IT202300001983A1 - NEW ORAL COMPOSITIONS BASED ON IRON, PROCEDURE FOR THEIR PREPARATION AND THEIR USE IN CONDITIONS OF IRON DEFICIENCY - Google Patents

Description

Description of the Industrial Invention entitled:

?NEW ORAL COMPOSITIONS BASED ON IRON, PROCEDURE FOR THEIR PREPARATION AND THEIR USE IN CONDITIONS OF IRON DEFICIENCY?

The present invention relates to new pharmaceutical and/or nutraceutical and/or food compositions based on iron and to their use in the treatment and/or prevention of conditions of absolute or relative iron deficiency in subjects in need. In particular, the present invention relates to new compositions comprising highly assimilable iron and to their use in the treatment and/or prevention of disorders and pathologies associated with iron deficiency. The invention also relates to processes for the preparation of said compositions.

In conditions of absolute or relative iron deficiency in the body, iron (iron (II) or iron (III)) is administered orally or, in more severe cases, parenterally. These conditions include iron deficiency anemia and iron supplementation during pregnancy, when necessary.

English: Although oral administration is preferred, iron supplementation through this route of administration has significant drawbacks and limitations. In fact, the administration of classic oral compositions based on ferrous sulphate or gluconate (iron (II)) leads to poor absorption of said iron salts due to their poor bioavailability. In addition, oral administration of iron can cause constipation and gastric pain, and in more serious cases peptic ulcer, gastritis and ulcerative colitis. For this reason, such compositions are generally taken with meals, which leads to a consequent and inevitable further strong reduction in iron absorption in the gastrointestinal tract. Because of these drawbacks, it is necessary to continue the therapy based on iron salts over time, even up to 3-6 months until the adequate restoration of iron deposits in the body.

Considering the limitations and side effects described above, often associated with an unpleasant odor and taste of the compositions, due to the easy degradation of the said ferrous salts, it is understood that the classic therapy based on ferrous sulphate or gluconate is not favorable to patient compliance.

Also known and commercially available are iron (III) salts which, although less soluble in water and less bioavailable than iron (II) salts, have the advantage of being more stable and consequently do not present organoleptic alterations even when said iron (III) salts are mixed with other components or ingredients to form a final composition.

Among the iron (III) salts is iron (III) pyrophosphate, which is commercially available in various compositions and degrees of hydration. Some of these compositions can sometimes present a difficulty in formulation and show a tendency to give insoluble precipitates that could hinder their dosage and use.

The aim of the present invention is therefore to provide new oral compositions comprising iron (III) salts, which are formulated and prepared in an easy and convenient way and such as to present an improved absorption and bioavailability of the iron, and are thus even more effective. The invention relates to oral compositions comprising iron (III) salts, having the characteristics reported in the attached claims and their use in therapy or in a method of prevention or cure treatment.

The invention also relates to oral compositions for use in the preventive and/or curative treatment of anemia or iron deficiency, including in pregnant women and during the postnatal period, having the characteristics reported in the attached claims.

The invention also relates to a process for the preparation of said oral compositions, as described herein.

First aspect of the invention? aspect A

According to a first aspect, the invention has as its object a mixture, for example a physical mixture obtained by mechanical means or by mixing, which comprises or, alternatively, consists of at least one iron salt selected from i) an iron (III) pyrophosphate salt, ii) an iron (III)-sodium pyrophosphate salt and/or a mixture thereof, and iii) a sodium or potassium pyrophosphate.

Iron(III) pyrophosphate, iron(III)-sodium pyrophosphate, and sodium or potassium pyrophosphate are all salts or compounds known in the prior art and, at a temperature of 25°C and a pressure of 1 atmosphere, all occur in solid form, for example, as powders or granules.

Preferably, said i) iron (III) pyrophosphate according to the invention is a hydrated salt and, preferably, has a chemical formula, for example, of the type [Fe4(P2O7)3xH2O] (CAS RN.

10058-44-3, dry molecular weight 745.22) and, preferably, may have for example an iron content of between 15% and 30%, preferably between 18% and 24%, more preferably between 20% and 22% by weight, with respect to the total weight of the molecule.

Preferably, called ii) iron(III)-sodium pyrophosphate is a salt and, preferably, has a chemical formula, for example, of the type Fe(III)NaO7P2 (CAS RN.10045-87-1).

Preferably, called iii) sodium or potassium pyrophosphate (in this description it is always intended to include sodium and/or potassium pyrophosphate, even where not explicitly indicated) is a salt and, preferably, can be in the form of, for example, a tetrasodium pyrophosphate having a chemical formula, for example, of the type Na4P2O7 (CAS RN. 1269628-79-6) for example in anhydrous, semi-hydrated or hydrated form or in any case with a number of water molecules known to the person skilled in the art. Tetrasodium pyrophosphate, at room temperature and pressure of 25?C and 1 atmosphere, appears as a colourless, odourless, water-soluble solid and is coded in the list of food additives as E450. Tetrasodium pyrophosphate is normally used in the food industry.

The Applicant has surprisingly found that bringing into contact, for example, in the form of a combination or association, a sodium pyrophosphate with an iron (III) pyrophosphate and/or an iron (III)-sodium pyrophosphate increases the absorption and bioavailability of the administered iron into the body. In particular, the Applicant has surprisingly found that a mechanical mixture or a mixture, preferably obtained, for example, through a series of mechanical processes, of a sodium pyrophosphate, for example a tetrasodium pyrophosphate, and an iron (III) pyrophosphate and/or an iron (III)-sodium pyrophosphate, in a completely unexpected way, significantly increases the uptake of iron into the body.

According to one embodiment, the invention relates to a mixture AM-1, which comprises or, alternatively, consists of i) an iron (III) pyrophosphate salt and iii) a sodium pyrophosphate salt, in a weight ratio iron (III) pyrophosphate:sodium pyrophosphate, for example, preferably in the form of tetrasodium pyrophosphate, of from 1:0.01 to 1:1, preferably in a weight ratio of from 1:0.05 to 1:0.9, more preferably of from 1:0.1 to 1:0.8, even ... preferably from 1:0.15 to 1:0.75, for example 1:0.20, or 1:0.25, or 1:0.30, or 1:0.35, or 1:0.40, or 1:0.45, or 1:0.50, or 1:0.55, or 1:0.60, or 1:0.65, or 1:0.70.

According to one embodiment, the invention relates to a mixture AM-2, which comprises or, alternatively, consists of ii) an iron (III)-sodium pyrophosphate salt and iii) a sodium pyrophosphate salt, in a weight ratio iron (III)-sodium pyrophosphate:sodium pyrophosphate, for example preferably in the form of tetrasodium pyrophosphate, of from 1:0.01 to 1:1, preferably in a weight ratio of from 1:0.05 to 1:0.9, more preferably of from 1:0.1 to 1:0.8, even ... preferably from 1:0.15 to 1:0.75, for example 1:0.20, or 1:0.25, or 1:0.30, or 1:0.35, or 1:0.40, or 1:0.45, or 1:0.50, or 1:0.55, or 1:0.60, or 1:0.65, or 1:0.70.

According to one embodiment, the invention relates to a mixture AM-3, which comprises or, alternatively, consists of i) an iron (III) pyrophosphate salt and ii) an iron (III)-sodium pyrophosphate salt, and iii) sodium pyrophosphate, in a weight ratio iron (III) pyrophosphate:iron (III)-sodium pyrophosphate:sodium pyrophosphate, for example preferably in the form of tetrasodium pyrophosphate, of from 1:0.01:0.01 to 1:0.1:0.1, preferably in a weight ratio of from 1:0.05:0.5 to 1:0.5:1:0.5:0.5, more preferably 1:1:1.

By ?mechanical mixture? or ?mixture, preferably obtained, for example, through a series of mechanical processes? it is intended here to indicate that the components or salts of the mixture are all mixed in the solid state, through the use of techniques and equipment known to those skilled in the field.

Mixtures AM-1, AM-2 and AM-3 are then prepared by mixing together the components or salts i) and ii) and/or iii) of the mixture in the solid state, preferably in the form of powder or granules.

According to aspect A, the invention also has as its object a process for the preparation of the AM-1, AM-2 and AM-3 mixtures which comprises at least one step of mixing, by means of mixing means, the components of said mixtures in the solid state, preferably in the form of powder or granules.

The subject of the present invention is a mixture (AM-1, AM-2 or AM-3) which comprises or, alternatively, consists of:

- at least one iron (III) salt selected from: i) iron (III) pyrophosphate and ii) iron (III)-sodium pyrophosphate and their mixtures, and

- iii) a sodium or potassium pyrophosphate.

Preferably, said mixture consists of i) iron (III) pyrophosphate and iii) sodium or potassium pyrophosphate, preferably called iii) sodium pyrophosphate ? tetrasodium pyrophosphate.

Preferably, said i) iron (III) pyrophosphate and iii) sodium or potassium pyrophosphate are present in said mixture in a weight ratio iron (III) pyrophosphate:sodium or potassium pyrophosphate of from 1:0.05 to 1:1, preferably from 1:0.1 to 1:0.5, more preferably from 1:0.2 to 1:04.

Preferably, said mixture consists of ii) iron (III)-sodium pyrophosphate and iii) sodium or potassium pyrophosphate; preferably said iii) sodium pyrophosphate is tetrasodium pyrophosphate.

Preferably, said ii) iron (III)-sodium pyrophosphate and iii) sodium or potassium pyrophosphate are present in said mixture in a weight ratio iron (III)-sodium pyrophosphate:sodium or potassium pyrophosphate of from 1:0.05 to 1:1, preferably from 1:0.1 to 1:0.5, more preferably from 1:0.2 to 1:04.

Preferably, said mixture consists of i) iron (III) pyrophosphate, ii) iron (III)-sodium pyrophosphate and iii) sodium or potassium pyrophosphate; preferably said iii) sodium pyrophosphate is tetrasodium pyrophosphate.

Preferably, said mixture is for use in therapy; preferably said mixture is for use in a method of treatment and/or prevention of conditions of total or relative iron deficiency, in particular for use in the treatment of disorders or diseases related to or resulting from iron deficiency. The subject of the present invention is a composition (AC-1, AC-2 or AC-3) comprising a mixture (AM-1, AM2 or AM-3) as described above and, optionally, at least one excipient and/or carrier of pharmaceutical or food grade. Preferably, said composition is in solid form in oral dosage units; more preferably, said composition may, furthermore, comprise mineral salts and/or vitamins.

According to aspect A, the invention also has as its object the compositions defined herein AC-1, AC-2 and AC-3 which comprise a mixture selected, respectively, from the mixtures AM-1, AM-2 and AM-3 together, optionally, with at least one excipient and/or carrier of pharmaceutical or food grade.

Compositions AC-1, AC-2 and AC-3 are prepared and formulated to be suitable for oral administration.

The oral compositions AC-1, AC-2 and AC-3 according to the invention are preferably solid state compositions, formulated in dosage units. By solid state it is meant that the composition may exist in the form of granules or microgranules or powders. The granular or powder compositions are then mixed with pharmacologically acceptable additives and excipients to provide a final product such as, for example, a food supplement, a medical device composition or a pharmaceutical composition. The final product may be in pharmaceutical dosage units such as granules in sachet, stick, tablet or capsule.

For example, tablets may have different shapes among those known in the field of pharmaceutical forms, such as a cylindrical or spheroidal shape. Tablets may have a weight between 100 mg and 2000 mg. Tablets may be coated or filmed with one or more layers of coating or film capable of passing through the gastric barrier, according to the methods and equipment known to those skilled in the art.

Gel capsules can, for example, weigh from 200 mg to 1200 mg, a hard capsule can weigh from 500 mg to 1000 mg, while a chewable tablet can weigh from 500 mg to 2000 mg. Capsules can be made of hard gelatin or soft gelatin or soft gel.

Preferably, the oral composition of the invention is a solid composition, as described above. However, if desired or necessary, the composition may also be formulated in liquid form, for example, as a suspension in water, preferably added with a physiologically acceptable acid, for example citric acid, and other substances or excipients capable of keeping the suspension stable and acceptable to the subject taking it.

The oral compositions AC-1, AC-2, and AC-3 of the invention may contain, as noted, conventional physiologically acceptable excipients and carriers, such as diluents, bulking agents, binders, disintegrants, flow promoters, lubricants, etc. Non-limiting examples of suitable carriers and excipients are described in "Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins." The compositions of the invention may, for example, include cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, glycol, water, ethanol, and the like. The composition may also contain pH buffering reagents and wetting or emulsifying agents commonly used in the art.

In addition to the components described above, if desired or necessary, the compositions of the invention may include further active components, for example components capable of assisting the active ingredient in carrying out its action in the organism of the treated subject, such as vitamins.

The oral compositions AC-1, AC-2 and AC-3 according to the invention, in solid or liquid form, are for use in therapy, in particular for use in therapy to treat conditions of total or relative iron deficiency, in particular for use in the treatment of disorders or diseases related to or resulting from iron deficiency.

The oral compositions AC-1, AC-2 and AC-3 for oral use, solid or liquid, according to any of the embodiments described above, are useful in particular in the treatment and prevention of disorders or diseases related to iron deficiency in pediatric age, adolescents, athletes, men, women, pregnant women and the elderly because they prevent and combat anemia and are useful for increasing hemoglobin and ferritin values. These compositions are suitable for administration over a period of 1 to 6 months, preferably 2 to 4 months, in pediatric subjects, adolescents, athletes, men, women, pregnant women and the elderly, at a dose of 5 mg to 50 mg of iron (III)/day, preferably 10 mg to 45 mg of iron (III)/day, more preferably 15 mg to 40 mg, even ... preferably between 20 mg and 30 mg, e.g. 25 mg, or 27 mg, or 29 mg, of iron (III)/day.

The invention also provides an iron-based supplement comprising one of the oral compositions AC-1, AC-2 and AC-3 of the invention, possibly together with other components, for example selected from minerals and/or vitamins, such as at least one vitamin from group B, C or D.

The invention also provides a method for the treatment and/or prevention of disorders or diseases related to iron deficiency, which comprises administering to a subject in need an oral composition selected from the compositions AC-1, AC-2 and AC-3 according to the invention.

Compositions AC-1, AC-2 and AC-3 of the invention comprise the iron (III) pyrophosphate salt in an amount by weight of from 10% to 90%, preferably from 25% to 75%, more preferably from 35% to 65%, even more preferably from 40% to 55%, based on the total weight of the composition.

Second aspect of the invention - aspect B

As mentioned above, many iron-containing compositions present formulation difficulties and show a tendency to give insoluble precipitates that hinder their dosage and use. In addition, they are often poorly tolerated at the gastric level and also have a poor palatability.

In order to overcome the above mentioned drawbacks, the Applicant has conducted a prolonged research activity which has led to the development of some compositions comprising iron (III) pyrophosphate and to the filing of two international patent applications WO2014/009806 and WO2015/033216. These applications (and the related granted patents) describe and claim compositions comprising minerals, and in particular iron (III) pyrophosphate, together with sucrose esters and lecithins, and are commercially available under the trade name of ?Sideral <?>?.

These compositions provide an improved absorption profile of minerals, and iron in particular, compared to previously used compositions and at the same time present good tolerability and organoleptic stability.

The intense research activity of the Applicant did not however stop at the compositions reported above but continued with the aim of further improving the said compositions, in particular with regard to the absorption and bioavailability of iron.

Another object of the present invention is therefore to provide an oral composition comprising iron (III) salts, which is formulated and prepared in such a way as to present improved absorption and bioavailability of the iron and is thus even more effective.

A further aim of the invention is to provide an oral composition comprising iron (III) salts that is well tolerated by the body, so that it can be administered even on an empty stomach, to all subjects, including pregnant women, that has good palatability and is stable over time from a chemical-physical and organoleptic point of view, i.e. that does not present alterations in colour, odour, aroma and taste over time.

In another of its aspects, aspect B1, the invention has as its object a mixture BM-1 which comprises or, alternatively, consists of:

- i) an iron(III) pyrophosphate salt;

- at least one lecithin;

- at least one successor; and

- iii) a sodium pyrophosphate salt, preferably tetrasodium pyrophosphate.

In another of its aspects, aspect B2, the invention has as its object a BM-2 mixture which comprises or, alternatively, consists of:

- i) an iron(III) pyrophosphate salt;

- at least one lecithin;

- at least one successor;

- iii) a sodium pyrophosphate salt, preferably tetrasodium pyrophosphate; and

- ii) an iron(III)-sodium pyrophosphate salt.

Preferably, the mixture BM-1 or BM-2 of the present invention may further comprise a further component selected from vegetable starches. Preferably, the vegetable starch is, for example, preferably selected from rice starches and/or corn starches and/or sunflower starches and/or soy starch, and mixtures thereof. For example, the preferred starch is a rice starch such as a gelatinized or pregelatinized native rice starch. For example, a pregelatinized rice starch that may be used has a CAS No. 9005-25-8; EINECS 232-679-6 with a moisture content of 10% to 20%, for example about 15%; a particle size distribution D10 ?m max. 20; D50 ?m max. 75 and D90 ?m max. 175. A commercial product that meets these characteristics is Remyline AX-FG-P from the company A.D.E.A. Srl.

Preferably, another type of pregelatinized rice starch usable in BM-1 or BM-2 mixtures may have the following chemical-physical characteristics: moisture from 1% to 10%; protein content from 0.1% to 1.5%; ash content from 0.1% to 1%; pH (10% solution) between 5.5 and 7.5; density 0.40-0.48 g/cm<3>; starch content from a minimum of 95% to 99% and fat content from 0.01% to 0.1%.

Preferably, gelatinized or pregelatinized vegetable starch is present in the mixtures BM-1 and BM-2 in an amount by weight of 1% to 50%, preferably 10% to 40%, more preferably 15% to 35%, even more preferably 20% to 30%, with respect to the total weight of the compositions BC-1 and BC-2.

Iron(III) pyrophosphate, iron(III)-sodium pyrophosphate, and sodium pyrophosphate are all salts or compounds known in the prior art.

Preferably, said i) iron (III) pyrophosphate according to the invention is a hydrated salt and, preferably, has a chemical formula, for example, of the type [Fe4(P2O7)3xH2O] (CAS RN.

10058-44-3, dry molecular weight 745.22) and, preferably, may have for example an iron content of between 15% and 30%, preferably between 18% and 24%, more preferably between 20% and 22% by weight, with respect to the total weight of the molecule.

Preferably, called ii) iron(III)-sodium pyrophosphate is a salt and, preferably, has a chemical formula, for example, of the type Fe(III)NaO7P2 (CAS RN.10045-87-1).

Preferably, called iii) sodium or potassium pyrophosphate is a salt and, preferably, may be in the form of, for example, a tetrasodium pyrophosphate having a chemical formula, for example, of the type Na4P2O7 (CAS RN.1269628-79-6). Tetrasodium pyrophosphate, at room temperature and pressure (25?C and 1 atmosphere), appears as a colourless, odourless, water-soluble solid and is coded in the list of food additives as E450. Tetrasodium pyrophosphate is normally used in the food industry.

Preferably, said i) iron (III) pyrophosphate salt according to the invention is present in the mixture BM-1 or BM-2 in an amount by weight of from 10% to 90%, preferably of from 25% to 75%, more preferably of from 35% to 65%, even more preferably of from 40% to 55%, with respect to the total weight of said mixture.

Preferably, said ii) iron (III)-sodium pyrophosphate salt according to the invention is present in the mixture BM-1 or BM-2 in an amount by weight of from 0.1% to 50%, preferably from 1% to 35%, more preferably from 5% to 30%, even more preferably from 10% to 25%, with respect to the total weight of said mixture.

Preferably, said iii) sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium phosphate, according to the invention is present in the mixture BM-1 or BM-2 in an amount by weight of from 0.1% to 50%, preferably from 1% to 35%, more preferably from 5% to 30%, even more preferably from 10% to 25%, with respect to the total weight of said mixture. The sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium phosphate, is present in the oral composition BC-1 or BC-2 of the present invention in an amount by weight of from 0.1% to 50%, preferably from 1% to 35%, more preferably from 5% to 30%, even more preferably from 10% to 25%, with respect to the total weight of said mixture. preferably 10% to 25% by weight, for example 12% to 20%, for example 14%, or 16%, or 18% relative to the total weight of the composition.

The term ?lecithin? is known to the art and is catalogued as a food additive, for example food additive E322, according to directive n.95/2/CE of 20.2.95, published in O.J. n. L61 of 18.9.95.

Lecithin, due to its chemical-physical properties, mainly performs an emulsifying function and, furthermore, being also rich in natural antioxidant substances, it also has a secondary antioxidant function.

Directive no. 2008/84/EC of 27 August 2008 (published in the European Community O.J. no. L253) establishes the purity criteria that lecithin must present in order to be considered of food quality (E322): Insoluble in acetone (practically the active part of lecithin): 60% minimum; Humidity: 2% maximum; Acidity number: 35 maximum; Peroxide number: 10 maximum; Insoluble in toluene (practically impurities): 0.3% maximum.

From a chemical point of view, it is known that lecithin is a mixture of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides and phospholipids.

Phospholipids are the main components of lecithins; they are derived from the structure of triglycerides, in which a fatty acid is replaced by a phosphate group, conferring a negative charge, and therefore polarity, to the molecule; this molecule has the generic name of phosphatide. A more complex organic molecule, usually serine, choline, ethanolamine, inositol or a single hydrogen atom is linked to the phosphate group through an ester bond, giving rise to a phospholipid called, respectively, phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol or phosphatidic acid. In a narrower sense, lecithin is often referred to as phosphatidylcholine.

Phospholipids are characterized by a water-soluble polar head, which dissolves well in water, while the two saturated fatty acids represent the two apolar tails, not water-soluble but lipophilic. These molecules are called amphipathic and when in the presence of water and fats, they arrange themselves between the fat molecules and those of the water, emulsifying them. Lecithin is therefore a natural emulsifier.

The lecithin used according to the invention is a lecithin as is available on the market, even of allergen-free grade; preferably it can be a non-hydrolyzed lecithin, for example a powdered lecithin. Preferably, a lecithin selected from lecithins of vegetal origin can be used, such as, for example, sunflower and/or corn and/or soy and/or rice lecithins, and mixtures thereof.

Preferably, the lecithin used according to the invention is a powdered lecithin having, for example, a water content of 0.5% to 10%, preferably 1.5% to 4.5%, more preferably 2% to 4%, even more preferably 2.5% to 3.5%. Preferably, the lecithin used is a powdered sunflower lecithin.

Preferably, sunflower or corn or soy or rice lecithin or mixtures thereof has a glucose content by weight of 20% to 60%, more preferably 30% to 50%, for example about 45% by weight.

Preferably, a sunflower or corn or soy or rice lecithin or mixtures thereof usable in the context of the present invention may have, for example, the following composition by weight (physical-chemical analysis): sunflower or corn or soy lecithin from 20% to 80%, preferably from 40% to 50%, carbohydrates from 30% to 60%, preferably from 40% to 50% (for example about 35% or 45% or 55%), proteins from 6% to 10%, ash from 3% to 8%, moisture from 2% to 5% and a sliding agent from 0.5% to 1.5%.

Preferably, one type of lecithin usable according to the present invention is a sunflower lecithin of the type spray dried on glucose syrup (Evra?); this lecithin is sold in the form of a composition comprising glucose syrup, sunflower lecithin, sodium caseinate and tricalcium phosphate. Preferably, another type of lecithin usable according to the present invention is a sunflower lecithin (allergen-free) of the type spray dried on rice flour (Evra?); this lecithin is sold in the form of a composition comprising sunflower lecithin, tricalcium phosphate and rice flour.

Preferably, lecithin is present in the oral composition of the present invention in an amount by weight of from 0.1% to 10%, preferably from 0.5% to 5%, more preferably from 1% to 4%, even more preferably from 1.5% to 3.5%, for example 2%, or 2.5%, or 3% by weight, based on the total weight of the composition.

The term "sucrosester" according to the invention is known in the art and designates a product obtained by esterification or transesterification of the methyl esters of fatty acids with carbohydrates, generally sucrose and other polysaccharides, for this reason it is also defined as "sucrose esters with fatty acids" or here also simply "sucrose esters". The chemical-physical properties of these esters depend on the number and type of esterified fatty acids.

Preferably, according to the invention, the at least one sucrose ester is, for example, a sucrose ester of the type E473. It is known that the abbreviation E473 indicates that sucrose esters are food additives authorised by European Union legislation and regulated by the Italian ministerial decree (M.D. 1996). They are essentially emulsifying agents and are added in order to obtain better stabilisation between an aqueous phase and a fatty phase.

Preferably, the sucrose esters according to the invention are for example sucrose esters of the type E473 and are used in the composition of the present invention having an HLB value of about 14-18, advantageously an HLB value of about 15 or 16, as emulsifiers, where HLB indicates ?Hydrophilic-Lipophilic Balance?.

Preferably, a sucrose ester of the type E473 for example contains 50% to 80%, preferably 60% to 70% mono-esters, obtained by esterification with fatty acids of vegetal origin (stearic and palmitic).

Preferably, a type of sucrose ester usable in the context of the present invention may have, for example, the following composition by weight: a total ester content of from 80% to 95%; a free fatty acid content (such as oleic acid) of from 0.1% to 10%, preferably from 0.5% to 5%, more preferably from 1.5% to 4%, for example 2%, or 2.5%, or 3%, or 3.5%; a free sucrose content of from 0.5% to 5%; a moisture content of from 0.5% to 10%, preferably from 1% to 5%, more preferably from 2% to 4%; an acidity value of from 1 mg to 10 mg KOH/g, preferably from 2.5% to 5 mg KOH/g. According to the invention, for example, sucrose esters SP70 from Sisterna BV, the Netherlands, can be used.

Preferably, the sucrose esters are present in the oral composition of the present invention in an amount by weight of from 5% to 75%, preferably from 10% to 60%, more preferably from 12% to 40%, even more preferably from 15% to 30%, for example from 16% to 18% by weight, with respect to the total weight of the composition.

The subject of the present invention is a mixture (BM-1 or BM-2) which comprises or, alternatively, consists of:

- i) an iron(III) pyrophosphate salt;

- at least one lecithin;

- at least one successor; and

- iii) a sodium or potassium pyrophosphate salt.

Preferably, said mixture further comprises ii) an iron (III)-sodium pyrophosphate salt; preferably said ii) an iron (III)-sodium pyrophosphate salt is present in said mixture in an amount by weight of from 0.1% to 50%, preferably from 1% to 35%, more preferably from 5% to 30%, even more preferably from 10% to 25%, based on the total weight of said mixture.

Preferably, said mixture further comprises a starch, preferably said starch is a vegetable starch selected from the group comprising or, alternatively, consisting of rice starch, corn starch, sunflower starch or soya starch, more preferably said vegetable starch is a pregelatinized rice starch.

Preferably, said starch is present in said mixture in an amount by weight of from 1% to 50%, preferably from 10% to 40%, more preferably from 15% to 35%, even more preferably from 20% to 30%, with respect to the total weight of said mixture.

Preferably, said i) an iron (III) pyrophosphate salt is present in said mixture in an amount by weight of from 10% to 90%, preferably of from 25% to 75%, more preferably of from 35% to 65%, even more preferably of from 40% to 55%, with respect to the total weight of said mixture.

Preferably, said at least one lecithin is a vegetable lecithin, preferably said vegetable lecithin is selected from the group comprising or, alternatively, consisting of a sunflower, corn, soya or rice lecithin; preferably said at least one lecithin is present in said mixture in an amount by weight of from 0.1% to 10%, preferably from 0.5% to 5%, more preferably from 1% to 4%, even more preferably from 1.5% to 3.5%, by weight, with respect to the total weight of said mixture.

Preferably, said at least one sucrose ester is present in said mixture in an amount by weight of from 5% to 75%, preferably from 10% to 60%, more preferably from 12% to 40%, still more preferably from 15% to 30%, with respect to the total weight of said mixture. Preferably, said (iii) sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium pyrophosphate, is present in said mixture in an amount by weight of from 0.1% to 50%, preferably from 1% to 35%, more preferably from 5% to 30%, still more preferably from 10% to 25%, with respect to the total weight of said mixture.

Preferably, said mixture is for use in therapy; preferably said mixture is for use in a method of treatment and/or prevention of conditions of total or relative iron deficiency, in particular for use in the treatment of disorders or diseases related to or resulting from iron deficiency. The present invention relates to a composition (BC-1 or BC-2) comprising a mixture (BM-1 or BM-2) as described above and, optionally, at least one excipient and/or carrier of pharmaceutical or food grade; preferably said composition is in solid form in oral dosage units.

The invention also relates to a BC-1 composition which comprises or, alternatively, consists of a BM-1 mixture, together with at least one pharmaceutical or food grade excipient and/or carrier.

The invention also relates to a BC-2 composition which comprises or, alternatively, consists of a BM-2 mixture, together with at least one pharmaceutical or food grade excipient and/or carrier.

Compositions BC-1 and BC-2 are prepared to be suitable for oral administration.

The oral compositions BC-1 and BC-2 according to the invention are preferably a solid state composition, formulated in dosage units. By solid state it is meant that the composition may exist in the form of granules or powders. The granular or powder compositions are then mixed with pharmacologically acceptable additives and excipients to provide a final product such as a food supplement, a medical device composition or a pharmaceutical composition. The final product may be in pharmaceutical dosage units such as granules in sachets, or sticks, tablets or capsules. The tablets may have, for example, different shapes among those known in the field of pharmaceutical forms, such as a cylindrical or spheroidal shape. The tablets may have, for example, a weight ranging from 100 mg to 2000 mg. The tablets may be coated or filmed with one or more layers of coating or film capable of passing through the gastric barrier, according to the methods and equipment known to those skilled in the art.

Gel capsules can have a weight of 200-1200 mg, for example, a hard capsule can have a weight of 500 mg to 1000 mg, while a chewable tablet can have a weight of 500 mg to 2000 mg. Capsules can be made of hard gelatin or soft gelatin or soft gel.

Preferably the oral composition of the invention is a solid composition, as described above. However, if desired or necessary, the composition may also be formulated in liquid form, for example, as a suspension in water, preferably added with a physiologically acceptable acid, for example citric acid, and other substances or excipients capable of keeping the suspension stable and acceptable to the subject taking it.

The solid compositions of the invention may contain, as noted, conventional physiologically acceptable pharmaceutical or food grade excipients and carriers, such as diluents, bulking agents, binders, disintegrants, flow promoters, lubricants, etc. Non-limiting examples of suitable carriers and excipients are described in "Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins." The compositions of the invention may also include, for example, cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene, glycol, water, ethanol, and the like. The composition may also contain, for example, pH buffering reagents and wetting or emulsifying agents.

In addition to the components described above, if desired or necessary, the BC-1 and BC-2 compositions of the invention may also preferably comprise further active components, for example components capable of assisting the active ingredient in carrying out its action in the organism of the treated subject, such as vitamins.

The oral compositions BC-1 and BC-2 according to the invention are for use in therapy, in particular in conditions of total or relative iron deficiency, in particular for use in the treatment of disorders or diseases related to or resulting from iron deficiency.

The composition for oral use, solid or liquid, according to any of the embodiments described above, is useful in therapy, in particular in a method of treatment and prevention of disorders or diseases related to iron deficiency in pediatric subjects, adolescents, athletes, men, women, pregnant women and the elderly because it prevents and combats anemia and is useful for increasing hemoglobin and ferritin values. Said composition is suitable for administration over a period of 1 to 12 months, preferably 2 to 6 months, in pediatric subjects, adolescents, athletes, men, women, pregnant women and the elderly, at a dose, for example, of 5 mg to 50 mg of iron (III)/day, preferably of 10 mg to 45 mg of iron (III)/day, more preferably of 15 mg to 40 mg, even ... or even more preferably of 15 mg to 40 mg. preferably between 20 mg and 30 mg, e.g. 25 mg, or 27 mg, or 29 mg, of iron (III)/day.

The invention also includes an iron-based supplement comprising a BC-1 or BC-2 composition of the invention, possibly together with other components, for example selected from minerals and/or vitamins such as, for example, one or more vitamins belonging to the B, C and D groups.

The invention also provides a method for the treatment and/or prevention of disorders or diseases related to iron deficiency, which comprises administering to a subject in need a BC-1 or BC-2 composition according to the invention.

Compositions BC-1 and BC-2 of the invention comprise the iron (III) pyrophosphate salt in an amount by weight of from 10% to 90%, preferably from 25% to 75%, more preferably from 35% to 65%, even more preferably from 40% to 55%, based on the total weight of the composition.

The Applicant has surprisingly found that contacting in the form of, for example, a combination or association, a sodium or potassium pyrophosphate salt, preferably a tetrasodium pyrophosphate, with a composition described in WO2014/009806 and WO2015/033216 and marketed under the trade name "Sideral <?>" increases the absorption and bioavailability of the administered iron in the body. In particular, the Applicant has surprisingly found that a mechanical mixture or a mixture, preferably obtained for example by mechanical means, of a sodium or potassium pyrophosphate salt, preferably a tetrasodium pyrophosphate, with a composition described in WO2014/009806 and WO2015/033216, in a completely unexpected manner, significantly increases the uptake of iron, preferably by increasing ferritin.

This surprising result will be described and demonstrated in detail in the Experimental Section that follows.

Preferably, said iii) a sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium pyrophosphate, is present in the oral composition BC-1 or BC-2 of the present invention in an amount by weight of from 0.1% to 50%, preferably from 1% to 35%, more preferably from 5% to 30%, even more preferably from 10% to 25% by weight, for example from 12% to 20%, for example 14%, or 16%, or 18% with respect to the total weight of the composition.

Preferably, said ii) an iron (III)-sodium pyrophosphate salt is present in the oral composition BC-1 or BC-2 of the present invention in an amount by weight of from 0.1% to 50%, preferably from 1% to 35%, more preferably from 5% to 30%, even more preferably from 10% to 25% by weight, for example from 12% to 20%, for example 14%, or 16%, or 18% with respect to the total weight of the composition.

The oral composition BC-1 of the present invention therefore comprises or, alternatively, consists of iron (III) pyrophosphate, a lecithin, for example a sunflower lecithin, sucrose esters or sucrose esters, for example E473, and a sodium or potassium salt, preferably in the form of tetrasodium pyrophosphate, in the percentage quantities by weight indicated above.

The oral composition BC-2 of the present invention therefore comprises or, alternatively, consists of iron (III) pyrophosphate, a lecithin, for example a sunflower lecithin, sucrose esters or sucrose esters, for example E473, and a sodium or potassium salt, preferably in the form of tetrasodium pyrophosphate, in the percentage quantities by weight indicated above.

As mentioned above, the oral composition BC-1 or BC-2 of the present invention may also comprise other conventional, physiologically acceptable components, excipients and vehicles.

Preferably, the oral composition BC-1 or BC-2 of the present invention may further comprise a further component selected from vegetable starches. Preferably, the vegetable starch is, for example, preferably selected from rice starches or corn starches or sunflower starches. For example, the preferred starch is a rice starch such as a gelatinized or pregelatinized native rice starch. For example, a pregelatinized rice starch that may be used has a CAS No. 9005-25-8; EINECS 232-679-6 with a moisture content of 10% to 20%, for example about 15%; a particle size distribution (particle size distribution) D10 ?m max. 20; D50 ?m max. 75 and D90 ?m max. 175. A commercial product that meets these characteristics is: Remyline AX-FG-P from the company? A.D.E.A. Ltd.

Preferably, another type of pregelatinized rice starch usable in the context of the present invention may have the following chemical-physical characteristics: moisture from 1% to 10%; protein content from 0.1% to 1.5%; ash content from 0.1% to 1%; pH (10% solution) between 5.5 and 7.5; density 0.40-0.48 g/cm<3>; starch content from a minimum of 95% to 99% and fat content from 0.01% to 0.1%.

Preferably, gelatinized or pregelatinized vegetable starch is present in the solid composition BC-1 or BC-2 in an amount by weight of 1% to 50%, preferably 10% to 40%, more preferably 15% to 35%, even more preferably 20% to 30%, based on the total weight of the compositions BC-1 and BC-2.

The oral composition BC-1 of the present invention comprises or, alternatively, consists of iron (III) salts, a lecithin, for example a sunflower lecithin, sucrose esters or sucrose esters, for example E473, a starch, preferably a vegetable starch such as, for example, a rice starch, and a sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium pyrophosphate, in the percentage amounts by weight indicated above.

The oral composition BC-1, the object of the present invention, comprises or, alternatively, consists of an iron (III) pyrophosphate salt, a lecithin, for example a sunflower lecithin, sucrose esters or sucrose ester, for example E473, a starch, preferably a vegetable starch such as, for example, a rice starch, and a sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium pyrophosphate, in the percentage quantities by weight indicated above.

The oral composition BC-2, the object of the present invention, comprises or, alternatively, consists of iron (III) salts, a lecithin, for example a sunflower lecithin, sucrose esters or sucrose ester, for example E473, a starch, preferably a vegetable starch such as, for example, a rice starch, and a sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium pyrophosphate and an iron (III)-sodium pyrophosphate, in the percentage amounts by weight indicated above.

The oral composition BC-2, the subject of the present invention, comprises or, alternatively, consists of an iron (III) pyrophosphate salt, a lecithin, for example a sunflower lecithin, sucrose esters or sucrose ester, for example E473, a starch, preferably a vegetable starch such as, for example, a rice starch, and a sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium pyrophosphate and iron (III)-sodium pyrophosphate in the percentage amounts by weight indicated above.

The present invention also provides a first method for preparing a BM-1 or BM-2 mixture which, once prepared, is added with physiologically acceptable excipients, diluents or carriers, to give rise, respectively, to the oral composition BC-1 or BC-2 of the present invention.

A first method of the present invention is directed to the preparation of a mixture comprising or, alternatively, consisting of i) iron (III) pyrophosphate, a lecithin, for example a sunflower lecithin, sucrose esters or sucrose ester, for example E473, iii) a sodium or potassium pyrophosphate salt, preferably tetrasodium pyrophosphate, optionally a vegetable starch, preferably a rice starch, to give rise to the mixture BM-1. If to this mixture BM-1 is also added, possibly, an ii) iron (III)-sodium pyrophosphate, in the percentage weight quantities indicated above, the mixture BM-2 is obtained.

Preferably, said i) iron (III) pyrophosphate in the solid state, is for example brought into contact with an iii) sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium pyrophosphate, and/or ii) iron (III)-sodium pyrophosphate, in the above-mentioned percentage weight quantities, by mixing to give a resulting mixture to which a vegetable lecithin, optionally a starch, and/or a sucrose ester are subsequently added. Preferably, the mixing is carried out in a mixer equipped with agitation and mixing means known in the field. Preferably, sieving steps are provided, with special sieves or sieve shakers, in order to make the solid powder mixture being processed more uniform and constant. Some further details of said first method of the invention are reported in the Experimental Section of the present invention.

Said i) iron (III) pyrophosphate, lecithin, sucrose ester, iii) sodium or patassium pyrophosphate (e.g. tetrasodium pyrophosphate), starch and, optionally, ii) iron (III)-sodium pyrophosphate used in the preparation method of the present invention have the characteristics and properties defined above.

Vegetable starch, for example in the form of gelatinized or pregelatinized vegetable starch, is fluid and flowable and can be dosed precisely without causing errors or weight variations. Furthermore, it is distributed more uniformly and homogeneously within the mixture during the mixing phase. Finally, vegetable starch improves the bioavailability of the iron cation, as the resulting compound dissolves better at temperatures between 15 and 30?C (1 atmosphere pressure), preferably from 20 to 25?C, even more preferably from 18 to 23?C. At the end of said first preparation method, a mixture BM-1 (and a solid composition for oral use BC-1) of the present invention is obtained, which comprises or, alternatively, consists of i) an iron (III) pyrophosphate, a vegetable lecithin, sucrose esters or sucrester, an iii) sodium or potassium pyrophosphate salt, such as tetrasodium pyrophosphate, and optionally a starch, and optionally an ii) iron (III)-sodium pyrophosphate in the mixture BM-2 (and in the composition BC-2) in the percentage weight amounts indicated above.

Preferably, by said first preparation method a mixture BM-1 (and a solid composition for oral use BC-1) of the present invention is obtained, which comprises or, alternatively, consists of i) an iron (III) pyrophosphate, a vegetable lecithin, for example a corn or soy or sunflower lecithin E322, sucrose esters or sucrose esters, for example of the E473 type, iii) a sodium or potassium pyrophosphate salt (for example a tetrasodium pyrophosphate) and, optionally, a starch (for example a rice starch), in the percentage weight quantities indicated above. Preferably, by said first preparation method a mixture BM-2 (and a solid composition for oral use BC-2) of the present invention is obtained, which comprises or, alternatively, consists of i) an iron (III) pyrophosphate, a vegetable lecithin, for example a corn or soy or sunflower lecithin E322, sucrose esters or sucrose ester, for example E473, iii) a sodium or potassium pyrophosphate salt (for example a tetrasodium pyrophosphate) ii) an iron (III)-sodium pyrophosphate and, optionally, a starch (for example a rice starch) in the percentage weight amounts indicated above.

Preferably, to further improve the bioavailability of the iron cation, it is useful to reduce the weight amount of lecithin to be used in the process to prepare the solid composition of the present invention as much as possible.

Furthermore, it has been found that to further enhance the bioavailability of the iron cation, it is preferable to use a specific amount by weight of sucrose esters or sucrester in association with a reduced amount by weight of lecithin.

Preferably, the weight ratio of sucrose ester or sucrester to lecithin is from 60:1 to 10:1, preferably from 50:1 to 20:1, more preferably from 45:1 to 30:1, for example from 40:1 to 35:1. In one embodiment, said ratio is from 45:1 to 35:1.

Preferably, lecithin is present in the BM-1 or BM-2 mixture in an amount by weight of from 0.01% to 10%, preferably from 0.05% to 5%, more preferably from 0.1% to 3.5%, even more preferably from 0.5% to 2%, for example from 0.8% to 1.5%, for example 0.9%, or 1%, or 1.1%, or 1.2%, or 1.3%, or 1.4% by weight, based on the weight of the mixture.

This method of the present invention allows to create a coating or encapsulation around the iron (III) in order to improve the stability and bioavailability of the cation (III) thanks to the presence of the sodium or potassium pyrophosphate salt and/or iron (III)-sodium pyrophosphate. In practice, this method involves the formation of agglomerates or granules comprising the iron (III) pyrophosphate and the sodium or potassium pyrophosphate salt and/or iron (III)-sodium pyrophosphate in the presence of lecithin, sucrose esters or sucrose esters and, optionally, a starch. The sucrose esters or sucrose esters and the lecithin act by promoting the absorption of the salt and, consequently, of the iron cation contained in said salt. The mixture with lecithin and starch gives rise to the formation of "chimeric" agglomerates capable of protecting and shielding the iron cation contained in the pyrophosphate salt from gastric acid.

The processing time, e.g. mixing and sieving, is between 5 and 90 minutes, preferably between 10 and 60, more preferably between 20 and 40 minutes.

The oral composition obtained with the method of the present invention can have a granulometric distribution of the D10 type of approximately 1.8 ?m, D50 of approximately 20.5 ?m and D90 of approximately 108 ?m.

The solid composition of the present invention has an iron (III) content of from 30 mg/g to 180 mg/g, preferably from 60 mg/g to 120 mg/g, more preferably from 90 to 110 mg/g.

The oral composition BC-1 or BC-2 according to the invention is for use in therapy, in particular in conditions of total or relative iron deficiency, in particular for use in the treatment of disorders or diseases related to or resulting from iron deficiency.

The oral composition BC-1 or BC-2 of the present invention comprises easily absorbable and effectively bioavailable iron, and is able to increase ferritin. Furthermore, the oral composition BC-1 or BC-2 has proven to be well tolerated by the body. The composition can be administered, even on an empty stomach, to all categories of patients, including pregnant women. The oral composition BC-1 or BC-2 has good palatability and has proven to be stable over time from a chemical-physical and organoleptic point of view, i.e. no changes in color, odor, flavor and/or taste have been observed.

Compositions BC-1 and BC-2 according to the invention are a solid state composition, formulated in dosage units. By solid state it is meant that the composition may exist in the form of granules, microgranules or powders or flakes. The granular or microgranular or powder compositions are then mixed with pharmacologically acceptable additives and excipients of pharmaceutical or food grade to provide a final product such as a food supplement product, a composition for a medical device reg. EU 745/2017 or a pharmaceutical composition. The final product may be in pharmaceutical dosage units such as, for example, granules in sachet, tablet or capsule.

Tablets may have different shapes among those known in the field of pharmaceutical forms, such as a cylindrical or spheroidal shape. Tablets may have a weight ranging from 100 to 2000 mg. Tablets may be coated or filmed with one or more layers of coating or film capable of passing through the gastric barrier, according to known methods.

Gel capsules can, for example, weigh from 200 mg to 1200 mg, a hard capsule can weigh from 500 to 1000 mg, while a chewable tablet can weigh from 500 to 2000 mg. Capsules can be made of hard gelatin or soft gelatin or soft gel.

Each dosage unit is 5 mg to 50 mg of iron (III)/day, preferably 10 mg to 45 mg of iron (III)/day, more preferably 15 mg to 40 mg, most preferably 20 mg to 30 mg, e.g. 25 mg, or 27 mg, or 29 mg, of iron (III)/day.

As stated, preferably the oral composition BC-1 or BC-2 of the invention is a solid composition, as described above. However, if desired or necessary, the composition may be formulated in liquid form, for example by suspension in water, preferably with the addition of a physiologically acceptable acid, for example citric acid.

The solid compositions of the invention may contain, as noted, conventional physiologically acceptable excipients and vehicles, such as diluents, bulking agents, binders, disintegrants, flow promoters, lubricants, etc. Non-limiting examples of suitable vehicles and excipients are described in "Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins." The compositions of the invention may, for example, contain cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, glycol, water, ethanol, and the like. The composition may also contain pH buffering reagents and wetting or emulsifying agents.

Preferred excipients include hydroxypropyl methyl cellulose and magnesium salts of fatty acids.

In addition to the components described above, if desired or necessary, the BC-1 and BC-2 compositions of the invention may include further active components, for example components capable of assisting the active ingredient in carrying out its action in the organism of the treated subject, such as vitamins.

The invention also provides a liquid oral composition comprising or, alternatively, consisting of a BC-1 or BC-2 composition according to the invention, water and citric acid.

The composition for oral use BC-1 or BC-2, solid or liquid, according to any of the embodiments described above, is useful in therapy, in particular in the treatment and prevention of disorders or diseases related to iron deficiency in pediatric subjects, adolescents, athletes, men, women, pregnant women and the elderly because it prevents and combats anemia and is useful for increasing hemoglobin and ferritin values. Said composition BC-1 or BC-2 is suitable for administration over a period of 1 to 5 months, preferably 2 to 4 months, in pediatric subjects, adolescents, athletes, men, women, pregnant women and the elderly, at a dose of 10 to 40 mg of iron (III)/day, preferably 14 to 30 mg of iron (III)/day, even more preferably 28 mg of iron (III)/day.

The compositions BC-1 and BC-2 can be administered throughout the entire pregnancy period, in particular from the 12th week, up to 6 weeks after delivery (postpartum). The recommended dose of iron (III) is between 10 and 40 mg/day, preferably between 14 and 30 mg/day, advantageously 28 mg/day.

Third aspect of the invention - aspect C

In another of its aspects, aspect C1, the invention has as its object a CM-1 mixture consisting of:

- i) an iron(III) pyrophosphate salt;

- at least one lecithin;

- at least one gum arabic (or acacia gum); and

- iii) a sodium or potassium pyrophosphate salt, preferably tetrasodium pyrophosphate.

In another of its aspects, aspect C2, the invention has as its object a CM-2 mixture consisting of:

- i) an iron(III) pyrophosphate salt;

- at least one lecithin;

- at least one gum arabic (or acacia gum);

- iii) a sodium pyrophosphate salt, preferably tetrasodium pyrophosphate; and

- ii) an iron(III)-sodium pyrophosphate salt.

Preferably, the CM-1 or CM-2 mixture of the present invention may further comprise a further component selected from vegetable starches. Preferably, the vegetable starch is, for example, preferably selected from rice starches or corn starches or sunflower starches or soy starch, or mixtures thereof. For example, the preferred starch is a rice starch such as a gelatinized or pregelatinized native rice starch. For example, a pregelatinized rice starch that may be used has a CAS No. 9005-25-8; EINECS 232-679-6 with a moisture content of 10% to 20%, for example about 15%; a particle size distribution (particle size distribution) D10 ?m max.20; D50 ?m max.75 and D90 ?m max. 175. A commercial product that meets these characteristics is Remyline AX-FG-P from the company A.D.E.A. Srl.

Preferably, another type of pregelatinized rice starch usable in CM-1 or CM-2 mixtures may have the following chemical-physical characteristics: moisture from 1% to 10%; protein content from 0.1% to 1.5%; ash content from 0.1% to 1%; pH (10% solution) between 5.5 and 7.5; density 0.40-0.48 g/cm<3>; starch content from a minimum of 95% to 99% and fat content from 0.01% to 0.1%.

Preferably, gelatinized or pregelatinized vegetable starch is present in the CM-1 and CM-2 mixtures in an amount by weight of 1% to 50%, preferably 10% to 40%, more preferably 15% to 35%, even more preferably 20% to 30%, based on the total weight of the compositions CC-1 and CC-2.

Iron(III) pyrophosphate, iron(III)-sodium pyrophosphate, and sodium pyrophosphate are all salts or compounds known in the prior art.

Preferably, said gum arabic or acacia gum is present in said CM-1 or CM-2 mixture in an amount by weight of from 5% to 45%, preferably from 10% to 40%, more preferably from 15% to 35%, even more preferably from 20% to 30%, with respect to the total weight of said mixture.

Iron(III) pyrophosphate, iron(III)-sodium pyrophosphate and sodium pyrophosphate are all salts or compounds known in the prior art and, at a temperature of 25°C, they all occur in solid form, for example, as powders or granules.

Preferably, said i) iron (III) pyrophosphate according to the invention is a hydrated salt and, preferably, has a chemical formula, for example, of the type [Fe4(P2O7)3xH2O] (CAS RN.

10058-44-3, dry molecular weight 745.22) and, preferably, may have an iron content of between 18% and 24%, even more preferably between 20% and 22% by weight, with respect to the total weight of the molecule.

Preferably, called ii) iron(III)-sodium pyrophosphate is a salt and, preferably, has a chemical formula, for example, of the type Fe(III)NaO7P2 (CAS RN.10045-87-1).

Preferably, called iii) sodium pyrophosphate is a salt and, preferably, may be in the form of, for example, a tetrasodium pyrophosphate having a chemical formula, for example, of the type Na4P2O7 (CAS RN.1269628-79-6) for example in anhydrous, semi-hydrated or hydrated form or in any case with a number of water molecules known to the person skilled in the art. Tetrasodium pyrophosphate, at room temperature and pressure of 25?C and 1 atmosphere, appears as a colourless, odourless, water-soluble solid and is coded in the list of food additives as E450. Tetrasodium pyrophosphate is normally used in the food industry.

Preferably, said i) iron (III) pyrophosphate salt according to the invention is present in the CM-1 or CM-2 mixture in an amount by weight of from 10% to 90%, preferably of from 25% to 75%, more preferably of from 35% to 65%, even more preferably of from 40% to 55%, with respect to the total weight of said mixture.

Preferably, said ii) iron (III)-sodium pyrophosphate salt according to the invention is present in the CM-1 or CM-2 mixture in an amount by weight of from 0.1% to 50%, preferably from 1% to 35%, more preferably from 5% to 30%, even more preferably from 10% to 25%, with respect to the total weight of said mixture.

Preferably, said iii) sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium phosphate, according to the invention is present in the CM-1 or CM-2 mixture in an amount by weight of from 0.1% to 50%, preferably from 1% to 35%, more preferably from 5% to 30%, even more preferably from 10% to 25% by weight, with respect to the total weight of said mixture. The term "lecithin" is known in the art and is catalogued as the food additive E322 according to directive no. 95/2/CE of 20.2.95, published in O.J. no. L61 of 18.9.95.

Lecithin, due to its chemical-physical properties, mainly performs an emulsifying function and, furthermore, being also rich in natural antioxidant substances, it also has a secondary antioxidant function.

Directive no. 2008/84/EC of 27 August 2008 (published in the European Community O.J. no. L253) establishes the purity criteria that lecithin must present in order to be considered of food quality (E322): Insoluble in acetone (practically the active part of lecithin): 60% minimum; Humidity: 2% maximum; Acidity number: 35 maximum; Peroxide number: 10 maximum; Insoluble in toluene (practically impurities): 0.3% maximum.

Chemically, lecithin is a mixture of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides and phospholipids.

Phospholipids are the main components of lecithins; they are derived from the structure of triglycerides, in which a fatty acid is replaced by a phosphate group, conferring a negative charge, and therefore polarity, to the molecule; this molecule has the generic name of phosphatide. A more complex organic molecule, usually serine, choline, ethanolamine, inositol or a single hydrogen atom is linked to the phosphate group through an ester bond, giving rise to a phospholipid called, respectively, phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol or phosphatidic acid. In a narrower sense, lecithin is often referred to as phosphatidylcholine.

Phospholipids are characterized by a water-soluble polar head, which dissolves well in water, while the two saturated fatty acids represent the two apolar tails, not water-soluble but lipophilic. These molecules are called amphipathic and when in the presence of water and fats, they arrange themselves between the fat molecules and those of the water, emulsifying them. Lecithin is therefore a natural emulsifier.

The lecithin used according to the invention is a non-hydrolyzed lecithin, in powder form, and is preferably selected from sunflower lecithin and/or corn and/or soy and/or corn and/or rice, or mixtures thereof. The lecithin used according to the invention is a powdered lecithin having a water content of 1.5% to 4.5%, preferably 2 to 4%, even more preferably 2.5% to 3.5%. Preferably, the lecithin used is a powdered sunflower lecithin.

In one embodiment, the sunflower lecithin has a glucose content of 20% to 60%, preferably 30% to 50%, e.g. about 45% by weight.

A sunflower lecithin usable in the context of the present invention may have the following composition by weight (physical-chemical analysis): sunflower lecithin from 40% to 50%, carbohydrates from 40% to 50% (e.g. approximately 42%), proteins from 6% to 10%, ash from 3% to 8%, moisture from 2% to 5% and a sliding agent from 0.5% to 1.5%.

Lecithin is present in the oral composition of the present invention in an amount by weight of 0.1% to 10%, preferably 0.5% to 5%, more preferably 1% to 4%, even more preferably 1.5% to 3.5%, based on the total weight of the composition.

The term "gum arabic" is known to the art and refers to a natural gum also known as acacia gum, because it is extracted from two species of acacia, Acacia senegal and Acacia seyal.

Gum arabic is commercially available and, in the context of the present invention, for example, a gum derived from Acacia senegal of the type E414 can be used.

Preferably, for example, gum arabic (acacia) of the type E414 can be used which appears as a white powder and has a CAS No. 9000-01-5 and EINECS No. 232-519-5, an average molecular weight of approximately 350,000, a viscosity of approximately 60-130 mPas (25% sol.) and is practically insoluble in ethanol (96%).

The subject of the present invention is a mixture (CM-1 or CM-2) which comprises or, alternatively, consists of:

- i) an iron(III) pyrophosphate salt;

- at least one lecithin;

- at least one gum arabic or gum acacia; and

- iii) a sodium or potassium pyrophosphate salt.

Preferably, said mixture further comprises ii) an iron (III)-sodium pyrophosphate salt; preferably said ii) an iron (III)-sodium pyrophosphate salt is present in said mixture in an amount by weight of from 0.1% to 50%, preferably from 1% to 35%, more preferably from 5% to 30%, even more preferably from 10% to 25%, based on the total weight of said mixture.

Preferably, said mixture further comprises a starch, preferably said starch is a vegetable starch selected from the group comprising or, alternatively, consisting of rice starch, corn starch, sunflower starch or soya starch, more preferably said vegetable starch is a pregelatinized rice starch.

Preferably, said starch is present in said mixture in an amount by weight of from 1% to 50%, preferably from 10% to 40%, more preferably from 15% to 35%, even more preferably from 20% to 30%, with respect to the total weight of said mixture.

Preferably, said i) an iron (III) pyrophosphate salt is present in said mixture in an amount by weight of from 10% to 90%, preferably of from 25% to 75%, more preferably of from 35% to 65%, even more preferably of from 40% to 55%, with respect to the total weight of said mixture.

Preferably, said at least one lecithin is a vegetable lecithin, preferably said vegetable lecithin is selected from the group comprising or, alternatively, consisting of a sunflower, corn, soya or rice lecithin; preferably said at least one lecithin is present in said mixture in an amount by weight of from 0.1% to 10%, preferably from 0.5% to 5%, more preferably from 1% to 4%, even more preferably from 1.5% to 3.5%, by weight, with respect to the total weight of said mixture.

Preferably, said gum arabic or acacia gum is present in said mixture in a quantity by weight of from 5% to 45%, preferably from 10% to 40%, more preferably from 15% to 35%, even more preferably from 20% to 30%, with respect to the total weight of said mixture.

Preferably, said (iii) sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium pyrophosphate, is present in said mixture in an amount by weight of from 0.1% to 50%, preferably from 1% to 35%, more preferably from 5% to 30%, even more preferably from 10% to 25%, with respect to the total weight of said mixture.

Preferably, said mixture is for use in therapy; preferably said mixture is for use in a method of treatment and/or prevention of conditions of total or relative iron deficiency, in particular for use in the treatment of disorders or diseases related to or resulting from iron deficiency.

The present invention provides a composition (CC-1 or CC-2) comprising a mixture (CM-1 or CM-2) as described above and, optionally, at least one excipient and/or vehicle of pharmaceutical or food grade; preferably said composition is in solid form in oral dosage units.

The invention also relates to a CC-1 composition which comprises, or secondarily consists of the CM-1 mixture, together with at least one excipient and/or carrier of pharmaceutical or food grade.

The invention also relates to a CC-2 composition which comprises, or secondarily consists of the CM-2 mixture, together with at least one excipient and/or carrier of pharmaceutical or food grade.

Compositions CC-1 and CC-2 are suitable for oral administration.

The oral compositions CC-1 and CC-2 according to the invention are for use in conditions of total or relative iron deficiency, in particular for use in the treatment of disorders or diseases related to or resulting from iron deficiency.

The oral compositions CC-1 and CC-2 of the present invention preferably do not contain a diglycerol fatty acid ester (?diglycerol fatty acid ester?).

The oral compositions CC-1 and CC-2 according to the invention are preferably a solid state composition, formulated in dosage units. By solid state it is meant that the composition may exist in the form of granules or powders. The granular or powder compositions are then mixed with pharmacologically acceptable additives and excipients to provide a final product such as a food supplement, a medical device or a pharmaceutical composition. The final product may be in pharmaceutical dosage units such as granules in a sachet, tablet or capsule.

Tablets may have different shapes among those known in the field of pharmaceutical forms, such as a cylindrical or spheroidal shape. Tablets may have a weight between 100 and 2000 mg. Tablets may be coated or filmed with one or more layers of coating or film capable of passing through the gastric barrier, according to known methods.

Gel capsules can for example weigh 200-1200 mg, a hard capsule can weigh between 500 and 1000 mg, while a chewable tablet can weigh between 500 and 2000 mg. Capsules can be made of hard gelatin or soft gelatin or soft gel.

Preferably the oral composition of the invention is a solid composition, as described above. However, if desired or necessary, the composition may be formulated in liquid form, for example as a suspension in water, preferably with the addition of a physiologically acceptable acid, for example citric acid.

The solid compositions of the invention may contain, as noted, conventional physiologically acceptable excipients and vehicles, such as diluents, bulking agents, binders, disintegrants, flow promoters, lubricants, etc. Non-limiting examples of suitable vehicles and excipients are described in "Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins." The compositions of the invention may, for example, include cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, glycol, water, ethanol, and the like. The composition may also contain pH buffering reagents and wetting or emulsifying agents.

In addition to the components described above, if desired or necessary, the compositions of the invention may include further active components, for example components capable of assisting the active ingredient in carrying out its action in the organism of the treated subject, such as vitamins.

The composition for oral use, solid or liquid, according to any of the embodiments described above, is useful in the treatment and prevention of disorders or diseases related to iron deficiency in pediatric subjects, adolescents, athletes, men, women, pregnant women and the elderly because it prevents and combats anemia and is useful for increasing hemoglobin and ferritin values. This composition is suitable for administration over a period of 1 to 5 months, preferably 2 to 4 months, in pediatric subjects, adolescents, athletes, men, women, pregnant women and the elderly, at a dose of 10 to 40 mg of iron (III)/day, preferably 14 to 30 mg of iron (III)/day, even more preferably 28 mg of iron (III)/day.

The invention also provides an iron-based supplement comprising a CC-1 or CC-2 composition of the invention, possibly together with other components, for example minerals and/or vitamins.

The invention also provides a method for the treatment and/or prevention of disorders or diseases related to iron deficiency, which comprises administering to a subject in need a CC-1 or CC-2 composition according to the invention.

Compositions CC-1 and CC-2 of the invention comprise iron (III) pyrophosphate in an amount of from 30 to 70%, preferably from 35 to 55%, even more preferably from 40 to 50% by weight, based on the total weight of the composition.

The Applicant has surprisingly found that the addition of a sodium or potassium pyrophosphate salt, e.g. tetrasodium pyrophosphate, to the compositions described in WO2014/009806 and WO2015/033216 and marketed under the trade name ?Sideral <?>? in a completely unexpected way, significantly increases iron uptake through the increase in ferritin.

This surprising result will be described and demonstrated in detail in the Experimental Section that follows.

Sodium pyrophosphate is preferably present as tetrasodium pyrophosphate and is present, in the oral composition CC-1 or CC-2 of the present invention, in an amount of from 0.1 to 30%, preferably from 1 to 20%, even more preferably from 12 to 16% by weight, based on the total weight of the composition.

The oral composition CC-1 of the present invention therefore comprises or, alternatively, consists of iron (III) pyrophosphate, a lecithin such as a lecithin of the E322 type, at least one gum arabic (or acacia gum) and sodium pyrophosphate, preferably tetrasodium pyrophosphate, in the percentage weight amounts indicated above.

The oral composition CC-2 of the present invention therefore comprises or, alternatively, consists of iron (III) pyrophosphate, a lecithin such as a lecithin of the E322 type, at least one gum arabic (or acacia gum), sodium pyrophosphate, preferably tetrasodium pyrophosphate and iron (III)-sodium pyrophosphate, in the percentage amounts by weight indicated above. As mentioned, the oral composition CC-1 or CC-2 of the present invention may also comprise other conventional, physiologically acceptable components, excipients and vehicles.

Preferably, the oral composition CC-1 or CC-2 of the present invention may further comprise a further component selected from vegetable starches.

Vegetable starch is preferably selected from rice starches or corn starches. Preferably, the starch is rice starch; more preferably, the rice starch is gelatinized or pregelatinized native rice starch.

A pregelatinized rice starch usable in the context of the present invention may have the following chemical-physical characteristics: moisture not exceeding 7%; protein content not exceeding 1%; ash content not exceeding 1%; pH (10% solution) between 5.5 and 7.5; density 0.40-0.48 g/cm<3>; starch content at least 97% and fat content not exceeding 0.1%. For example, a pregelatinized rice starch may be used.

Gelatinized or pregelatinized vegetable starch is present in the solid composition in an amount of 10 to 40%, preferably 15 to 35%, even more preferably 20 to 30% by weight, with respect to the total weight of the compositions CC-1 and CC-2.

The oral composition CC-1 of the present invention comprises or, alternatively, is constituted by iron (III) salts, a lecithin such as a lecithin of the E322 type, at least one gum arabic (or an acacia gum), sodium pyrophosphate preferably tetrasodium pyrophosphate and, preferably, a vegetable starch, in the percentage weight quantities indicated above.

The oral composition CC-2 of the present invention comprises or, alternatively, is constituted by iron (III) salts, a lecithin such as a lecithin of the E322 type, at least one gum arabic (or an acacia gum), sodium pyrophosphate preferably tetrasodium pyrophosphate, iron (III)-sodium pyrophosphate and, preferably a vegetable starch, in the percentage amounts by weight indicated above.

The present invention also provides a first method for preparing an oral composition CC-1 or CC-2 of the present invention.

A first method of the present invention is aimed at the preparation of an oral composition comprising or, alternatively, consisting of iron (III) pyrophosphate, a sunflower lecithin, gum arabic, tetrasodium pyrophosphate, a vegetable starch, preferably pregelatinized rice starch, and optionally iron (III)-sodium pyrophosphate, in the percentage quantities by weight indicated above.

Said first method of the present invention comprises or, alternatively, consists of a series of processing steps through which the iron (III) pyrophosphate is coated or wrapped or encapsulated with said lecithin and/or said gum arabic and/or said vegetable starch.

Preferably, the iron (III) pyrophosphate in the solid state is placed in contact in order with said gum arabic, then with said lecithin, then with said tetrasodium pyrophosphate and finally with said vegetable starch.

The iron (III) pyrophosphate, lecithin, gum arabic, tetrasodium pyrophosphate, optionally iron (III)-sodium pyrophosphate and starch used in the method of the invention have the characteristics and properties defined above.

Starch in the form of gelatinized or pregelatinized starch has the advantage of being more fluid and flowing and can be dosed precisely without causing errors or variations in weight. Furthermore, it is distributed more uniformly and homogeneously. Finally, pregelatinized starch improves the bioavailability of the iron cation, as the compound obtained dissolves better at temperatures between 15 and 30?C (pressure 1 atmosphere), preferably from 20 to 25?C, even more preferably from 18 to 23?C.

At the end of said first preparation method, an oral composition CC-1 or CC-2 of the present invention is obtained, which comprises or, alternatively, is constituted by iron (III) pyrophosphate, a sunflower lecithin, gum arabic, tetrasodium pyrophosphate, optionally iron (III)-sodium pyrophosphate (CC-2) and a pregelatinized rice starch, in the percentage weight quantities indicated above.

In particular, by means of said first preparation method a solid composition CC-1 or CC-2 of the present invention is obtained, which comprises or, alternatively, is constituted by iron (III) pyrophosphate, a sunflower lecithin E322, gum arabic, tetrasodium pyrophosphate, optionally iron (III)-sodium pyrophosphate (CC-2) and a pregelatinized rice starch, in the percentage quantities by weight indicated above.

The Applicant has found that to further improve the absorption of the iron cation, it is useful to reduce the amount by weight of lecithin to be used in the process to prepare the solid composition of the present invention as much as possible.

Furthermore, the Applicant found that to further enhance the absorption of the iron cation, it is important to use a specific amount by weight of gum arabic in combination with a reduced amount by weight of lecithin.

Advantageously, the weight ratio of gum arabic to lecithin is between 40:1 and 10:1. In one embodiment, this ratio is between 35:1 and 15:1; in any case, the lecithin is present in the composition in a quantity by weight of between 0.01% and 10%, preferably from 0.1% to 5%, more preferably from 0.5% to 2.5%, even more preferably from 0.8% to 1.2%.

Details of the first method of the invention are reported in the Experimental Section of the present invention.

The present invention also provides a second method for preparing an oral composition CC-1 or CC-2 of the present invention.

A second method of the present invention is directed to the preparation of a solid composition CC-1 or CC-2 comprising or, alternatively, consisting of an iron salt, gum arabic, a lecithin, tetrasodium pyrophosphate, optionally iron (III)-sodium pyrophosphate (CC-2) and a gelatinized or pregelatinized starch.

Said second method of the present invention comprises or, alternatively, consists of a technology developed to create a coating or encapsulation around the iron so as to improve the stability and bioavailability of the cation.

In practice, the second method involves the formation of agglomerates or granules comprising iron (III) pyrophosphate, gum arabic, lecithin, tetrasodium pyrophosphate, possibly iron (III)-sodium pyrophosphate and a gelatinized or pregelatinized starch. All these components have the characteristics reported above.

Gum arabic and lecithin act by promoting the absorption of salt and, consequently, of the iron cation contained in said salt. The mixture with lecithin and starch gives rise to the formation of "chimeric" agglomerates capable of protecting and shielding the iron cation contained in the pyrophosphate salt from gastric acid.

The processing time is between 1 and 60 minutes, preferably between 10 and 50, even more preferably between 20 and 40 minutes.

The oral composition obtained with the methods of the present invention has a granulometry (which is understood as the average granulometry measured by the available equipment and techniques) of the D50 type of approximately 20.5 ?m (?m micrometer, 10?6 meters); for example, it can have a granulometric distribution of the D10 type of approximately 1.8 ?m, D50 of approximately 20.5 ?m and D90 of approximately 108 ?m.

The solid composition of the present invention has an iron (III) content of between 60 mg/g and 140 mg/g, preferably between 80 mg/g and 120 mg/g, even more preferably between 90 and 110 mg/g.

The oral composition CC-1 or CC-2 according to the invention is for use in conditions of total or relative iron deficiency, in particular for use in the treatment of disorders or diseases related to or resulting from iron deficiency.

The oral composition CC-1 or CC-2 of the present invention comprises easily absorbable and effectively bioavailable iron, and capable of increasing ferritin. Furthermore, the oral composition CC-1 or CC-2 has proven to be well tolerated by the body. The composition can be administered, even on an empty stomach, to all categories of patients, including pregnant women. The oral composition CC-1 or CC-2 has good palatability and has proven to be stable over time from a chemical-physical and organoleptic point of view, i.e. no changes in color, odor, flavor and/or taste have been observed.

Compositions CC-1 and CC-2 according to the invention are a solid state composition, formulated in dosage units. By solid state it is meant that the composition may exist in the form of granules or powders. The granular or powder compositions are then mixed with pharmacologically acceptable additives and excipients to provide a final product such as a dietary supplement, a medical device or a pharmaceutical composition. The final product may be in pharmaceutical dosage units such as granules in sachets, tablets or capsules.

The tablets may have different shapes among those known in the field of pharmaceutical forms, such as a cylindrical or spheroidal shape. The tablets may have a weight between 200 and 2000 mg. The tablets may be coated or filmed with one or more layers of coating or film capable of passing through the gastric barrier, according to known methods.

Gel capsules can for example weigh 500 mg, a hard capsule can weigh between 800 and 1000 mg, while a chewable tablet can weigh between 1000 and 2000 mg. Capsules can be made of hard gelatin or soft gelatin or soft gel.

Each dosage unit comprises 5 to 50 mg of iron (III), preferably 10 to 40 mg. Preferably the oral composition CC-1 or CC-2 of the invention is a solid composition, as described above. However, if desired or necessary, the composition may be formulated in liquid form, for example by suspension in water, preferably with the addition of a physiologically acceptable acid, for example citric acid.

The solid compositions of the invention may contain, as noted, conventional physiologically acceptable excipients and vehicles, such as diluents, bulking agents, binders, disintegrants, flow promoters, lubricants, etc. Non-limiting examples of suitable vehicles and excipients are described in "Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins." The compositions of the invention may, for example, include cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, glycol, water, ethanol, and the like. The composition may also contain pH buffering reagents and wetting or emulsifying agents.

Preferred excipients include hydroxypropyl methyl cellulose and magnesium salts of fatty acids.

In addition to the components described above, if desired or necessary, the CC-1 and CC-2 compositions of the invention may include further active components, for example components capable of assisting the active ingredient in carrying out its action in the organism of the treated subject, such as vitamins.

The invention also provides a liquid oral composition comprising or, alternatively, consisting of a CC-1 or CC-2 composition according to the invention, water and citric acid.

The oral composition CC-1 or CC-2, solid or liquid, according to any of the embodiments described above, is useful in the treatment and prevention of disorders or diseases related to iron deficiency in pediatric subjects, adolescents, athletes, men, women, pregnant women and the elderly because it prevents and combats anemia and is useful for increasing hemoglobin and ferritin values. Said composition CC-1 or CC-2 is suitable for administration over a period of 1 to 5 months, preferably 2 to 4 months, in pediatric subjects, adolescents, athletes, men, women, pregnant women and the elderly, at a dose of 10 to 40 mg of iron (III)/day, preferably 14 to 30 mg of iron (III)/day, even more preferably 28 mg of iron (III)/day.

Compositions CC-1 and CC-2 can be administered throughout the entire pregnancy, in particular from the 12th week, up to 6 weeks after delivery (postpartum). The recommended dose of iron (III) is between 10 and 40 mg/day, preferably between 14 and 30 mg/day, advantageously 28 mg/day.

The invention also provides an iron-based supplement comprising a CC-1 or CC-2 composition of the invention, possibly together with other components, for example minerals and/or vitamins.

The invention also provides a method for the treatment and/or prevention of disorders or diseases related to iron deficiency, which comprises administering to a subject in need a CC-1 or CC-2 composition according to the invention.

The Applicant has conducted numerous experimental studies and has been able to observe that the mixtures and compositions of the invention present improved performances compared to commercially available compositions and even compared to the compositions marketed under the trade name "Sideral".

Details of the tests conducted and the results obtained are reported in the Experimental Section that follows, which illustrates representative forms of the invention in a non-limiting manner. The embodiments of the present invention are reported below.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows a schematic of the static permeation assay.

Figure 2 shows the results of the comparison in the solubility tests of Iron sulphate, Iron (III) pyrophosphate, Sideral r.m. (commercial product containing iron (III) pyrophosphate, lecithin, sucrester and starch), Sideral NaPP (Sideral r.m. added with tetrasodium pyrophosphate according to the invention - Example 1).

Figure 3 shows the comparison results in the simulated gastric digestion test of Sideral r.m. (commercial product containing iron (III) pyrophosphate, lecithin, sucrester and starch), Sideral NaPP (Sideral r.m. added with tetrasodium pyrophosphate according to the invention - Example 1). Figure 4 shows the comparison results in the ferritin accumulation test (Sideral_L ABS = composition of Example 1 of the invention with Lecithin ABS LecySpray; Sideral_NaPP_L AF NVH = composition of Example 1 of the invention with Lecithin L AF NVH; Sideral Liquido_NaPP_L AF NVH = composition of Example 2 with Lecithin L AF NVH).

Figure 5 shows the comparison results in the apparent permeability tests and ferritin accumulation of Sideral with two different lecithins (L063 and LAFNVH) compared to the same Sideral added with tetrasodium pyrophosphate.

Figure 6 shows the comparison results in apparent permeability tests and ferritin accumulation of Sideral-like (composition containing gum arabic instead of sucrester CM1/CC1 and CM2/CC2) with two different lecithins (L063 and LAFNVH) compared to the same Siderallike added with tetrasodium pyrophosphate.

EXPERIMENTAL SECTION

Example 1

Preparation of a composition of the first aspect of the invention.

Table 1

Mixing protocol

Preparation of 300 g of prototype following the relevant Master Formula with NOVINOX mixer for 100 g of finished product.

1) Add the following components:

IRON (III) PYROPHOSPHATE

TO SUCREST

LECITHIN

SODIUM PYROPHOSPHATE

2) Mix 30 minutes 8.7 rpm clockwise rotation

3) Add: rice starch

4) Mix 30 minutes, 8.7 rpm clockwise rotation

5) Sift automatically for about 10 minutes

6) Mix 30 minutes, 8.7 rpm clockwise rotation

7) Measure the yield at the end of the process

Example 2

Composition of the first aspect of the invention in liquid form

Table 2

Example 3

Preparation of a composition of the third aspect of the invention, as in Example 1

Table 3

Example 4

Static permeation test ? Transwell system

EXPERIMENTAL PROTOCOL

Material

Cells: Caco-2 (HTB-37?), ATCC.

Insert: TC insert, for 12-well plates, PET, transparent, pore size: 0.4 μm, Sarstedt.

Plate: 12 wells.

Complete medium: Dulbecco's Modified Eagle's Medium (DMEM - reduced glucose,

with 1000 mg/L glucose, and sodium bicarbonate, without L-glutamine and phenol red, liquid, sterilefiltered, suitable for cell cultures) (87%), L-Glutamine in solution 200 mM (2%), MEM Non-essential amino acid solution (100?) (1 %), fetal bovine serum (10%).

Complete medium without FBS: Dulbecco's Modified Eagle's Medium (DMEM - reduced glucose,

with 1000 mg/L glucose, and sodium bicarbonate, without L-glutamine and phenol red, liquid, sterile-filtered, suitable for cell cultures) (87%), L-Glutamine in solution 200 mM (2%), MEM Solution of non-essential amino acids (100?) (1 %).

DMEM: Dulbecco's Modified Eagle's Medium with pH indicator phenol red (DMEM - with 1000 mg/L glucose, and sodium bicarbonate, without L-glutamine and phenol red, liquid, sterile-filtered, suitable for cell cultures).

CelLyticTM MT: Mammalian Tissue Lysis/Extraction Reagent, Sigma Aldrich.

MTT 1 mg/mL: 3,2,5-diphenyltetrazolium bromide, a standard colorimetric assay for measuring the activity of enzymes that reduce MTT to formazan, giving the substance a blue/purple color. This coloration indicates cell viability.

Acid Alcohol: 19 parts 2 Propanol: 1 part 2M HCl.

TEER: Trans-Epithelial Electrical Resistance, a measurement of the integrity and strength of the intestinal barrier at the confluence of the cell monolayer.

Treatments: Iron (III) pyrophosphate, Sideral r.m., Composition of Example 1 (Sideral NaPP), Blank.

Supernatants of simulated gastrointestinal digests.

Cell proliferation:

- Place 12 0.4 ?m inserts in a 12 well plate. Repeat for 2 plates.

- Plate 1mL of Caco-2 cells in complete medium in the Apical compartment at a density of 0.5 x 105 cells per insert. Cells should be plated at passages greater than 25.

- Add 1.5 mL of complete medium to the basal compartment.

- Maintain the cells in an incubator at 37?C with 5% CO2.

- Change the soil every other day for 21 days.

- On day 21 the cells are ready for experimentation.

Simulated gastrointestinal digestion:

Apply the simulated gastrointestinal digestion protocol to the following samples: Blank (B), Iron (III) pyrophosphate (FeP), Sideral r.m. (SID), Sideral with sodium pyrophosphate (SID NaPP). Oral compartment: 3.5 mL of a 2 mg/mL aqueous solution of element iron (3.5 mL of water for the blank) are maintained at 37?C for 5 min under agitation.

Gastric compartment: Add 6.5 mL of FGS (Simulated gastric fluid: 0.2 g NaCl in 100 mL of water adjusted to pH 1.2 with concentrated HCl). Maintain the solution at 37?C with agitation for 2 h.

Intestinal Compartment: 10 mL of gastric digest are added to 1 mL of 1M NaHCO3 and 4 mL of FIS (Simulated intestinal fluid: 0.68 g anhydrous KH2PO4 in 100 mL H2O pH 7.5 with 1M NaOH). Maintain the solution at 37?C under agitation for 2 h.

Upon completion of the simulated gastrointestinal digestion, centrifuge the samples at 8000 rpm for 5 min and collect the supernatant. Quantify the supernatant with the ICP-OES instrument. Experimentation

Treatment preparation: dilute the supernatant of the gastrointestinal digests with complete medium without FBS to a final concentration of 1 ?g/mL.

1. Move the inserts to a clean 12-well plate and remove the medium from the apical compartment. 2 complete plates of 24 inserts are needed per experiment.

2. Wash cells with 500 μL PBS 2 times.

3. Add 400 ?L of treatment to the apical compartment and 1600 ?L of complete medium without FBS to the basal compartment.

4. Measure the TEER for the 24 inserts at T0, i.e. immediately after treatment.

5. Wait 3 hours of treatment in an incubator at 37?C.

6. At the completion of the 3 hours of treatment, measure the TEER for all 24 inserts and subsequently take Apical and Basal samples.

7. Wash the cells with 500 ?l of PBS twice for both plates.

8. To plate 1 (12 inserts) add 400 uL of CelLyticTM MT and shake for 10 min.

9. At the end of 10 min, remove the CelLyticTM MT from each insert and centrifuge at 8000 rpm for 5 min. Remove the supernatant and retain the cell pellet.

From plate 1 obtain apical, basal, pellet, cell supernatant of each insert. From plate 2 obtain apical and basal.

10. To evaluate barrier integrity, an additional parameter to TEER, in plate 2 add 400 uL of DMEM with phenol red indicator in the apical compartment of each insert. Add 1600 uL of complete medium without FBS in the basal compartment. Wait 1 h in an incubator at 37?C. The same procedure is applied to a triplicate insert that has not undergone treatment (Positive Control) and a triplicate empty insert without cells (Negative Control).

11. After 1 h, take the baseline and analyze the coloration with a spectrophotometer at a wavelength of 479 nm. The result is compared with the positive and negative control.

12. Remove the apical and wash the cells with 500 ?l of PBS for 2 times.

13. Add 400 ?L MTT to the apical compartment and 1600 ?L of complete medium without FBS to the basal compartment. Wait 2h in an incubator at 37?C.

14. At the end of 2 hours, remove the liquid from the two compartments and add 400 ?L to the Apical compartment and 1600 ?L to the basal compartment of acid alcohol. Wait 24 hours in an incubator at 37?C.

15. At the end of 24 hours, read the color obtained at the wavelength of 570 and 650 nm using the spectrophotometer and compare it to the positive control (cell viability on the insert that did not receive the treatment).

Through plate 2, the integrity value of the cell monolayer and its vitality is obtained, to be associated with the TEER values at T0 and T3h.

Figure 1 shows a schematic of the static permeation system. The test results are shown in Figures 2 and 3.

From the results shown in the Figures, it is understood that the composition according to any of the aspects of the invention shows an improved bioavailability of the iron contained therein and a surprising increase in ferritin. For these reasons, the composition according to any of the aspects of the invention represents a significant technical progress compared to known iron-based compositions.

Claims (10)

1. A mixture comprising or, alternatively, consisting of: - at least one iron (III) salt selected from: i) iron (III) pyrophosphate and ii) iron (III)-sodium pyrophosphate and their mixtures, and - iii) a sodium or potassium pyrophosphate. 2. The mixture according to claim 1, wherein said mixture consists of i) iron (III) pyrophosphate and iii) sodium or potassium pyrophosphate, preferably said iii) sodium pyrophosphate ? tetrasodium pyrophosphate. 3. The mixture according to claim 2, wherein said i) iron (III) pyrophosphate and iii) sodium or potassium pyrophosphate are present in said mixture in a weight ratio iron (III) pyrophosphate:sodium or potassium pyrophosphate of from 1:0.05 to 1:1, preferably from 1:0.1 to 1:0.5, more preferably from 1:0.2 to 1:04. 4. The mixture according to claim 1, wherein said mixture consists of ii) iron (III)-sodium pyrophosphate and iii) sodium or potassium pyrophosphate; preferably said iii) sodium pyrophosphate is tetrasodium pyrophosphate. 5. The mixture according to claim 4, wherein said ii) iron (III)-sodium pyrophosphate and iii) sodium or potassium pyrophosphate are present in said mixture in a weight ratio iron (III)-sodium pyrophosphate:sodium or potassium pyrophosphate of from 1:0.05 to 1:1, preferably from 1:0.1 to 1:0.5, more preferably from 1:0.2 to 1:04. 6. The mixture according to claim 1, wherein said mixture consists of i) iron (III) pyrophosphate, ii) iron (III)-sodium pyrophosphate and iii) sodium or potassium pyrophosphate; preferably said iii) sodium pyrophosphate is tetrasodium pyrophosphate. 7. The mixture according to any of the preceding claims, wherein said mixture is for use in therapy; preferably said mixture is for use in a method of treatment and/or prevention of total or relative iron deficiency conditions, in particular for use in the treatment of disorders or diseases related to or resulting from iron deficiency. 8. A composition comprising a mixture comprising or, alternatively, consisting of a mixture according to any of the preceding claims and, optionally, at least one pharmaceutical or food grade excipient and/or carrier. 9. The composition according to claim 8, wherein said composition is in solid form in oral dosage units. 10. The composition according to claim 8 or 9, wherein said composition may, furthermore, comprise mineral salts and/or vitamins.