GB2553099A

GB2553099A - Use

Info

Publication number: GB2553099A
Application number: GB1614181.4A
Authority: GB
Inventors: Raymond Sampson Mark
Original assignee: Shield Tx UK Ltd
Current assignee: Shield Tx UK Ltd
Priority date: 2016-08-19
Filing date: 2016-08-19
Publication date: 2018-02-28
Also published as: GB201614181D0

Abstract

The use of iron hydroxypyrones such as ferric trimaltol, ferric tri-hydoxypyrone or a hydroxyl-4-pyrone such as 3-hydroxy-4-pyrone in the treatment or prevention of iron deficiency in subjects having elevated hepcidin levels such as those with anaemia of chronic disease or anaemia of chronic inflammation is disclosed.

Description

(71) Applicant(s):

Shield TX (UK) Ltd

Northern Design Centre, Gateshead Quays, Newcastle, NE8 3DF, United Kingdom (72) Inventor(s):

Mark Raymond Sampson (74) Agent and/or Address for Service:

Potter Clarkson LLP

The Beigrave Centre, Talbot Street, NOTTINGHAM, NG1 5GG, United Kingdom (56) Documents Cited:

WO 2016/063228 A1 WO 2002/024196 A1

WO 2015/101971 A1 US 20160120902 A1

Alimentary Pharmacology & Therapeutics (2016) 44 259-270 Schmidt et al 'Ferric maltol therapy for iron deficiency anaemia in patients with inflammatory bowel disease: long-term extension data from a Phase 3 study'

Seminars in Hematology (2015) 52 313-320 Weiss 'Anemia of Chronic Disorders: New Diagnostic Tools and New Treatment Strategies'

Kidney International (2011) 80 240-244 Coyne 'Hepcidin: clinical utility as a diagnostic tool and therapeutic target

European Journal of Drug Metabolism and Pharmacokinetics (2017) 42 229-238 Bokemeyer et al 'Randomized Open-Label Phase 1 Study of the Pharmacokinetics of Ferric Maltol in Inflammatory Bowel Disease Patients with Iron Deficiency* (58) Field of Search:

Other: WPI, EPODOC, BIOSIS, MEDLINE, Patent Fulltext, XPOAC, SPRINGER, XPESP (54) Title of the Invention: Use

Abstract Title: Iron hydroxypyrone for use in the treatment of iron deficiency in patients having elevated hepcidin levels.

(57) The use of iron hydroxypyrones such as ferric trimaltol, ferric tri-hydoxypyrone or a hydroxyl-4-pyrone such as 3hydroxy-4-pyrone in the treatment or prevention of iron deficiency in subjects having elevated hepcidin levels such as those with anaemia of chronic disease or anaemia of chronic inflammation is disclosed.

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FIGURE

USE

The invention relates to iron hydroxypyrones for use in the prevention and/or treatment of iron deficiency in a subject, or for use in increasing the level of iron in the body or bloodstream of a subject.

Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation of iron in mammals and can block the absorption of iron from the gut.

Bregman et al (Am J Hematol. 88 (2) 97-101) describes that levels of hepcidin may identify patients with iron deficiency anaemia who will not respond to oral iron therapy comprising a course of ferrous sulfate. Bregman et al also discloses that screening hepcidin levels were significantly higher in non-responders versus responders.

Gasche et al (Inflamm Bowel Di, Vol. 21, 3, March 2015) discloses that ferric trimaltol is effective in correcting iron deficiency anaemia in patients with inflammatory bowel disease as demonstrated by a phase-3 clinical trial.

Harvey et al (Aliment Pharmacol Ther 1998:12: 845-848) describes that ferric trimaltol can correct iron deficiency anaemia in patients intolerant of iron.

There remains a need for effective regimens for the prevention and treatment of iron deficiency in subjects, particularly subjects with elevated levels of hepcidin, such as those sufficient to block enteral absorption of iron.

The present invention recognises that iron hydroxypyrones, particularly ferric hydroxypyrones, such as when delivered by enteral administration, provide an effective prevention or treatment regimen for iron deficiency in subjects or patients having elevated levels of hepcidin, such that, for example, enteral absorption of iron is blocked in the absence of the therapy of the present invention.

In particular, the efficacy of the iron hydroxypyrone in increasing levels of iron in the body or bloodstream, such as when delivered by enteral or oral administration, is surprisingly independent of the hepcidin level. It was unexpected that iron could be effectively absorbed from enteral administration of an iron hydroxypyrone when levels of hepcidin are elevated due the fact that hepcidin is known to inhibit iron absorption from the gut.

In a first aspect, the present invention provides an iron hydroxypyrone for use in the prevention and/or treatment of iron deficiency in a subject, or for use in increasing the level of iron in the body or bloodstream of a subject, wherein the subject has an elevated hepcidin level and preferably wherein the iron hydroxypyrone is for enteral administration.

In a second aspect, the present invention provides an iron hydroxypyrone for use in the prevention and/or treatment of iron deficiency in a subject, or for increasing the level of iron in the body or bloodstream of a subject, wherein the subject has, or is at risk of having, an inflammatory condition and wherein the iron hydroxypyrone does not provoke any inflammatory response, or exacerbate or substantially affect the condition.

In a further aspect, there is provided a method for preventing and/or treating iron deficiency in a subject in need thereof, or for increasing the level of iron in the body or bloodstream of a subject in need thereof, comprising the step of administering to the subject an iron hydroxypyrone ora composition comprising an iron hydroxypyrone and wherein the subject has an elevated hepcidin level, or wherein the subject has, or is at risk of having, an inflammatory condition and wherein the iron hydroxypyrone does not substantially affect the condition.

In a yet further aspect, the present invention provides the use of an iron hydroxypyrone in the manufacture of a medicament for the prevention and/or treatment of iron deficiency in a subject, or for increasing the level of iron in the body or bloodstream of a subject, wherein the subject has an elevated hepcidin level and preferably wherein the iron hydroxypyrone is for enteral administration.

Figure 1 shows the baseline hepcidin versus change from baseline to week 12 haemoglobin.

Figure 2 shows the baseline hepcidin versus change from baseline to week 12 TSAT.

Figure 3 shows the baseline hepcidin versus change from baseline to week 12 ferritin.

Figure 4 shows the baseline CRP verus change from baseline to week 12 haemoglobin.

Figure 5 shows the baseline CRP versus change from baseline to week 12 TSAT.

The term “hepcidin” as used herein typically refers to biologically active hepcidin-25 which is the active form comprising 25 amino acids, rather than, for example, truncated derivatives of this, such as hepcidin-20 (a truncated N-terminal pentapeptide), or prepropeptide (84 amino acids), or propeptide (60 amino acids) forms.

In the invention, the subject to be treated has an elevated level of hepcidin, such as hepcidin-25. The level of hepcidin in the subject may be increased compared to, or higher than, the maximum level of hepcidin in, for example, a normal healthy subject. For example, it is preferred that the level of hepcidin is greater than about 55 ng/ml or 60 ng/ml of clinical sample when measured using SELDI mass spectrometry.

The elevated level of hepcidin is typically a level sufficient to block the enteral absorption of iron in the absence of the present invention.

The level of hepcidin is generally that measured in a biological fluid of the subject, such as serum or plasma.

The level of hepcidin, such as hepcidin-25, in the biologic fluid of the subject, such as serum or plasma, may be at least about 13, 15 or 20 ng of hepcidin per ml of biologic fluid, such as serum or plasma, or greater preferably as determined by mass spectrometry such as SELDI mass spectrometry, for example SELDI-TOF-MS. For example, the hepcidin-25 level may preferably be greater than or equal to about 20 or 25 ng/ml, greater than or equal to about 30 ng/ml, such as for example, greater than or equal to about 40 ng/ml, 50 ng/ml,60 ng/ml of serum or plasma. In a preferred embodiment, the elevated hepcidin-25 level is greater than about 70 ng/ml, or greater than about 80 ng/ml. The elevated hepcidin level may preferably be greater than about 90 ng/ml or about 100 ng/ml, such as greater than about 150 ng/ml or greater than about 200 ng/ml. The level of hepcidin is typically that measured according to SELDI mass spectrometry, such as described herein.

Preferably, the level of hepcidin is from about 22 to about 90 ng/ml, such as from 25 to 75 ng/ml, or from 30 to 60 ng/ml, when measured using mass spectrometry, such as SELDI mass spectrometry.

In the present invention the hepcidin level is typically measured using SELDI mass spectrometry, such as SELDI-TOF-MS. A preferred method for determining the hepcidin level is described in Ward et al (Proteome Science, 2008, 6:28), which is incorporated by reference herein. The method for measuring hepcidin preferably comprises the use of a stable isotope labelled hepcidin spiking in conjunction with SELDI-TOF-MS.

In the present invention, the iron deficiency may comprise iron deficiency with or without anaemia. Thus, the subject as defined herein may be diagnosed with, or at risk of developing iron deficiency with or without anaemia.

Typically, the level of iron uptake in the subject from the iron hydroxypyrone is substantially independent of the hepcidin level in the subject. This is surprising since it was previously thought that iron could not be absorbed effectively from the gut when hepcidin levels are high.

Preferably, the hepcidin level, such as set out above, is determined from serum or plasma taken from the subject and analysed ex vivo. The subject may be a mammal, such as a human. The hepcidin-25 level is typically measured using mass spectrometry as described above, on a biological sample from the subject which may be, for example, a serum or plasma sample.

In the invention, the subject to be treated has an elevated level of hepcidin. The subject may also have, or be diagnosed with, an inflammatory condition such as, for example, inflammatory bowel disease. Preferably, the inflammatory bowel disease is selected from colitis, ulcerative colitis or Crohn’s disease. Alternatively, the subject may not have or be diagnosed with an inflammatory condition as described above.

Preferably, the subject has an active inflammatory condition. The level of inflammation can be measured using markers typical in the field, such as CRP (C-reactive protein) using methods known in the art. The CRP level is preferably measured by an immunoturbidimetry method, such as, for example, the Roche Immunoturbidimetry Generation 3 methodology Alternatively, the inflammatory condition may be considered as extreme, such as where the CRP level in the subject serum or plasma is from 40 mg/L to about 200 mg/L, or greater than 200 mg/L.

The level of CRP in the serum or plasma of the subject may be greater than about 5 mg/L, such as at least about 10 mg/L, for example at least about 15 mg/L or at least about 20 mg/L or 30 mg/L. The level of CRP in the serum or plasma may be greater than about 40, 50 or 60 mg/L. For example the level of CRP may be from about 5 mg/L to about 40 mg/L, or from about 10 to about 30 mg/L.

The level of CRP in the subject is preferably measured by an immunoturbidimetry method, such as the Roche Immunoturbidimetry Generation 3 methodology.

Preferably, the subject has a hepcidin-25 level of from about 22 to about 90 ng/ml in the serum or plasma, as determined by mass spectrometry, for example, SELDI mass spectrometry such as described above and a CRP level of from about 5 mg/L to about 40 mg/L such as measured by an immunoturbidimetry method. The subject is typically a human and the iron hydroxypyrone is selected from ferric tri(maltol) or ferric tri(ethylmaltol) or mixtures thereof.

Typically, the iron hydroxypyrone has no substantial effect on the level of hepcidin and/or inflammation in the subject.

Preferably, the elevated hepcidin level is from about 20 ng/ml to about 200 ng/ml of biologic fluid such as serum or plasma, more preferably, from greater than about 20 ng/ml to about 100 ng/ml, such as from greater than 20 ng/ml to about 60 ng/ml of biologic fluid.

The level of hepcidin, such as hepcidin-25, as defined herein is preferably that measured using mass spectrometry, such as MALDI or SELDI, most preferably SELDI. The method for measuring hepcidin preferably comprises the use of a stable isotope labelled hepcidin spiking in conjunction with SELDI-TOF-MS, such as described in Ward et al (Proteome Science, 2008, 6:28).

The term “subject” as used herein includes animals, such as mammalian animals, for example, humans, as well as animals such as cows, dogs, cats, sheep, monkeys, rats, horses, rabbits, and pigs. Hence, the uses and method of treatment discussed above may include the treatment of a human or animal body.

Preferably, by the term “subject” or “patient” we include a mammal, more preferably a human. The terms “subject” and “patient” may be used interchangeably. The subject is 5 typically a subject in need of prevention or treatment for iron deficiency or low levels of iron in the body or bloodstream and which has an elevated level of hepcidin such as defined herein. An effective amount of the iron hydroxypyrone or compositions comprising an iron hydroxypyrone is typically used.

The subject having an elevated hepcidin level may be one in which hepcidin levels are upregulated compared to a normal healthy subject, such as a human adult (male or female aged from 16 to 90).

For example, the subject having an elevated hepcidin level may have a hepcidin level which inhibits enteral iron absorption, absent the therapy of the present invention. Preferably, the subject is one in which iron absorption from the gut is reduced or inhibited by hepcidin absent the therapy of the present invention.

The iron hydroxypyrone may be as defined in any of the embodiments herein. Preferably, the iron hydroxypyrone is selected from ferric tri(maltol) or ferric tri(ethylmaltol). The iron hydroxypyrone may be administered without other pharmaceutically active components, for example in a gel capsule consisting essentially of the iron hydroxypyrone and the capsule, or be present in a composition, such as a pharmaceutical composition as defined herein.

The amounts of the components in the composition may also be as defined in any of the embodiments disclosed herein.

The term “iron hydroxypyrone” as used herein includes compounds or compositions which comprise a hydroxypyrone and iron. The term includes, for example, complexes of iron with a hydroxypyrone, such as, for example, ferric tri(maltol), as well as mixtures comprising an iron compound, such as a salt or a complex of iron, and a hydroxypyrone, preferably in a substantially non-complexed form (such as less than 10%, 5%, 2%, or 1% hydroxypyrone complexed), for example ferrous gluconate and maltol or ferric maltol gluconate, preferably in the solid state.

The term “iron hydroxypyrone” preferably refers to a 1:3 molar complex of ferric iron to hydroxypyrone. This complex is neutral. The term “iron hydroxypyrone” may or may not include carboxylic acids as counterions. In addition, the term may or may not include charged complexes of iron with hydroxypyrone, such as 1:1, or 1:2 molar complexes of iron to hydroxypyrone, with counteranions, such as carboxylate anions. In a preferred embodiment of the invention, the molar ratio of iron to hydroxypyrone is 1: at least 3.

The term “iron hydroxypyrone” may, in a preferred embodiment, refer to mixture comprising or consisting of a ferrous or ferric salt and a hydroxypyrone.

The ferric salt can be an iron (111) salt with any pharmaceutically acceptable anion. For example, the ferric salt can be an iron (III) inorganic salt, such as ferric sulphate or a ferric halide, such as ferric chloride. Alternatively, the ferric salt can be an iron (III) organic salt, such as, for example, a ferric carboxylate such as ferric citrate. Preferably, the iron (III) salt is an iron (III) organic salt.

The ferrous salt can be an iron (II) salt with any pharmaceutically acceptable anion. Preferably, the iron (II) salt is iron (II) carbonate or an iron (II) carboxylate. Suitable iron (II) carboxylates also include, for example, iron (II) gluconate, iron (II) succinate, and iron (II) fumarate. These ferrous salts are readily available at pharmaceutically acceptable levels of purity.

The molar ratio of the ferric or ferrous salt to the hydroxypyrone is preferably from 1:1 to 1:10, such as about 1:5, 1:4.4, 1:4 or 1:3.

The iron hydroxypyrone is typically the sole or only source of iron in the composition but other iron sources may be used in other embodiments. Preferably, the iron hydroxypyrone is the sole source of iron in the composition. The iron hydroxypyrone may be produced according to the methods disclosed in, for example, WO 03/097627 and WO 2012/101442, the disclosure of which is incorporated herein by reference.

In the invention, the iron hydroxypyrone is typically pharmaceutically acceptable. This means that the iron hydroxypyrone is suitable for enteral or oral administration to a subject or patient in need of iron treatment.

The iron hydroxypyrone suitable for use in the present invention typically is a neutral complex comprising iron cations and hydroxypyrone anions and without additional charge balancing anions, such as hydroxide or chloride. Preferably, the iron hydroxypyrone is an iron tri(hydroxypyrone) i.e., Fe(hydroxypyrone)3, such as ferric tri(hydroxypyrone).

Preferably, the iron hydroxypyrone is a ferric tri(hydroxypyrone), where the hydroxypyrone is as defined herein, such as ferric tri(maltol) or ferric tri(ethylmaltol).

By “neutral complex”, it is intended to mean that the positive charge on the iron cation is balanced by the negative charge on the ligands in the complex. Therefore the total charge on the iron hydroxypyrone complex is zero. Because there is an internal balance of charges between the iron cation and the hydroxypyrone ligands, there is no need for any additional non-covalently bound anions, such as chloride, to balance any remaining charge on the iron cation.

Typically, the iron hydroxypyrone compound comprises iron in the ferric (Fe³⁺) oxidation state.

When the iron is present in the ferric state, the neutral iron hydroxypyrone complex comprises hydroxypyrone and ferric iron in the stoichiometric ratio of 3:1 hydroxypyrone: ferric iron. The neutral complex of ferric iron and hydroxypyrone comprises three monobasic, bidentate hydroxypyrone ligands covalently bound to a ferric ion. The hydroxypyrone ligand is a bidentate ligand and is monobasic. The singly charged hydroxypyrone ligand contains an -O- group in place of the -OH group present in the neutral hydroxypyrone ligand.

The hydroxypyrone ligands in the iron hydroxypyrone may be the same or different. In a preferred embodiment, all of the hydroxypyrone ligands are the same.

Advantageously, the iron hydroxypyrone compound may or may not be completely or substantially free of charged ferric hydroxypyrone complexes and neutral mixed ligand ferric complexes comprising covalently bound carboxylate ligands.

By “charged ferric hydroxypyrone complexes”, it is intended to mean ferric hydroxypyrone complexes in which the stoichiometric ratio of hydroxypyrone to ferric iron is 2:1 or 1:1 so that the charge on the ferric cation is not internally balanced by the charge on the hydroxypyrone ligand. The total charge on the complex may be +1 or +2 and at least one counterion, such as, for example, chloride will be required in order to balance the charge.

By “substantially free”, it is meant that the charged ferric complexes or neutral mixed ligand ferric complexes comprising carboxylate ligands comprise less than 10 % by weight of the 8 total weight of the iron species in the final composition, based on the composition, and preferably less than 5%, such as less than 2 wt.% or 1 wt.% or about 0 wt.%.

Where the iron hydroxypyrone compound has one or more chiral centres, the iron hydroxypyrone compound may be obtained as either pure enantiomer or diastereoisomer, a racemic mixture or a mixture enriched in either enantiomer or diastereoisomer. The mixture of enantiomers or diastereoisomers may be separated and purified using any of the known methods in the art. However, the mixture of optical isomers is typically not separated and purified.

Preferably, the hydroxypyrone for use in the present invention is a hydroxy-4-pyrone. For example, the hydroxy-4-pyrone can be a 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to the ring carbon atoms is replaced by an aliphatic hydrocarbon group having 1 to 6 carbon atoms.

The substituted 3-hydroxy-4-pyrones may comprise more than one type of aliphatic hydrocarbon group. However, it is generally preferred if there is substitution by one rather than two or three aliphatic hydrocarbon groups.

The hydroxypyrone ligand may also be a 5-hydroxypyrone, such as Kojic acid (5-hydroxy2-(hydroxymethyl)-4-pyrone). In a further embodiment, the hydroxypyrone used in the present invention may comprise mixtures of the hydroxypyrone ligands mentioned above.

The hydroxypyrone may not comprise a hydroxymethyl, hydroxyethyl or hydroxyalkyl substituent, where the alkyl is preferably C1 to C10, such as C1 to C6. For example, the hydroxypyrone may not comprise or consist of Kojic acid.

The term “aliphatic hydrocarbon group” is used herein to include both acyclic and cyclic groups that may be unsaturated or saturated, the acyclic groups having a branched chain or preferably a straight chain. Particularly preferred groups are those having from 1 to 4 carbon atoms, more preferably those having from 1 to 3 carbon atoms. Saturated aliphatic hydrocarbon groups are preferred, these being either cyclic groups such as the cycloalkyl groups cyclopropyl, and particularly cyclohexyl, or more preferably acyclic groups such as methyl, ethyl, n-propyl and isopropyl. Methyl and ethyl are particularly preferred.

Substitution at the 2- or 6- position is of particular 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 system. This system is involved in the formation of a complex with iron and the close proximity of one of the larger aliphatic hydrocarbons may lead to steric effects that inhibit complex formation.

Preferred hydroxypyrone ligands present in complexes according to the present invention have the formula (I), specific hydroxypyrones of particular interest have the formulae (II) and (III):

(I) (II) <^ln>

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 an alkyl group when n is 0).

Among these compounds, 3-hydroxy-2-methyl-4-pyrone (maltol; II, R = Me) is of most interest, whilst 3-hydroxy-4-pyrone (pyromeconic acid; I, n = 0), 3-hydroxy-6-methyl-4pyrone (isomaltol, III, R = Me) and particularly 2-ethyl-3-hydroxy-4-pyrone (ethylmaltol; II, R = Et) are also of especial interest. For convenience, the compound 3-hydroxy-2-methyl4-pyrone is referred to herein as “maltol”.

Preferably, the hydroxy-4-pyrone is selected from maltol, ethyl maltol or mixtures thereof. Maltol is most preferred and the iron hydroxypyrone compound used in the composition is most preferably ferric tri(maltol).

Certain hydroxypyrones, such as maltol, are available commercially. With others, a convenient starting material in many instances consists of 3-hydroxy-4-pyrone, which is readily obtainable by the decarboxylation of 2,6-dicarboxy-3-hydroxy-4-pyrone (meconic acid). For example, 3-hydroxy-4-pyrone may be reacted with an aldehyde to insert a 1hydroxyalkyl group at the 2-position, which group may then be reduced to produce a 2-allyl3-hydroxy-4-pyrone. Other preparative methods are described by Spielman, Freifelder, J. Am. Chem. Soc. Vol. 69, page 2908 (1947).

The skilled person will appreciate that these are not the only routes to these hydroxypyrone compounds and that various alternatives known in the art may equally be used.

Preferably, the hydroxypyrone in the invention is a hydroxy-4-pyrone preferably selected from the group consisting of: a 3-hydroxy-4-pyrone and a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to the ring carbon atoms are replaced by an aliphatic hydrocarbon group having 1 to 6 carbon atoms.

It is particularly preferred where the hydroxypyrone is selected from maltol, ethyl maltol, or mixtures thereof.

The iron hydroxypyrone may be present in a composition such as a pharmaceutical composition. The composition is preferably a pharmaceutical composition comprising an iron hydroxypyrone together with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the treatment of the invention.

By “pharmaceutically acceptable” we include the normal meaning that the adjuvant, diluent or carrier must be “acceptable” in the sense of being compatible with the active ingredient (the iron hydroxypryone) and not deleterious to the recipients thereof.

The compound or composition for use in the invention is preferably for enteral administration to the subject or patient. Enteral administration includes, for example, oral, sublingual, buccal, and rectal administration. Preferably, the compound or composition is not for parenteral administration although it could be used for such administration in certain embodiments.

The composition may further comprise a hydroxypyrone in addition to the iron hydroxypyrone. The hydroxypyrone may be as defined in any of the above embodiments but is preferably selected from maltol, ethyl maltol, or mixtures thereof. The further hydroxypyrone is added, typically in an uncomplexed form, to the composition in addition 11 to the hydroxypyrone present in the iron hydroxypyrone. The further hydroxypyrone may be the same as or different from the hydroxypyrone in the iron hydroxypyrone. Typically, they are the same. The molar ratio of the further hydroxypyrone to the iron hydroxypyrone may be from about 10:1 to 1:10, such as about 5:1 to 1:5, 3:1 to 1:3, or 2:1 to 1:2.

Preferably the composition of the invention as defined in any of the embodiments herein does not comprise a pH lowering agent such as an inorganic or organic acid.

The iron hydroxypyrone may, however, be combined with other therapeutic agents to form the composition, for instance those that are also useful in the treatment of iron deficiency with or without anaemia, such as iron deficiency anaemia. Alternatively, the iron hydroxypyrone may be the sole therapy used. The iron hydroxypyrone may also be combined with other therapies. For example, the iron hydroxypyrone or composition may be administered before, at the same time or after a different therapy.

More than one iron hydroxypyrone compound may be contained in the composition, such as a pharmaceutical composition, and other active compounds may also be included. Typical additives include compounds having the ability to facilitate the treatment of anaemia, such as folic acid. A zinc source may also be included. The iron hydroxypyrone may be the only pharmaceutically active component present in the composition. For example, the iron hydroxypyrone may be the only source of iron present in the composition.

Typically, the iron hydroxypyrone is the sole iron therapy which is used in the invention. Preferably, the iron hydroxypyrone, such as ferric tri(maltol), is administered orally, in the form of a capsule, such as a gelatin capsule, preferably a hard gelatin capsule. No other components are typically present in the capsule. The iron hydroxypyrone is preferably in the form of a powder in the capsule and for oral administration to a mammal such as a human.

Suitable pharmaceutical compositions include those in which the active ingredient (i.e. the iron hydroxypyrone) is present in at least 1% (or at least 10%, at least 30% or at least 50%) by weight of the composition. The ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.

The composition may be in the form of a solid, such as a powder, capsule or tablet, or liquid. Suitable solid diluents and carriers include starch, dextrin and magnesium stearate. Stabilising and suspending agents such as methylcellulose and povidone and other tableting agents such as lactose and flow aids such as Aerosil 2000™ may also be used.

Particularly useful diluents and carriers are wetting agents or surfactants, preferably nonionic or ionic surfactants. Examples of suitable non-ionic surfactants include polyoxyl-10oleyl ether and polysorbates. An example of a suitable ionic surfactant is sodium lauryl sulfate.

The composition of the invention may also be in the form of a liquid or a liquid suspension. Alternatively, the composition of the invention may be in the form of a solid, such as a powder, tablet or capsule. The term “liquid” is intended to include a solution of the iron hydroxypyrone in a solvent, such as water. In a liquid form, the iron hydroxypyrone is generally dissolved in the solvent to form a continuous phase. The term “liquid” can also encompass emulsions such as oil-in-water liquid emulsions, or water-in-oil liquid emulsions but in one embodiment of the invention, emulsions are not encompassed. The term “liquid” may or may not also encompass a semisolid. In an embodiment of the invention, the composition as defined in any of the embodiments herein is in the form of a semisolid. A semisolid typically does not hold its shape like a solid but does not flow like a liquid. Examples of semisolids include, for example, foodstuffs such as yoghurt or mayonnaise.

The liquid or liquid suspension may also be fully or partially frozen subsequent to its formation. In one embodiment, the liquid or liquid suspension is not fully or partially frozen after formation.

The term “liquid suspension” is intended to mean a composition which comprises a suspension of the iron hydroxypyrone in a liquid medium, for example an aqueous or nonaqueous liquid. The suspension may also comprise dissolved iron hydroxypyrone. In the case where the solubility of the iron hydroxypyrone is exceeded, the composition may comprise a mixture of dissolved and non-dissolved iron hydroxypyrone. In a suspension, the iron hydroxypyrone is generally suspended in the liquid medium. The iron hydroxypyrone, such as ferric trimaltol, may be visible as suspended particles.

The liquid typically comprises an aqueous solution. The aqueous solution comprises or preferably consists of water. A non-aqueous liquid may include, for example, oils and/or alcohols, or other pharmaceutically acceptable liquids.

Advantageously, when the composition is or comprises a liquid suspension, the composition further comprises a suspending agent. A suspending agent helps to reduce the sedimentation rate of particles in suspension. These are insoluble particles that are dispersed in a liquid medium. Suitable examples of suspending agents include methylcellulose, carboxy methyl cellulose, sodium alginate or povidone and combinations thereof. The amount of the suspending agent may be from about 0.01 to about 15 % (w/v), or from about 0.02 to about 10 % (w/v) or from about 0.1 to about 5 % (w/v) based on the total volume of the composition.

The composition may further comprise a flavouring agent. The flavour may be any suitable flavour. The amount of the flavouring agent may be from about 0.01 to about 15 wt.%, or from about 0.02 to about 10 wt. % or from about 0.1 to about 5 wt.% based on the total weight of the composition. The flavour may, for example, be selected from the group consisting of apple, blackcurrant, orange, lemon, grape, maple, raspberry, cherry, menthol, peppermint, spearmint, vanilla, chocolate, and strawberry and combinations thereof. The flavouring agent may be any commercially available flavouring agent.

The composition may comprise a liquid or liquid medium which is selected from water or an oil, or mixtures thereof. The water may be water from a public or private supply, such as a tap, and may be water which has been subjected to pharmaceutical purification. In general the liquid, such as water or an edible oil, is suitable for oral administration. The oil may be any edible oil. The liquid may be sterile and pyrogen-free but preferably not: examples are saline and water. The composition of the invention may be particularly suitable for oral and enteral administration. Typically, the composition comprises water as the liquid component of the composition.

The iron hydroxypyrone or the composition is preferably for enteral, such as oral administration, and not for parenteral administration, such as injection or infusion. Preferably, the liquid composition is suitable for delivery via a nasopharyngeal or gastric feeding tube.

Preferably the compound and composition is for enteral, such as oral, administration to an animal such as a mammal, for example a human. The animal, such as a mammal, may have a renal disorder or be diabetic. The composition may be for administration to children (for example, under the age of 12, such as from 5 to 11 years old) and in that case is preferably packaged and labelled for children. The liquid composition may also be suitable for administration to adults who cannot swallow tablets, or have swallowing difficulties. This swallowing difficulty may be for neurological reasons such as, for example, a stroke, multiple sclerosis (MS); or for subjects who have had oesophageal or throat surgery or radiation or who have inflamed mucosa such as mucositis.

The composition of the invention may be for administration to subjects with chronic kidney disease (CKD), subjects with diabetes, such as Type I or Type II diabetes or subjects who are children (for example, under the age of 12, such as from 5 to 11 years old). The subject may be an animal as defined herein and is preferably a mammal such as a human.

The subject may have or be at risk of developing anaemia, such as iron deficiency anaemia or Vitamin B12 anaemia. The anaemia may be associated with blood loss, such as following surgery, or an inflammatory disease of the gastrointestinal tract, or anaemia associated with pregnancy or a poor diet.

The liquid composition is especially useful for oral administration to patients who have difficulty in swallowing solid forms. Such difficulties are common in patient groups such as children and geriatrics.

Whilst the dosage of the compound or composition given in each particular case will depend upon various factors, including the particular components of the composition, it may be stated by way of guidance that maintenance at a satisfactory level of the amount of iron present in the human (or animal) body will often be achieved using a daily dosage, in terms of the iron content of the compound, which lies in a range from about 1 to 150 mg, such as from 10 to 120 mg (preferably as iron).

However, it may be appropriate in certain cases to give daily dosages either below or above these levels. Compositions containing 15 to 50 mg iron, to be taken once daily, twice daily or three times daily (depending on the severity of the anaemia) are, for example, suitable for the treatment of anaemia. The amount of the compound or composition defined herein which represents a unit dose may be, for example, from about 20 mg to about 400 mg, such 15 as about 100 mg or about 200 mg. Each unit dose may comprise, for example, from about ^υ10 to about 120 mg of iron, such as for example, from about 20 mg to about 80 mg iron. The unit dose may be from, for example, 90 to 120 mg of iron.

For oral administration in humans it is more usual to use compositions incorporating a solid carrier, for example, starch, lactose, dextrin or magnesium stearate. Such solid compositions may conveniently be shaped, for example in the form of tablets, capsules (including spansules), etc. However, liquid preparations are especially useful for oral administration to patients who have difficulty in swallowing solid forms. Such difficulties are common in patients suffering from anaemias associated with arthritis.

The iron hydroxypyrone, such as ferric tri(maltol), is preferably administered to the subject in the form of a capsule, such as a gelatin capsule. The capsule may be coloured and preferably is a hard capsule, such as any of those known in the art. The administration is preferably oral administration.

In one embodiment of the invention, the compound or composition provides a dose of iron of from about 10 mg to about 120 mg, such as from 60 to 90 mg, in from about 50 mg to about 200 mg of the composition.

Depending on the disorder, and the patient to be treated, as well as the route of administration, the iron hydroxypyrone and compositions comprising iron hydroxypyrones may be administered at varying therapeutically effective doses to a subject or patient in need thereof. However, the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe. One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.

In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient. The abovementioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

The compound or composition may be packaged and/or labelled with the use and dosage. The compound or composition may be packaged in the form of: a bottle, which could be, for example, glass or plastic; a sachet; or a carton, such as made from a plastic or plastic coated paper; or cardboard.

The compositions of the invention suitably contain from 0.1% to 20% by weight iron, such as 0.1% to 10% by weight, for example, preferably 2 to 10% by weight.

The compound and compositions of the present invention are particularly useful for preventing or treating mild and serious anaemias in a subject as defined herein. Many of the patients with such disorders are intolerant of standard ferrous anti-anaemia compounds. Ferrous preparations are contra-indicated or the subject of warnings in such conditions. Furthermore, patients who may need blood transfusions or in-patient treatment with intravenous injections can be treated on an outpatient basis saving substantial costs of treatment.

In addition, the compositions of the invention may be for the treatment of anaemia in children with, for example, Stevens-Johnson syndrome.

The compositions of the invention may be used in a method for the treatment of a subject to effect an increase in the levels of iron in the subject’s body, such as the bloodstream, and/or the prevention and/or treatment of iron deficiency, such as iron-deficiency anaemia, which comprises administering to a subject as defined herein an effective amount of the iron hydroxypyrone compound or composition as defined herein.

The iron hydroxypyrone or composition as defined herein is preferably administered in an effective amount. An “effective amount” typically refers to an amount of a compound or composition, which confers a preventative or therapeutic effect on the treated patient. The effect may be objective (e.g. measurable by some test or marker) or subjective (e.g. the subject gives an indication of or feels an effect).

The compounds and compositions defined herein may be administered orally, buccally, rectally, nasally, tracheally, sublingually, in a pharmaceutically acceptable dosage form. 17

For instance, the pharmaceutical compositions may be administered systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by enteral administration in the form of solutions or suspensions, or by rectal administration in the form of suppositories. Preferably the compounds and compositions defined herein are administered orally.

The compounds may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, or suppositories for rectal administration. The type of pharmaceutical formulation may be selected with due regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.

Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques and/or in accordance with standard and/or accepted pharmaceutical practice.

Other forms of enteral administration than through the oral route may also be considered, for example the use of suppositories.

The compounds and compositions defined herein are particularly useful for the treatment of serious anaemias arising from bleeding disorders, particularly of the gastrointestinal tract. Many of the patients with such disorders are intolerant of standard ferrous anti-anaemia compounds. Ferrous preparations can be contra-indicated or be the subject of warnings in such conditions. Furthermore, patients who may need blood transfusions or in-patient treatment with intravenous injections can be treated on an outpatient basis with the compounds and compositions defined herein saving substantial costs of treatment.

The compounds and compositions defined herein may be used in a method for the treatment of a subject to effect an increase in the levels of iron in the subject’s body or bloodstream and/or the prevention and/or treatment of iron deficiency, such as iron deficiency with or without anaemia, which comprises administering to a subject as defined herein an effective amount of the compound or composition as defined herein.

The compounds and compositions described herein are useful in the treatment of iron deficiency with or without anaemia. The term “iron deficiency” as used herein refers to iron deficiency without anaemia - this could be, for example, iron deficiency which has not progressed to anaemia. For the avoidance of doubt, iron deficiency with or without anaemia relates to all diseases and conditions associated with iron deficiency and for which treatment with iron would be therapeutically beneficial. Such diseases are those which are recognised as having iron deficiency as a complication or leading to signs and symptoms. Iron deficiency is also referred to as sideropenia or hypoferremia and results from a prolonged period of inadequate iron intake; deficiency in absorption and/or excessive blood (iron) loss.

Symptoms and signs of iron deficiency can be apparent before iron deficiency anaemia occurs and include but are not limited to fatigue, hair loss, twitches, irritability, dizziness, brittle or grooved nails, appetite disorders such as pica and pagophagia, impaired immune function, chronic heart failure, growth retardation, behaviour and learning problems in children, cognition in the elderly and Plummer-Vinson syndrome (PVS).

Conditions associated with iron deficiency anaemia include, but are not limited to chronic kidney disease (CKD), Systemic Lupus (SLE), rheumatoid arthritis, haematological cancers (e.g. Hodgkin’s disease), chronic bacterial infection (e.g. osteomyelitis), viral hepatitis, HIV, AIDS, diseases of the gastrointestinal tract for example inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis, gynaecological and obstetric situations such as heavy uterine bleeding, pregnancy and childbirth.

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

The following non-limiting examples illustrate the invention and do not limit its scope in any way. In the examples and throughout this specification, all percentages, parts and ratios are by weight unless indicated otherwise. Average molecular weights are based on weight unless otherwise specified. It will be appreciated that the various percentage amounts of the different components that are present in the products of the invention, including any optional components, will add up to 100%.

EXAMPLES:

Example 1:

Iron Hydroxypyrone for admininstration

The iron hydroxypyrone (ST10) composition used comprises a gelatin capsule containing 213.5 mg of ferric trimaltol (equivalent to 30 mg of elemental iron).

Example 2:

Double blind study

Details of the subjects tested in a double blind study are set out in the table below. Samples of serum were taken at week 0 and week 12. The subjects were either administered the iron hydroxypyrone composition described above or a placebo.

C haractcristk·	ST19	Placebo (A=C4)
Age (years)
Mean (SR)	40 I (13.52)	3X.5 112 .30)
Median (Range)	3K. MIS to 75,	37.5(19 to7t\i
-'Ml fn (%ij	w)i*>3 8%i	60 (93.8%)
fn (‘kill	4 ¢63%)	4 (6.3%1
Gender, it (%)
Male	24(57.5%)	21 (32.X“.O
Female	40 ¢62 5 ·,)	43 (67.2.)
Rate, n (%)
Ά iiiie	62 y%)	n0(93.8“,»)
Black or African Aaieocni	u	1 (1 6%i
Asian	1 d.n%5	2iJ.l%>)
Other	1 (1.6%)	1 (t 6%)
Elhnkity. n
Hispanic nr Latino	0	0
Nut-Hispanic ar Latino	61 (953%)	?t3 (98.4%)
I'nknown	3 (4,7%)	1 (1 c»%i
Height (ttnl
MwtuiSDi	170,4(7,75)	17()5 (9,79)
Median (Range)	170,0(158 to 192)	170 0(152 to 194»

The method for determining the hepcidin level in the samples from the subjects was that described in Ward et al (Proteome Science, 2008, 6:28), which is incorporated by reference herein. The method for measuring hepcidin in the samples from the subjects comprises the use of a stable isotope labelled hepcidin spiking in conjunction with SELDI-TOF-MS.

The level of CRP in the subjects was measured by the Roche Immunoturbidimetry Generation 3 methodology.

The data in Figures 1 to 3 indicate that the absorption of iron from iron hydroxypyrones in the subjects is independent of the hepcidin level and so iron hydroxypyrones can be used to treat iron deficiency in subjects with high levels of hepcidin which would otherwise not be considered capable of absorbing iron.

Claims

CLAIMS:

1. An iron hydroxypyrone for use in the prevention and/or treatment of iron deficiency in a subject, or for use in increasing the level of iron in the body or bloodstream of a subject, wherein the subject has an elevated hepcidin level.

2. The iron hydroxypyrone for use according to Claim 1, wherein the elevated hepcidin level is equal to or greater than about 20 ng of hepcidin-25 /ml of serum or plasma.

3. The iron hydroxypyrone for use according to Claim 1 or Claim 2, wherein the iron deficiency comprises iron deficiency with or without anaemia.

4. The iron hydroxypyrone for use according to any one of Claims 1 to 3, wherein the level of iron uptake in the subject from the iron hydroxypyrone is substantially independent of the hepcidin level in the subject.

5. The iron hydroxypyrone for use according to any one of Claims 1 to 4, wherein the hepcidin level is determined from serum or plasma taken from the subject.

6. The iron hydroxypyrone for use according to any one of Claims 1 to 5, wherein the hepcidin level is measured using SELDI mass spectrometry.

7. The iron hydroxypyrone for use according to any one of Claims 1 to 6, wherein the subject has an active inflammatory condition.

8. The iron hydroxypyrone for use according to any one of Claims 1 to 7, wherein the iron hydroxypyrone has no substantial effect on the level of hepcidin and/or inflammation in the subject.

9. The iron hydroxypyrone for use according to any one of Claims 1 to 8, wherein the iron hydroxypyrone is administered enterally, such as orally.

10. The iron hydroxypyrone for use according to any one of Claims 1 to 9, wherein the hydroxypyrone comprises a hydroxy-4-pyrone.

11. The iron hydroxypyrone for use according to Claim 10, wherein the hydroxy-4pyrone is selected from the group consisting of: a 3-hydroxy-4-pyrone and a 3-hydroxy-4pyrone in which one or more of the hydrogen atoms attached to the ring carbon atoms are replaced by an aliphatic hydrocarbon group having 1 to 6 carbon atoms.

12. The iron hydroxypyrone for use according to any one of Claims 1 to 11, wherein the hydroxypyrone is selected from maltol, ethyl maltol or mixtures thereof.

13. The iron hydroxypyrone for use according to any one of Claims 1 to 12, wherein the 10 iron hydroxypyrone compound comprises an iron tri(hydroxypyrone), such as ferric tri(hydroxypyrone).

14. The iron hydroxypyrone for use according to any one of Claims 1 to 13, wherein the iron hydroxypyrone comprises ferric tri(maltol), optionally in the form of a gelatin capsule.

15. A method for preventing and/or treating iron deficiency in a subject, or for increasing the level of iron in the body or bloodstream of a subject, comprising the step of administering to the subject an iron hydroxypyrone, and wherein the subject has an elevated hepcidin level.

Intellectual

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Application No: GB1614181.4 Examiner: Dr Graham Feeney