product coming from step b), with an aqueous solution of an inorganic salt of the heavy metal, thereby obtaining the heavy metal salt of succinic acid hemiester with hyaluronic acid or with a partial ester of hyaluronic acid, and recovering said salt by filtration and vacuum drying.
- 17. The process according to claim 16, wherein in step a) the hyaluronic acid sodium salt is converted to said hyaluronic acid pyridinium salt by using the following operating conditions:
- i) dissolving said hyaluronic acid sodium salt in a mixture of water and dimethylformamide,
- ii) treating the solution coming from step i) with a cationic exchange resin to obtain free hyaluronic acid,
- iii) neutralizing the reaction mixture with pyridine, thereby obtaining said hyaluronic acid pyridinium salt.
- 18. The process according to claim 16, wherein step b) is carried out at 70.degree. C. wherein the ratio of moles of succinic anhydride to moles of total free OH groups present in the following repeating unit (III) of the starting hyaluronic acid or hyaluronic acid partial ester is from 15:1 to 90:1: ##STR8## wherein R.sub.3 is selected from the group consisting of H and CO--(CH.sub.2).sub.2 --COOY, and Y is H, R is OH or R is an alcoholic residue, provided that at least in one repeating unit R is OH, in the presence of a catalyst selected from the group consisting of 4-dimethylaminopyridine, pyridine, and mixtures thereof.
- 19. The process according to claim 16, for preparing Ag salts of the succinic acid hemiester with hyaluronic acid or with a hyaluronic acid partial ester wherein in step (c) the succinic acid hemiester with hyaluronic acid or the succinic acid hemiester with a hyaluronic acid partial ester is treated with an aqueous solution of silver nitrate.
- 20. The process according to claim 16, for preparing Zn salts of the succinic acid hemiester with hyaluronic acid or with a hyaluronic acid partial ester wherein in step (c) the succinic acid hemiester with hyaluronic acid or with hyaluronic acid partial ester is treated with an aqueous solution of ZnCl.sub.2.
- 21. The process according to claim 16, for preparing Cu salts of the succinic acid hemiester with hyaluronic acid or with a hyaluronic acid partial ester wherein in step (c) the succinic acid hemiester with hyaluronic acid or the succinic acid hemiester with hyaluronic acid partial ester is treated with an aqueous solution of CuCl.sub.2.
- 22. The process according to claim 16, for preparing Au salts of the succinic acid hemiester with hyaluronic acid or with a hyaluronic acid partial ester, wherein in step (c) the succinic acid hemiester with hyaluronic acid or the succinic acid hemiester with hyaluronic acid partial ester is treated with an aqueous solution of HAuCl.sub.4.
- 23. The process according to claim 16, for preparing Fe salts of the succinic acid hemiester with hyaluronic acid or with a hyaluronic acid partial ester, wherein in step (c) the succinic acid hemiester with hyaluronic acid or with a hyaluronic acid partial ester is treated with an aqueous solution of FeCl.sub.2.
- 24. A process for preparing a heavy metal salt of succinic acid hemiester with a hyaluronic acid total ester, said salt having the following repeating unit (II): ##STR9## wherein R.sub.1, R.sub.2, and R.sub.3 have the same or different meanings selected from the group consisting of H and CO--(CH.sub.2).sub.2 --COO.sup.-, R is an alcoholic residue, (X.sup.z+) is a cation of a heavy metal in which z is a number between 1 and 6, p is an integer or a decimal number between 0.1 and 5, selected from the group consisting of Ag, Cu, Zn, Au, Ce, W and Fe, provided that p(X.sup.Z+) is equal to the number of anionic groups COO.sup.- present in said repeating unit, said process comprising the following steps:
- b') treating hyaluronic acid total ester dissolved or suspended in a mixture of water and an aprotic solvent with succinic anhydride in the presence of an organic base, thereby obtaining said succinic acid hemiester with a hyaluronic acid total ester, said hemiester having the repeating unit (I): ##STR10## wherein R.sub.1, R.sub.2 and R.sub.3 have the same or different meanings selected from the group consisting of H and CO--(CH.sub.2).sub.2 --COOY, wherein Y is H, and R is a residue of an alcohol, and optionally recovering succinic acid hemiester with a hyaluronic acid total ester as a solid product by freeze-drying.
- c') treating the solution directly coming from step b'), or an aqueous solution of said recovered solid product coming from step b'), with an aqueous solution of an inorganic salt of a heavy metal, thereby obtaining the heavy metal salt of succinic acid hemiester with hyaluronic acid total ester, and recovering said salt by filtration and vacuum drying.
- 25. The process according to claim 24, wherein step b') is carried out at 70.degree. C., wherein the ratio of moles of succinic anhydride to total free OH groups present in the following repeating unit (III) of the starting hyaluronic acid total ester is from 15.1: to 90:1: ##STR11## wherein R.sub.3 is selected from the group consisting of H and CO--(CH.sub.2).sub.2 --COOY and Y is H, and R is an alcoholic residue in the presence of a catalyst selected from the group consisting of 4-dimethylpyridine, pyridine, and mixtures thereof.
- 26. The process according to claim 24, for preparing Ag salts of the succinic acid hemiester with a hyaluronic acid total ester wherein in step c') the succinic acid hemiester with a hyaluronic acid total ester is treated with an aqueous solution of silver nitrate.
- 27. The process according to claim 24, for preparing Zn salts of the succinic acid hemiester with a hyaluronic acid total ester wherein in step c') the succinic acid hemiester with a hyaluronic acid total ester is treated with an aqueous solution of ZnCl.sub.2.
- 28. The process according to claim 24, for preparing Cu salts of the succinic acid hemiester with a hyaluronic acid total ester wherein in step c') the succinic acid hemiester with a hyaluronic acid total ester is treated with an aqueous solution of CuCl.sub.2.
- 29. The process according to claim 24, for preparing Au salts of the succinic acid hemiester with a hyaluronic acid total ester wherein in step c') the succinic acid hemiester with a hyaluronic acid total ester is treated with an aqueous solution of HAuCl.sub.4.
- 30. The process according to claim 24, for preparing Fe salts of the succinic acid hemiester with a hyaluronic acid total ester wherein in step c') the succinic acid hemiester with a hyaluronic acid total ester is treated with an aqueous solution of FeCl.sub.2.
- 31. A therapeutic composition containing as an active ingredient at least one heavy metal salt of succinic acid hemiester with hyaluronic acid or with a hyaluronic acid total or partial ester, said salt having the following repeating unit (II): ##STR12## wherein R.sub.1, R.sub.2 and R.sub.3 have the same or different meanings selected from the group consisting of H and CO--(CH.sub.2).sub.2 --COO.sup.-, R is O.sup.- or R is an alcoholic residue, (X.sup.z+) is a cation of a heavy metal in which z is a number between 1 and 6, p is an integer or a decimal number between 0.1 and 5, provided that p(X.sup.z+) is equal to the number of anionic groups COO.sup.- present in said repeating unit, optionally in association with other active ingredients.
- 32. The therapeutic composition according to claim 31, in the form of an ointment, cream or gel.
- 33. The therapeutic composition according to claim 31, containing as the active ingredient an Ag salt of a succinic acid hemiester with hyaluronic acid or with a hyaluronic acid total or partial ester.
- 34. The therapeutic composition according to claim 31, containing as the active ingredient at least one heavy metal salt of succinic acid hemiester with hyaluronic acid or with a hyaluronic acid partial or total ester, selected from the group consisting of salts of Au, Cu, Zn, Fe, and mixtures thereof.
- 35. A heavy metal salt of succinic acid hemiester with hyaluronic acid or with a hyaluronic acid total or partial ester, said salt having the following repeating unit (II): ##STR13## wherein R.sub.1, R.sub.2 and R.sub.' have the same or different meanings selected from the group consisting of H and CO--(CH.sub.2).sub.2 --COO.sup.-, R is O.sup.- or R is an alcoholic residue, (X.sup.z+) is a cation of a heavy metal in which z is a number between 1 and 6, p is an integer or a decimal number between 0.1 and 5, provided that p(X.sup.z+) is equal to the number of anionic groups COO.sup.- present in said repeating unit, wherein said heavy metal is a radioactive isotope.
- 36. A diagnostic composition for the in vivo diagnosis of tumours according to claim 35, containing the heavy metal salt either as a contrast medium or in association with a known radioactive or a non-radioactive contrast medium.
- 37. An antitumoral composition containing the heavy metal salts according to claim 35, optionally in association with known radioactive or non radioactive antitumoral agents.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a Continuation-in-Part of PCT Application No. PCT/EP96/01979, filed on May 8, 1996.
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Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
PCTEP9601979 |
May 1996 |
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