HK1156552B - Mono (iron hydroxypyrone) and combination (iron hydroxypyrone and gi inflammation inhibiting agents) compositions for anaemia or h. pylori infections - Google Patents

Description

Compositions of iron hydroxypyrones alone and in combination (iron hydroxypyrones and inhibitors of gastrointestinal inflammation) for anemia or helicobacter pylori infection

The present invention relates to therapeutic compositions comprising ferric ions and their medical use.

The supply of sufficient iron into the body is a necessary condition for the growth and maintenance of good health of both human and animal tissues. In addition, in certain pathological conditions of occult blood loss or maldistribution of iron in the body, the body may be in a state of low iron storage and associated chronic anemia. This condition can be seen in inflammatory diseases of the gastrointestinal tract, such as gastric and peptic ulcers, reflux esophagitis, ulcerative colitis and Crohn's disease.

Anemia can also result from surgery leading to severe blood loss and may be associated with gastrointestinal infections such as those caused by Helicobacter pylori (Helicobacter pylori).

Achlorhydria and achlorhydria refer to states in which no or low levels of gastric acid are produced in the stomach, respectively. Achlorhydria may be caused by a variety of causes, including: pernicious anemia, autoimmune gastritis, other autoimmune disorders, such as autoimmune thyroid disease, any cause of severe chronic gastritis (helicobacter pylori is the most common substance that can cause destruction of intragastric wall cells (cells that make hydrochloric acid) leading to achlorhydria), mucolipidosis type IV (an autosomal recessive lysosomal storage disease), use of antacids or drugs to reduce gastric acid production or transport, or atrophic gastritis.

The listing or discussion of an obvious prior publication in this specification is not necessarily an admission that the publication is part of the state of the art or is common general knowledge.

WO 96/41627 describes ferric iron complexes comprising hydroxypyrones of carboxylic acids, such as citric acid. The composition can be used for treating iron deficiency anemia.

WO 98/16218 discloses the use of certain metal ion complexes for the treatment of infections of the gastrointestinal tract caused by helicobacter pylori. The complex includes an iron complex in the trivalent state. However, the patients did not receive treatment with acid reducing regimens (acid reducing regimens).

WO01/89534 describes the selective treatment of gastrointestinal infections caused by H.pylori using cobalt salts.

WO 02/24196 discloses compositions in solid form (e.g. various powders) comprising a mixture of ferrous salts and hydroxypyrones, which may be used to increase the iron level in the bloodstream of a patient or may be used to treat and/or prevent gastrointestinal infections.

WO 2005/048912 describes methods and compositions for treating conditions associated with H.pylori using compounds containing endoperoxide bridges.

WO3/097627 discloses a process for forming iron hydroxypyrones.

US 2007/0161600 describes the use of iron-carbohydrate complexes for the treatment of iron-related disorders.

Gastric acid secretion is known to aid iron absorption, and when iron is in the ferrous state, absorption is more susceptible. Antacids are also known to impair iron absorption by forming insoluble complexes (Martindale, page1347, 32nd Edition, 1999). Studies have shown that administration of antacid drugs can cause iron deficiency due to reduced iron absorption (aynard et al, med. toxicol. adapt Drug exp.1988, vol.3, pp 430-448). Thus, one skilled in the art would not expect that iron would be absorbed in the stomach in the presence of an acid-reducing agent (www.numarkpharmacists.com/hn/Drug/Famotidin-e.html).

The gastric environment is not conducive to iron absorption and there are many medical conditions that require iron absorption to address anemia. For example, in the case of gastritis and high pH (e.g., greater than 6.5), iron absorption may be too low to effectively treat anemia. In addition, treatment regimens for conditions such as helicobacter infection typically include the use of an acid reducing agent. The present invention may be considered, at least in part, to be directed to the following unexpected findings: acid reduction regimens (e.g., for treatment needs such as ulcers, gastritis, and acid reflux) are compatible with certain iron hydroxypyrones and can effectively absorb iron from the iron hydroxypyrones despite the use of acid reduction regimens.

The object of the present invention is to alleviate some of the problems of existing anemia treatments.

In a first aspect, the present invention provides a composition for increasing the level of iron in the bloodstream of a patient, comprising one or more compounds capable of treating and/or preventing an inflammatory disease of the gastrointestinal tract; and iron hydroxypyrone.

Another aspect provides a composition for the prevention and/or treatment of anemia (e.g. iron deficiency anemia) comprising one or more compounds capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract; and iron hydroxypyrone.

In a further aspect, there is provided a composition or kit for increasing the level of iron in the bloodstream of a patient, comprising one or more compounds capable of treating and/or preventing an inflammatory disease of the gastrointestinal tract; and iron hydroxypyrone, preferably wherein the iron hydroxypyrone comprises iron in the ferrous state.

In a further aspect, compositions and kits are provided for increasing the level of iron in the bloodstream of a patient, comprising one or more compounds capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract and iron hydroxypyrone, preferably with the proviso that when iron is trivalent iron, the compound is not a cobalt salt. Preferably, the composition does not comprise an antibiotic.

Another aspect provides a composition comprising an iron hydroxypyrone for administration to a subject having, or at risk of having, achlorhydria.

In one aspect of the invention, there is provided a composition comprising an iron hydroxypyrone for administration to a subject, wherein the gastric pH of the subject is equal to or greater than about 4, such as greater than 5 or 6, for example about 6.5 or above.

In another aspect of the invention there is provided a composition comprising an iron hydroxypyrone for administration to a subject, wherein the subject has or is suffering from an inflammatory disease of the gastrointestinal tract and preferably the gastric pH of the subject is equal to or greater than about 4, for example greater than 5 or 6, for example about 6.5 or above.

In one embodiment of the invention, the inflammatory disease of the gastrointestinal tract requires a gastric acid-reducing therapeutic regimen as defined herein. However, in one embodiment, the inflammatory disease may not require a gastric acid-reducing treatment regimen as defined herein.

The iron hydroxypyrones, the inflammatory diseases and the gastric pH and combinations thereof in each of the above aspects are preferably as defined herein.

In one embodiment of the invention, the iron hydroxypyrone is administered alone, e.g., in the absence of other pharmaceutically active compounds, e.g., in the absence of one or more compounds capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract.

In one embodiment of the invention, the composition and/or iron hydroxypyrone is used for iron absorption, preferably for iron absorption after oral administration, e.g. after entering the blood and/or body of a subject.

Examples of such inflammatory diseases of the gastrointestinal tract, preferably where a gastric acid reduction regimen is required, include gastric or peptic ulcers, reflux esophagitis, ulcerative colitis, crohn's disease, gastritis, Zollinger-Ellison syndrome, or acid reflux.

In all aspects or embodiments of the invention, the one or more compounds capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract, preferably diseases for which a gastric acid reducing treatment regimen is required, preferably comprises an acid reducing regimen. Such acid reduction schemes are well known to those skilled in the art. For example, the acid reduction regimen may include one or more compounds capable of treating and/or preventing an inflammatory disease of the gastrointestinal tract, such as gastric or peptic ulcer, reflux esophagitis, ulcerative colitis, crohn's disease, gastritis, zollinger-ellison syndrome, or acid reflux.

In all aspects or embodiments of the invention, the peptic ulcer is preferably a gastric ulcer and the anemia is preferably iron deficiency anemia. The anemia is preferably associated with an inflammatory disease of the gastrointestinal tract as defined herein.

In one embodiment of the invention, the anemia is caused by post-operative blood loss and/or is associated with gastrointestinal infections, such as gastrointestinal infections caused by helicobacter pylori.

The compositions and/or kits of the invention are preferably for administration to humans.

The term "subject" as used herein preferably refers to a mammal, e.g. a human. The term "mammal" also includes livestock animals, such as horses, cattle, sheep, and pigs, and pets such as dogs, cats, and hamsters.

In one embodiment of the invention, the subject has been administered, will be administered or is being administered with an acid lowering regimen as defined herein or one or more compounds capable of treating and/or preventing an inflammatory disease of the gastrointestinal tract.

In one embodiment of the invention, the one or more compounds capable of treating and/or preventing an inflammatory disease of the gastrointestinal tract comprise an acid lowering regimen. Surprisingly, it was found that the iron hydroxypyrones of the present invention can be administered in combination with an acid reducing treatment for the treatment of gastrointestinal disorders resulting from excess gastric acid. The iron hydroxypyrone may also be administered to a patient who normally has a high gastric pH, e.g., equal to or greater than about 4, e.g., greater than 5 or 6, e.g., about 6.5 or above, e.g., greater than 4-8, 4.5-7, 5-6.5, or 5.5-6.0, and is effectively absorbed. The high gastric pH may be, for example, the result of achlorhydria, administration of an acid reduction regimen as defined herein, or an inflammatory disease of the gastrointestinal tract as defined herein, and combinations thereof. The iron hydroxypyrone may be administered for iron absorption (e.g., after oral administration), and/or may be administered to maintain iron levels in the subject, i.e., to provide or maintain normal, healthy, or nutritional iron levels.

According to the present invention, the iron hydroxypyrone may be administered simultaneously, before or after one or more compounds or acid reduction regimens capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract. In one embodiment, the iron hydroxypyrone is administered simultaneously with or after one or more compounds or acid reduction regimens. For example, the iron hydroxypyrone may be administered 1 minute to 2 hours after the compound is administered, more preferably 10 minutes to 1 hour after the compound is administered, and most preferably about 30 minutes after the compound is administered.

In one embodiment of the invention, the composition as defined in all aspects or embodiments of the invention is for administration to a human or animal suffering from or suffering from an inflammatory disease of the gastrointestinal tract, preferably a gastric acid reducing treatment regimen. For example, the human or animal may have gastric or peptic ulcers, reflux esophagitis, ulcerative colitis, crohn's disease, gastritis, zollinger-ellison syndrome, acid reflux and/or peptic ulcers and be in need of such treatment.

In a preferred embodiment of the invention, the composition is for administration to a human or animal suffering from a gastrointestinal infection, as defined herein.

Although the infection of the gastrointestinal tract may be any infection, it is preferred that the infection of the gastrointestinal tract is caused by helicobacter pylori.

Suitable molar ratios of the one or more compounds or acid reducing schemes to the iron hydroxypyrone are from 100: 1 to 1: 100, preferably from 50: 1 to 1: 50, more preferably from 10: 1 to 1: 10, for example from 5: 1 to 1: 5, for example from 2: 1 to 1: 2. Preferably, the ratio of the one or more compounds to the iron hydroxypyrone is from 10: 1 to 1: 10 by weight.

The acid reduction regimen can be administered to a human patient in a normal dosage range for therapeutic or prophylactic treatment. In one embodiment of the invention, the composition may be employed for maintenance therapy or for prevention of inflammatory diseases of the gastrointestinal tract, wherein the disease state is as defined in any of the embodiments herein. Thus, the composition may comprise the compound and iron hydroxypyrone at a lower dose than the initial therapeutic dose for the identified disease.

In one embodiment of the invention, the composition comprises a maintenance dose of one or more compounds or acid-lowering regimens capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract, and a nutritional dose (iron) of iron hydroxypyrane. For example, the daily dose of the compound may be less than 400mg, such as less than 300mg, 200mg or 100 mg. Typically, the daily maintenance dose of the compound (e.g. omeprazole, pantoprazole or ranitidine) may be from 5mg to 140mg, such as from 10mg to 100mg, preferably from 20mg to 50mg, administered in one or more doses per day.

Examples of suitable nutritional doses (preferably daily nutritional doses) of the iron hydroxypyrone include less than 40mg (iron) or 60mg (iron) per day, such as 5mg to 20mg (iron), for example about 15mg (iron). Typically, the dosage may be administered for 1-4 weeks.

In yet another embodiment of the present invention, the one or more compounds capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract as defined herein comprise one or more acid reducing agents. The acid-lowering agent may reduce acid levels directly (i.e., by neutralizing the acid) or indirectly (i.e., by, for example, inhibiting the receptor that causes excessive acid secretion or by treating the underlying disease state).

Compositions comprising metal salts, antibiotics and proton pump inhibitors for the treatment of gastrointestinal disorders in a method called "triple therapy" are known. Antibiotics and proton pump inhibitors are suitable for use in the compositions of the invention as defined herein. Suitable antibiotics include, for example, amoxicillin, metronidazole, clarithromycin, and mixtures thereof. Suitable proton pump inhibitors include, for example, lansoprazole, omeprazole, pantoprazole, and rabeprazole. H₂Receptor antagonists, such as ranitidine, famotidine, nizatidine, cimetidine, may also be used in the present invention. The omeprazole may be in the form of magnesium omeprazole or sodium omeprazole. The ranitidine may be in the form of bismuth citrate ranitidine or ranitidine hydrochloride.

In any aspect or embodiment of the invention, the one or more compounds or acid-lowering agents capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract may be selected from proton pump inhibitors, H₂A receptor antagonist or a substance capable of neutralizing an acid, such as an alkaline agent as defined herein or a combination thereof or a cobalt compound as defined herein. The term "material capable of neutralizing an acid" is intended to include pharmaceutically acceptable bases. Suitable examples of such bases include bicarbonate commonly used to treat acid refluxA salt, hydroxide, oxide or carbonate. Preferably, the bicarbonate, hydroxide, oxide or carbonate is combined with a pharmaceutically acceptable cation, such as an alkali metal (e.g. sodium or potassium) or an alkaline earth metal (e.g. magnesium, calcium) or a transition metal (e.g. cobalt) or a metal (e.g. aluminium).

In one embodiment of the present invention, the acid reducing agent as defined herein is selected from omeprazole, lansoprazole, pantoprazole, ranitidine, famotidine, nizatidine, cimetidine, sodium bicarbonate, potassium bicarbonate, calcium carbonate, aluminum hydroxide, magnesium carbonate, cobalt carbonate or combinations thereof.

In any aspect or embodiment of the invention, the composition may further comprise an antibiotic, such as amoxicillin, metronidazole, clarithromycin, and mixtures thereof.

In an embodiment or aspect of the invention, the one or more compounds capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract preferably comprise or consist of a cobalt compound.

The cobalt compound may include a cobalt salt. Suitable examples of cobalt salts are defined in WO01/89534, the teachings of which are incorporated herein by reference. The cobalt salt is preferably a cobalt (ii) salt, as it is well known that, unlike trivalent cobalt salts (iii), divalent cobalt salts (ii) are readily available and long-term safety concerns exist for trivalent cobalt salts (iii).

The cobalt salt must be capable of providing cobalt ions (in hydrated form) at the site of infection in the gastrointestinal tract. Preferably, the cobalt salt, such as cobalt (ii), comprises an anion which is not too strongly bound to the cobalt ion. Preferably the anion is a strong acid anion (i.e. having a pKa of less than about 3, 4, 5 or 6, for example less than 2) and/or is monovalent.

Suitable anions include chloride, gluconate, nitrate, sulfate, phosphate, carbonate, hydroxide, acetate, and mixtures thereof, including salts containing two or more anions. Among them, hydrochloride, carbonate, gluconate, hydroxide and acetate are more preferable.

The cobalt salt preferably contains cobalt ions in non-complexed form (i.e., Co (H) is formed, for example, when the salt is in aqueous solution₂O)₆ ²⁺Ion) or in the form of a complex, e.g. in which the cobalt ion is relatively weakly bound so that the complex is at least partially dissociated to provide a cobalt ion form suitable for uptake by helicobacter pylori at the site of infection.

Alternatively, the cobalt compound may comprise a cobalt complex. Examples of ligands suitable for forming cobalt complexes are defined in WO 98/16218, the teachings of which are incorporated herein by reference. Preferred cobalt complexes (cobaltcomplex) include, for example, cobalt complexed with ascorbate, aspartate, citrate, gluconate, histidine, malate, maltol, glutamate, glutamine, succinate, gluconate, or tartrate or combinations thereof (preferably in the (II) or (III) valence state).

In one embodiment of the invention, said cobalt compound (cobaltcompound) as defined herein comprises cobalt (II) gluconate or cobalt (II) chloride (preferably in hydrated form, i.e. the dihydrate of cobalt (II) gluconate or the hexahydrate of cobalt (II) chloride) or a combination thereof.

In one embodiment of the invention, the amount of cobalt compound is selected to be selectively used in the treatment of gastrointestinal infections caused by helicobacter pylori, i.e. the cobalt compound is present in an amount below the MIC for other microorganisms (especially beneficial bacteria) in the intestinal tract.

The daily dosage of the cobalt compound, e.g. cobalt (II) gluconate or cobalt (II) chloride, is preferably less than 200mg (cobalt), e.g. less than 100mg (cobalt), e.g. 2mg to 50mg (cobalt), e.g. 5mg to 20mg (cobalt).

In one embodiment, for example, the amount of compound (e.g., cobalt, such as a cobalt salt) required to treat a gastrointestinal disorder of the invention is 1mg to 50mg per day, more preferably 1mg to 30mg per day, such as 5mg or 20mg per day (preferably cobalt). A suitable dosage form comprises 10mg (preferably cobalt) of the compound and this dose is typically administered twice a day for several weeks (e.g. 1-4 weeks) to treat the infection. It will be appreciated by those skilled in the art that other dosage regimens may be equally applicable to the present invention. For example, the cobalt compound may be in a slow release form as described in WO 01/89534.

The term "iron hydroxypyrone" as used herein is intended to encompass compositions comprising hydroxypyrone and iron. The term includes, for example, complexes of iron with hydroxypyrone (e.g., ferriprotopanolate), and mixtures comprising an iron compound (e.g., an iron salt or iron complex) and hydroxypyrone in substantially non-complexed form (e.g., less than 10%, 5%, 2%, or 1% hydroxypyrone complexed), such as ferrous or ferric gluconate and ferrous or ferric maltol (preferably in the solid state).

Suitably, the iron hydroxypyrone may comprise ferrous iron (Fe)²⁺) Or ferric iron (Fe)³⁺) Iron in the oxidized state. Alternatively, the iron hydroxypyrone may comprise ferrous iron (Fe)²⁺) And ferric iron (Fe)³⁺) Iron mixtures in the oxidized state.

In one embodiment of the invention, the iron hydroxypyrone comprises iron in the trivalent state. In another embodiment, the iron hydroxypyrone comprises sub-state iron, particularly where the iron hydroxypyrone is in solid form (e.g., a powder or tablet).

The hydroxypyrone is preferably 3-hydroxy-4-pyrone. Suitable pyrones include 3-hydroxy-4-pyrone itself or 3-hydroxy-4-pyrones in which one or more hydrogen atoms attached to a ring carbon atom are substituted with an aliphatic hydrocarbon group of 1-6 carbon atoms, or 5-hydroxypyrones (e.g., kojic acid). The most preferred pyrones are maltol (3-hydroxy-2-methyl-4-pyrone) and ethyl maltol. Alternatively, the hydroxypyrone may be a natural product (e.g. mecconic acid or isomalt) which can be converted in vivo to another hydroxypyrone.

Certain hydroxypyrones, such as maltol, are commercially available. For other hydroxypyrones, in many cases a convenient starting material consists of 3-hydroxy-4-pyrone, which is readily obtained by decarboxylation of 2, 6-dicarboxy-3-hydroxy-4-pyrone (meconic acid). For example, a 3-hydroxy-4-pyrone can be reacted with an aldehyde to insert a 1-hydroxyalkyl group at the 2-position, which is then reduced to produce a 2-alkyl-3-hydroxy-4-pyrone. The preparation of 2-ethyl-3-hydroxy-4-pyrone and the like by the above-described route is described in published U.S. application No. 310141(1960 series). Other preparation methods are described in Spielman, Freifelder, j.am.chem.soc.vol.69 Page 2908 (1947).

Those skilled in the art will appreciate that these are not the only routes to the above compounds and that a variety of other protocols may be used.

In one embodiment of the invention, the iron hydroxypyrone is a trivalent iron complex with hydroxypyrone. Preferably, the ferric iron complex is a 1: 3 molar complex of iron with hydroxypyrone.

Preferably, the iron hydroxypyrone is ferric maltol, ferric ethylmaltol or a mixture thereof. It is particularly preferred that the ferric maltol is ferric maltol. The ferric trimaltol can be prepared according to any method known in the art. Preferably, trimarafen ferric iron can be prepared as described in WO 03/097627, the teachings of which are incorporated herein by reference.

In another embodiment of the invention, the iron hydroxypyrone is in the form of a solid, a liquid or a suspension in a liquid and comprises a ferrous or ferric salt as defined herein and a mixture of hydroxypyrone. The solid mixture may also be dry (e.g., substantially free of liquid (e.g., water), i.e., the mixture contains less than 10 wt.%, 5 wt.%, or 2 wt.%, such as less than 1 wt.% liquid). Solid mixtures of ferrous salts and hydroxypyrones are stable when stored under substantially dry conditions for periods of moderate length. However, upon dissolution in water, the composition undergoes some or all of the reaction of the ferrous iron being oxidized to ferric iron.

The ferrous or ferric salts may be ferrous (ii) or ferric (iii) salts with any pharmaceutically acceptable anion. Preferably, the iron (II) salt Is Iron (II) carbonate or iron (II) carboxylate.

The ferrous or ferric salt is preferably ferrous (II) or ferric (III) carboxylate. The iron (II) carboxylate may be selected, for example, from iron (II) gluconate, iron (II) succinate or iron (II) fumarate and mixtures thereof. The iron (III) carboxylate is preferably selected from the group consisting of iron (III) citrate, iron (III) ammonium citrate or iron (III) tartrate and mixtures thereof.

In any aspect or embodiment of the invention, the compound (or acid reduction regimen) preferably comprises a cobalt compound, such as cobalt (II) gluconate or cobalt (II) chloride, preferably for example in a daily dose of less than 100mg (cobalt), and the iron hydroxypyrone comprises a mixture of a ferrous or ferric salt of a carboxylic acid and a solid form of a hydroxypyrone, such as maltol or ethylmaltol, preferably in a daily dose (in terms of iron content), for example in the range of 15mg to 50mg (iron). In any embodiment of the invention, the daily dose of the compound is preferably a maintenance dose and the daily dose of iron hydroxypyrone is preferably a nutritional dose (i.e. it is capable of maintaining stored iron levels in the body, e.g. by "leaking" in place of any iron).

The composition or kit of the invention for increasing the level of iron in the bloodstream of a patient and/or treating and/or preventing anemia may comprise any one of the compounds described above or iron hydroxypyrone or a combination thereof.

In particular, the kit may comprise the one or more compounds capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract or acid reducing agent, e.g. one or more compounds capable of treating gastritis, acid reflux and/or peptic ulcer, and iron hydroxypyrone, wherein the compounds and iron hydroxypyrone are packaged separately and optionally instructions for administration are provided for the two separate parts. This may be appropriate when there is storage incompatibility between the compound and the iron hydroxypyrone.

In one embodiment, the composition comprises a co-formulation (e.g., in the same solid or liquid) of one or more compounds or acid reducing agents capable of treating and/or preventing an inflammatory disease of the gastrointestinal tract, such as a co-formulation of one or more compounds capable of treating gastritis, acid reflux and/or peptic ulcer as defined herein and iron hydroxypyrone as defined herein. This may be appropriate when there is no storage incompatibility between the compound and the iron hydroxypyrone.

In a preferred composition or kit of the invention, the iron hydroxypyrone comprises a solid or dry (i.e. substantially free of liquid (e.g. water), i.e. liquid constitutes less than 10 wt.%, 5 wt.% or 2 wt.%, such as less than 1 wt.%) mixture of ferrous carboxylates, such as ferrous gluconate and ferrous maltol or ferrous ethylmaltol, and the one or more compounds or antacids capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract comprise cobalt compounds, such as cobalt gluconate (preferably cobalt (ii) and cobalt gluconate hydrate). The molar ratio of ferrous salt to maltol or ethyl maltol is preferably about 1: 3.

In another preferred composition or kit of the invention, the iron hydroxypyrone comprises ferric trimaltol and the one or more compounds capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract or acid reducing agent, for example, one or more compounds capable of treating gastritis, acid reflux and/or peptic ulcer, comprises potassium bicarbonate. The potassium bicarbonate can be present in a solid or liquid (e.g., aqueous) state.

Conveniently, the composition of the invention is in the form of a powder (which term includes both fine powders and granules) comprising a mixture of powdered iron hydroxypyrone and the one or more compounds. The iron hydroxypyrone may be in crystalline form, amorphous form, or other solid form, but is preferably in crystalline form. Ferrous or ferric salts may contain water of crystallization, i.e. they may be in the form of hydrates.

In a further aspect, the compositions of the invention are for use in medicine, and in a further aspect the invention provides a pharmaceutical composition comprising a composition of the invention and a pharmaceutically acceptable diluent or carrier.

The invention also provides a method of forming a composition of the invention, which method comprises admixing one or more compounds or acid reducing agents capable of being used in the treatment and/or prevention of an inflammatory disease of the gastrointestinal tract with iron hydroxypyrone (both as defined herein). The mixing can be carried out in solid or liquid state. For example, both ingredients may be in the form of a substantially dry solid (e.g., a powder or tablet) preferably having a moisture and moisture content of less than 10 wt.%, 5 wt.%, 2 wt.%, or 1 wt.%.

In the above aspects and embodiments of the invention, the pharmaceutical composition or kit of the invention may be adapted for oral administration. Forms suitable for oral administration include powders, tablets and capsules (e.g., gelatin capsules) as well as solutions and suspensions in aqueous or non-aqueous solutions, water-in-oil liquid emulsions or oil-in-water liquid emulsions.

Suitable pharmaceutically acceptable diluents and carriers include, for example, lubricating oils (such as magnesium stearate), stabilizers and suspending agents (such as methylcellulose and povidone) and other tableting agents as well as dosing fillers (such as lactose) and glidants (such as Aerosil 2000)^TM). Particularly useful diluents and carriers are wetting agents or surfactants, preferably nonionic or ionic surfactants. Suitable examples of nonionic surfactants include polyoxyethylene 10 oleyl ether (polyoxyl 10 oleyl ether) and polysorbates. A suitable example of an ionic surfactant is sodium lauryl sulfate.

Alternatively, the pharmaceutical composition may be provided as a suspension in liquid or liquid form, as a powder for reconstitution prior to oral or parenteral administration, or it may be formulated for use as a suppository. Liquid carriers are preferably sterile and pyrogen-free, such as saline and water. Liquid formulations are particularly suitable for oral and parenteral administration.

The pharmaceutical compositions of the invention may comprise more than one iron hydroxypyrone of the invention or one or more compounds capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract or acid-lowering agents, and may also comprise other active compounds. Typical possible additives include, for example, flavoring and coloring agents known to those skilled in the art, as well as those listed herein.

The pharmaceutical compositions of the present invention may be prepared in unit dosage form, i.e., in the form of separate portions containing one or more unit doses or sub-unit doses. Preferably, the compositions of the present invention are formulated to provide rapid release of iron for optimal absorption in the body.

Also, the dosage of the composition given in each particular case will depend on a variety of factors including the particular ingredients of the composition, and may be dictated by such guidance: the amount of iron present in the human (or animal) body is generally maintained at a satisfactory level using a daily dose (iron content of the compound) of about 1mg to 150mg, such as 10mg to 120mg (preferably iron). However, in some cases it may also be appropriate to administer daily doses below or above the levels indicated above. Administration of a composition containing 15mg to 50mg of iron once daily, twice daily or three times daily (depending on the severity of the anemia) is suitable for the treatment of, for example, anemia.

Suitably, the composition of the invention comprises 0.1 wt% to 20 wt% iron, such as 0.1 wt% to 10 wt% iron, for example preferably 2 wt% to 10 wt% iron.

One embodiment of the present invention provides a composition for administration to a subject having, or at risk of having, achlorhydria, comprising iron hydroxypyrone; and optionally one or more compounds capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract, preferably requiring a gastric acid-reducing treatment regimen.

The composition is preferably used for increasing the level of iron in the blood of a patient and/or for preventing and/or treating anemia such as iron deficiency anemia as described above.

The achlorhydria may be caused by any of the causes mentioned above or known to the person skilled in the art, for example pernicious anemia, autoimmune gastritis, other autoimmune disorders, such as autoimmune thyroid disease, any cause of severe chronic gastritis (helicobacter pylori is the most common substance that can cause destruction of intragastric wall cells (cells that make hydrochloric acid) leading to achlorhydria), mucolipidosis type IV (an autosomal recessive lysosomal storage disease), use of antacids or drugs to reduce gastric acid production or transport, or atrophic gastritis.

In one embodiment of the invention, achlorhydria is associated with or caused by an inflammatory disease of the gastrointestinal tract, such as, for example, gastric or peptic ulcers, reflux esophagitis, ulcerative colitis, crohn's disease, gastritis, zollinger-ellison syndrome, acid reflux and/or peptic ulcers.

In one embodiment of the invention, achlorhydria is associated with or caused by atrophic gastritis or a gastrointestinal infection (e.g. caused by helicobacter pylori).

The composition for administration to a subject suffering from or at risk of suffering from achlorhydria may be as defined in the various aspects or embodiments herein, in particular, the compound and iron hydroxypyrone may be as defined in any of the embodiments above.

In one embodiment of the invention, the subject may have detectable anti-H despite stimulation (e.g., pentagastrin maximal stimulation) and/or detectable high gastrin levels and/or maximal acid production of less than 6.9 m/mole/hr (e.g., less than 5.0 m/mole/hr)⁺/K⁺Atpase proton pump antibodies and/or can maintain high gastric pH (e.g., greater than 4.0, 5.0, 6.0, or 6.5).

In any aspect or embodiment of the invention, the pH of the environment of iron absorption (e.g. the gastric environment or the gastrointestinal tract), e.g. the gastric pH, is preferably equal to or greater than about 4, e.g. greater than 5 or 6, e.g. about 6.5 or more for iron absorption, e.g. from 4 to 8, 4.5 to 7, 5 to 6.5. Thus, the one or more compounds or acid lowering regimen in any one of the aspects or embodiments may also be defined as being suitable for raising the pH (e.g. gastric pH) of the environment in which iron is absorbed (e.g. the gastric environment or the gastrointestinal tract) to or capable of raising the pH (e.g. gastric pH) of the environment in which iron is absorbed (e.g. the gastric environment or the gastrointestinal tract) to greater than about 4, such as greater than 5 or 6, for example about 6.5 or more (e.g. 4-8, 4.5-7, 5-6.5 or 5.5-6.0, 5-8, preferably 6-7) prior to or at the time of iron absorption.

The invention is illustrated by the following non-limiting examples, which do not limit the scope of the invention. In the examples and throughout the specification, all percentages, integers and ratios are by weight unless otherwise specified.

Examples

Example 1

Patient 1

Said patient has taken Gaviscon containing sodium bicarbonate^TMAs an acid reducing agent to reduce acid reflux. The patient suffers from rupture of the gallbladder requiring surgery and is extremely anemic due to blood loss. The patient continued to take Gaviscon^TMBut ferrous sulfate tablets are also taken for anemia. The patient developed severe side effects of gastric intolerance and severe headache, and ferrous sulfate did not correct his anemia. Beginning treatment of said patient with maltol and ferrous gluconate while continuing to take Gaviscon^TMAfter one month, the anemia improved (hemoglobin increased from 8.8 g% to 11.8 g%). At a dose of 45 mg/day, the patient is well tolerated iron.

Example 2

Patient 2

The patient takes the Luoxing for a long time^TM(omeprazole, a proton pump inhibitor that inhibits gastric acid secretion). The patient had undergone hip replacement surgery, and a large amount of blood loss during surgery resulted in iron deficiency anemia. The anemia in the patient was not corrected until after a period of daily administration of maltol and ferrous gluconate (15mg) (Hb > 11.0 g%). Due to the patientThe hemoglobin level of (b) is always on the left of the normal level, and when the patient is tired, maltol and ferrous gluconate are taken as "boosters".

Example 3

The following are examples of pharmaceutical compositions of the present invention, which are suitable for formulation into gelatin capsules.

Ingredient content (mg)

Ferrous gluconate 240

Maltol 200

Cobalt gluconate 100

The balance of the capsule is filled with carrier (lactose)

Example 4

Method of producing a composite material

Thirteen normal female volunteers were treated with 0.5M sodium bicarbonate solution (deacidification protocol) to adjust their gastric pH to > 6.5. The ferric maltol formulation was administered orally using a Haidelberg (Heidelberg) capsule and the percentage of dose absorbed into the blood and throughout the body was determined.

Results

The iron absorbed from the 10mg dose of maltoferric preparation was 10.72%. For a 20mg dose of the maltophenol preparation, the iron absorption was 8.00%.

This is the expected absorption level of a standard iron preparation (e.g., ferrous sulfate) in normal volunteers at normal gastric pH.

Conclusion of the study

In a study in which the 13 female subjects participated, the ferric maltol formulation and sodium bicarbonate (acid reduction regimen) were administered simultaneously and the gastric pH exceeded 6.5. Surprisingly, absorption was not inhibited at this higher pH. The presence of maltol makes the formulation suitable for use in certain medical conditions associated with iron deficiency anemia, with gastritis and a higher pH.

Discussion of the related Art

This work shows that the iron hydroxypyrones of the present invention can be absorbed well at high pH (greater than 6.5). Thus, surprisingly, iron hydroxypyrones can deliver iron in a high pH environment, such as in the presence of an acid reduction regimen for treatment of helicobacter infection. The use of iron preparations containing hydroxypyrones (e.g., maltol) has unexpected advantages because high pH (e.g., caused by the presence of an acid reduction regimen) does not alter the solubility or bioavailability of iron, which has been thought to alter the solubility or bioavailability of iron. Other work also showed that low doses of cobalt had beneficial activity for the treatment of helicobacter infections. Based on these results, co-formulations of cobalt with iron products containing maltol are particularly useful for treating anemia arising from helicobacter infection.

Claims (21)

1. Use of a composition for the manufacture of a medicament for the prevention and/or treatment of iron deficiency anemia, wherein the patient suffers from or is at risk of achlorhydria, and wherein the composition comprises a ferric complex with a hydroxypyrone, or a mixture of a ferrous or ferric salt and a hydroxypyrone, and wherein the hydroxypyrone comprises a 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more hydrogen atoms attached to a ring carbon atom are substituted with an aliphatic hydrocarbon group of 1-6 carbon atoms.

2. Use of a composition for the manufacture of a medicament for the prevention and/or treatment of iron deficiency anemia, wherein the patient has a gastric pH equal to or greater than 4, and wherein the composition comprises a ferric complex with a hydroxypyrone, or a mixture of a ferrous or ferric salt and a hydroxypyrone, and wherein the hydroxypyrone comprises 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more hydrogen atoms attached to a ring carbon atom are substituted with an aliphatic hydrocarbon group of 1-6 carbon atoms.

3. Use according to claim 2, wherein the gastric pH is greater than 5 or 6.

4. Use according to claim 3, wherein the gastric pH is 6.5 or above.

5. Use of a composition for the manufacture of a medicament for the prevention and/or treatment of iron deficiency anemia, wherein the patient has an inflammatory disease of the gastrointestinal tract and the patient has a gastric pH equal to or greater than 4, and wherein the composition comprises a ferric complex with a hydroxypyrone, or a mixture of a ferrous or ferric salt and a hydroxypyrone, and wherein the hydroxypyrone comprises 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone wherein one or more hydrogen atoms attached to a ring carbon atom are substituted with an aliphatic hydrocarbon group of 1-6 carbon atoms.

6. Use according to claim 5, wherein the gastric pH is greater than 5 or 6.

7. The use according to claim 6, wherein the gastric pH is 6.5 or above.

8. The use of claim 2 or 5, wherein the patient has or is at risk of having achlorhydria.

9. The use according to claim 1, 2 or 5, wherein an acid lowering regimen or one or more compounds capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract have been, will be or are being administered to the patient.

10. The use according to claim 1, 2 or 5, wherein the composition further comprises one or more compounds or an acid lowering regimen capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract.

11. The use according to claim 9 or 10, wherein the inflammatory disease of the gastrointestinal tract requires a gastric acid reducing treatment regimen.

12. The use according to claim 1 or 8, wherein the achlorhydria is associated with an inflammatory disease of the gastrointestinal tract.

13. The use according to claim 1 or 8, wherein the achlorhydria is associated with atrophic gastritis or a gastrointestinal infection.

14. The use according to claim 13, wherein the infection of the gastrointestinal tract is caused by Helicobacter pylori (Helicobacter pylori).

15. Use according to claim 1, 2 or 5, wherein the iron hydroxypyrone comprises ferric trimaltol or iron (II) carboxylate or ferric (III) carboxylate and maltol.

16. The use according to claim 1, 2 or 5, wherein the iron hydroxypyrone is administered simultaneously, before or after one or more compounds capable of treating and/or preventing inflammatory diseases of the gastrointestinal tract or an acid-lowering regimen.

17. The use of claim 16, wherein the iron hydroxypyrone is administered simultaneously with or after the one or more compounds or acid reduction regimen.

18. The use of claim 1, 2 or 5, wherein the composition is administered by oral administration.

19. Use according to claim 1, 2 or 5, wherein the composition is for the absorption of iron.

20. Use according to claim 1, 2 or 5, wherein the hydroxypyrone is maltol or ethyl maltol.

21. The use of claim 1, 2 or 5, wherein the patient has, is about to, or is administering an acid-reducing agent selected from proton pump inhibitors, H₂A receptor agonist or a substance capable of neutralizing an acid or a combination thereof.