Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-12-09
2002-01-15
Pak, John (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S460000, C514S502000, C514S574000, C514S814000, C514S815000, C549S206000, C549S210000, C424SDIG001
Reexamination Certificate
active
06339080
ABSTRACT:
The present invention relates to iron compounds for use in medicine, notably in the treatment and prevention of iron deficiency anaemia and to methods of making such compounds.
An adequate supply of iron to the body is an essential requirement for tissue growth in both man and animals. Although there is normally an ample amount of iron in the diet, the level of absorption of iron from food is generally low so that the supply of iron to the body can easily become critical under a variety of conditions. Iron deficiency anaemia is commonly encountered in pregnancy and may also present a problem in the newly born. Moreover, in certain pathological conditions where there is blood loss, or where there is a mal distribution of iron in the body, there may be a state of chronic anaemia. This is seen in diseases such as Crohn's disease, rheumatoid arthritis, certain haemolytic diseases and cancer.
Iron in the ferrous state (Fe
II
) is a strong reducing agent and can also interact with and damage proteins carbohydrates and lipids and therefore be harmful to the body. Therefore iron is best delivered to the body and kept in the body in the ferric state (Fe
III
). However, it is difficult to do this because its solubility, and therefore its bioabsorption, is poor. The absorption rate of ferrous salts such as ferrous sulphate is typically 30% when given on an empty stomach but this causes unpleasant side effects particularly with chronic medication. When given with food, the absorption may fall to 1 to 3% of the administered dose. For some anaemias a daily uptake of 30 milligrams of iron is required, and although a wide range of iron compounds is already marketed for the treatment of iron deficiency anaemia, the poor levels of iron uptake by the body from these compounds necessitate relatively high dosage levels. However, the administration of high doses of poorly absorbed iron complexes may cause siderosis of the gut wall, and a variety of side effects such as stomach pains, nausea, vomiting, constipation and heavy black stools which can result in poor patient compliance with their treatment.
GB 2128998 and EP 0159194 describe neutral ferric iron complexes of various 3-hydroxy-4-pyrones in an iron:hydroxypyrone molar ratio of 1:3. The complexes are described for use at relatively low dosage levels for ferric compounds in the treatment of iron deficiency anaemia. In the body, these complexes were considered to be transferred into the gastrointestinal cell and then dissociate to provide iron for absorption and transfer on to the body's natural uptake processes. However, the complexes of iron described in the above documents suffer from the significant problem that if dissociation of the complex occurs in an unfavourable environment in the body, particularly the gastrointestinal tract, native iron can be formed which precipitates and is therefore not absorbed.
GB 2128998 teaches that only a neutral complex comprising maltol and iron in the ferric state in a molar ratio of 3:1 (maltol:iron) confers a therapeutic effect. By contrast, charged complexes having maltol:iron molar ratios of 1:1 or 2:1 are shown by in vitro tests to be unsatisfactory so that iron from these complexes would not be expected to be taken up to a satisfactory extent in vivo, making them unsuitable for use in medicine.
It is an object of the invention to provide iron complexes for use in medicine, notably in the treatment of iron-deficiency anaemias, which complexes do not suffer from, or substantially mitigate, the above and other problems of known complexes.
It is also an object of the invention to provide methods for making iron complexes and pharmaceutical compositions.
According to a first aspect, the invention provides an iron complex comprising iron in the ferric state and a hydroxypyrone ligand; charcterised in that the iron and hydroxypyrone ligand are provided in combination with a carboxylic acid, most preferably a hydroxycarboxylic acid as a counter ion.
Preferably the carboxylic acid is a C
1
to C
6
acid, particularly those having from 1 to 3 carboxylic groups.
Preferably the acid is selected from one or more of citric acid, isocitric acid, gluconic acid, succinic acid, fumaric acid and tartaric acid. Conveniently, it is the tri-basic acid, citric acid and is present in a formulation in an amount sufficient to generate a concentration in solution in the blood of from 0.1 to 100 mM following administration, preferably in an amount of 10 to 1000 mg per dose.
It should be appreciated that carboxylic acids such as citric acid, being iron chelators, would have been expected to form mixed ligand complexes with the iron chelates of the aforesaid hydroxypyrones, but these complexes would have been charged. Surprisingly, when citric acid was added to iron complexes of 3-hydroxy-4-pyrones no mixed ligand complexes were identified, but in solution the citric acid behaves as a counter ion (anion) to the iron/hydroxypyrone complex, helping to maintain more iron in solution and available for absorption.
Unlike the neutral chelated mixed ligand complexes mentioned in GB 2 157 686 A (National Research Development Corporation), in which there is an internal balance of charges between the ferric cation and the ligands bound covalently thereto (see page 1, lines 45 to 48), it will be appreciated that the carboxylic acid acts as a counter ion (non-covalently bound anion) in the complexes of the invention.
Certain aspects of the carboxylic acid containing compositions of the first aspect of the invention may enhance the activity of the iron complexes in particular contexts. Thus, although the neutral ferric complexes containing a 1:3 molar proportion of iron:hydroxypyrone are of particular value as being stable over a wide pH range from about 4 to 5 up to 10, if administered orally, they will dissociate at the pH values of less than 4 prevailing in the stomach to form a mixture of the 1:2 and 1:1 complex together with free ligand. Unexpectedly, the presence of carboxylic acid enhances the solubility of these intermediate complexes rather than the formation of mixed ligand complexes and any excess iron generated is trapped as carboxylated iron rather than being precipitated as insoluble hydrated iron forms which are not available for bioabsorption. This effect is entirely unexpected because a carboxylic acid such as citrate on its own is very poor in enhancing iron transport across cell membranes. Advantageously, the presence of a carboxylic acid such as a citrate also maintains solubility at the wide pH range found in the upper intestinal tract.
The pH of the stomach can vary before and after meals and can also be dependent on other medications, such as antacids. The enhanced solubility provided by the compositions of the invention provides a more regular and reproducible supply of iron on a day to day basis than known compositions.
In a further aspect, the invention provides a method of preparing the iron complexes according to the first aspect of the invention comprising reacting ferric iron with at least one hydroxypyrone and combining the resultant complex with a carboxylic acid, preferably citric acid.
The iron hydroxypyrone complexes of the invention can be prepared by dissolving iron (III) carboxylate, especially citrate, in unbuffered water at a concentration of from 0.1 to 1M. A quantity of hydroxypyrone dissolved in a solvent is added to the solution in the desired 1:1:1 iron:hydroxypyrone:carboxylic acid molar proportion with rapid stirring. This ensures that the reaction is non-covalent, ie. the carboxylic acid acts as a counterion. In the preferred method using 1:1 molar proportions of iron citrate to ethylmaltol dissolved in ethanol, a deep red coloured solution of [Fe
III
ethylmaltol]
2+
citrate
2−
is formed. After stirring for 15 mins, the ethanol is removed by evaporation at atmospheric pressure. The resulting solution is freeze dried to yield a deep red powder.
Alternatively, iron complexes are prepared in accordance with the methods described in example 1 of GB 2128998 and EP
Hider Robert Charles
Stockham Michael Arthur
Pak John
Sterne Kessler Goldstein & Fox P.L.L.C.
Vitra Pharmaceuticals Ltd.
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