Pharmaceutical compositions

A pharmaceutical composition suitable for increasing the level of iron in a patient's bloodstream, comprising a physiologically effective amount of a neutral 3:1 iron complex containing three monobasic, bidentate ligands, of which at least two are different, in combination with a ferric cation, each ligand separately being 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 a C.sub.1-4 aliphatic or alicyclic hydrocarbon group;
• (2) a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one in which (a) the hydrogen atom attached to the nitrogen atom of the 3-hydroxypyridone ring is replaced by a formyl, alkylcarbonyl, cycloalkylcarbonyl, C.sub.1-6 aliphatic or alicyclic hydrocarbon group, or a C.sub.1-8 aliphatic or alicyclic hydrocarbon group substituted by one or two substituents selected from formyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxy, aliphatic amido, alicyclic amido, halo, hydroxy and aliphatic or alicyclic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl or hydrocarbyloxysulphonyl, and (b) wherein one or more of the hydrogen atoms attached to carbon atoms of the 3-hydroxypyridone ring can be replaced by one of said substituents, by a C.sub.1-6 aliphatic or alicyclic hydrocarbon group, or by a C.sub.1-8 aliphatic or alicyclic hydrocarbon group substituted by alkoxy, halo, hydroxy or aliphatic or alicyclic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl or hydrocaryloxysulphonyloxy;
• or
• (3) a compound selected from the group consisting of formic acid, acetic acid, propionic acid, lactic acid, gluconic acid, ascorbic acid, glycine, isoleucine, leucine, methionine, phenylalanine, tyrosine and valine;
• said compound of type (1), (2) or (3) when metal free having a partition coefficient at 20.degree. C. between n-octanol and 20 mM tris hydrochloride, pH 7.4, of above 0.02 but less the 3.0 for the ratio (concentration of compound in organic phase)/(concentration of compound in aqueous phase), with the proviso that at least one of the ligands is provided by a compound of type (1) or (2), and wherein the said neutral 3:1 iron complex contains 10% by weight or less of any 1:1 or 2:1 iron (III) complex in which the ligand or ligands are selected from those present in the 3:1 complex.

A method for increasing the level of iron in a patient's bloodstream, said method comprising the step of administering to said patient an amount effective to achieve said increase of a 3:1 neutral iron complex comprising three monobasic, bidentate ligands, of which at least two are different, in combination with a ferric cation, the ligands each separately being 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 a C.sub.1-4 aliphatic or alicyclic hydrocarbon group;
• (2) a 3-hyroxypyrid-2-one or 3-hydroxypyrid-4-one in which (a) the hydrogen atom attached to the nitrogen atom of the 3-hydroxypyridone ring is replaced by a formyl, alkylcarbonyl, cycloalkylcarbonyl, C.sub.1-6 aliphatic or alicyclic hydrocarbon group, or a C.sub.1-8 aliphatic or alicyclic hydrocarbon group substituted by one or two substituents selected from formyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxy, aliphatic amido, alicyclic amido, halo, hydroxy and aliphatic or alicyclic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl or hydrocarbyloxysulphonyl, and (b) wherein one or more of the hydrogen atoms attached to the carbon atoms of the 3-hydroxypyridone ring can be replaced by one of said substituents, by a C.sub.1-6 aliphatic or alicyclic hydrocarbon group, or by a C.sub.1-8 aliphatic or alicyclic hydrocarbon group substituted by alkoxy, halo, hydroxy or aliphatic or alicyclic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl or hydrocarbyloxysulphonyl;
• or
• (3) a compound selected from the group consisting of formic acid, acetic acid, propionic acid, lactic acid, gluconic acid, ascorbic acid, glycine, isoleucine, leucine, methionine, phenylalanine, tyrosine and valine;
• said compound of type (1), (2) or (3) when metal free having a partition coefficient at 20.degree. C. between n-octanol and 20 mM tris hydrochloride, pH 7.4, of above 0.02 but less the 3.0 for the ratio (concentration of compound in organic phase)/(concentration of compound in aqueous phase), and with the proviso that at least one of the ligands is provided by a compound of type (1) or (2).

A method for increasing the level of iron in a patient's bloodstream, said method comprising the step of administering to said patient an amount effective to achieve said increase of a neutral 3:1 iron complex containing three monobasic, bidentate ligands, of which at least two are different, in combination with a ferric cation, each ligand separately being 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 a C.sub.1-4 aliphatic or alicyclic hydrocarbon group;
• (2) a 3-hyroxypyrid-2-one or 3-hydroxypyrid-4-one in which (a) the hydrogen atom attached to the nitrogen atom of the 3-hydroxypyridone ring is replaced by a formyl, alkylcarbonyl, cycloalkylcarbonyl, C.sub.1-6 aliphatic or alicyclic hydrocarbon group, or a C.sub.1-8 aliphatic or alicyclic hydrocarbon group substituted by one or two substituents selected from formyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxy, aliphatic amido, alicyclic amido, halo, hydroxy and aliphatic or alicyclic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl or hydrocarbyloxysulphonyl, and (b) wherein one or more of the hydrogen atoms attached to the carbon atoms of the 3-hydroxypyridone ring can be replaced by one of said substituents, by a C.sub.1-6 aliphatic or alicyclic hydrocarbon group, or by a C.sub.1-8 aliphatic or alicyclic hydrocarbon group substituted by alkoxy, halo, hydroxy or aliphatic or alicyclic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl or hydrocarbyloxysulphonyl;
• or
• (3) a compound selected from the group consisting of formic acid, acetic acid, propionic acid, lactic acid, gluconic acid, ascorbic acid, glycine, isoleucine, leucine, methionine, phenylalanine, tyrosine and valine;
• said compound of type (1), (2) or (3) when metal free having a partition coefficient at 20.degree. C. between n-octanol and 20 mM tris hydrochloride, pH 7.4, of above 0.02 but less the 3.0 for the ratio (concentration of compound in organic phase)/(concentration of compound in aqueous phase), with the proviso that at least one of the ligands is provided by a compound of type (1) or (2), and wherein the said neutral 3:1 iron complex contains 10% by weight or less of any 1:1 or 2:1 iron (III) complex in which the ligand or ligands are selected from those present in the 3:1 complex.