CA1253803A - Buccal and nasal compositions containing iron complexes of 3-hydroxy-4-pyrones - Google Patents

Abstract

ABSTRACT
Pharmaceutical buccal and nasal compositions for the buccal containing iron complexes of 3-hydroxy-4-pyrones or nasal administration of a neutral 3:1 hydroxypyrone:iron (III) complex of 3-hydroxy-4-pyrone or of 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 are of value for the treatment of iron deficiency anemia.

Description

~i31~303 'I -BUCCAL APID NASAL COMPOSITIONS CONTAlNING IRON

-This invention rela-tes to pharmaceutical compositions containing iron compounds for the treatment of iron defic;ency anaemia.
An adequate supply of iron to the body is an essential 05 requirement for tissue growth in both man and animals. Although there is normally an ample amount of iron in the diet, the level of absorption of iron from food is generally low so that the supply of iron to the body can easily become critical under a variety of conditions. Iron deficiency anaemia is commonly encountered in pregnancy and may also present a problem in the newly born, particularly in certain animal species such as the pig. Moreover, in certain pathological conditions there is a mal distribution of body iron leading to a state of chronic anaemia. This is seen in chronic diseases such as rheumatoid arthritis, certairl haemolytic diseases and cancer.
Although a wide range of iron compounds is already marketed for the treatment of iron deficiency anaemia, the level of iron uptake by the body frorn these compounds is oFten quite low thereby necessitating the administration of relatively high dosage levels of the compound. The administration of high dose, poorly absorhed, iron complexes may cause siderosis of the gut wall and a variety of s1de effects such as nausea, vomiting, constipatiorl an(l heavy malodorous stools.
In published UK patent application number ~B 212~993A, and corresponding Canadian application number 446932 and US Patent Number 4~5751502~ a group of iron complexes is described which have been identified as being of particular value for use at relatively low dosage levels in the treatment of iron deficiency anaemia. It is an object of the present invention to provide an alternative method of formulating these iron compounds having certain advantages over the methods described in this previous application.

~ i~ S ~

According to the present invention a pharmaceutical composition comprises a neutral 3:1 hydroxypyrone:iron(III) complex of 3-hydroxy-4-pyrone or of a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms 05 are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, said composi-tion being adapted for buccal or nasal administration.
The iron complexes present in the pharmaceutical compositions according to the present invention contain iron in the ferric state and are neutral, i.e. there being an internal balance of charges between the ferric cation and the chree anions derived from the hydroxypyrone (through the conversion OH --~ O ). The iron complexes of use in the present invention are thus of the 3:1 form, as opposed to complexes of the 2:1 and 1:1 forms which instead contain a 2:1 or 1:1 molar proportion of hydroxypyrone anion:iron(III) and require the presence of an additional non-covalently bound anion or anions, such as chloride, to balance the charge on the ferric cation.
The substituted 3~hvdroxy-4-pyrones may carry more than one type of aliphatic hydrocarbon group but this is not usua:L and, indeed, substitution by two rather than three, and particularly by only one allphatlc llydrocarbon group is preferred. The tenn aLlpl-latlc lly(lrocarbon groul) 18 used hereln to inclu(le both acycl:Lc alld cycli groups wllich may be unsaturated or saturated, the acyclic groups having a branched chain or especially a straight chain. Groups of from 1 to 4 carbon atoms and particularly of 1 to 3 carbon atoms are of most interest. Saturated allphatic hydrocarbon groups are preferred, these being either cyclic groups such as the cycloalkyl groups cyclopropyl and especially cyclohexyl or, more particularly, acyclic groups such as the alkyl groups n-propyl and isopropyl, and especially ethyl and methyl~ Substi-tution at the 2- or 6-position is of especial interest although, when the ring is substituted by the larger aliphatic hydrocarbon group~s, there may be an advantage in avoiding substitution on a carbon atom alpha ~o the -C-C ~ system. This system is involved O ()~
in the complexing Wittl iron and the close proximity of one ~s'~

of the larger aliphatic hydrocarbon groups may lead to steric effects which inhibit complex formation.
Preferred hydroxypyrones of use in complexes according to the present invention have the formula (I~, with specific hydroxypyrones 05 of particular interest having tbe formulae (II) and (III):-O O O
5,J~0H s,J~H s~J~OH

~2 6 ~ o J~R R'1 o J
(I) (Il) (111) in which R is a cycloalkyl or 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 cycloalkyl or 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 (pyro-meconic acid; I, n = 0) 3-hydroxy-6-methyl-4-pyrone (isomaltol;
III, R = CH3) an(l particularly 2-ethyl-3-hydroxy-~-pyrone (ethyl-pyromeconic aci~; II, R - C2~15) are also of especlal lnterest.
Ln the C;.l.'3e of certaln of the hydroxypyrones referred to above, for example maltol, ethylpyromeconic acid and lsomaltol, the formatlon of an iron complex of the compound has been referred to in the literature, although it should be noted that the proce dures described in the literature for the production of such complexes often would not provide complexes of the 3:1 form which are used in the pharmaceutical compositions according to the present invention.
The iron complexes are conveniently prepared by the reaction of the hydroxypyrone and iron ions, the latter conveniently being derived from an iron salt, particularly a ferric halide and especially ferric chloride. The reaction is conveniently effectecl in a suitable mutual solvent and water may often be used for this purpose. If desired, however, an aqueous/organic solvent mixture may be used or an organic solvent, for example ethanol, methanol ~s~

or chloroform and mixtures of these solvents together and/or with water where appropriate. In particular, meth~nol or especially ethanol 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 05 by precipitation whilst the iron complex is retained in solution.
It should be appreciated that the nature of the iron complex obtained by the reaction of a hydroxypyrone and iron ions will depend both on the proportion of these two reactants and upon the pH of the reaction medium. Thus, for the preparation of the 3:1 ferric complex, the hydroxypyrone and the ferric salt are convenientlv mixed in solution in a 3:1 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 hydroxypyrone:iron is employed but no adjustment is made of the acidic pll which results on the admixture of the hydroxypyrone and an iron salt such as ferric chloride, then a mixture of the 2:1 and 1:1 complex will instead be obtained. Adjustment of the pH may conveniently be effected by the addition of solid sodium carbonate. However, a possible alternative, which is of particular interest when preparlng the iron complexes in batche6 of 20 g or more, is to use a hyclroxi.de ba.se SUCil as .sodluwl or ammoniulD hydroxide. When using 1 hyclroxLde base, the react:Loll may convenLentLy be carrie~l out in 4:1 v/v etllanoL:w,ltcr as a soLvent and the p~l adjusted by the addltion of a 2 moLar aqlleous solutLon of the hase. ~t will be apprec:Lated that the presence of a proportion of water in the reaction mlxture will lead to the retention of a by-product in the iron complex on evaporation of the solvent (a chloride where the iron salt is ferric chloride). However, this can be removed9 if desired, by procedures such as crystallisation from a suitable solvent system or sublimation in the particular case of ammonium chloride.
Keaction to form the iron complex is generally rapid and will usually have proceeded substantially to completion after 5 minutes at about 20C, although a longer reaction time may be used if necessary. Following separation of any precipitated by-product, SUCtl 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 solid iron complex. This may, if desired, be crystallised from a suitable solven-t, for example wa-ter, an alcohol such as ethanol, or a solvent mixture, 05 including mixtures containing an ether.
Whilst for some uses it may be appropriate to prepare the iron complex in subs-tantially pure form, i.e. substantially free from by-products of manufacture, in other cases, for example with a solid oral formulation as described hereinafter, the presence of by-products such as sodium chloride may be quite acceptable. In general, however, the neutral 3:1 hydroxypyrone:iron(III) complex is of particular interest in a form which is substantially free at least from those by-products which are complexes containing different proportions of hydroxypyrone and iron, in particular the 2:1 and 1:1 complexes. The term "substantially free from" is used herein to indicate the presence of 10% by weight or less of the material referred to.
As indicated hereinaf-ter, it may be advantageous under some circumstances for the iron complex to be used in admixture with the free pyrone. It is possLble -to produce SUCi1 a mixture by mlxing th~ two componentfi either in the soLId form or in solution, followed by isoLatlon oE u soLid mlxture Ln the latter case when a solld composLtLon -Ls requLred. Ilowever, -It may be more convenient to obtaln such a mlxture by reactLng a molar proportlon of the pyrone and lron ions of greater -than 3:1. It should be stressed, however, that the conditions as well as the proportion of reac-tants used Ln the reaction are of importance if a mixture of the free pyrone and the preferred neutral 3:1 complex is to be obtained.
In particular, as indicated previously, the pH of the reaction mixture is particularly important and, because of this fact, certain prior art procedures concerned with the use of iron pyrone complexes in food colouring, for example as described in US
paten-t 4,018,907, substantially fail to yield the 3:1 complex even though an excess of the pyrone is present, owing to the lack of pH
COntrol ;3~3 Certain hydroxypyrones, such as maltol, are available commer-cially. With others, a convenien-t starting material in many instances consists of pyromeconic acid which is readily ob-tainable by the decarboxylation of meconic acid. Thus, for example, pyro-05 meconic acid may be reacted with an aldehyde to insert a 1-hydroxy-alkyl group at the 2-position, which group may then be reduced to produce a 2-alkyl-3-hydroxy-4-pyrone. The preparation of 2-ethyl-3-hydroxy-4-pyrone, etc, by this route is described in US application serial number 310,141 (series of 1960) which is available from the US
Patent Office.
It will be appreciated that these are not the only routes available to these compounds and their iron complexes and that various alternatives may be used as will be apparent to those skilled in the art.
The iron complexes described herein have been found to be particularly suited to the treatment of iron deficiency anaemia, both in humans and also in a veterinary context and particularly for the treatment of various mammalian species, especially pigs.
The pharmaceutical compositions of the present invention areV
however, mos-t especially suited to human use. The chelating agents which the iron complexes contain, and particularly malto]., have a hlgl1 afflnlty for iron (log R3 = 30 for maltol) but a ]ower aEflnLty for copper (~ lnc (II), calclum and rllagneslum. Both the hLgll affinity of maltol for lron and lts low afflnity for calclum are retlected in its KSol value log KsOl is defined as belng equal to log eFe(L)n + ~1 [P sp L
log aL(Ca )] wllere log BFe(L)n is the cumulative affinity constant of the ligand in question for iron(III), pK is the negative logarithm of the solubility product for Fe(0H)3 and has a value of 39, n and m are the number of hydrogen and calcium ions, respectively, which are bound to the ligand, and aL(H ) and aL(Ca are the affinitles of the iigand for hydrogen ions and calcium ions, respectively . In order to solubilise iron(III) hydroxide, log K 1 must be greater than 0. The value of Ks 1 for maltol is 8.0 and this is also sufficiently large to preven~ appreciable competition from phytate, phosphate, thiols and other potential ~i31~

ligands likely to occur in the intestinal lumen. In order to exchange iron efficiently with transferrin, the log K l value should be close to that of apotransferrin, ~Jhich is 6.0, so that maltol is also suitable in this respect. Moreover, although the 05 neutral 3:1 maltol:iron(III) complex is thermodynamically s-table (thermodynamic stability constant = 30) it is also extremely labile and is therefore able to donate iron to high affinity sites, such as those found in apotransferrin. The half life for the exchange of iron(III) between the maltol complex and apotrans-ferrin is 1 minute whereas, by contrast, the corresponding figurefor the 3:1 complex of EDTA with iron(III) is ~I days.
It will be appreciated, however, that in addition to possessing properties such as those described above for iron maltol, a compound which is to act as a source of iron through oral administration is required to to show a high level of membrane permeability. An indication of the properties of a compound in this respect is provided by the value of the partitLon coefficient (K rt) obtained on partition between n-octanol and Tris hydrochloride (20 mM, p~l 7.l~;
Tris representLng 2-amino-Z-hydroxymethylpropane 1,3-diol) at 20 C
and expressed as the ratio (concentratLon of compound itl OrgalllC
phase)/(concentration of compound in aqueous phase). The vallle oE
Kplrt for the nelltral 3:1 rna:ltol:lrorl([Ii) complex ls 0.5, whlch ls welL placed Ln the preferred range of 0.2 to 1.0 and compares favourably with the flgures of 0.001 and 0.0015 for the EDTA:iron(III) complex and iron(III) ascorbate, respectively.
The value of the iron complexes used ln the present invention is confirmed by various in vitro and in vivo tests. Thus, -their ability to permeate biological membranes is confirmed in practice by tests of the abili-ty of the 59Fe labelled iron complexes to permeate erythrocytes. Moreover, iron complexes of the present invention have been found to exhibit a high level of efficiency in promoting iron uptake, as measured in the rat small intestine, as compared with a range of other iron complexes currently marlceted for the treatment of iron deflciency anaemia. In vivo experimen-ts in the cat and rat have confirmed the value of iron maltol compounds ~ 8 --as a source of iron, the iron uptake obtained either on intravenous administration or on direct administration into the small intestine being markedly superior to that obtained with commercially available iron compounds such as iron sulphate, iron EDTA and iron gluconate.
05 It was found from these experiments that the iron was not excreted to any signiEicant extent in the urine but became generally distri-buted thoughout the body, the complexes donating iron to transferrin to an equilibrium level once they are present in the bloodstream.
The neutral 3:1 hydroxypyrone ferric complexes are of particular interest in the treatment of iron deficiency anaemia, rather than the 2:1 and 1:1 complexes. However, as reported in UK patent applica-tion GB 2128998A~ although these 3:1 complexes are stable over a wide pH range from about 4 or 5 up to 10, they will dissociate at the pH values of less than ~ prevailing in the s-tomach to form a mixture of the 2:1 and 1:1 complex together with the free hydroxypyrone, and it has been found that the blood levels of 59Fe achieved on administration of the 3:1 complex into the small intestine are much higher than when administration is made into the stomach. However, when the stomach contents is flushed to the small intestine in in vivo cat experimen-ts an increase of iron uptalce occurs almost immediately. Several methods oE over--comLng the undesLrclble effects of thLs dissociation on iro~ uptake have heen propo~;ed Ln ~K l'atent Applicatloll GB 2128998A but the present lnvenLIon Lnvolves another, quite different approach which ls not described therein and which is of particular value.
It has been found that formulation of the iron complexes described herein as a pharmaceutical composition adapted for buccal or nasal administration has a number of advantages.
Firstly, since the buccal and nasal cavities represent an environment with a pH in the region of 7, a 3:1 neutral iron(III) complex will be taken up by the membranes of the buccal cavi-ty (including the tongue) and the nasal passages ln the neutral form, without any significant degree of disproportionation to the corres-ponding 2:1 and 1:1 complexes. Such a form of administration thus o~ten provides a simpler alternative to the use of pharmaceutical 3~

compositions of the type described in ~K Patent Application GB 2128998A which are intended to protect the 3:1 neutral iron(III) complex from the strongly acid environment of the stomach. Buccal or nasal administration is applicable to the iron complexes of the 05 present invention in view of the accep-table taste thereof, particu-larly as compared with the very bit-ter taste of many of the existing commercial preparations for the treatment of iron deficiency anaemia.
A second advantage of ~he compositions according to the present invention is that they provide some fonn of safety measure as regards overdoses, for example those arising from the taking by children of medication prescribed for adults in the same household.
This can pose a considerable problem with exis-ting iron preparations and, although the present iron complexes in any case generally have the advantage of lower toxicity and lower unit dosage levels~
the compositions of the present invention provide an added advantage.
Thus, it is difficult rapidly to ingest a large quan-tity of the iron complex from the buccal cavity or nasal passages and overdosage problems are more likely to arise through swallowing the medicamen-t.
If this is done, however, and the iron comp:Lex is not formulated in such a way a~ to protect lt from the acld environment oL the stomacll, d-Lsproportionatlotl to the 2:1 and 1:1 complexes will occur whlcl1 has the effect of reduclng the level of iron uptuke froln the over(lose. 'rhe lower toxicity of the iron complexes of the present Invention will avoid much of the local damage to the gastrointestinal tract which can occur in such circumstances with many commercial iron preparations.
It will be seen, therefore, that the method of formulation described herein has certain significant advantages in the par-ti-cular context of the present iron complexes.
In formulating the iron complexes in the form of a pharma-ceutical composition according to the present invention they may conveniently be combined with a physiologically acceptable diluent or carrier adapted to buccal or nasal administration. Such diluents and carriers may include various materials in current use in compositions for buccal or nasal administration. Buccal adminis-tration is of particular interes-t and in this case a solid c~mposition is preferred. Such compositions adapted for retention in the mou-th rather than swallowing, and consequent release of the active 05 component in the buccal cavity, may take very many forms. These include chewing or bubble gum, lollipops, boiled sweets, effervescent tablets and particularly pastilles and loæenges. Most usually, therefore, the composition will be chewed or sucked to lead to release of the iron complex in the mouth, although it is possible to use tablets, for example in the form of a disc of polymeric material, which are attached to the wall of the buccal cavity and which gradually release the iron complex without being sucked. If desired, liquid compositions may be used in the buccal cavity, particularly aerosol sprays, but these are of less interest. All of these forms of compositions are taken through the mouth but, in contrast to the oral compositions described in the earlier patent application, are adapted to release of the iron complex in -the mouth rather than on being swallowed (although in the process of chewing, sucking etc. a proportion of -the iron complex may oE
course pass into the stomach). PreEerrecl forms of compositions are pastilles and lozenges and such compositLons are some-tLnles described by tt1e term "lingue-t", this being a composLtion suLtable Eor sllb-llnglltll use.
SpeciELc carrlers ~hich may be used in pastilles ancl lo~enges are descrLbed in various tests including -the British Pharmacoepia, the British Pharmacoepia Codex and Martindale, the Extra Pharmacopoeia. One particular example of a base for pastilles is described in the 1980 British Pharmacoepia and consists of a mixture of gela-tin, glycerine, sugar, citric acid and amaranth.
The rate at which the pastille dissolves in the mouth may be varied as desired with a view -to achieving a good level of uptake of iron, the ra-te of dissolution being reduced, for example, by increasing the proportion of gelatin used. Pastilles may conveni-ently be prepared by forming a melt containing a suitable amount of the iron complex and the carrier and then pouring this into a 31~

mould and allowing to dry. One particular example of a base for lozenges is described in the 1959 British Pharmacoepia Codex and consists of a mixture of sucrose, acacia and rose oil water. Once again, the rate of dissolution may be controlled by variation of 05 the ingredients in the base material. Lo~enges may conveniently be prepared either by forming a "dough" from which the lo~enges are cut or, preferably, by compression. If desired, further flavourings can be incorporated in the pastilles or lozenges but the taste of the iron complexes is so acceptable that this may be unnecessary, except perhaps for paediatric formulations.
Where compositions for nasal administration are employed these will usually be liquid and may comprise water and/or suitable organic solvents. Such compositions may conveniently be used either as drops or in the form of an aerosol spray. It is, however, possible to use solid compositions in the form of a snuff iE so desired. In the case of compositions for nasal administration, the physical characteristics of the composition may not differ so markedly from those of compositions for other modes of administra-tion as in the case wi-th compositions for buccal administration.
However, the intended mode of all forms of composition accorcling to the present invention will in general be clear ~rom the packaging oE the composition, for example ln a container for the dispersin~
o~ u spray or dro~/s, and/or the Instr-lctLorls provLded therewLth speclEyln~ buccaL or nusal usage.
~rhe comyositLons according to the present invention may be formulated in unit dosage form, i.e. in the form of discrete portions containing a unit dose, or a multiple or sub-unit dose.
Whilst the dosage of hydroxypyrone iron complex given will depend on various factors, including the particular compound which is employed in the composition, it may be stated by way of guidance that main-tenance at a satisfactory level of the amount of iron present in the human body will often be achieved using a daily dosage, in terms of the iron content of the compound~ which lies in a range from abou-t 0.1 to 100 mg and often in a range from 0.5 to 10 mg, for example 1 or 2 mg, veterinary doses being on a ~5~

similar g/Kg body weight ratio. However, it will be apppreciated that it may be appropriate under certain circumstances to give daily dosages either below or above these levels. In general, the aim should be to provide the amount of iron required by the patient 05 without administering any undue excess and -the properties of the pharmaceutical composi-tions according to the present invention are particularly suited to the acheivement of this aim. Similarly, the concentration of iron in the pharmaceutical composition in the form of the hydroxypyrone complex may vary quite widely, for example over a range from about 0.001 to about 20% w/w. However, i~ is more usual for the concentration to exceed 0.01% w/w and it may often exceed 0.05 or 0.1% w/w, whilst a more usual limit for the upper end of the range is about 13% w/w. A common range of concentration is 0.05 to 5% w/w, for example 0.2 to 0.5, 1 or 2% w/w.
Where desired, more than one hydroxypyrone iron complex as described above may be present in the pharmaceutical composition or indeed other active compounds may be included in the composi-tion, for example compounds having the ability to facilitate the treatment of anaemia, such as folic acid. Another additional component which may be included in the composition, lf deslred, i~s a source of ZillC. Iron compounds llsed in the treatment of iron de~:Lclellcy anl~emlfl can LnhlbLt the mechanisal of zLnc uptake Ln the body and thiF; cnrl cause serlous side effects in the foetus when treflting anflemia is in a pregnant female. It is believed, however, that the iron complexes of the present invention have a f~rther advantage in that they either do not have this effect or exhibit the effect at a lower level than the compounds at present used in the treatment of anaemia. Accordingly, it may often be the case that the level of zinc providing compound added to the composition may not require to be high or, with preferred formulations of the iron complexes, may be dispensed with altogether.
A further approach to countering the effect of the acidic conditions prevailing in the stomach which is described in UK
patent application GB 2128998A involves formulation of the complex ~3~3~3 in the pharmaceutical composition together with the metal-free hydroxypyrone from which it is derived. The dissociation of the neutral 3:1 ferric complex involves various equilibria between this complex, the 2:1 and 1:1 complexes, and the metal-free 05 compound, so that the presence of the latter will inhibit this dissociation. Any proportion of the free compound can be advan-tageous in this context but little further advantage accrues from increasing the proportion beyond a certain level, a suitable range for the molar proportion of the free compound which is present being from 0 to 100 moles of free hydroxypyrone:1 mole of iron complex, particularly of the neutral 3:1 iron(III) complex.
Conveniently9 a proportion of up to no more than 20, 30 or 50 moles:1 mole is used with a lower level of 0.5, 1 or 2 moles:1 mole.
Although to obtain a marked effect upon dissociation of the iron complex by this means a proportion of at least 5 or 10 moles:1 mole is usually required, it should be emphasised that even a 1:1 molar ratio will achieve some degree of acid stabilisa-tion of the iron complex.
It is possible to include amounts of the free hydroxypyrone in compositions according to the present invention, for exarnple in a proportion as indicated above or particularly in a range of from 1 mole:10 or 20 moles of the iron complex. This -ls less lLkely Ln the context oE the present -Lnvention to make a really marked contributlon ln terms of avoiding dissociation of the 3:1 complex since the nature of the composi-tions should insure that the major part of the iron complex is released in an essentlally neutral environment. However, as described in the earlier application, the use of an uncomplexed hydroxypyrone in admixture with its iron complex may also have another advantage in addition to the prevention of dissociation of the iron complex under acidic conditions. Thus, in certain pathological conditions there may be an excess of iron deposi-ted at certain sites even though the patient exhibits an overall anaemia. In these patients the use of such a mixture has the advantage that the iron complex will remedy the overall anaemia whilst the free hydroxypyrone will act to remove ;~2~

iron from pathological to physiological sites. However, although it is preferable for the hydroxypyrone present in an iron do~or to be rapidly metabolized ln order that iron may be efficiently transferred to the binding proteins and eventually to the iron 05 requiring mechanisms within the body, it is preferable for a hydroxypyrone being used as an iron remover not to be rapidly metabolized so -that it remains in the system, taking up iron, for an extended period. Thus, for example, maltol is rapidly metabo-lized and is therefore particularly suited for use as an iron complex, but for this same reason it is not appropriate for use in the free form. It is also the case that different compounds may function more efficiently either in the free form as an iron remover or in complex form as an iron donor for quite other reasons. Alternatively, the different 3-hydroxy-4-pyrone may be replaced by a quite different form of iron chelating agent.
Examples of such other iron chelating agents which may be used include the substituted 3-hydroxypyrid-2-ones and -4~ones, and 1-hydroxypyrid-2-one and substituted 1-hydroxypyrid-2-ones (and salts of these various pyridones containing a physiologically acceptable cation) described in co-pending UK Patent Applica-tions 8308056 (published as GB 2118176A), 8407181 (published as GB 2136807A) and 8423800 (claimlng priority from UK Patent Apl)llcatLon 8325496; to be publlshed as GB 2146990A).
Whell a fre~e hydroxy-4-pyrorle, hydroxypyrid-2-one, hydroxypyrid-4-one, or other iron chelating agent is present in admixture with the iron complex of a hydroxy-4-pyrone for the purpose of acting as an iron remover 9 then the amount of this agent used may be different than when a free hydroxypyrone necessarily corresponding to that present in the iron complex is present primarily to prevenL
dissociation. Thus the daily dosage of the iron complex may be as above and the daily dosage of the free iron chelating agent, particularly when this is a hydroxypyrid-2- or -4-one or a 1-hydroxy-pyrid-2-one, may be that quoted in the co-pending applications referred to above, i.e. about 0.1 g to 5 g for human use, particu-larly 0.5 g to 2 g, from which it will be seen that the proportion ~,5~

of iron complex and free iron chelating agent used in such a context may extend across a wide range but preferred amounts of the free iron chelating agent tend to be higher than when this is necessarily a hydroxypyrone.
05 The present invention thus also includes a method for the treatment of a human or other mammalian patient to effect an incr~ase in the level of iron in the patient's bloodstream which comprises administering to said patient an amount effective to achieve such an increase of a neutral 3:1-hydroxypyrone:iron(III) complex of 3-hydroxy-4-pyrone or of 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, said complex being administered through absorption by the membranes of the buccal cavity or the nasal passages. The adminis-tration is preferably effected by a composition which isretained in the mouth with consequent absorption by the membranes of the buccal cavity.
It will be appreciated from the foregoing discussion that it may happen that, in use, a proportion of the iron complex in a composition for buccal or nasal admLnistratiorl may be swallowed.
Mowever, particularly in view of the dissoclatLon in the stomach of nentral 3:1 lron coMplex wtlicll Ls swallowed ln a Eorm unprotected from the acL~ condLtiotls of the stomach, it will generally be the case that a major part oE lron uptake will be by the membranes of the buccal cavity or the nasal passages and, indeed, iron uptake may often be essentially limited to this route.
This invention is illustrated by the following Examples:-EXAMPLES
Example 1 The preparation of iron maltol A chloroform solution of maltol is mixed with a lM solution of ferric chloride in ethanol to provide a 3:1 molar ratio of maltol:iron in the mixture. After 5 minutes at 20C, 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 ~ 16 -solvent evaporated to give the neutral complex containing maltol and the ferric cation in 3:1 proportion. Recrystallisation of the 3:1 complex from ethanol gives wine red needle crystals in an essentially quantita-tive yield, m.pO 275, v (nujol) 1600cm 1.
05 The use of an excess of maltol above the 3:1 molar ratio leads to an essentially quantitative yield of a solid mixture of the excess maltol and the 3:1 iron maltol complex on rotary evapora-tion, this mixture not being deliquescent.
The partition coefficient K a t (concentration in n-octanol/
concentration in aqueous phase~ between n-octanol and Tris hydro-chloride (20 mM, pH 7.4) of maltol and of its 3:1 iron complex is measured at 10 4M by spectrophotometry. Acid washed glassware is used throughout and, following mixing for 1 minute, the aqueous/
n-octanol mixture is centrifuged at 1000 g for 30 seconds. The two resulting phases are separated for a concentration determina-tion by spectrophotometry on each. For maltol, the range 220-340 nm is used for the concentration determination whilst for the complex the range 340-640 nm is used. Typically, a value of 0.66 is obtained for maltol and of 0.50 for its iron complex, whilst comparative experiments on iron([II) ~DTA and iron(III) ascorbate glve much smaLler values of 0.001 and 0.0015, respec-tLvely.
~ 'he clhlllty of the lron compLex oL maltol to blnd to haemo-globln Ls lnve.qtLgclted by studying the elution profile of a 59Fe label when a mixture of haemoglobin and the 59Fe-labelled complex (at 1 mM concentration) in NaCl (130 mM) buffered to pH 7.4 by Tris hydrochloride is applied to a PD-10 column (Sephadex G-10 gel permeation column - Pharmacia). Typically, no evidence is found for binding of the complex to haemoglobin which is an advantageous finding since such binding reduces availability of the iron.
The ability of the iron complex of maltol to bind to bovine serum albumen (BSA) is investigated through a similar procedure in which -the complex is applied to a column with BSA rather than haemoglobin. The iron complex also shows little ability to bind to BSA.

3f~

Example 2 In vi-tro tests on permeation of iron complexes into human erythrocytes The accumulation of iron by human erythrocytes which are associated with the iron complex of maltol described in Example 1, and various other iron compounds by way of comparison, was studied by incubating the erythrocytes for 1 hour at 37C in a medium consisting of the 59Fe labelled iron compound in aqueous sodium chloride (130 mM) buffered to a pH of 7.4 by Tris hydrochloride.
Following this period of incubation an aliquot of -the erythrocy-te/
medium rnixture was placed above a layer of silicone oil (P= 1.06) and the erythrocytes separated by centrifugation through the oil.
The 59Fe levels associated with the erythrocytes and the incubation medium were then counted and presented as a distribution ratio (concentration in ery-throcytes/ concentra-tion in medium). The ratios obtained for the various iron compounds after incubation for 1 hour are shown in Table 1 where it will be seen that the uptake of iron is clearly much greater wi-th the iron maltol complex than with the other compounds. Values of less than 0.1 are probably associated with binding to the external surface and do not represent transmembrane movement of iron. Moreover, although a perlod of 1 hour was employed in orcler to facLlitate monitoring of the rnore slowly permeatlllg~ lron compouncls, the uptclke of the iron maltol complex reachecl eqllLlihrLum at the Level shown after about 15 mirlutes.
Table 1 l ~ l ConcentrationDistribution Compound (rnM) ratio Fe (maltol)3 3 1.60 Fe gluconate 1 0.03 Fe ascorba-te 1 0.12 Fe ci-trate 1 0.05 Fe EDTA 1 O.OS i ~5~31~

When the above described procedure was applied using ratios of maltol to iron of less than 3:1 larger apparen-t distribution ratios were observed than 1.60. However, this is explained by the non-specific binding of the positively charged 2:1 and 1:1 maltol:
05 iron complexes to the surface of the ery-throcytes which possesses a net negative charge, being rich in both phosphate and sulphate moieties. Experiments to determine the percentage of 59Fe associated with erthrocyte ghosts after lysis confirm this hypothesis. In one experiment, lysis was initiated by a small volume of 10% v/v Triton X100 (Trade ~lark) and in a second experiment by a 10 fold excess of water. In each case the resulting ghosts were centrifuged through silicone oil (P = 1.02) and7 as will be seen from Table 2, very little of the 3:1 maltol:iron complex was found to be bound to the membranes, in contrast with the situation with the 2:1 and 1:1 complexes. Such binding is of course undesirable as the complex is likely to remain tightly bound to the membrane by electrostatic interactions and not be transmitted across it.
Table 2 . _ _ . . .. ~
Iron associatied wLth Ra~lo of with ghosts (%) maltol:iron _~ _ Triton Iysis llypotonic lysis __~_ . ~
0:1 100_ 1:1 5563

2:1 2239 _ _ _ _ <5 Example 3 In vitro tests on permeation_of rat jejunal sac by iron complexes The iron uptake into the serosal space of the rat jejunal sac was compared for the iron complex of maltol described in Example 1 and various other iron compounds by way of comparison. Rats (male - 19 ~
Sprague Dawley, 60 g) were killed and the jejunum removed, everted and cut into three segments (4 cm length). The segments were tied at both ends, filled with Krebs Ringer buffer (0.2 ml) and incubated in Krebs Ringer buffer containing the appropriate 59Fe compound 05 at 37C for periods up to 90 minutes. The contents of the sac were counted for 59Fe and measured spectrophotometrically.
The results obtained for the iron maltol complex and for 6 other iron compounds which are each contained in preparations marketed for the treatment of iron deficiency anaemia are shown in Table 33 the iron uptake for each at 15 and 60 minutes after the initiation of the experiment being shown relative to that for ferric chloride as 1. It will be seen that the iron maltol complex provides a level of iron uptake which is significantly higher than the levels observed for any of the 6 compounds in current use for the treatment of iron deficiency anaemia. The uptake of the iron maltol complex was linear for a period of 90 minutes. Moreover, the uptake increased linearly as the concentration of the complex was increased over a range from 0.5 to 10 mM, so it does not show saturation kinetics and the process i9 thus non-facilitated and thereEore should occur in aLl natural melnbranes.
Table 3 __ ~ Relat-Lve iron uptake .__ ____ _ Compollnd 15 minutes 60 minutes . . ~_. , ~
FeC13 1 Fe (maltol)3 40 5.8 Fe sulphate 2.4 1O4 Fe fumarate 4.0 1.8 FeII gluconate 1.6 0.8 Fe succinate 2.0 1.0 Fe ascorba-te 0.4 0.8 Fe ci-trate 2.0 1.8 ~3~ 3 The procedure described above was used to compare the uptake of iron from buffer containing differing molar proportions of maltol:iron. The results obtained are presented in Table 4 which shows the amount of iron transferred via the maltol complex into 05 the serosal contents of the sac, the basal uptake of iron measured in a control experimen-t being subtracted in each case. It will be seen that the amount of iron transferred in the case of a 3:1 molar proportion of maltol:iron(III) is much higher than in the other two cases and, moreover the low, but significant level of iron uptake observed in the case of a 2:1 ratio is attributed to the proportion of the 3:1 complex (containLng 13% of the total iron) present under these conditions.

Table 4 Maltol/iron Iron uptake (molar ratio) (n mole) 1:1 1.6 2:1 ~.0

3:1 30.0 ______ __.
~x~L~ 4 . . _ In vlvo test of action of lron compounds in the rat The action of the iron complex of maltol described in Example 1 was compared with that of iron(II) sulphate, iron(III) ~DTA (1:1 molar ratio) and iron(II~ gluconate.
Groups of rats (300-350 g) were anaesthetised with nembutal (0.25 ml) and then with ether. A mid-line incision was made and the 59Fe labelled sample (100 ~g Fe, 10 ~Ci) ~as passed into the lumen of the duodenum via a small incision. The abdominal well was then closed with a suture. The animals were sacrificed 1, 2, ~ and 6 hours after the administration of the compound and the various organs were moni-tored for their 59Fe content, The data is presented as histograms in Figures 1 to 4 i3~ 3 which relate to lron maltol, iron sulphate, iron EDTA and iron gluconate, respectively, and show the levels of 59Fe in cpm after various time intervals for the different organs, the data in each case representing a mean of the results for three individual U5 animals. In the case of the data for blood and sternum (bone marrow) the counts given are cpm/ml and cpm/g respectively, whilst in all other cases they are the total cpm counts. The various histograms have been normalised and consequently are directly comparable.
A comparison between Figures 1 and 2 shows that the neutral 3:1 maltol:iron(III) complex is markedly superior to iron(II) sulphate for the introduction of iron via the rat intestine. The gut washings (which contain non-absorbed iron) show a much lower level of counts for the maltol complex, and the counts associated with the gut wall, liver, blood, bone marrow and spleen are correspondingly greater. It is clear from Figure 1 that 59Fe associated with maltol en-ters the intestine wall very rapidly and from there it is efficiently removed by the blood supply. Iron is deposited in -the bone marrow continuously throughou-t the 6 hour period at an apparen-tly constant rate.
The maltol complex is also more efflcient than lron(lII) El)TA as shown by Flgure 3. Wl-th the later complex, the gut washlngs re~mlln hLgtl for 4 hour6 and may be presumed to decrease only dl~e to the efect of natural bowel movements translocating materiaL from the portion under investigation to lower portions of the intestine. The levels in the intestine wall and blood are extremely low. Although iron is transferred to both bone marrow and spleen, this is at reduced rates as compared to those obtained with the maltol complex. As shown by Figure 4, iron(II) gluconate proved more effective than the sulphate or -the EDTA complex, although deposition in the gut wall was less than that observed with the maltol complex. The decrease was reflected in the lower levels of 59Fe in both bone marrow and the spleen~ the difference being particularly marked after 6 hours. In view of the much higher levels of 59Fe trapped in the intestine wall in the case of ~253~303 the maltol complex, it may be predicted that this compound facili-tates a more prolonged supply of iron than iron(II) gluconate.
This test illustrates the superiority of the neutral 3:1 maltol:iron(III) complex as compared with three commonly used 05 "soluble iron" preparations for the movement of iron across the rat jejunal wall into the blood circulation, the iron maltol being very rapidly removed from the lumen of the intestine.
Example 5 In vivo test of action of iron complexes in the cat The action of the iron complex of maltol described in Example 1 was compared with that of iron(III) EDTA (1:1 molar ratio) which is one of the iron compounds currently marketed for the treatment of iron deficiency anaemia. Cats were anaesthe-tised with chlora-lase (60 mg/kg) and pentobarbitone sodium (60 mg/kg) (i.p.), having been kept free of food for 18 hours. In each animal the trachea was cannulated to maintain a clear airway and to allow positive pressure artificial respiration if necessary. The left femoral vien was cannulated for the intravenous administration of drugs and physiological saline solution. Arterial blood pressure was monitored by a Washington pressure transducer through a cannula inserted into the femoral artery of the right hind leg. Arterial blood samples were taken at appropriate intervals from a short cannula inserted into an external carotid artery. Body tempera-ture was monitored with a rectal thermometer. Each animal was given heparin (1000 iu/kg) as anticoagulant and additional small amounts of pentabarbitone sodium if needed to maintain a satis-factory level of anaesthesia.
In those animals where the iron compounds were to be admini-stered into the duodenum, a mid-line incision was made in the abdomen to reveal the intestines. A cannula was then inserted through a small cut such that its tip rested approximately 5 cm below the opening of the bile duct. The cannula was then sutured in place and the abdominal wall closed with stitches.
The iron maltol complex (100 ~g Fe) alone (3:1 molar ratio of maltol:iron) and together with a large excess of maltol (40:1 ~5~ 3 molar ratio of maltol:iron) was injected intravenously in separa-te experiments and 0.25 ml samples of blood were taken at intervals.
The apparent volume of distribution of the compound was calculated by extrapolation of the log-linear blood concentration curve 05 to zero. (The volume corresponds to a value between that of the total extracellular space of the animal and the blood volume.) Elimination of 59Fe from the blood followed first order kinetics with a rate constant of 0.022/minute in the presence and absence of excess maltol, as illustrated in Figure 5 which shows the 59Fe level in the blood in cpm/0.25 ml plotted against time in the case of one typical experiment of each type in an individual cat.
The distribution of 59Fe in the tissues of the animal after the same intravenous experiment to which Figure 5 relates (the lower end of the ordinate in this Figure represents the background level) was investigated and the typical results are shown in Table 5. The amoun-t of 59Fe administered in this experiment was 4 ~Ci or 2.2 x 10 cpm. It will be seen that approximately 10%
of -the dose was located in the combined tissue of the heart, liver and spleen. ~s less than 0.2% of the dose was located in the urine, the bulk (approximately 90%) of the 5 Fe was almost certainly directed to the bone marrow and extremely high leveLs were found to be located ln the sternulll.
As lnclLcclt-lcl prevlousLy, the maltol complex Ls able to donate Iron rapldLy to transferrin and lt is hypothesLsed that such an exchange occurs as soon as the complex is delivered to the plasma;
and that the initial plateau (represented in Figure 5 by a dotted line) represents saturation of the plasma transferrin pool with Fe.
~hen there is net dona-~ion of 59iron from the plasma into the organs of the animal, the blood levels of radioactivity begin to fall, the major route of transfer of iron bound to transferrin being to the bone marrow, liver and spleen. Binding of 59Fe to transferrin prevents its excretion in the urine.

- 2~1 -Table 5 (Iron maltol, i.v) _ 59 NetSg SampleNet Fe total Fe TissueTotal tissue welghtcontent content weight (g) (g)(cpm/g) (cpm) Heart 1~.4 0.91 490 7 9 056 Liver 105 1.3 510 53,550 Spleen 8.4 0.86 14,890 125,076 Kidney 12.2 1.05 546 6,661 Skeletal muscle _ 1.85 0 0 Sternum _ 1.2 3,200 (bone marrow) ~rine 1 152 <3,000 Identical experiments carried out with 59Fe labelled iron(III) EDTA gave a en-tirely different picture as will be seen 05 for the results of a -typical experiment illustra-ted in Figure 6 (in whLch the ]ower end of the ordinate represel1ts the backgrouncl level) and Table 6 (the amount oE 9Fe administered in thls experL-ment WclS 2 IlCL but the fLgures given in the table have beerl adjusted to correspotld to a dosage oE 2.2 x 106 cpm in order to facilLtate comparlson with Table 5). In this experiment the radioactivity in the blood showed no ini-tial plateau. Instead, loss of radioactivity followed at least a two-component process such that a large amount found its way to the urine rather than to the tissues. The rate constant of the elimination from the blood of the linear phase of the regression was 0.023/minute. The concentration of radioactivity in the kidney and urine, and not in the bone marrow or spleen, would indicate -that iron in thLs form does not appear to be able to attach to transferrin in the plasma and protect itself from urinary excretion. ~he combined tissue of heart, liver and spleen contained only 1% of -the original dose at the end of the experiment, ;~53~D3 whereas the urine contained over 50%. This is ln accord with the fact that EDTA does not exchange iron with transferrin rapidly.
Table 6 -(Iron EDTAL i.v.) _ _ _ Ne-t SampleNet Fe total Fe Tissue Total tissue weight content content weight (g) (g)(cpm/g) (cpm) _ Heart 15.5 1.01 209 3,248 Liver 75 1.21 261 19,600 Sternum _ 0.281,164 (bone marrow) Spleen 11. 2 0.89 162 1,~14 Kidney 19.2 1.471,134 21,770 Skeleta] muscle _ 2.59 95 Urine 19 ml 2 ml62,156 1,180,900 05 The iron maltol complex (100 ~g Fe) was also administered to the duodenum of the cat :Ln the presence of a 40 fold excess oE
maltol followed by 5 ml oE 150 ml Tris hydrochlorlde buffer (pU 7.
In thls case the 59Fe content oE the blood, as shown in Figure 7, reflCheS fl ~lxiMum leveL 2 hours aEter the lnitLal administration (the readlng6 start at about 300 cpm/0.5 ml which represents the background reading). The distributlon of 59Fe in the tissues of the animal after the same duodenal experiment to which Figure 7 relates were investigated and the typical results are shown in Table 7. The amount of 59Fe administered in this experiment was 10 ~Ci or 5.327 x 1o6 cpm into a 2.9 kg cat. It will be seen that the distribution of the 59Fe after 4 hours was similar to that after in-travenous infusion, with low levels in the kidney and urine and high levels in both the spleen and bone marrow.

31~3~3 Table 7 -(Iron mal_ l per duodenum) SampleNet 59Fetotal Fe Tissue Total tissue weightcontentcontent weight (g)(g)(cpm/g) (cpm) Heart 14 0O633 50 1,106 Liver 81 1.45 400 32,400 Spleen 12,7 1.19 3,783 48,047 Kidney 14.4 0.835 79 1,138 Sternum 10 1.26 790 7,905 (bone marrow) Bile ~5 ml 1 ml 2,200 ~11,000 Urine ~10 ml 1 ml 22 ~220 When Fe labelled iron(III) EDTA was administered duodenally in the same manner, the plasma levels of radioactivity hardly exceeded the background level and are therefore not illustra-ted in a Figure.
The distribution of 59Fe in the tissues of the animaL aLter thQ
same cluodel1aL experlment were ir~vestigated and the typicaL resuLt~
arc StlOWQ Ln 'L'able ~. The amount of 59Fe a(llnLr1istered ln thLs experllllcllt wa~ 10 ~CL or 2.65 x 106 cpm into a 2.9 kg cat. It wlll be seen that, a]though some Fe entered the tissues, rather low levels were detec-ted in the spleen and bone marrow (sternum) whereas a large proportion of the dose was located in the urine.

c~(3~'3 _able 8 (Iron EDTA, per duodenum) _ _ 59 Net59 SampleNet Fetotal Fe Tissue Total tlssueweightcontent content weight (g~ (g)(cpm/g) (cpm) _ Heart 15.3 1.1~3 188 2,878 Liver 59.3 0.78 499 29,574 Kidney 11.3 0.901,762 19,913 Spleen 4.4 0.42 200 880 Sternum _ 0.78 917 (bone marrow) Skeletal muscle _ 1.48 117 Urine 15 ml 5 ml36,306 544,596 Exampl _6 Formulation 05 In a formulation utilising a pastille base desc-ribed in the 1973 edition of Martindale, the Extra Pharmacoepia, but with the replacement o~ bordeaux B by amaranth, pastilles are preparecl frcJm the followlng inKredients: 3:1 maLtol:iron(III) complex, 0.25 g;
gelatln, 20 g; g1ycerin, 40 g; sucrose, 5 g; citric acld, 2 g;
soclLum benzoate, 0.2 g; oil of lemon, 0.1 ml; concentra-ted orange flavour water, 0.52 ml; solution of amaranth, 1.0l~ ml;
and water to a total weight of 100 g.
The gelatin is mixed with one and a half times its volume of water and the glycerin is added to the mixture, the product being heated on a water bath until a solution is produced. The iron maltol, sucrose, citric acid, sodium benzoate and amaranth are then added as a solution in a small volume of water. The solution is cooled, orange flavour wa-ter and oil of lemon are added, and the remaining water is added to bring the weigh~ of the mixture -to 100 g. The mixture is then strained through muslin, poured into a pastille mould and allowed to dry to give pastil]es containing approximately 5 mg of iron maltol.

Claims (19)

- 29 -

1. A pharmaceutical composition comprising a neutral 3:1 hydroxypyrone:iron(III) complex of 3-hydroxy-4-pyrone or of 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, said composition being adapted for buccal or nasal administration.

2. A pharmaceutical composition comprising a neutral 3:1 hydroxypyrone:iron(III) complex of 3-hydroxy-4-pyrone or of 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, said composition being in a form suitable for retention in the mouth without swallowing thereof to thereby effect release of said complex in the buccal cavity.

3. A pharmaceutical composition according to Claim 2 which contains a solid carrier and is adapted to be chewed or sucked.

4. A pharmaceutical composition according to Claim 3 in the form of pastilles or lozenges.

5. A pharmaceutical composition comprising a neutral 3:1 hydroxypyrone:iron(III) complex of 3-hydroxy-4-pyrone or of 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, said composition being in aerosol form.

6. A pharmaceutical composition according to Claim 1, 2 or 5, in which the or each aliphatic hydrocarbon group is an acyclic group of 1 to 4 carbon atoms.

7. A pharmaceutical composition according to Claim 1, 2 or 5, in which the or each aliphatic hydrocarbon group is an alkyl group.

8. A pharmaceutical composition according to Claim 1, 2 or 5, in which the complex is of 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 the group consisting of methyl, ethyl, n-propyl and isopropyl.

9. A pharmaceutical composition according to Claim 1, 2 or 5, in which one or two of the hydrogen atoms attached to ring carbon atoms are replaced in the substituted 3-hydroxy-4-pyrone.

10. A pharmaceutical composition according to Claim 1, 2 or 5, in which one of the hydrogen atoms attached to ring carbon atoms is replaced in the substituted 3-hydroxy-4-pyrone.

11. A pharmaceutical composition according to Claim 1, 2 or 5, in which the hydrogen atom attached to the ring carbon atom at either the 2- or 6- position is replaced in the substituted 3-hydroxy-4-pyrone.

12. A pharmaceutical composition according to Claim 1, 2 or 5, in which the 3:1 iron complex is of 3-hydroxy-4-pyrone, 3-hydroxy-2-methyl-4-pyrone, 3-hydroxy-6-methyl-4-pyrone or 2-ethyl-3-hydroxy-4-pyrone.

13. A pharmaceutical composition according to Claim 1, 2 or 5, in which the 3:1 iron complex is of 3-hydroxy-2-methyl-4-pyrone.

14. A pharmaceutical composition according to Claim 1, 2 or 5, in which the 3:1 iron complex is of 2-ethyl-3-hydroxy-4-pyrone.

15. A pharmaceutical composition according to Claim 1, 2 or 5, which additionally contains an iron chelating agent.

16. A pharmaceutical composition according to Claim 1, 2 or 5, which additionally contains an uncomplexed 3-hydroxy-4-pyrone or an uncomplexed 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 I to 6 carbon atoms, or a salt thereof containing a physiologically acceptable cation.

17. A pharmaceutical composition according to Claim 1, 2 or 5, which additionally contains the same hydroxypyrone or a salt thereof containing a physiologically acceptable cation in uncomplexed form.

18. A pharmaceutical composition according to Claim 1, 2 or 5 which additionally contains folic acid.

19. A pharmaceutical composition according to Claim 1, 2 or 5, in unit dosage form.