Source: http://www.google.com/patents/US4665064?dq=5,266,072
Timestamp: 2015-03-04 08:53:41
Document Index: 654719710

Matched Legal Cases: ['Application No. 8308053', 'Application No. 8308056', 'Application No. 8407181', 'Application No. 8327612', 'Application No. 8407180', 'Application No. 8410289', 'art          0']

Patent US4665064 - In blood; zinc chelate - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsZinc(II) complexes in which at least one ligand is provided by a compound being: (1) 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms; or (2) a 3-hydroxypyrid-2-one...http://www.google.com/patents/US4665064?utm_source=gb-gplus-sharePatent US4665064 - In blood; zinc chelateAdvanced Patent SearchPublication numberUS4665064 APublication typeGrantApplication numberUS 06/666,905Publication dateMay 12, 1987Filing dateOct 31, 1984Priority dateOct 31, 1983Fee statusPaidAlso published asCA1290096C, DE3484098D1, EP0145228A1, EP0145228B1, US4894455Publication number06666905, 666905, US 4665064 A, US 4665064A, US-A-4665064, US4665064 A, US4665064AInventorsRobert C. Hider, George Kontoghiorghes, Jack Silver, Michael A. StockhamOriginal AssigneeNational Research Development CorporationExport CitationBiBTeX, EndNote, RefManPatent Citations (9), Non-Patent Citations (23), Referenced by (27), Classifications (18), Legal Events (6) External Links: USPTO, USPTO Assignment, EspacenetIn blood; zinc chelate
US 4665064 AAbstract
1. A method for the treatment of a patient to effect an increase in the levels of zinc in the patient's bloodstream which comprises administering to said patient an amount effective to achieve such an increase of a zinc(II) complex in which the said zinc(II) complex comprises one or more ligands provided by the same or a different compound selected from the group consisting of:(1) 3-hydroxy-4-pyrone and a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms; and (2) a 3-hydroxypyrid-2-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and in which one or more of the hydrogen atoms attached to ring carbon atoms optionally may be replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group. 2. The method according to claim 1, in which at least one ligand is provided by a compound of type (1).
3. A method for the treatment of a patient to effect an increase in the levels of zinc in the patient's bloodstream which comprises administering to said patient an amount effective to achieve such an increase of a zinc(II) complex in which each ligand is provided by the same or a different compound being 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms.
4. A method according to claim 3, in which each ligand is provided by the same compound.
5. A method according to claim 4, in which the compound is 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an acyclic group of 1 to 4 carbon atoms.
6. The method according to claim 4, in which the compound is 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by the same or different substituents selected from methyl, ethyl, n-propyl and isopropyl groups.
7. A method according to claim 6, in which the substituted 3-hydroxy-4-pyrone has a single substituent at the 2- or 6-position.
8. A method according to claim 6, in which the compound is 3-hydroxy-4-pyrone, 3-hydroxy-2-methyl-4-pyrone, 3-hydroxy-6-methyl-4-pyrone or 2-ethyl-3-hydroxy-4-pyrone.
9. A method according to claim 1, in which at least one ligand is provided by a compound of type (2).
10. A method for the treatment of a patient to effect an increase in the levels of zinc in the patient's bloodstream which comprises administering to said patient an amount effective to achieve such an increase of a zinc (II) complex in which each ligand is provided by the same or a different 3-hydroxypyrid-2-one or in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and in which one or more of the hydrogen atoms attached to ring carbon atoms may be replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group.
11. A method according to claim 10, in which each ligand is provided by the same compound.
12. A method according to claim 11, in which the compound is a 3-hydroxypyrid-2-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by the same or a different aliphatic hydrocarbon group of 1 to 6 carbon atoms.
13. A method according to claim 12, in which the or each aliphatic hydrocarbon group is an acyclic group of 1 to 4 carbon atoms.
14. A method according to claim 12, in which the compound is a 3-hydroxypyrid-2-one substituted on the nitrogen atom by a substituent selected from methyl, ethyl, n-propyl and isopropyl groups.
15. A method according to claim 14, in which the compound is 3-hydroxy-1-methylpyrid-2-one, 1-ethyl-3-hydroxyprid-2-one, 3-hydroxy-1-propylpyrid-2-one, or 3-hydroxy-1-(1'-methylethyl)pyrid-2-one.
16. A method according to claim 1, in which the complex is a neutral 2:1 ligand:zinc(II) complex.
17. A method for the treatment of a patient to effect an increase in the levels of zinc in the patient's bloodstream which comprises administering to said patient an amount effective to achieve such an increase of a neutral 2:1 hydroxypyrone:zinc(II) complex in which each of the two ligands is provided by the same compound being 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms.
18. A method according to claim 17, in which the hydroxypyrone is 3-hydroxy-2-methyl-4-pyrone or 2-ethyl-3-hydroxy-4-pyrone.
19. A method for the treatment of a patient to effect an increase in the levels of zinc in the patient's bloodstream which comprises administering to said patient an amount effective to achieve such an increase of a neutral 2:1 hydroxypyridone:zinc(II) complex in which each of the two ligands is provided by the same compound being a 3-hydroxypyrid-2-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms and in which one or more of the hydrogen atoms attached to ring carbon atoms optionally may be replaced by the same or a different aliphatic hydrocarbon group of 1 to 6 carbon atoms.
20. A method for the treatment of a patient to effect an increase in the levels of zinc in the patient's bloodstream which comprises administering to said patient an amount effective to achieve such an increase of a mixture of (a) a neutral 2:1 ligand:zinc (II) complex in which each ligand is provided by the same or a different compound selected from the group consisting of:(1) 3-hydroxy-4-pyrone and a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms; and (2) a 3-hydroxypyrid-2-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and in which one or more of the hydrogen atoms attached to ring carbon atoms optionally may be replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group; and (b) the same compound or one or more of the same compounds in uncomplexed form, the molar proportion of component (b) to component (a) being from 0.5:1 to 100:1. 21. A method according to claim 20 in which the mixture is of (a) a neutral 2:1 hydroxypyrone:zinc(II) complex in which each of the two ligands is provided by the same compound being 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms; and (b) the same hydroxypyrone in uncomplexed form.
22. A method according to claim 20, in which the mixture is of (a) one or more neutral 2:1 hydroxypyrone:zinc(II) complexes in which each of the two ligands is provided by the same or a different compound selected from 3-hydroxy-2-methyl-4-pyrone and 2-ethyl-3-hydroxy-4-pyrone each compound providing a ligand or ligands present in the complex or complexes in uncomplexed form and (b) an uncomplexed compound corresponding to each ligand in the complex.
23. A method for the treatment of a patient to effect an increase in the levels of zinc and iron in the patient's bloodstream which comprises administering to said patient an amount effective to achieve such an increase of a mixture of (a) a zinc (II) complex in which each ligand is provided by the same or a different compound selected from the group consisting of:(1) 3-hydroxy-4-pyrone and a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms; and (2) a 3-hydroxypyrid-2-one in which the hydrogen atom attached to the nitrogen atoms is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and in which one or more of the hydrogen atoms attached to ring carbon atoms optionally may be replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group; and (b) a physiologically acceptable iron complex or iron salt. 24. A method according to claim 23, in which the mixture is of (a) a neutral 2:1 ligand:zinc(II) complex in which each ligand is provided by the same or a different compound selected from the group consisting of:(1) 3-hydroxy-4-pyrone and a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms; and (2) a 3-hydroxypyrid-2-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and in which one or more of the hydrogen atoms attached to ring carbon atoms may be replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group; and (b) a neutral 3:1 ligand:iron (III) complex in which each ligand is provided by the same or a different compound selected from the group consisting of compounds as defined under (1) and (2) and by a 3-hydroxypyrid-4-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and in which one or more of the hydrogen atoms attached to ring carbon atoms optionally may be replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group. 25. A method according to claim 24 in which the mixture is of (a) a neutral 2:1 hydroxypyrone:zinc(II) complex in which each of the two ligands is provided by the same compound being 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, and (b) a neutral 3:1 hydroxypyrone:iron(III) complex in which the three ligands are the same as the ligands present in the zinc complex.
26. A method according to claim 24 in which the mixture is of (a) one or more neutral 2:1 hydroxypyrone:zinc(II) complexes in which each ligand is provided by the same or a different compound selected from 3-hydroxy-2-methyl-4-pyrone and 2-ethyl-3-hydroxy 4-pyrone, and (b) one or more neutral 3:1 hydroxypyrone:iron(III) complexes in which each ligand is independently provided by a compound selected from 3-hydroxy-2-methyl-4-pyrone and 2-ethyl-3-hydroxy-4-pyrone.
27. A method according to claim 24 in which the mixture additionally contains an uncomplexed compound or compounds corresponding to one or more of the ligands complexed to zinc or iron.
28. A method according to claim 25 in which the mixture additionally contains the uncomplexed hydroxypyrone.
29. A method for the treatment of a patient having a bacterial or fungal infection which comprises administering to said patient an antibacterially or anti-fungally effective amount of a zinc(II) complex in which each ligand is provided by the same or a different compound selected from the group consisting of:(1) 3-hydroxy-4-pyrone and a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms; (2) a 3-hydroxypyrid-2-one and a 3-hydroxypyrid-4-one, in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and in which one or more of the hydrogen atoms attached to ring carbon atoms optionally may be replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group; and (3) an alternative compound providing a physiologically acceptable, monobasic, bidentate ligand which is capable of bonding covalently to zinc and which either contains a first grouping which is an enolic hydroxy group or a carboxy group and a second grouping which is an amine group or a hydroxy group, or is a monocarboxylic acid selected from the group consisting of formic acid, acetic acid and propionic acid; but with the proviso that at least one ligand is of type (1) or (2). 30. A method according to claim 29, in which the zinc(II) complex is administered topically.
31. A method according to claim 29, in which each ligand is independently provided by a compound selected from those of types (1) and (2).
32. A method according to claim 31, in which the complex is a neutral 2:1 ligand:zinc(II) complex.
33. A method according to claim 31, in which both ligands of the complex are provided by the same compound of type (1).
34. A method according to claim 33, in which the compound is 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by the same or a different substituent selected from methyl, ethyl, n-propyl and isopropyl groups.
35. A method according to claim 32, in which the complex is the neutral 2:1 hydroxypyrone:zinc(II) complex of 3-hydroxy-2-methyl-4-pyrone or 2-ethyl-3-hydroxy-4-pyrone.
36. A method according to claim 29, in which an uncomplexed compound or compounds corresponding to one or more of the ligands in the complex is additionally administered to the patient.
37. A method according to claim 36, in which the patient is treated with one or both of (a) a zinc(II) complex in which each ligand is provided by 3-hydroxy-2-methyl-4-pyrone together with uncomplexed 3-hydroxy-2-methyl-4-pyrone, and (b) a zinc(II) complex in which each ligand is provided by 2-ethyl-3-hydroxy-4-pyrone together with uncomplexed 2-ethyl-3-hydroxy-4-pyrone.
38. A pharmaceutical composition comprising a physiologically effective amount of a zinc (II) complex in which each ligand is provided by the same or a different compound selected from the group consisting of:(1) 3-hydroxy-4-pyrone and a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1-6 carbon atoms; and (2) a 3-hydroxypyrid-2-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and in which one or more of the hydrogen atoms attached to ring carbon atoms optionally may be replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group; together with a physiologically acceptable diluent or carrier, said diluent or carrier being either a solid or a sterile and pyrogen-free liquid. 39. A pharmaceutical composition according to claim 38 in unit dosage form.
40. A pharmaceutical composition according to claim 38 which additionally comprises an uncomplexed compound or compounds corresponding to one or more of the ligands present in the zinc complex.
41. A pharmaceutical composition according to claim 38 in which the molar proportion of each uncomplexed compound:zinc complex is from 0.5:1 to 100:1.
42. A pharmaceutical composition according to claim 38, in which the complex is a neutral 2:1 ligand:zinc(II) complex.
43. A pharmaceutical composition according to claim 42, in which both ligands of the complex are provided by the same compound of type (1).
44. A pharmaceutical composition according to claim 1, in which the zinc complex is a neutral 2:1 ligand:zinc(II) complex and which additionally comprises an iron complex being a neutral 3:1 ligand:iron(III) complex in which each ligand is separately provided by a compound of type (1) or (2).
45. A pharmaceutical composition comprising (a) a physiologically effective amount of a zinc(II) complex in which each ligand is provided by the same or a different compound selected from the group consisting of:(1) 3-hydroxy-4-pyrone and a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms; and (2) a 3-hydroxypyrid-2-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and in which one or more of the hydrogen atoms attached to ring carbon atoms optionally may be replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group; and (b) a physiologically acceptable iron complex or iron salt. 46. A pharmaceutical composition according to claim 45 which comprises one or more of (a) the neutral 2:1 3-hydroxy-2-methyl-4-pyrone:zinc(II) complex together with uncomplexed 3-hydroxy2-methyl-4-pyrone, and (b) the neutral 2:1 2-ethyl-3-hydroxy-4-pyrone:zinc(II) complex together with uncomplexed 2-ethyl-3-hydroxy-4-pyrone.
47. A pharmaceutical composition according to claim 46 which additionally comprises one or both of the neutral 3:1 3-hydroxy-2-methyl-4-pyrone:iron(III) complex and the neutral 3:1 2-ethyl-3-hydroxy-4-pyrone:iron(III) complex.
48. A pharmaceutical composition comprising a physiologically effective amount of a zinc(II) complex in which each ligand is provided by the same or a different compound selected from the group consisting of:(1) 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms; and (2) a 3-hydroxypyrid-2-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and in which one or more of the hydrogen atoms attached to ring carbon atoms optionally may be replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group; together with a physiologically acceptable diluent or carrier which is sterile and pyrogen-free. 49. A pharmaceutical composition according to claim 48, in which the complex is a neutral 2:1 ligand:zinc(II) complex.
50. A pharmaceutical composition according to claim 49, in which both ligands of the complex are provided by the same compound of type (1).
51. A pharmaceutical composition according to claim 50, in which the compound is 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atom attached to ring carbon atoms are replaced by the same or a different substituent selected from methyl, ethyl, n-propyl and isopropyl groups.
52. A pharmaceutical composition according to claim 50, in which the complex is the neutral 2:1 hydroxypyrone:zinc(II) complex of 3-hydroxy-2-methyl-4-pyrone or 2-ethyl-3-hydroxy-4-pyrone.
53. A pharmaceutical composition according to claim 48, which additionally comprises an uncomplexed compound or compounds corresponding to one or more of the ligands present in the zinc complex.
54. A pharmaceutical composition comprising a physiologically effective amount of a zinc(II) complex in which each ligand is provided by the same or a different compound selected from the group consisting of:(1) 3-hydroxy-4-pyrone and a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms; and (2) a 3-hydroxypyrid-2-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substitutents selected from aliphatic acyl, alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and in which one or more of the hydrogen atoms attached to ring carbon atoms optionally may be replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group; together with a physiologically acceptable solid carrier. 55. A pharmaceutical composition according to claim 54 which is a delayed release composition adapted to release the complex in the intestine rather than in the stomach.
56. A pharmaceutical composition according to claim 55, in which the complex is encapsulated by a solid material which is resistant to dissociation under acidic aqueous conditions but which is adapted for dissociation under non-acidic aqueous conditions.
57. A pharmaceutical composition according to claim 54, in which the complex is a neutral 2:1 ligand:zinc(II) complex.
58. A pharmaceutical composition according to claim 57, in which both ligands of the complex are provided by the same compound of type (1).
59. A pharmaceutical composition according to claim 58, in which the compound is 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by the same or a different substituent selected from methyl, ethyl, n-propyl and isopropyl groups.
60. A pharmaceutical composition according to claim 58, in which the complex is the neutral 2:1 hydroxypyrone:zinc(II) complex of 3-hydroxy-2-methyl-4-pyrone or 2-ethyl-3-hydroxy-4-pyrone.
61. A pharmaceutical composition according to claim 54, which additionally comprises an uncomplexed compound or compounds corresponding to one or more of the ligands present in the zinc complex.
62. A pharmaceutical composition according to claim 57, which is adapted for oral administration.
63. A pharmaceutical composition comprising a physiologically effective amount of a zinc(II) complex in which each ligand is provided by the same or a different compound selected from the group consisting of:(1) 3-hydroxy-4-pyrone and a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms; and (2) a 3-hydroxypyrid-2-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and in which one or more of the hydrogen atoms attached to ring carbon atoms optionally may be replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group; together with a physiologically acceptable diluent or carrier, said composition being adapted for topical application and having the form of a cream or shampoo. 64. A pharmaceutical composition according to claim 63, which additionally comprises an uncomplexed compound or compounds corresponding to one or more of the ligands present in the zinc complex.
65. A foodstuff comprising a zinc complex as defined in claim 1, together with a nutritional material.
66. A foodstuff comprising a mixture as defined in claim 20, together with a nutritional material.
67. A foodstuff comprising a mixture as defined in claim 24, together with a nutritional material.
The present invention involves the treatment of zinc depletion through the administration of zinc in complex rather than salt form, utilising a group of zinc complexes which we have identified as being of particular value for use at relatively low dosage levels. The value of these complexes in this context was hitherto quite unrecognised and indeed, this is believed to be the first use of a complex for the treatment of systemic zinc depletion.
The use in the treatment of iron deficiency anaemia of iron complexes containing ligands present in certain of the zinc complexes of the present invention has been described in UK Patent Application No. 8308053, published as GB No. 2,117,766A, corresponding to U.S. application Ser. No. 478,494. However, there has never been any suggestion that the hydroxypyridones contained in the iron complexes described in that application might serve any role in the treatment of zinc depletion. In particular, it will be appreciated that the successful administration of iron and zinc are two quite separate problems as is confirmed by the fact that very many different complexes of iron are marketed for the treatment of iron deficiency anaemia, whilst zinc depletion has in the past been treated with zinc salts.
(2) a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or, except in the case of ionisable groups, more than one substituent selected from aliphatic acyl, alkoxy, aliphatic amine, aliphatic amide, carboxy, aliphatic ester, halogen, hydroxy and sulpho groups and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by one of said substituents, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group; together with a physiologically acceptable diluent or carrier.
The zinc complexes present in the pharmaceutical compositions according to the present invention contain zinc in the divalent state. The zinc complexes are preferably neutral, i.e. there being an internal balance of charges between the metal cation and the ligand(s) bound covalently thereto without the necessity for the presence of a non-covalently bound ion or ions to achieve balance. However, the use of hydroxypyridones containing ionisable substituent groups is of less interest and it is preferred that this internal balance of charges is achieved by complexing with the zinc cation the appropriate number of monobasic, bidentate ligands, such ligands being provided by the hydroxypyrones, and by hydroxypyridones not containing ionisable groups, through the loss of a proton from the hydroxy group (OH→O-). Zinc(II) complexes containing a 2:1 proportion of monobasic, bidentate ligand:zinc(II) are therefore preferred since complexes containing a 1:1 or 3:1 proportion of monobasic, bidentate ligand:zinc(II) require an additional physiological acceptable ion, for example a chloride anion or a sodium cation, respectively, to establish neutrality. It will be appreciated, however, that although of less interest, the use of such 3:1 and especially 1:1 complexes is not excluded from the invention, particularly when in admixture with the 2:1 complex.
(2) 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one as defined hereinbefore; or
(3) an alternative compound providing a physiologically acceptable, monobasic, bidentate ligand which is capable of bonding covalently to zinc; but with the proviso that at least one of the ligands is of type (1) or (2);
together with a physiologically acceptable diluent or carrier.
As indicated, the hydroxypyrone ligands of type (1) are of particular interest and the complexes according to the present invention may conveniently contain at least one such ligand. The substituted 3-hydroxy-4-pyrones may carry more than one type of aliphatic hydrocarbon group but this is not usual and, indeed, substitution by one rather than two or three aliphatic hydrocarbon groups is preferred. The aliphatic hydrocarbon groups may be cyclic or acyclic, having a branched chain or especially a straight chain in the latter case, and may be unsaturated or especially saturated. Groups of 1 to 4 carbon atoms and particularly of 1 to 3 carbon atoms are of most interest. Alkyl groups are preferred, for example cyclic groups such as cyclopropyl and especially cyclohexyl but, more particularly preferred are acyclic alkyl groups such as n-propyl and isopropyl, and especially ethyl and methyl. Substitution at the 2- or 6-position is of especial interest although, when the ring is substituted by the larger aliphatic hydrocarbon groups, there may be an advantage in avoiding substitution on a carbon atom alpha to the ##STR1## This system is involved in the complexing with zinc and the close proximity of one of the larger aliphatic hydrocarbon groups may lead to steric effects which inhibit complex formation.
Examples of hydroxypyrones providing ligands which may be used in complexes according to the present invention have the formula (I), specific hydroxypyrones of particular interest having the formulae (II) and (III): ##STR2## in which R is an alkyl group, for example methyl, ethyl, n-propyl isopropyl or butyl, and n is 0, 1, 2 or 3 (the ring being unsubstituted by any alkyl group when n is 0). Among these compounds 3-hydroxy-2-methyl-4-pyrone (maltol; II, R=CH3) is of most interest, whilst 3-hydroxy-4-pyrone (pyromeconic acid; I, n=0) 3-hydroxy-6-methyl-4-pyrone (isomaltol; III, R=CH3) and particularly 2-ethyl-3-hydroxy-4-pyrone (ethylpyromeconic acid; II, R=C2 H5) are also of especial interest.
As regards the hydroxypyridone ligands of type (2), these may be derived from hydroxypyridones of the type described in UK Patent Application No. 8308056, published as GB No. 2,118,176A (corresponding to U.S. application Ser. No. 478,493), or of the type described in UK Patent Application No. 8407181, published as GB No. 2,136,870A (corresponding to U.S. application Ser. No. 592,271). The former consist of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are also replaced by the same or a different aliphatic hydrocarbon group of 1 to 6 carbon atoms, whilst the latter consist of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one which is substituted as defined under (2) hereinbefore but excluding those compounds in which the replacement of hydrogen atoms is effected only by aliphatic hydrocarbon groups these compounds being the substituted hydroxypyridones of the former application). Hydroxypyridones providing ligands which may be used in complexes according to the present invention have the formulae (IV) and (V) ##STR3## in which X and Y are substituents as defined hereinbefore and n is 0, 1, 2 or 3, the 3-hydroxypyrid-2-ones generally being of somewhat greater interest than the 3-hydroxypyrid-4-ones.
Preferences as to the nature and position of the substituent groups present in the hydroxypyridones are broadly as expressed in the two earlier applications. Thus, substituted aliphatic hydrocarbon groups present in the hydroxypyridones may as indicated carry more than one substituent group, except that substitution by more than one ionisable group (amine, carboxy or sulpho) is specifically excluded (substitution by more than one group, only one of which is ionisable not being excluded), but it is preferred that only one substituent group is present. Such substituted aliphatic hydrocarbon group substituents may conveniently contain groups of 1 to 8 and particularly of 1 to 6 carbon atoms, but the simpler hydroxypyridones of UK Patent Application GB No. 2,118,176A containing only unsubstituted aliphatic hydrocarbon group substituents are of the greatest interest. The preferences among the aliphatic hydrocarbon groups present in these hydroxypyridones correspond largely to those expressed in relation to the hydroxypyrones, with methyl groups conveniently being used for substitution on ring carbon atoms but larger alkyl groups also being of particular interest for substitution on the ring nitrogen atoms. Substitution of the ring carbon atoms, which is again preferably by one rather than two or three aliphatic hydrocarbon groups, is of particular interest in the case of the 3-hydroxypyrid-4-ones, for example at the 6- or particularly the 2-position, whilst the 3-hydroxypyrid-2-ones may more often be used without additional aliphatic hydrocarbon group substituent on the ring carbon atoms. Specific hydroxypyridones of particular interest have formulae (VI), (VII), and (VIII) ##STR4## in which R is an alkyl group, for example methyl, ethyl, n-propyl, isopropyl or butyl, and R1 is hydrogen or particularly an alkyl group, for example methyl. Among such compounds 1-ethyl-3-hydroxypyrid-2-one, 3-hydroxy-1-propylpyrid-2-one, 3-hydroxy-1-(2'-methylethyl)-pyrid-2-one, 1-butyl-3-hydroxypyrid-2-one, 1-ethyl-2-methyl-3-hydroxypyrid-4-one, 2-methyl-1-propyl-3-hydroxypyrid-4-one, 3-hydroxy-2-methyl-1-(2'-methylethyl)-pyrid-4-one and 1-butyl-3-hydroxy-2-methylpyrid-4-one are of particular interest with the 3-hydroxypyrid-2-ones such as 1-ethyl-3-hydroxypyrid-2-one being especially preferred.
The ligands of type (3) may be derived from various forms of compound, many of which are natually occurring, and include physiologically acceptable, monobasic, bidentate ligands known in the art. The compounds which provide such ligands will generally comprise (a) a first grouping containing an acidic proton which is lost to provide both the single negative charge on the ligand and also one of its chelating sites and (b) a second grouping which provides the second chelating site. The groups (a) is preferably either an enolic hydroxy group or a carboxy group whilst the grouping (b) is preferably an amine group, conveniently a primary amino group, or a hydroxy group. In a particular case, one grouping can fulfil both function (a) and function (b). Thus, some monocarboxylic acids can provide an anion capable of a bidentate mode and containing a grouping ##STR5## which will fulfil both functions.
Examples of specific zinc(II) complexes according to the present invention are the 2:1 zinc complexes containing two identical ligands drawn from the lists of hydroxypyrones and hydroxypyridones of particular interest given hereinbefore, particularly the hydroxypyrones, for example (maltol)2 zinc(II) and (ethylpyromeconic acid)2 zinc(II). Among complexes containing two different ligands, specific examples are (1-ethyl-3-hydroxypyrid-2-one)(1-butyl-3-hydroxyprid-4-one) zinc(II), (maltol)(1-ethyl-3-hydroxypyrid-2-one) zinc(II), (maltol)(leucine) zinc(II), (maltol)(glycine) zinc(II), (maltol)(ascorbic acid) zinc(II), (maltol)(gluconic acid) zinc(II) and especially (maltol)(ethylpyromeconic acid) zinc(II). It will be appreciated that "maltol" is used in the names of these complexes to represent the ligand derived from maltol, and similarly for the other ligands, this usage being employed throughout the specification.
The zinc complexes are conveniently prepared by the reaction in a suitable mutual solvent of the ligand providing compound(s) and zinc ions, the latter conveniently being derived from a zinc salt, particularly a zinc halide and especially zinc chloride. For the best results, it is preferred to avoid the use of water alone as a reaction solvent, the use of an aqueous/organic solvent mixture or particularly an organic solvent being preferred. The solvent may, for example, be ethanol, methanol or chloroform and mixtures of these solvents together and/or with water where appropriate. In particular, methanol or especially ethanol, or a mixture thereof with chloroform, may be used where it is desired to effect the separation of at least a major part of a by-product such as sodium chloride by precipitation whilst the zinc complex is retained in solution.
The nature of the product obtained will depend in part upon the molar proportion of the various reactants but also upon the pH of the reaction medium. Thus, for the preparation of 2:1 zinc complexes, for example, the ligand-providing compound(s) and the zinc salt are conveniently mixed in solution in a 2:1 molar proportion and the pH adjusted to a value in the range of 6 to 9, for example 7 or 8. If a similar excess of the compound(s):zinc is employed but no adjustment is made of the acidic pH which results on the admixture of the compound(s) and a zinc salt such as zinc chloride then a mixture of the 2:1 complex or complexes and the 1:1 complex or complexes will be obtained. Adjustment of the pH may conveniently be effected by the addition either of sodium carbonate or of a hydroxide base such as sodium or ammonium hydroxide, the use of a hydroxide base being of particular interest when preparing the zinc complexes in batches of 20 g or more. When using a hydroxide base, the reaction may conveniently be carried out in a medium containing a proportion of water as the solvent, for example in an ethanol:water mixture such as 4:1 v/v ethanol:water, and the pH adjusted by the addition of a 2 molar aqueous solution of the base. It will be appreciated that the presence of water in the reaction mixture will lead to the retention of a by-product in the zinc complex on evaporation of the solvent (a chloride where the zinc salt is zinc chloride). However, this can be removed, if desired, by procedures such as crystallisation from a suitable solvent system where possible or sublimation in the particular case of ammonium chloride. In general, however, the use of a non-aqueous reaction medium in conjunction with sodium carbonate is preferred.
Reaction to form the zinc complex is generally rapid and will usually have proceeded substantially to completion after 5 minutes at about 20� C., although a longer reaction time may be used if necessary. Following separation of any precipitated by-product, such as sodium chloride in the case of certain solvent systems, the reaction mixture may conveniently be evaporated on a rotary evaporator or freeze dried to yield the zinc complex which is usually in solid form. A solid complex may, if desired, be crystallised from a suitable solvent, for example water, an alcohol such as ethanol, or a solvent mixture, including mixtures containing an ether. Whether the zinc complex is obtained in anhydrous or dihydrate form will depend both on the solvent system used for the reaction and on the subsequent working up procedure. Thus rigorous drying may remove the water molecules from a hydrated complex formed in a reaction mixture containing water and recrystallisation from an aqueous medium may add them. If a dihydrate is specifically required, freeze drying of the mixture resulting from the reaction of the ligand-providing compound(s) and a zinc salt such as the chloride or acetate in an aqueous/organic solvent medium may be employed.
Certain of the ligand-providing compounds, such as maltol, are available commercially. With others, routes for their preparation are described in UK Patent Applications GB No. 2,118,176A and GB No. 2,136,807A referred to hereinbefore and in UK Patent Application No. 8327612, published as GB No. 2,128,998A, relating to hydroxypyrone iron complexes. Thus, for example, with the hydroxypyrones a convenient starting material in many instances consists of pyromeconic acid which is readily obtainable by the decarboxylation of meconic acid and may be reacted with an aldehyde to insert a 1-hydroxyalkyl group at the 2-position, which group may then be reduced to produce a 2-alkyl-3-hydroxy-4-pyrone. The preparation of ethylpyromeconic acid, 2-ethyl-3-hydroxy-4-pyrone, etc., by this route is described in U.S. application Ser. No. 310,141 (series of 1960).
The zinc complexes according to the present invention may be formulated for use as pharmaceuticals for both veterinary, for example in an avian or particularly a mammalian context, and especially human use by a variety of methods. For instance, they may be applied as an aqueous, oily or emulsified composition incorporating a liquid diluent which may often be employed for parenteral administration and therefore may conveniently be sterile and pyrogen free. Oral administration is often preferred for the treatment of zinc depletion in humans and the complexes of the present invention may be given by such a route. Although compositions incorporating a liquid diluent may be used for oral administration, it is more usual, at least in humans, to use compositions incorporating a solid carrier, for example a conventional solid carrier material such as starch, lactose, dextrin or magnesium stearate. It may even be possible in human and particularly veterinary contexts to use the corresponding metal-free ligand-providing compound or compounds as the solid carrier material or in an extreme instance to use the zinc complex or complexes in solid form as their own carrier. Such solid compositions may conveniently be of a formed type, for example as tablets, capsules (including spansules), etc.
Where desired, more than one zinc complex as described above may be present in the pharmaceutical composition, for example a mixture of the 2:1 maltol:zinc(II) and ethylpyromeconic acid:zinc(II) complexes being used. Other active compounds may also be included in the composition, for example compounds having the ability to facilitate the treatment of zinc depletion. Other components of interest are compounds having the ability to facilitate the treatment of iron deficiency anaemia (in its broadest sense), such as folic acid and, more particularly, a compound providing a source of iron, for example one of those presently marketed for the treatment of iron deficiency anaemia, such as ferrous sulphate, ferrous fumarate, ferrous gluconate, ferrous succinate, ferric EDTA, ferric ascorbate and ferric citrate.
Of particular interest in the context of pharmaceutical compositions containing an iron compound in addition to the zinc complex are those in which this iron compound is an iron complex, particularly a neutral 3:1 iron(III) complex in which the ligands are selected from the same compounds as are discussed hereinbefore for providing the ligands of the zinc complexes. Iron complexes such as this are the subject of U.K. Patent application GB No. 2,117,766A (corresponding to U.S. application Ser. No. 478,494) and GB No. 2,128,998A (corresponding to U.S. application of Ser. Nos. 542,976, 601,485 and 717,660), and of U.K. Patent Application No. 8407180, published as GB No. 2,136,806A, (corresponding to U.S. application Ser. No. 592,543) and U.K. Patent Application No. 8410289, published as GB No. 2,156,686A (corresponding to U.S. application Ser. No. 723,277). Of special interest among these iron complexes are those in which at least one and conveniently all of the ligands derive from a hydroxypyrone. Iron complexes in which each ligand is derived from the same compound are also of especial interest so that the iron complexes in which each ligand is derived from the same hydroxypyrone are preferred. Although the ligands present in the iron complex need not be the same as those present in the zinc complex, there is a particular interest in pharmaceutical compositions in which at least one and conveniently all of the ligands of each iron and zinc complex are derived from hydroxypyrones, particularly one hydroxypyrone for each ligand of the zinc complex and the same or another hydroxypyrone for each ligand of the iron complex. A particularly preferred combination is that of a zinc complex, especially the neutral 2:1 complex, of maltol (3-hydroxy-2-methyl-4-pyrone) or of ethylpyromeconic acid (3-hydroxy-2-methyl-4-pyrone) and an iron complex, especially the neutral 3:1 complex, of maltol or of ethylpyromeconic acid. The combinations may consist of two maltol complexes, two ethylpyromeconic acid complexes or one maltol and one ethylpyromeconic acid complex. Combinations containing both zinc complexes and/or both iron complexes may also be used as may combinations which involve complexes containing mixed maltol and ethylpyromeconic acid ligands.
The daily requirement of iron for the adult human is generally regarded to be 2 to 4 mg whilst that of zinc is 10 to 15 mg. A suitable human daily dosage for the preferred forms of iron complex referred to above is thus somewhat less than the dosage quoted hereinbefore for the zinc complexes being, in terms of the iron content of the complex, in a range from about 0.1 to 10 mg and often in a range from 0.5 to 10 mg, for example 1 or 2 mg, veterinary doses being on a similar g/kg of body weight ratio. However, the relative requirement of zinc and iron can vary quite widely from one patient to another depending on the actual degree of zinc depletion and iron deficiency anaemia exhibited by that patient. As with existing combined mixed iron and zinc preparations, therefore, a range of zinc/iron ratios may be present, for example spanning any combination within the range of 1 part by weight of zinc to 0.25 or 0.4 parts by weight of iron up to 1 part by weight of zinc to 30 or 50 parts by weight of iron. A preferred range as 1 part by weight of zinc to from 1 to 20 parts by weight of iron, for example a 1:7.5 ratio. In general, mixtures containing the higher proportions of zinc are of value when the patient is already exhibiting both zinc depletion and iron deficiency anaemia whilst the lower proportions of zinc are of value when the patient is exhibiting only iron deficiency anaemia but it is desired to avoid any possible zinc depletion.
There are many reports in the literature of the non-specific binding of zinc to cell surfaces and also of a mutual inhibition of bioavailability between zinc and iron. In experiments with radiolabelled zinc in the everted rat jejunum we have found that, in the absence of binding to hydroxypyridone and particularly hydroxypyrone ligands such as maltol and ethylpyromeconic acid, zinc is rapidly removed from the incubation medium by binding to the mucosal surface but that, despite this extensive binding, little permeation occurs. In contrast, when the zinc is bound to such ligands, such non-specific binding is avoided. As discussed hereinafter in more detail, it is desirable, in order to ensure that the zinc is bound, for an excess of the ligand-providing compound to be present, for example to provide a 1:5 or larger molar ratio of zinc:ligand-providing compound or compounds (both bound and unbound), since in the absence of an excess of the compound(s) above the 1:2 molar ratio required to form the 2:1 neutral complex much of the zinc may not in fact be bound. Such non-specific binding may well be associated with the powerful emetic properties of zinc compounds, so that the use of the zinc complexes according to the present invention may well abolish this undesirable side effect. Moreover, studies with radiolabelled iron and zinc in the everted rat jejunum have shown that there is no inhibition on the uptake of zinc from the 2:1 maltol:zinc(II) complex when it is used in admixture with either the 3:1 maltol:iron(III) complex or with ferrous sulphate, nor is there any inhibition on the uptake of iron from the 3:1 maltol:iron(III) complex when it is in admixture with the 2:1 maltol:zinc(II). In each case the avoidance of inhibition is assisted by the presence of excess maltol.
When orally administered, zinc is absorbed by the intestine and is transferred via the portal blood stream where it is predominantly bound to apotransferrin. Although the affinity of apotransferrin for zinc is considerably less than that for iron, apotransferrin is rarely saturated with iron and normally carries only about 35% of the possible saturation level. The apotransferrin in the body thus usually has the potential for further metal complexing and the affinity of zinc for apotransferrin, despite being lower than that of iron, is nevertheless quite considerable, the value of β2 being 14.6. In order for a zinc complex to donate zinc efficiently with apotransferrin, the β2 value for the compound(s) from which the complex is derived should be similar to or less than that of apotransferrin. The affinity of maltol for zinc (β2 =9.8) is therefore such that a complex formed with this compound is very suitable for the oral administration of zinc, since the affinity is relatively high but at the same time is less than that of apotransferrin, thereby allowing the efficient exchange of zinc bound to maltol with apotransferrin. It should be noted that maltol is also suitable for the oral administration of zinc in that it has a lower affinity for calcium (β2 =7.2) than for zinc. Interference with phytic accid, phosphate and tetracycline is predicted to be minimal. Moreover, although the neutral 2:1 maltol:zinc complex is thermodynamically stable; it is also extremely labile and is therefore able to donate zinc to high affinity sites, such as those found in apotransferrin.
It will be appreciated, however, that in addition to possessing properties such as those described above for zinc maltol, a compound which is to act as a source of zinc through oral administration is required to show a high level of membrane permeability. A good indication of the physical properties of a ligand-providing compound and of an zinc complex in this respect is provided by the value of the partition coefficient (Kpart) obtained on partition between n-octanol and Tris hydrochloride (20 mM, pH 7.4; Tris representing 2-amino-2 hydroxymethylpropane 1,3-diol) at 20� C. and expressed as the ratio (concentration in organic phase)/(concentration in aqueous phase). Preferred complexes show a value of Kpart for each ligand-providing compound of above 0.02 or 0.05 but less than 3.0, especially of above 0.2 but less than 1.0, together with a value of Kpart for the 2:1 zinc(II) complex of above 0.02 but less than 6.0, especially of 0.05 or 0.1 to 1.0. The value of Kpart for maltol is 0.66 and for the neutral 2:1 maltol:zinc complex is 0.11 which values lie in the especially preferred ranges. It will be appreciated, however, that the wide range of ligands which may be present in zinc complexes according to the present invention allows the preparation of complexes having partition coefficients lying throughout the entire ranges given. Thus, for example, a 2:1 complex having a higher partition coefficient than 0.1 may be obtained by using maltol as one ligand and another compound as the second ligand. Alternatively, higher partition coefficients may be obtained, if desired, by the use of hydroxypyrone compounds containing additional and/or larger aliphatic hydrocarbon group substituents on the ring. Thus, for example the values of Kpart for ethylpyromeconic acid and its 2:1 zinc complex are higher than those for maltol, the higher partition coefficient for the ethyl compound being reflected in the greater uptake of the 2:1 complex in tests on the permeation of erythocytes (further specific data on partition coefficients is to be found in the Examples and, as regards the free compounds, in the earlier applications previously referred to). It should be emphasised, however, that despite the fact that its Kpart value is not particularly high, the 2:1 complex containing two ligands derived from maltol has proved to be very suitable as an in vivo source of zinc in the tests we have carried out.
Certain aspects of their formulation will enhance the activity of the zinc complexes of the present application in particular contexts. Thus, the preparation of the 2:1 neutral zinc(II) complexes can be effected at neutral pH in essentially quantitative yield using a 2:1 molar proportion of the ligand and a zinc salt, such preparations involving the use of relatively concentrated solutions which preferably contain an organic solvent. However, when a 2:1 ratio of the ligand-providing compound:zinc is present at low concentration, for example 10-4 M, in water at pH 7.4 it has been found that only a small proportion of the zinc will be present as the 2:1 zinc(II) complex, a significant proportion being present as the free metal and the 1:1 complex. Thus, in the case of a 2:1 ratio of maltol:zinc ions the proportion of zinc present as the 2:1 zinc(II) complex under these conditions is only about 15%, about 30% being present as the 1:1 complex and about 50% as the free metal, whilst very little of the 3:1 complex is present. In the presence of a higher ratio of free ligand-providing compound:zinc ions, however, the proportion of zinc present as the 2:1 maltol:zinc(II) complex is much increased, being about 68% for a 10:1 ratio of maltol:zinc and about 82% for a 20:1 ratio. The position is similar with the hydroxypyridone ligands but with a slightly higher proportion of the 2:1 zinc(II) complex at any particular ratio.
When using a mixture of one 2:1 neutral zinc complex containing two ligands derived from one compound and a second 2:1 neutral zinc complex containing two ligands derived from another compound, it will be usual to combine this mixture together with both ligand-providing compounds in the free form. It will also be usual to use the mixture of both ligand-providing compounds in the free form when the 2:1 neutral zinc complex contains two ligands derived from different compounds. A specific example of such a mixture of complexes and free compounds is the mixture consisting of zinc maltol, zinc ethylpyromeconic acid, maltol and ethylpyromeconic acid. A mixture of these compounds in the solid form may either be produced by admixture of the four individual components or directly by reaction of a mixture of an excess maltol and ethylpyromeconic acid with a zinc in solution, followed by the isolation of a solid product which will also contain a proportion of the mixed (maltol) (ethylpyromeconic acid) 2:1 neutral zinc complex. Mixtures containing more than one metal-free compound may also be used with advantage when a 2:1 neutral zinc complex containing two ligands derived from one compound is used together with a 3:1 neutral iron complex containing three ligands derived from another compound.
It can be advantageous therefore to include any proportion of the metal-free compound or compounds in admixture with the zinc complexes according to the present invention, particularly the 2:1 neutral complexes, but little further advantage accrues from increasing the proportion beyond a certain level and the administration of large amounts of the free compound or compounds may be physiologically undesirable in certain instances. A preferred range for the molar proportion of the free compound present in compositions according to the present invention which contain a zinc complex in which each ligand is identical is thus from 0 to 100 moles of free compound:1 mole of zinc complex, particularly of the neutral 2:1 zinc complex. Conveniently, a proportion of up to no more than 50, 30 or especially 20 moles:1 mole is used with a lower level of 0.5, 1 or 2 moles:1 mole. A particularly preferred range is from 2 or 3 up to 18 or 20 moles of free compound:1 mole of zinc complex, particularly 2 or 3 up to 8 or 10 moles:1 mole. When there is more than one zinc bound ligand present in the composition, either in the form of a mixed ligand zinc complex and/or of a mixture of zinc complexes, then the proportion of each free ligand-providing compound to the zinc complex containing that ligand may conveniently also fall in the ranges indicated above. It will be appreciated, however, when more than one ligand-providing compound is present it is less likely that the proportion of each will be towards the upper end of the widest range of 0 to 100 moles of free compound:1 mole of zinc complex, the proportion being more likely to lie in a range of 0.5 to 50 moles:1 mole or such lower ranges as are quoted above. When a iron complex is present containing a different ligand from any present in a zinc complex, it may be advantageous to include in the composition a similar proportion of free compound to iron complex as discussed above for the zinc complexes.
Zinc complexes according to the present invention, such as the 2:1 neutral zinc (II) maltol complex, are superior when used alone to zinc sulphate which is currently in use for the treatment of zinc depletion, both in relation to absorption and to emetic effect. However, it should be stressed that the use of these complexes in admixture with the free ligand-providing compound or compounds leads to an even further improvement with a significantly higher uptake of zinc, and that such mixtures are therefore a very important feature of the present invention.
The preparation of solid compositions adapted to resist dissociation under acidic conditions but adapted towards dissociation under non-acidic conditions is well known in the art and most often involves the use of enteric coating, whereby tablets, capsules (including spansules), etc., or the individual particles or granules contained therein, are coated with a suitable material. Such procedures are described, for example, in the article entitled "Production of enteric coated capsules" by Jones in Manufacturing Chemist and Aerosol News, May 1970, and in such standard reference books as "Pharmaceutical Dosage Forms", Volume III by Liebermann and Lackmann (published by Marcel Decker). One particular method of encapsulation involves the use of gelatine capsules coated with a cellulose acetate phthalate/diethylphathalate layer. This coating protects the gelatin capsule from the action of water under the acid conditions of the stomach where the coating is protonated and therefore stable. The coating is however destablished under the neutral/alkaline conditions of the intestine where it is not protonated, thereby allowing water to act on the gelatin. Once released in the intestine the rate of permeation of the intestine wall by the water soluble 2:1 zinc(II) complex is relatively constant irrespective of the position within the intestine, i.e. whether in the jejunum, ileum or large intestine. Other examples of methods of formulation which may be used include the use of polymeric hydrogel formulations which do not actually encapsulate the zinc complex but which are resistant to dissociation under acidic conditions.
Such infant formulae are well known, being described for example by Lonnerdal et al in the American Journal of Diseases of the Child, 1983, 137, 433, being based on a human milk substitute such as cow's milk or soy protein and often containing supplies of other metals such as iron, copper and manganese. Of particular interest are foodstuffs which comprise a zinc complex/iron complex mixture as discussed hereinbefore in view of the lack of mutual inhibitory effect on biovailability of the metals as previously discussed. It will be appreciated, however, that where the complex(es) contained in the foodstuff are not protected from the acid conditions of the stomach the additional incorporation into the foodstuff of the metal-free compound will be of particular convenience in controlling dissociation, and/or aiding reformation of the complex on clearance from the stomach, a quite large excess of the free compound sometimes being appropriate in these circumstances.
A chloroform solution of maltol.sup.(1) is mixed with a 1M solution of zinc chloride in ethanol to provide a 2:1 molar ratio of maltol:zinc in the mixture. After 5 minutes at 20� C., a 10 molar excess of solid sodium carbonate is added and the mixture is stirred for 10 minutes. The mixture is then filtered and the solvent evaporated to give the neutral complex containing maltol and Zn++ in a 2:1 proportion. Recrystallisation of the 2:1 complex from ethanol gives a white crystalline solid in essentially quantitative yield, m.p. 203�-204� C. (with decomposition); νmax (nujol) 1632, 1603 cm-1 ; δ(d6 DMSO) 7.96 (d, 1H), 6.40 (d, 1H), 2.20 (s, 3H).
The preparation of (malto)(ethylpyromeconic acid) zinc complex
A chloroform solution containing 1 molar equivalent of each of maltol and ethylpyromeconic acid.sup.(2) is mixed with a 1M solution of zinc chloride in ethanol to provide a 2:1 molar ratio of ligand-providing compound:zinc in the mixture. After 5 minutes at 20� C., a 10 molar excess of solid sodium carbonate is added and the mixture is stirred for 10 minutes. The mixture is then filtered and the solvent evaporated to give a white crystalline solid containing the neutral 2:1 (malto) (ethylpyromeconic acid) zinc(II) complex as the predominant product, m.p. 136�-138� C.; νmax (nujol) 1610, 1570 cm-1 ; δ(d6 DMSO) 8.0 (d, 2H), 6.4 (d, 2H), 2.6 (q, 2H), 2.2 (s, 3H), 1.0 (t, 3H). (The solid is not recrystallised as this could lead to a redistribution of the ligands.)
The partition coefficient Kpart, being the ratio (concentration in n-octanol)/(concentration in aqueous phase) on partition between n-octanol and aqueous tris hydrochloride (20 mM, pH 7.4; Tris represents 2-amino-2-hydroxymethylpropane 1,3-diol), is measured at 20� C. for zinc complexes containing various ligands and for their corresponding ligand-providing compounds as listed in Table 1. In the case of certain of the complexes the partition coefficient for the 2:1 ligand:zinc(II) complex is also measured in the presence of various amounts of the metal-free ligand-providing compound in excess of a b 1:2 zinc(II):compound ratio.
By the use of simultaneous equations and the known populations of complexes containing different proportions of zinc:ligand present under the conditions used in this experiment, it is possible to calculate theoretical Kpart values for neutral 2:1 ligand:zinc(II) complexes of maltol and ethylpyromeconic acid, those being 0.11 and 1.33 respectively as quoted hereinbefore. It will be seen that the value quoted in the Table for a 1:2 zinc(II):compound ratio is in each case considerably less but it will be appreciated that these are measured values which reflect the fact that only a proportion of the maltol or ethylpyromeconic acid is bound to zinc as the 2:1 ligand:zinc(II) complex under these conditions. As the ratio is increased with a consequent increase in the amount of the 2:1 complex which is present, it will be seen that the measured values approach the calculated values.
TABLE 1______________________________________Partition coefficients        Free    Zinc complexLigand-providing          compound  Zinc:compoundcompound       Kpart                    molar ratio Kpart______________________________________maltol         0.66      1:2         0.038                    1:6         0.078                     1:20       0.109ethylpyromeconic acid          0.75      1:2         0.172                    1:6         0.653                     1:20       1.2413-hydroxy-1-methylpyrid-          0.44      1:2         0.132-one1-ethyl-3-hydroxypyrid-          0.52      1:2         0.762-one3-hydroxy-1-propylpyrid-          0.78      1:2         2.742-one______________________________________
TABLE 2______________________________________Uptake of zinc complexes by erythrocytesLigand-providing          Zinc:compound                      Uptake of zinccompound       molar:ratio (n. mole)______________________________________none           1:0         2.0maltol         1:2         6.7          1:5         7.9           1:10       8.5           1.20       14.4ethylpyromeconic acid          1:2         8.5          1:5         20.0           1.10       28.0           1:20       35.0______________________________________
TABLE 3______________________________________Permeation of rat jejunal sac by zinc complexesLigand-providing          Zinc:compound Uptake of zinccompound       molar ratio   (n. mole)______________________________________none           1:0           10.0maltol         1:2           12.2          1:5           32.4           1:10         41.8           1:20         76.5ethylpyromeconic acid           1:10         33.4           1:20         41.91-ethyl-3-hydroxypyrid-          1:2           36.42-one           1:10         24.23-hydroxy-1-propylpyrid-          1:2           22.02-one______________________________________
The contents of the sac are counted for 65 Zn or 59 Fe, the results obtained being shown in Tables 4 and 5 where the amount of zinc or iron entering the serosal compartment of the sac is given in n.mole, the quoted values being in each case the mean of three determinations. It will be seen that in the presence of an excess of the hydroxypyrone ligand-providing compound there is no significant mutual inhibition of the uptake of either iron or zinc from a neutral complex formed with that hydroxypyrone ligand. Although a slight inhibition of iron uptake from iron maltol in admixture with free maltol was observed in the presence of zinc sulphate, this inhibition was not observed in the presence of zinc maltol. (In these various experiments the 1:10 proportions of zinc:maltol is required in order to ensure that a substantial proportion of the metal is bound to the ligand in the form of the neutral 2:1 maltol:zinc(II) complex, and a similar proportion of iron:maltol is employed for conformity).
TABLE 4______________________________________Influence of iron on zinc uptakeComponent containing         Component containing                        Uptake of zinczinc          iron           (n. mole)______________________________________1:10 zinc(II):maltol         none           421:10 zinc(II):maltol         iron(II) sulphate                        391:10 zinc(II):maltol         1:10 iron(III):maltol                        46______________________________________
TABLE 5______________________________________Influence of zinc on iron uptakeComponent containing         Component containing                        Uptake of zinciron          zinc           (n. mole)______________________________________1:10 iron(III):maltol         none           441:10 iron(III):maltol         zinc sulphate  331:10 iron(III):maltol         1:10 zinc(II):maltol                        45______________________________________
TABLE 6______________________________________Distribution of zinc in various rat tissues        Amount of zinc as a percentage        of the original dose          Rat sacrificed                     Rat sacrificedTissue         at 2 hours at 4 hours______________________________________Gut washings   57.8       44.8Gut wall       15.1       12.1Bone marrow    1.3        2.0Kidneys and urine4        10.4          1.0        2.0Blood          2.3        2.5Spleen         0.2        0.4Heart          0.1        0.2Skeletal muscle            N.D.sup.(1)                     2.7Lungs          N.D.       0.3Testes         N.D.       0.1Brain          N.D.       &lt;0.01______________________________________ .sup.(1) N.D. indicates that these values were not determined in the rat sacrificed at 2 hours.
(A) A preparation of 2:1 maltol:zinc(II) in admixture with maltol (containing 1 part by weight of zinc to 20 parts by weight of maltol) is obtained by mixing 2:1 maltol:zinc(II) prepared as described in Example 1 with maltol in a 1:3.2 proportion by weight. The resulting preparation is divided into 50 mg quantities and added to standard gelatine capsules (16�5 mm), each capsule containing about 2.5 mg of zinc. The capsules are then coated with a cellulose acetate phthalate/diethylphthalate layer (6 mg coat per cm2 of capsule surface) in a small scale procedure analogous to the procedure described by Jones, ibid. Such capsules are resistant to dissociation in the stomach but will undergo dissociation in the intenstine.
(B) In an alternative preparation, the mixture of 2:1 maltol:zinc(II) and maltol used in (A) is replaced by a mixture of 2:1 maltol:zinc(II), 3:1 maltol:iron(III) and maltol in a 2:23:5 proportion by weight to provide a 2:15:135 proportion by weight of zinc:iron:maltol (bound and unbound). Each capsule contains about 0.65 mg of zinc and 5 mg of iron.
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