Novel iron and acacia gum oral compositions, their preparation methods and their use in iron deficiency conditions

Abstract

The present invention relates to novel iron-containing pharmaceutical and / or nutraceutical and / or food compositions, and their use in the treatment and / or prevention of absolute or relative iron deficiency conditions in individuals in need thereof. Specifically, the present invention relates to novel compositions containing highly assimilable iron, and their use in the treatment and / or prevention of disorders and conditions associated with iron deficiency. The present invention also relates to methods for preparing said compositions.

Description

[Technical Field]

[0001] The present invention relates to novel iron-containing pharmaceutical and / or nutraceutical and / or food compositions, and their use in the treatment and / or prevention of absolute or relative iron deficiency conditions in individuals in need thereof. Specifically, the present invention relates to novel compositions containing highly assimilable iron, and their use in the treatment and / or prevention of disorders and conditions associated with iron deficiency. The present invention also relates to methods for preparing said compositions.

[0002] In conditions of absolute or relative iron deficiency in the body, iron (iron(II) or iron(III)) is administered orally or, in the most severe cases, parenterally. Such conditions include iron deficiency anemia and, when necessary, iron supplementation during pregnancy.

[0003] Although oral administration is preferred, iron supplementation by this route has serious drawbacks and limitations.In fact, the administration of classical oral compositions based on ferrous sulfate or ferrous gluconate (iron(II)) leads to poor absorption of the iron salt due to their poor bioavailability.In addition, oral administration of iron can cause constipation and stomach pain, and in the most severe cases, can cause peptic ulcer, gastritis and ulcerative colitis.For this reason, such compositions are generally taken with meals, which inevitably leads to a further significant reduction in iron absorption in the gastrointestinal tract.

[0004] Because of these drawbacks, iron salt therapy must be continued for a prolonged period of up to 3 to 6 months until the body's iron stores are fully restored.

[0005] Considering the above limitations and side effects, and often associated with the unpleasant odor and taste of the compositions due to the easy decomposition of said ferrous salts, it is understood that classical ferrous sulfate or ferrous gluconate therapy is unfavorable for patient compliance.

[0006] Iron(III) salts are also known and commercially available and are less soluble in water and less bioavailable than iron(II) salts, but have the advantage of being more stable and therefore exhibiting no organoleptic changes when the iron(III) salts are mixed with other components or ingredients to form the final composition.

[0007] Among the iron(III) salts is iron(III) pyrophosphate, which is commercially available in a variety of compositions and with varying degrees of hydration. Some of these compositions can sometimes be difficult to formulate and tend to give insoluble precipitates that can make their administration and use difficult.

[0008] Patent application CN101455401 describes a multifunctional composition for enhancing the iron, zinc and calcium content to stabilize liquid milk systems; the composition (embodiment 3) has a total weight of 100 kg and contains, inter alia, 4% iron(III) pyrophosphate, 13.5% sucrose ester and 6% sodium pyrophosphate.

[0009] Scientific paper XP055661417 by Colin I. Cercamondi et al. suggests that sodium pyrophosphate may affect the absorption of iron present in bouillon cubes fortified with iron pyrophosphate. However, in vitro data on the dissolution of iron pyrophosphate (FePP) in the presence of sodium pyrophosphate (NaPP) suggest that higher NaPP:FePP ratios (greater than 1 equivalent) further improve iron bioavailability, due to the presence of multiple pyrophosphate ligands for the iron cation available to form soluble complexes.

[0010] Patent application WO 2016 / 037836 A1 discloses water-oil emulsions containing iron(III) and other divalent cations for the preparation of margarine or mayonnaise. Example 1, Table 1, describes a suspension of iron pyrophosphate (FePP) in water (8.4 g / L) (37.5 mmol of iron(III)) and the resulting solution of 1 L by adding 10 g of sodium pyrophosphate to 1 L of water.

[0011] Scientific paper XP029527322 by Tian Tian et al. discloses that the solubility of iron pyrophosphate depends on pH and the amount of pyrophosphate ions. Tetrasodium pyrophosphate (NaPP) Na4P2O7, molar mass 265.9 g / mol, CAS No. 13472-36-1. Iron pyrophosphate (FePP) Fe4(P2O7)3, molar mass 745.21 g, CAS No. 10058-44-3.

[0012] Patent application WO2014 / 009806A1 (Alesco) discloses a composition comprising 30% to 70% iron(III) pyrophosphate, 10% to 30% sucroester E473, 0.1% to 1.5% lecithin E322, in which the weight ratio of sucroester:lecithin is 25:1 to 20:1, and optionally 15% to 40% starch.

[0013] Patent application WO2022 / 190072A1 (Pharmanutra) discloses a composition comprising iron(III) pyrophosphate, a sucroester, and lecithin, wherein the weight ratio of sucroester to lecithin is between 50:1 and 10:1, and the composition may also contain starch.

[0014] Patent application EP1743530A1 discloses in Examples 1 and 4 the use of gum arabic for preparing iron(II) pyrophosphate nanoparticles and iron(III) pyrophosphate nanoparticles.

[0015] It is therefore an object of the present invention to provide novel oral compositions containing iron(III) salts that are easily and conveniently formulated and prepared to exhibit improved iron absorption and bioavailability, thereby making them more effective.

[0016] The subject of the present invention is oral compositions containing iron(III) salts having the characteristics described in the appended claims, and their use in therapy or in methods of prophylactic or curative treatment.

[0017] A further object of the present invention is an oral composition having the characteristics set out in the appended claims for use in the preventive and / or curative treatment of anemia or iron deficiency, and for use in pregnant women and in the postpartum period.

[0018] A further object of the present invention is a method for preparing the oral compositions described herein.

[0019] First Aspect of the Invention - Aspect A According to a first aspect, the subject of the present invention is a mixture, such as a physical mixture obtained by mechanical means or mixing, comprising or consisting of i) iron(III) pyrophosphate salts, ii) sodium iron(III) pyrophosphate salts and / or mixtures thereof, and iii) at least one iron salt chosen from sodium pyrophosphate or potassium pyrophosphate.

[0020] Iron(III) pyrophosphate, sodium iron(III) 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, they all exist in solid form, for example as powders or granules.

[0021] Preferably, the i) iron(III) pyrophosphate according to the present invention is a hydrated salt, preferably having a chemical formula of the type [Fe(P0)H0] (CAS RN.10058-44-3, dry molecular weight 745.22), and may preferably have an iron content of 15% to 30% by weight, preferably 18% to 24% by weight, more preferably 20% to 22% by weight, based on the total weight of the molecule.

[0022] Preferably, the ii) sodium iron(III) pyrophosphate is a salt, preferably having a chemical formula of the type Fe(III)NaO7P2 (CAS RN.10045-87-1), for example.

[0023] Preferably, the iii) sodium or potassium pyrophosphate (this description is always intended to include sodium pyrophosphate and / or potassium pyrophosphate, even if not explicitly stated) is a salt, preferably in the form of, for example, tetrasodium pyrophosphate, having a chemical formula of NaPO (CAS RN.1269628-79-6), for example, in anhydrous, hemihydrate, or hydrate form, or in other forms with a large number of water molecules known to those skilled in the art. Tetrasodium pyrophosphate at room temperature and pressure of 25°C and 1 atmosphere exists as a colorless, odorless, water-soluble solid and is coded, for example, as E450 in the food additive list. Tetrasodium pyrophosphate is commonly used in the food industry.

[0024] The applicant has surprisingly found that contacting sodium pyrophosphate with iron(III) pyrophosphate and / or sodium iron(III) pyrophosphate, for example in the form of a complex or association, increases the absorption and bioavailability of administered iron in the body. In particular, the applicant has surprisingly found that, preferably, a mechanical mixture or mixture obtained by a series of mechanical treatments of sodium pyrophosphate, such as tetrasodium pyrophosphate, and iron(III) pyrophosphate and / or sodium iron(III) pyrophosphate, significantly increases the uptake of iron in the body, quite unexpectedly.

[0025] According to an embodiment, the present invention relates to a mixture AM-1 comprising or consisting of i) an iron(III) pyrophosphate salt and iii) a sodium pyrophosphate salt, in which the weight ratio of iron(III) pyrophosphate to sodium pyrophosphate (e.g., preferably in the form of tetrasodium pyrophosphate) is in the range of 1:0.01 to 1:1, preferably 1:0.05 to 1:0.9, more preferably 1:0.1 to 1:0.8, even more preferably 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.

[0026] According to an embodiment, the present invention relates to a mixture AM-2 comprising or consisting of ii) sodium iron(III) pyrophosphate salt and iii) sodium pyrophosphate salt, in which the weight ratio of sodium iron(III) pyrophosphate to sodium pyrophosphate (e.g., preferably in the form of tetrasodium pyrophosphate) is in the range of 1:0.01 to 1:1, preferably 1:0.05 to 1:0.9, more preferably 1:0.1 to 1:0.8, even more preferably 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.

[0027] According to an embodiment, the present invention relates to a mixture AM-3 comprising or consisting of i) iron(III) pyrophosphate salt, ii) sodium iron(III) pyrophosphate salt, and iii) sodium pyrophosphate, in which the weight ratio of iron(III) pyrophosphate:sodium iron(III) pyrophosphate:sodium pyrophosphate (for example, preferably in the form of tetrasodium pyrophosphate) is in the range of 1:0.01:0.01 to 1:0.1:0.1, preferably in the range of 1:0.05:0.5 to 1:0.5:1:0.5:0.5, more preferably 1:1:1.

[0028] A "mechanical mixture" or a "mixture, preferably obtained, for example, by a series of mechanical treatments" is understood to mean that the components or salts of the mixture are all mixed in the solid state using techniques and equipment known to a person skilled in the art.

[0029] The mixtures AM-1, AM-2 and AM-3 are prepared by mixing together the components or salts of the mixture i) and ii) and / or iii) in the solid state, preferably in the form of a powder or granules.

[0030] According to aspect A, the subject of the present invention is also a process for preparing mixtures AM-1, AM-2 and AM-3, comprising at least one step of mixing the components of said mixtures in the solid state, preferably in the form of powders or granules, by using a mixing means.

[0031] The subject of the present invention is - at least one iron(III) salt selected from i) iron(III) pyrophosphate and ii) sodium iron(III) pyrophosphate and mixtures thereof, and - iii) sodium pyrophosphate or potassium pyrophosphate A mixture (AM-1, AM-2 or AM-3) comprising or consisting of:

[0032] Preferably, the mixture consists of i) iron(III) pyrophosphate and iii) sodium or potassium pyrophosphate, and preferably, the iii) sodium pyrophosphate is tetrasodium pyrophosphate.

[0033] Preferably, the i) iron(III) pyrophosphate and the iii) sodium or potassium pyrophosphate are present in the mixture in a weight ratio of iron(III) pyrophosphate:sodium or potassium pyrophosphate of 1:0.05 to 1:1, preferably 1:0.1 to 1:0.5, and more preferably 1:0.2 to 1:0.4.

[0034] Preferably, the mixture consists of ii) sodium iron(III) pyrophosphate and iii) sodium or potassium pyrophosphate; preferably, the iii) sodium pyrophosphate is tetrasodium pyrophosphate.

[0035] Preferably, the ii) sodium iron(III) pyrophosphate and the iii) sodium or potassium pyrophosphate are present in the mixture in a weight ratio of sodium iron(III) pyrophosphate:sodium or potassium pyrophosphate of 1:0.05 to 1:1, preferably 1:0.1 to 1:0.5, and more preferably 1:0.2 to 1:0.4.

[0036] Preferably, the mixture consists of i) iron(III) pyrophosphate, ii) sodium iron(III) pyrophosphate, and iii) sodium or potassium pyrophosphate; preferably, the iii) sodium pyrophosphate is tetrasodium pyrophosphate.

[0037] Preferably, the mixture is for use in therapy; preferably, the mixture is for use in a method for treating and / or preventing a state of total or relative iron deficiency, in particular for use in the treatment of a disorder or disease associated with or caused by iron deficiency.

[0038] The subject of the present invention is a composition (AC-1, AC-2 or AC-3) containing the above mixture (AM-1, AM-2 or AM-3) and optionally containing at least one pharmaceutical or food excipient and / or vehicle. Preferably, the composition is in the form of a solid oral dosage unit; more preferably, the composition may further contain mineral salts and / or vitamins.

[0039] According to aspect A, the subject of the present invention is also compositions, designated herein as AC-1, AC-2 and AC-3, comprising mixtures selected from AM-1, AM-2 and AM-3, respectively, optionally together with at least one pharmaceutical or food excipient and / or vehicle.

[0040] Compositions AC-1, AC-2 and AC-3 are prepared and formulated to be suitable for oral administration.

[0041] The compositions AC-1, AC-2, and AC-3 for oral use of the present invention are preferably solid-state compositions formulated into dosage units. By solid state, the compositions can be in the form of granules, fine granules, or powder. The granular or powdered compositions are then mixed with pharmacologically acceptable additives and excipients to produce final products such as supplement products, medical device compositions, or pharmaceutical compositions. The final products can be pharmaceutical dosage units such as granules in sachets, sticks, tablets, or capsules.

[0042] For example, tablets can have a variety of shapes, such as cylindrical or spherical, among those known in the field of pharmaceutical dosage forms. Tablets can range in weight from 100 mg to 2000 mg. Tablets can be coated or filmed with one or more coating or film layers capable of passing through the gastric barrier, according to methods and devices known to those skilled in the art.

[0043] For example, gel capsules may weigh from 200 mg to 1200 mg, hard capsules may weigh from 500 mg to 1000 mg, and chewable tablets may weigh from 500 mg to 2000 mg. Capsules can be made from hard gelatin or soft gelatin or soft gel.

[0044] Preferably, the oral compositions of the present invention are solid compositions as described above. However, if desired or necessary, the compositions can also be formulated in liquid form, for example as a suspension in water, preferably with the addition of a physiologically acceptable acid, such as citric acid, and other substances or excipients that can keep the suspension stable and are acceptable to the recipient.

[0045] Oral compositions AC-1, AC-2, and AC-3 of the present invention may contain conventional physiologically acceptable excipients and vehicles, such as diluents, fillers, binders, disaggregants, flow aids, lubricants, etc., as described above. Non-limiting examples of suitable vehicles and excipients are described in "Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins." For example, the compositions of the present invention may contain cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat powdered milk, glycerol, propylene, glycol, water, ethanol, etc. The compositions may also contain pH buffers and wetting or emulsifying agents commonly used in the art.

[0046] In addition to the above components, if desired or necessary, the compositions of the present invention may contain further active components, such as vitamins, which can assist the active ingredient in exerting its action in the body of the treated subject.

[0047] The oral compositions AC-1, AC-2 and AC-3 according to the invention, in solid or liquid form, are intended for use in therapy, in particular for use in therapy for treating conditions of total or relative iron deficiency, especially for use in the treatment of disorders or diseases associated with or caused by iron deficiency.

[0048] Oral compositions AC-1, AC-2, and AC-3 (solid or liquid) according to any of the above embodiments are useful for preventing and counteracting anemia and increasing hemoglobin and ferritin levels, and are therefore particularly useful for treating and preventing disorders or diseases associated with iron deficiency in children, adolescents, athletes, men, women, pregnant women, and the elderly. The compositions are suitable for administration to pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly at doses of 5 mg to 50 mg of iron(III) per day, preferably 10 mg to 45 mg of iron(III) per day, more preferably 15 mg to 40 mg of iron(III) per day, and even more preferably 20 mg to 30 mg of iron(III) per day, e.g., 25 mg of iron(III) per day, 27 mg of iron(III) per day, or 29 mg of iron(III) per day, for a period of 1 month to 6 months, preferably 2 months to 4 months.

[0049] The subject of the present invention is also an iron supplement comprising one of the oral compositions AC-1, AC-2 and AC-3 of the present invention, optionally together with other components selected, for example, from minerals and / or vitamins (for example, at least one vitamin of group B, group C or group D).

[0050] The subject of the present invention is also a method for the treatment and / or prevention of disorders or diseases associated with iron deficiency, comprising administering to a subject in need thereof an oral composition selected from compositions AC-1, AC-2 and AC-3 according to the present invention.

[0051] Compositions AC-1, AC-2 and AC-3 of the present invention comprise iron(III) pyrophosphate in an amount of 10% to 90% by weight, preferably 25% to 75% by weight, more preferably 35% to 65% by weight, and even more preferably 40% to 55% by weight, based on the total weight of the composition.

[0052] Preferably, in the mixtures AM-1, AM-2 and AM-3 and compositions AC-1, AC-2 and AC-3 of the present invention, the i) iron(III) pyrophosphate salt is present in the mixture in an amount of 10% by weight to 90% by weight, more preferably 25% by weight to 75% by weight, more preferably 35% by weight to 65% by weight, and even more preferably 40% by weight to 55% by weight, relative to the total weight of the mixture.

[0053] Preferably, in the mixtures AM-1, AM-2 and AM-3 and compositions AC-1, AC-2 and AC-3 of the invention, the i) iron(III) pyrophosphate salt is always present in an amount greater than 10% by weight and less than 75% by weight, relative to the total weight.

[0054] Preferably, the mixtures AM-1, AM-2 and AM-3 and compositions AC-1, AC-2 and AC-3 of the present invention are all administered in solid form, for example as powders or granules, for example in the form of tablets, capsules, sachets or sticks. The powders and granules of the mixtures AM-1, AM-2 and AM-3 and compositions AC-1, AC-2 and AC-3 of the present invention are produced by a method using equipment and techniques known to those skilled in the art in that the individual components i)-ii)-iii) are dry-mixed and processed in solid form without the use of liquid solutions or water.

[0055] Preferably, in the mixtures AM-1, AM-2 and AM-3 and compositions AC-1, AC-2 and AC-3 of the present invention, the iron pyrophosphate is present in a weight ratio relative to the sodium pyrophosphate (preferably tetrasodium pyrophosphate) of greater than 1 ((FePP:NaPP)>1); or the iron pyrophosphate is present in a molar ratio relative to the sodium pyrophosphate (preferably tetrasodium pyrophosphate) of greater than 1; or the iron pyrophosphate is present in an equivalent ratio greater than 1 ((FePP:NaPP)>1 equivalent)).

[0056] Preferably, the FePP:NaPP weight ratio is greater than 1 and not greater than 15; more preferably, the weight ratio is 2 to 10; even more preferably, the weight ratio is 3 to 6, and even more preferably, the weight ratio may be 3.5; or 4; or 4.5; or 5; or 5.5.

[0057] Preferably, the FePP:NaPP molar or millimolar ratio is greater than 1 and not greater than 15; more preferably, the molar or millimolar ratio is 2 to 10; even more preferably, the molar or millimolar ratio is 3 to 6, and even more preferably, the molar or millimolar ratio may be 3.5; or 4; or 4.5; or 5; or 5.5.

[0058] Preferably, the FePP:NaPP equivalent ratio is greater than 1 and not greater than 15; more preferably, the equivalent ratio is 2 to 10; even more preferably, the equivalent ratio is 3 to 6, and even more preferably, the equivalent ratio may be 3.5; or 4; or 4.5; or 5; or 5.5.

[0059] The subject of the present invention is a process for preparing mixtures AM-1, AM-2 and AM-3 and compositions AC-1, AC-2 and AC-3, which process comprises at least one step of mixing the individual components i) and / or ii) and / or iii) in solid state to provide said mixtures and said compositions in solid state, preferably as powders or granules.

[0060] Second Aspect of the Invention - Aspect B As noted above, many iron-containing compositions are difficult to formulate and tend to give insoluble precipitates that make the compositions difficult to administer and use. In addition, the compositions are often poorly tolerated in the gastrointestinal tract and are very poorly palatable.

[0061] In order to overcome the above-mentioned drawbacks, the applicant has carried out a long period of research which has led to the development of several compositions comprising iron(III) pyrophosphate and 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, in particular iron(III) pyrophosphate, together with sucroesters and lecithin, which are commercially available under the trade name "Sideral®".

[0062] The compositions provide an improved absorption profile of minerals, particularly iron, compared to previously used compositions, while exhibiting good tolerability and organoleptic stability.

[0063] However, the applicant's intensive research efforts did not stop at the above composition, but continued with the intention of further improving the composition, particularly with regard to iron absorption and bioavailability.

[0064] Therefore, another object of the present invention is to provide oral compositions containing iron(III) salts that are formulated and prepared to exhibit improved iron absorption and bioavailability and thus be more effective.

[0065] It is a further object of the present invention to provide an oral composition comprising an iron(III) salt that is well tolerated by the body so that it can be administered to all subjects, including pregnant women, even on an empty stomach, has good palatability, and is chemically and organoleptically stable over time, i.e., does not exhibit changes in color, odor, flavor, and taste over time.

[0066] In another of its embodiments, embodiment B1, the subject of the invention is - i) iron(III) pyrophosphate salts; - at least one type of lecithin; - at least one sucroester; and - iii) sodium pyrophosphate salts, preferably tetrasodium pyrophosphate The mixture BM-1 comprises or consists of

[0067] In another of its embodiments, embodiment B2, the subject of the invention is - i) iron(III) pyrophosphate salts; - at least one type of lecithin; - at least one sucroester; - iii) sodium pyrophosphate salt, preferably tetrasodium pyrophosphate; and - ii) Iron(III) pyrophosphate sodium salt and mixture BM-2, comprising or consisting of:

[0068] Preferably, the mixture BM-1 or BM-2 of the present invention may further comprise a component selected from vegetable starches. The vegetable starch is preferably selected from, for example, rice starch, corn starch, sunflower starch, and / or soybean starch, and mixtures thereof. For example, the preferred starch is rice starch, such as gelatinized native rice starch or pregelatinized native rice starch. For example, pregelatinized rice starch that can be used is CAS No. 9005-25-8; EINECS 232-679-6 (moisture content 10% to 20%, for example, about 15%; particle size (particle size distribution) D10 μm max 20; D50 μm max 75; and D90 μm max 175). A commercially available product that meets these characteristics is Remyline AX-FG-P from ADEA Srl.

[0069] Preferably, another type of pregelatinized rice starch that can be used in mixture BM-1 or BM-2 can have the following physicochemical properties: moisture 1% to 10%; protein content 0.1% to 1.5%; ash content 0.1% to 1%; pH (10% solution) 5.5 to 7.5; density 0.40 to 0.48 g / cm 3 ;Starch content minimum 95%-99%, and fat content 0.01%-0.1%.

[0070] Preferably, the gelatinized or pregelatinized vegetable starch is present in mixtures BM-1 and BM-2 in an amount of 1% to 50% by weight, preferably 10% to 40% by weight, more preferably 15% to 35% by weight, and even more preferably 20% to 30% by weight, relative to the total weight of compositions BC-1 and BC-2.

[0071] Iron (III) pyrophosphate, sodium iron (III) pyrophosphate and sodium pyrophosphate are all salts or compounds known in the prior art.

[0072] Preferably, the i) iron(III) pyrophosphate according to the present invention is a hydrated salt, preferably having a chemical formula of the type [Fe(P0)H0] (CAS RN.10058-44-3, dry molecular weight 745.22), and may preferably have an iron content of 15% to 30% by weight, preferably 18% to 24% by weight, more preferably 20% to 22% by weight, based on the total weight of the molecule.

[0073] Preferably, the ii) sodium iron (III) pyrophosphate is a salt, preferably having a chemical formula such as Fe(III)NaO7P2 (CAS RN.10045-87-1).

[0074] Preferably, the iii) sodium or potassium pyrophosphate is a salt, preferably in the form of, for example, tetrasodium pyrophosphate, having a chemical formula of the type Na4P2O7 (CAS RN.1269628-79-69). At room temperature and pressure (25°C and 1 atmosphere), tetrasodium pyrophosphate exists as a colorless, odorless, water-soluble solid, and is coded as E450 in the food additive list. Tetrasodium pyrophosphate is commonly used in the food industry.

[0075] Preferably, the i) iron(III) pyrophosphate salt according to the present invention is present in mixture BM-1 or BM-2 in an amount of 10% by weight to 90% by weight, preferably 25% by weight to 75% by weight, more preferably 35% by weight to 65% by weight, and even more preferably 40% by weight to 55% by weight, relative to the total weight of the mixture.

[0076] Preferably, the ii) iron(III) pyrophosphate sodium salt according to the present invention is present in mixture BM-1 or BM-2 in an amount of 0.1% by weight to 50% by weight, preferably 1% by weight to 35% by weight, more preferably 5% by weight to 30% by weight, and even more preferably 10% by weight to 25% by weight, relative to the total weight of the mixture.

[0077] Preferably, the iii) sodium or potassium pyrophosphate according to the present invention, preferably in the form of tetrasodium phosphate, is present in mixture BM-1 or BM-2 in an amount of 0.1% to 50% by weight, preferably 1% to 35% by weight, more preferably 5% to 30% by weight, and even more preferably 10% to 25% by weight, relative to the total weight of the mixture.

[0078] The sodium or potassium pyrophosphate, preferably in the form of tetrasodium phosphate, is present in oral composition BC-1 or BC-2 of the present invention in an amount of 0.1% to 50% by weight, preferably 1% to 35% by weight, more preferably 5% to 30% by weight, even more preferably 10% to 25% by weight, such as 12% to 20% by weight, for example 14% by weight, or 16% by weight, or 18% by weight, relative to the total weight of the composition.

[0079] The term "lecithin" is known in the art and is classified as a food additive, e.g., food additive E322, in accordance with Directive No. 95 / 2 / EC of February 20, 1995, published in OJ No. L61 of September 18, 1995.

[0080] Due to its physicochemical properties, lecithin primarily performs an emulsifying function, and as it is also rich in natural antioxidants, it also has a secondary antioxidant function.

[0081] Directive No. 2008 / 84 / EC of 27 August 2008 (published in European Community OJ No. L253) lays down the purity standards that lecithin must meet to be considered food-grade (E322): insoluble in acetone (substantially the active part of the lecithin): minimum 60%; water: maximum 2%; acidity number: maximum 35; peroxide number: maximum 10; insoluble in toluene (substantially impurities): maximum 0.3%.

[0082] Chemically, lecithin is known to be a mixture of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides and phospholipids.

[0083] Phospholipids constitute the main components of lecithin; they are derived from the triglyceride structure in which fatty acids are replaced by phosphate groups, giving the molecule a negative charge and polarity; the collective term for such molecules is phosphatide. More complex organic molecules, usually serine, choline, ethanolamine, inositol, or a single hydrogen atom, are attached to the phosphate group via an ester bond to produce phospholipids called phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, or phosphatidic acid, respectively. In the narrower sense, phosphatidylcholine is often referred to as lecithin.

[0084] Phospholipids are characterized by a water-soluble polar head, which dissolves well in water, and two saturated fatty acids, which dissolve in water but have two non-polar tails that are lipophilic. These molecules are called amphiphilic, and in the presence of water and fat, they place themselves between the fat and water molecules to emulsify. Therefore, lecithin is a natural emulsifier.

[0085] The lecithin used in accordance with the present invention may be the same as commercially available lecithin, including allergen-free grades; preferably, it may be non-hydrolyzed lecithin, such as lecithin powder. Preferably, the lecithin may be selected from plant-derived lecithins, such as sunflower lecithin, corn lecithin, soybean lecithin, and / or rice lecithin, and mixtures thereof.

[0086] Preferably, the lecithin used in the present invention is a lecithin powder having a water content of 0.5% to 10%, preferably 1.5% to 4.5%, more preferably 2% to 4%, and even more preferably 2.5% to 3.5%. Preferably, the lecithin used is sunflower lecithin powder.

[0087] Preferably, the sunflower lecithin or corn lecithin or soybean lecithin or rice lecithin or mixtures thereof has a weight percent glucose content of 20% to 60%, more preferably 30% to 50%, for example about 45%.

[0088] Preferably, the sunflower lecithin or corn lecithin or soybean lecithin or rice lecithin or mixtures thereof that can be used in connection with the present invention can have, for example, the following composition by weight (chemical-physical analysis): sunflower lecithin or corn lecithin or soybean lecithin 20% to 80%, preferably 40% to 50%, carbohydrates 30% to 60%, preferably 40% to 50% (e.g., about 35% or about 45% or about 55%), protein 6% to 10%, ash 3% to 8%, moisture 2% to 5%, and flow agent 0.5% to 1.5%.

[0089] Preferably, one type of lecithin that can be used according to the invention is spray-dried sunflower lecithin on glucose syrup (Evra®); this lecithin is sold in the form of a composition containing glucose syrup, sunflower lecithin, sodium caseinate, and tricalcium phosphate. Preferably, another type of lecithin that can be used according to the invention is spray-dried (allergen-free) sunflower lecithin on rice flour (Evra®); this lecithin is sold in the form of a composition containing sunflower lecithin, tricalcium phosphate, and rice flour.

[0090] Preferably, lecithin is present in the oral composition of the invention in an amount of 0.1% to 10% by weight, preferably 0.5% to 5% by weight, more preferably 1% to 4% by weight, even more preferably 1.5% to 3.5% by weight, such as 2% by weight or 2.5% by weight or 3% by weight, relative to the total weight of the composition.

[0091] The term "sucroesters" according to the present invention is known in the art and refers to products obtained by esterification or transesterification of methyl esters of fatty acids with carbohydrates, usually sucrose and other polysaccharides, which is why they are also called "sucrose esters with fatty acids" and simply "sucrose esters" herein. The chemical and physical properties of these esters depend on the number and type of fatty acids esterified.

[0092] Preferably, according to the present invention, the at least one sucroester is, for example, a sucroester of the E473 type. The abbreviation E473 is known to indicate that sucroesters are food additives authorized by European Union law and regulated by Italian Ministerial Decree (MD 1996). They are essentially emulsifiers, added with the aim of achieving better stabilization between the aqueous and fatty phases.

[0093] Preferably, the sucroesters according to the invention, for example sucroesters of the E473 type, are used as emulsifiers in the compositions of the invention having an HLB value of about 14 to 18, advantageously about 15 or about 16 (where HLB indicates the "hydrophilic-lipophilic balance").

[0094] Preferably, for example the sucroesters of E473 type contain 50% to 80%, preferably 60% to 70%, of monoesters obtained by esterification with vegetable-derived fatty acids (stearic acid and palmitic acid).

[0095] The type of sucrose ester that can be used in the present invention preferably has, for example, the following weight composition: total ester content 80% to 95%; free fatty acid content (as oleic acid) 0.1% to 10%, preferably 0.5% to 5%, more preferably 1.5% to 4%, for example 2%, 2.5%, 3%, or 3.5%; free sucrose content 0.5% to 5%; water content 0.5% to 10%, preferably 1% to 5%, more preferably 2% to 4%; acidity 1 mg to 10 mg KOH / g, preferably 2.5 mg to 5 mg KOH / g. For example, sucrose ester SP70 from Sisterna BV (The Netherlands) can be used according to the present invention.

[0096] Preferably, the sucroester is present in the oral composition of the invention in an amount of 5% to 75% by weight, preferably 10% to 60% by weight, more preferably 12% to 40% by weight, even more preferably 15% to 30% by weight, for example 16% to 18% by weight, relative to the total weight of the composition.

[0097] The subject of the present invention is - i) iron(III) pyrophosphate salts; - at least one type of lecithin; - at least one sucroester; and - iii) sodium pyrophosphate or potassium pyrophosphate and mixtures (BM-1 or BM-2) comprising or consisting of:

[0098] Preferably, the mixture also comprises ii) iron(III) pyrophosphate sodium salt; preferably, the ii) iron(III) pyrophosphate sodium salt is present in the mixture in an amount of 0.1 wt % to 50 wt %, preferably 1 wt % to 35 wt %, more preferably 5 wt % to 30 wt %, and even more preferably 10 wt % to 25 wt %, based on the total weight of the mixture.

[0099] Preferably, the mixture also comprises starch, preferably the starch is a vegetable starch selected from the group comprising or consisting of rice starch, corn starch, sunflower starch or soybean starch, more preferably the vegetable starch is pregelatinized rice starch.

[0100] Preferably, the starch is present in the mixture in an amount of from 1% to 50% by weight, preferably from 10% to 40% by weight, more preferably from 15% to 35% by weight, even more preferably from 20% to 30% by weight, relative to the total weight of the mixture.

[0101] Preferably, the i) iron(III) pyrophosphate salt is present in the mixture in an amount of 10% by weight to 90% by weight, preferably 25% by weight to 75% by weight, more preferably 35% by weight to 65% by weight, and even more preferably 40% by weight to 55% by weight, based on the total weight of the mixture.

[0102] Preferably, the at least one lecithin is a vegetable lecithin, preferably the vegetable lecithin is selected from the group comprising or consisting of sunflower lecithin, corn lecithin, soybean lecithin or rice lecithin; preferably, the at least one lecithin is present in the mixture in an amount of 0.1% to 10% by weight, preferably 0.5% to 5% by weight, more preferably 1% to 4% by weight, even more preferably 1.5% to 3.5% by weight, relative to the total weight of the mixture.

[0103] Preferably, the at least one sucroester is present in the mixture in an amount of from 5% to 75% by weight, preferably from 10% to 60% by weight, more preferably from 12% to 40% by weight, and even more preferably from 15% to 30% by weight, relative to the total weight of the mixture.

[0104] Preferably, the iii) sodium or potassium pyrophosphate, preferably in the form of tetrasodium pyrophosphate, is present in the mixture in an amount of 0.1% to 50% by weight, preferably 1% to 35% by weight, more preferably 5% to 30% by weight, and even more preferably 10% to 25% by weight, based on the total weight of the mixture.

[0105] Preferably, the mixture is for use in therapy; preferably, the mixture is for use in a method for the treatment and / or prevention of conditions of total or relative iron deficiency, in particular for use in the treatment of disorders or diseases associated with or caused by iron deficiency.

[0106] The subject of the present invention is a composition (BC-1 or BC-2) comprising the above mixture (BM-1 or BM-2), optionally containing at least one pharmaceutical or food excipient and / or vehicle; preferably, said composition is in the form of a solid oral dosage unit.

[0107] The subject of the present invention is also composition BC-1, which comprises or consists of mixture BM-1 together with at least one pharmaceutical or food excipient and / or vehicle.

[0108] The subject of the present invention is also composition BC-2, which comprises or consists of mixture BM-2 together with at least one pharmaceutical or food excipient and / or vehicle.

[0109] Compositions BC-1 and BC-2 are formulated to be suitable for oral administration.

[0110] Compositions BC-1 and BC-2 according to the present invention are preferably solid-state compositions formulated into dosage units.Solid state means that the composition can be in the form of granules or powder.The granules or powders are then mixed with pharmacologically acceptable additives and excipients to produce final products such as supplement products, medical device compositions or pharmaceutical compositions.The final product can be granules in a sachet, or pharmaceutical dosage units such as sticks, tablets or capsules.

[0111] For example, tablets can have a variety of shapes, such as cylindrical or spherical, among those known in the field of pharmaceutical dosage forms. For example, tablets can range in weight from 100 mg to 2000 mg. Tablets can be coated or filmed with one or more coating or film layers capable of passing through the gastric barrier, according to methods and devices known to those skilled in the art.

[0112] For example, gel capsules may weigh from 200 mg to 1200 mg, hard capsules may weigh from 500 mg to 1000 mg, and chewable tablets may weigh from 500 mg to 2000 mg. Capsules can be made from hard gelatin or soft gelatin or soft gel.

[0113] Preferably, the oral compositions of the present invention are solid compositions as described above. However, if desired or necessary, the compositions can also be formulated in liquid form, for example as a suspension in water, preferably with the addition of a physiologically acceptable acid, such as citric acid, and other substances or excipients that can keep the suspension stable and are acceptable to the recipient.

[0114] The solid composition of the present invention may contain conventional physiologically acceptable pharmaceutical or food excipients and vehicles, such as diluents, fillers, binders, disaggregants, flow aids, lubricants, etc., as described above. Non-limiting examples of suitable vehicles and excipients are described in "Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins." For example, the composition of the present invention may also contain cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat powdered milk, glycerol, propylene, glycol, water, ethanol, etc. The composition may also contain a pH buffering agent and a wetting agent or emulsifier.

[0115] In addition to the above components, if desired or necessary, compositions BC-1 and BC-2 of the present invention may contain further active components, e.g., components such as vitamins, which can help the active ingredient to exert its action in the body of the treated subject.

[0116] The oral compositions BC-1 and BC-2 according to the present invention are intended for use in the therapy of conditions of total or relative iron deficiency, in particular for the treatment of disorders or diseases associated with or caused by iron deficiency.

[0117] Oral compositions (solid or liquid) according to any of the above embodiments are useful for preventing and counteracting anemia and increasing hemoglobin and ferritin levels, and are therefore useful in therapy, particularly in methods for treating and preventing disorders or diseases associated with iron deficiency in pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly. The compositions are suitable for administration at doses of 5 mg to 50 mg of iron(III) per day, preferably 10 mg to 45 mg of iron(III) per day, more preferably 15 mg to 40 mg of iron(III) per day, and even more preferably 20 mg to 30 mg of iron(III) per day, e.g., 25 mg of iron(III) per day, 27 mg of iron(III) per day, or 29 mg of iron(III) per day, to pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly, for a period of 1 month to 12 months, preferably 2 months to 6 months.

[0118] The subject of the present invention is also an iron supplement comprising the composition BC-1 or BC-2 of the present invention, optionally together with other components selected, for example, from minerals and / or vitamins (for example, one or more vitamins belonging to the B, C or D groups).

[0119] A subject of the present invention is also a method for the treatment and / or prevention of disorders or diseases associated with iron deficiency, comprising administering to a subject in need thereof composition BC-1 or BC-2 according to the present invention.

[0120] Compositions BC-1 and BC-2 of the present invention contain iron(III) pyrophosphate in an amount of 10% to 90% by weight, preferably 25% to 75% by weight, more preferably 35% to 65% by weight, and even more preferably 40% to 55% by weight, based on the total weight of the composition.

[0121] The applicant has surprisingly found that contacting the compositions described in WO 2014 / 009806 and WO 2015 / 033216 and sold under the trade name "Sideral®" with sodium or potassium pyrophosphate, preferably tetrasodium pyrophosphate, for example in the form of a complex or association, increases the absorption and bioavailability of administered iron. Specifically, the applicant has surprisingly found that mechanical mixtures or mixtures, preferably obtained by mechanical means, of sodium or potassium pyrophosphate, preferably tetrasodium pyrophosphate, and iron(III) pyrophosphate and / or sodium iron(III) pyrophosphate with the compositions described in WO 2014 / 009806 and WO 2015 / 033216 significantly increase iron uptake, preferably via an increase in ferritin, quite unexpectedly.

[0122] This surprising result is described and demonstrated in detail in the experimental section below.

[0123] Preferably, the iii) sodium or potassium pyrophosphate, preferably in the form of tetrasodium pyrophosphate, is present in oral composition BC-1 or BC-2 of the present invention in an amount of 0.1% to 50% by weight, preferably 1% to 35% by weight, more preferably 5% to 30% by weight, even more preferably 10% to 25% by weight, for example 12% to 20% by weight, for example 14% by weight or 16% by weight or 18% by weight, relative to the total weight of the composition.

[0124] Preferably, ii) iron(III) pyrophosphate sodium salt is present in oral composition BC-1 or BC-2 of the present invention in an amount of 0.1 wt % to 50 wt %, preferably 1 wt % to 35 wt %, more preferably 5 wt % to 30 wt %, even more preferably 10 wt % to 25 wt %, for example 12 wt % to 20 wt %, for example 14 wt %, or 16 wt %, or 18 wt %, relative to the total weight of the composition.

[0125] Thus, the oral composition BC-1 that is the subject of the present invention comprises or consists of iron(III) pyrophosphate, a lecithin, such as sunflower lecithin, a sucrose ester or sucroester, such as E473, and a sodium or potassium salt (preferably in the form of tetrasodium pyrophosphate), in the weight percentages indicated above.

[0126] Thus, the oral composition BC-2 that is the subject of the present invention comprises or consists of iron(III) pyrophosphate, a lecithin, such as sunflower lecithin, a sucrose ester or sucroester, such as E473, and a sodium or potassium salt (preferably in the form of tetrasodium pyrophosphate), in the weight percentages indicated above.

[0127] As noted above, oral compositions BC-1 or BC-2 of the present invention may also contain other conventional physiologically acceptable components, excipients and vehicles.

[0128] Preferably, the oral composition BC-1 or BC-2 of the present invention may further comprise a component selected from vegetable starches. The vegetable starch is preferably selected from, for example, rice starch, corn starch, or sunflower starch. For example, a preferred starch is rice starch, such as gelatinized native rice starch or pregelatinized native rice starch. For example, pregelatinized rice starch that can be used is CAS No. 9005-25-8; EINECS 232-679-6 (moisture content: 10% to 20%, e.g., about 15%; particle size (particle size distribution): D10 μm max 20; D50 μm max 75; and D90 μm max 175). A commercially available product that meets these characteristics is Remyline AX-FG-P from ADEA Srl.

[0129] Preferably, another type of pregelatinized rice starch that can be used within the scope of the present invention can have the following physicochemical properties: moisture content 1% to 10%; protein content 0.1% to 1.5%; ash content 0.1% to 1%; pH (10% solution) 5.5 to 7.5; density 0.40 to 0.48 g / cm 3 ;Starch content minimum 95%-99%, and fat content 0.01%-0.1%.

[0130] Preferably, the gelatinized or pregelatinized vegetable starch is present in solid composition BC-1 or BC-2 in an amount of 1% to 50% by weight, preferably 10% to 40% by weight, more preferably 15% to 35% by weight, and even more preferably 20% to 30% by weight, relative to the total weight of compositions BC-1 and BC-2.

[0131] The oral composition BC-1 that is the subject of the present invention comprises or consists of, in the weight percentages indicated above, an iron(III) salt, a lecithin, such as sunflower lecithin, a sucrose ester or sucroester, such as E473, a starch, preferably a vegetable starch, such as rice starch, and sodium or potassium pyrophosphate (preferably in the form of tetrasodium pyrophosphate).

[0132] The oral composition BC-1 that is the subject of the present invention comprises or consists of, in the weight percentages indicated above, iron(III) pyrophosphate, lecithin, such as sunflower lecithin, sucrose ester or sucroester, such as E473, starch, preferably vegetable starch, such as rice starch, and sodium or potassium pyrophosphate (preferably in the form of tetrasodium pyrophosphate).

[0133] The oral composition BC-2 that is the subject of the present invention comprises or consists of, in the weight percentages indicated above, an iron(III) salt, a lecithin such as sunflower lecithin, a sucrose ester or sucroester such as E473, a starch, preferably a vegetable starch such as rice starch, and a sodium or potassium pyrophosphate salt (preferably in the form of tetrasodium pyrophosphate and sodium iron(III) pyrophosphate).

[0134] The oral composition BC-2 that is the subject of the present invention comprises or consists of, in the weight percentages indicated above, iron(III) pyrophosphate, lecithin, such as sunflower lecithin, sucrose esters or sucroesters, such as E473, starch, preferably vegetable starch, such as rice starch, sodium or potassium pyrophosphate (preferably in the form of tetrasodium pyrophosphate and sodium iron(III) pyrophosphate).

[0135] The subject of the present invention is also a first method for preparing the mixture BM-1 or BM-2, which mixture is prepared by adding a physiologically acceptable excipient, diluent or carrier to give the oral composition BC-1 or BC-2 of the present invention, respectively.

[0136] The first method of the present invention is directed to preparing a mixture comprising or consisting of i) iron(III) pyrophosphate, lecithin, such as sunflower lecithin, a sucrose ester or sucroester, such as E473, iii) sodium or potassium pyrophosphate, preferably tetrasodium pyrophosphate, and optionally vegetable starch, preferably rice starch, to obtain mixture BM-1. Optionally, ii) sodium iron(III) pyrophosphate is also added to this mixture BM-1 in the above weight percentages to obtain mixture BM-2.

[0137] Preferably, the solid i) iron(III) pyrophosphate is contacted with, for example, iii) sodium pyrophosphate or potassium pyrophosphate (preferably in the form of tetrasodium pyrophosphate) and / or ii) sodium iron(III) pyrophosphate in the above weight percentages to obtain a mixture, to which vegetable lecithin, optionally starch, and / or sucroester are then added. Preferably, the mixing is carried out in a mixer equipped with stirring and mixing means known in the art. Preferably, a sieving step using a suitable sieve or sieving machine is provided to make the solid powder mixture to be processed more uniform and consistent. Some further details of the first method of the present invention are described in the experimental section of the present invention.

[0138] The i) iron(III) pyrophosphate, lecithin, sucroester, iii) sodium or potassium pyrophosphate (e.g., tetrasodium pyrophosphate), starch, and optionally ii) sodium iron(III) pyrophosphate used in the preparation method of the present invention have the properties and characteristics defined above.

[0139] Plant starch (e.g., in the form of gelatinized or pregelatinized plant starch) is fluid and free-flowing, allowing it to be accurately dosed without causing errors or weight variations. It also distributes more evenly and homogeneously within the mixture during the mixing process. Finally, plant starch improves the bioavailability of iron cations, and the resulting compound dissolves better at temperatures ranging from 15 to 30°C (1 atmosphere pressure), preferably 20 to 25°C, and even more preferably 18 to 23°C.

[0140] Upon completion of the first preparation method, a mixture BM-1 (and oral solid composition BC-1) of the present invention is obtained, which comprises or consists of, in the above-mentioned weight percentages, in a mixture BM-2 (and composition BC-2), i) iron(III) pyrophosphate, vegetable lecithin, a sucrose ester or sucroester, iii) sodium or potassium pyrophosphate, such as tetrasodium pyrophosphate, and optionally starch, and, if possible, ii) sodium iron(III) pyrophosphate.

[0141] Preferably, the first preparation method results in the mixture BM-1 (and oral solid composition BC-1) of the present invention comprising or consisting of, in the above weight percentages, i) iron(III) pyrophosphate, vegetable lecithin, such as corn lecithin or soybean lecithin or sunflower lecithin E322, sucrose ester or sucroester (e.g., E473 type), iii) sodium pyrophosphate or potassium pyrophosphate (e.g., tetrasodium pyrophosphate), and optionally starch (e.g., rice starch).

[0142] Preferably, the first preparation method results in the inventive mixture BM-2 (and oral solid composition BC-2) comprising or consisting of, in the above weight percentages, i) iron(III) pyrophosphate, vegetable lecithin, such as corn lecithin or soybean lecithin or sunflower lecithin E322, a sucrose ester or sucroester, such as E473, iii) sodium pyrophosphate or potassium pyrophosphate salt (e.g., tetrasodium pyrophosphate), ii) sodium iron(III) pyrophosphate, and optionally starch (e.g., rice starch).

[0143] Preferably, to further improve the bioavailability of the iron cations, it is useful to use as little lecithin by weight as possible in the process of preparing the solid composition of the present invention.

[0144] Furthermore, it has been found that it is preferable to use a particular weight of sucrose ester or sucroester in combination with a reduced weight of lecithin to further enhance the bioavailability of the iron cations.

[0145] Preferably, the weight ratio of sucrose ester or sucroester to lecithin is in the range of 60:1 to 10:1, preferably 50:1 to 20:1, more preferably 45:1 to 30:1, for example 40:1 to 35:1. In an embodiment, the ratio is in the range of 45:1 to 35:1.

[0146] Preferably, lecithin is present in mixture BM-1 or BM-2 in an amount of 0.01% to 10% by weight, preferably 0.05% to 5% by weight, more preferably 0.1% to 3.5% by weight, even more preferably 0.5% to 2% by weight, such as 0.8% to 1.5% by weight, for example 0.9% by weight or 1% by weight or 1.1% by weight or 1.2% by weight or 1.3% by weight or 1.4% by weight, relative to the weight of the mixture.

[0147] The methods of the present invention allow for the creation of a coating or encapsulation around iron(III) to improve the stability and bioavailability of the cation(III) due to the presence of sodium or potassium pyrophosphate salts and / or sodium iron(III) pyrophosphate salts.

[0148] In practice, the method comprises the formation of agglomerates or granules comprising iron(III) pyrophosphate and sodium or potassium pyrophosphate and / or sodium iron(III) pyrophosphate in the presence of lecithin, a sucrose ester or sucroester, and optionally starch.

[0149] The sucrose ester or sucroesters and lecithin act by facilitating the absorption of the salt and, consequently, the iron cations contained in said salt. The mixture with lecithin and starch forms "chimeric" aggregates that are able to protect and shield the iron cations contained in the pyrophosphate salt from stomach acid.

[0150] The processing time, for example, mixing and sieving, is 5 to 90 minutes, preferably 10 to 60 minutes, more preferably 20 to 40 minutes.

[0151] The oral composition obtained by the method of the present invention may have a particle size distribution of the type in which D10 is about 1.8 μm, D50 is about 20.5 μm and D90 is about 108 μm.

[0152] The solid composition of the present invention has an iron (III) content in the range of 30 mg / g to 180 mg / g, preferably 60 mg / g to 120 mg / g, and more preferably 90 to 110 mg / g.

[0153] The oral composition BC-1 or BC-2 according to the present invention is intended for use in therapy, especially in the treatment of disorders or diseases associated with or caused by iron deficiency, especially in conditions of total or relative iron deficiency.

[0154] The oral composition BC-1 or BC-2 of the present invention contains iron, which is easily absorbed, effectively bioavailable, and can increase ferritin.Furthermore, the oral composition BC-1 or BC-2 has been shown to be well tolerated by the body.The composition can be administered to all categories of patients, including pregnant women, even on an empty stomach.The oral composition BC-1 or BC-2 has been shown to have good palatability and to be chemically and organoleptically stable over time, i.e., no changes in color, odor, taste, and / or flavor have been observed.

[0155] Compositions BC-1 and BC-2 according to the present invention are solid compositions formulated in dosage units. By solid state, the compositions can be in the form of granules, fine granules, powder, or flakes. The granular, fine granular, or powdered composition is then mixed with pharmaceutically acceptable pharmaceutical or food additives and excipients to provide a final product such as a supplement product, a medical device registration EU745 / 2017 composition, or a pharmaceutical composition. The final product can be, for example, a pharmaceutical dosage unit such as a granule sachet, tablet, or capsule.

[0156] Tablets can have a variety of shapes, including cylindrical or spherical, known in the art of pharmaceutical dosage forms. Tablets range in weight from 100 to 2000 mg. Tablets can be coated or filmed with one or more coating or film layers capable of passing through the gastric barrier, according to known methods.

[0157] For example, gel capsules may weigh from 200 mg to 1200 mg, hard capsules may weigh from 500 mg to 1000 mg, and chewable tablets may weigh from 500 mg to 2000 mg. Capsules can be made from hard gelatin or soft gelatin or soft gel.

[0158] Each dosage unit contains 5 mg to 50 mg of iron(III) per day, preferably 10 mg to 45 mg of iron(III) per day, more preferably 15 mg to 40 mg of iron(III) per day, even more preferably 20 mg to 30 mg of iron(III) per day, for example, 25 mg of iron(III) per day, or 27 mg of iron(III) per day, or 29 mg of iron(III) per day.

[0159] As mentioned above, the oral composition BC-1 or BC-2 of the present invention is preferably a solid composition as described above. However, if desired or necessary, the composition can be formulated in a liquid form, such as a suspension in water, preferably with the addition of a physiologically acceptable acid, such as citric acid.

[0160] The solid composition of the present invention may contain conventional physiologically acceptable excipients and vehicles, such as diluents, fillers, binders, disaggregants, flow aids, lubricants, etc., as described above. Non-limiting examples of suitable vehicles and excipients are described in "Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins." The composition of the present invention may contain, for example, cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat powdered milk, glycerol, propylene, glycol, water, ethanol, etc. The composition may also contain a pH buffering agent and a wetting agent or emulsifier.

[0161] Preferred excipients include hydroxypropyl methylcellulose and magnesium salts of fatty acids.

[0162] In addition to the above components, if desired or necessary, compositions BC-1 and BC-2 of the present invention may contain further active components, e.g., components such as vitamins, which can help the active ingredient to exert its action in the body of the treated subject.

[0163] The subject of the present invention is also a liquid oral composition comprising or consisting of composition BC-1 or BC-2 according to the invention, water and citric acid.

[0164] Oral compositions BC-1 or BC-2 (solid or liquid) according to any one of the above embodiments are useful for preventing and counteracting anemia and increasing hemoglobin and ferritin levels, and are therefore useful in therapy, particularly in methods for treating and / or preventing disorders or diseases associated with iron deficiency in pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly. Compositions BC-1 or BC-2 are suitable for administration at doses of 10-40 mg of iron(III) / day, preferably 14-30 mg of iron(III) / day, and even more preferably 28 mg of iron(III) / day, to pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly, for a period of 1-5 months, preferably 2-4 months.

[0165] Compositions BC-1 and BC-2 can be administered throughout pregnancy, in particular from the 12th week until the 6th week after delivery. The recommended dose of iron(III) is 10-40 mg / day, preferably 14-30 mg / day, advantageously 28 mg / day.

[0166] Preferably, in mixtures BM-1 and BM-2 and compositions BC-1 and BC-2 of the present invention, the i) iron(III) pyrophosphate salt is present in the mixture in an amount of 10% by weight to 90% by weight, more preferably 25% by weight to 75% by weight, more preferably 35% by weight to 65% by weight, and even more preferably 40% by weight to 55% by weight, based on the total weight of the mixture.

[0167] Preferably, in the mixtures BM-1 and BM-2 and compositions BC-1 and BC-2 of the invention, the salt i) iron(III) pyrophosphate salt is always present in an amount greater than 10% by weight and less than 75% by weight, relative to the total weight.

[0168] Preferably, the mixtures BM-1 and BM-2 and compositions BC-1 and BC-2 of the present invention are all in solid form, for example in the form of powder or granules, and are administered in the form of, for example, tablets, capsules, sachets or sticks. The powders and granules of the mixtures BM-1 and BM-2 and compositions BC-1 and BC-2 of the present invention are produced by a method using equipment and techniques known to those skilled in the art, in which the individual components i)-ii)-iii) in solid state are dry-mixed without the use of liquid solutions or water.

[0169] Preferably, in mixtures BM-1 and BM-2 and compositions BC-1 and BC-2 of the present invention, iron pyrophosphate is present in a molar ratio relative to sodium pyrophosphate (preferably tetrasodium pyrophosphate) of greater than 1 ((FePP:NaPP)>1); or iron pyrophosphate is present in a molar ratio relative to sodium pyrophosphate (preferably tetrasodium pyrophosphate) of greater than 1; or iron pyrophosphate is present in an equivalent ratio greater than 1 ((FePP:NaPP)>1 equivalent)).

[0170] Preferably, the FePP:NaPP weight ratio is greater than 1 and not greater than 15; more preferably, the weight ratio is 2 to 10; even more preferably, the weight ratio is 3 to 6, and even more preferably, the weight ratio may be 3.5; or 4; or 4.5; or 5; or 5.5.

[0171] Preferably, the FePP:NaPP molar or millimolar ratio is greater than 1 and not greater than 15; more preferably, the molar or millimolar ratio is 2 to 10; even more preferably, the molar or millimolar ratio is 3 to 6, and even more preferably, the molar or millimolar ratio may be 3.5; or 4; or 4.5; or 5; or 5.5.

[0172] Preferably, the FePP:NaPP equivalent ratio is greater than 1 and not greater than 15; more preferably, the equivalent ratio is 2 to 10; even more preferably, the equivalent ratio is 3 to 6, and even more preferably, the equivalent ratio may be 3.5; or 4; or 4.5; or 5; or 5.5.

[0173] The subject of the present invention is a process for preparing mixtures BM-1 and BM-2 and compositions BC-1 and BC-2, which process comprises at least one step of mixing the individual components i) and / or ii) and / or iii) in solid state to provide said mixtures and said compositions in solid state, preferably as powders or granules.

[0174] Third Aspect of the Invention - Aspect C In another of its embodiments, embodiment C1, the subject of the invention is - i) iron(III) pyrophosphate salts; - at least one type of lecithin; - at least one type of gum arabic (or gum acacia); and - iii) sodium or potassium pyrophosphate, preferably tetrasodium pyrophosphate The mixture CM-1 consists of:

[0175] In another of its embodiments, embodiment C2, the subject of the invention is - i) iron(III) pyrophosphate salts; - at least one type of lecithin; - at least one type of gum arabic (or gum acacia); - iii) sodium pyrophosphate salt, preferably tetrasodium pyrophosphate; and - ii) Iron(III) pyrophosphate sodium salt The mixture CM-2 consists of:

[0176] Preferably, the mixture CM-1 or CM-2 of the present invention may further comprise a component selected from vegetable starches. The vegetable starch is preferably selected from, for example, rice starch, corn starch, sunflower starch, or soybean starch, and mixtures thereof. For example, the preferred starch is rice starch, such as gelatinized native rice starch or pregelatinized native rice starch. For example, pregelatinized rice starch that can be used is CAS No. 9005-25-8; EINECS 232-679-6 (moisture content 10% to 20%, for example, about 15%; particle size (particle size distribution) D10 μm max 20; D50 μm max 75; and D90 μm max 175). A commercially available product that meets these characteristics is Remyline AX-FG-P from ADEA Srl.

[0177] Preferably, another type of pregelatinized rice starch that can be used in mixture CM-1 or CM-2 can have the following physicochemical properties: moisture 1% to 10%; protein content 0.1% to 1.5%; ash content 0.1% to 1%; pH (10% solution) 5.5 to 7.5; density 0.40 to 0.48 g / cm 3 ;Starch content minimum 95%-99%, and fat content 0.01%-0.1%.

[0178] Preferably, the gelatinized or pregelatinized vegetable starch is present in the mixtures CM-1 and CM-2 in an amount of 1% to 50% by weight, preferably 10% to 40% by weight, more preferably 15% to 35% by weight, and even more preferably 20% to 30% by weight, relative to the total weight of the compositions CC-1 and CC-2.

[0179] Iron (III) pyrophosphate, sodium iron (III) pyrophosphate and sodium pyrophosphate are all salts or compounds known in the prior art.

[0180] Preferably, the gum arabic or gum acacia is present in the mixture CM-1 or CM-2 in an amount ranging from 5% to 45% by weight, preferably from 10% to 40% by weight, more preferably from 15% to 35% by weight, and even more preferably from 20% to 30% by weight, relative to the total weight of the mixture.

[0181] Iron(III) pyrophosphate, sodium iron(III) pyrophosphate and sodium pyrophosphate are all known in the prior art and all exist in solid form at a temperature of 25° C., for example as a powder or granules.

[0182] Preferably, the i) iron(III) pyrophosphate according to the present invention is a hydrated salt, preferably having a chemical formula of the type [Fe(P0)H0] (CAS RN.10058-44-3, dry molecular weight 745.22), and may preferably have an iron content of 18% to 24% by weight, even more preferably 20% to 22% by weight, relative to the total weight of the molecule.

[0183] Preferably, the ii) sodium iron(III) pyrophosphate is a salt, preferably having a chemical formula of the type Fe(III)NaO7P2 (CAS RN.10045-87-1), for example.

[0184] Preferably, the iii) sodium pyrophosphate is a salt, preferably in the form of tetrasodium pyrophosphate, such as an anhydrous form, a hemihydrate form, a hydrate form, or other forms with a large number of water molecules known to those skilled in the art, such as tetrasodium pyrophosphate having the chemical formula Na4P2O7 (CAS RN.1269628-79-6). At room temperature and pressure of 25°C and 1 atmosphere, tetrasodium pyrophosphate exists as a colorless, odorless, water-soluble solid, and is coded as E450 in the food additive list. Tetrasodium pyrophosphate is commonly used in the food industry.

[0185] Preferably, the i) iron(III) pyrophosphate salt according to the present invention is present in mixture CM-1 or CM-2 in an amount of 10% to 90% by weight, preferably 25% to 75% by weight, more preferably 35% to 65% by weight, and even more preferably 40% to 55% by weight, based on the total weight of the mixture.

[0186] Preferably, the ii) iron(III) pyrophosphate sodium salt according to the present invention is present in mixture CM-1 or CM-2 in an amount of 0.1% by weight to 50% by weight, preferably 1% by weight to 35% by weight, more preferably 5% by weight to 30% by weight, and even more preferably 10% by weight to 25% by weight, based on the total weight of the mixture.

[0187] Preferably, the iii) sodium or potassium pyrophosphate according to the present invention, preferably in the form of tetrasodium phosphate, is present in mixture CM-1 or CM-2 in an amount of 0.1% to 50% by weight, preferably 1% to 35% by weight, more preferably 5% to 30% by weight, and even more preferably 10% to 25% by weight, relative to the total weight of the mixture.

[0188] The term "lecithin" is known in the art and is classified as a food additive E322 according to Directive No. 95 / 2 / EC of 20 February 1995, published in OJ No. L61 of 18 September 1995.

[0189] Due to its physicochemical properties, lecithin primarily performs an emulsifying function, and as it is also rich in natural antioxidants, it also has a secondary antioxidant function.

[0190] Directive No. 2008 / 84 / EC of 27 August 2008 (published in European Community OJ No. L253) lays down the purity standards that lecithin must meet to be considered food-grade (E322): insoluble in acetone (substantially the active part of the lecithin): minimum 60%; water: maximum 2%; acidity number: maximum 35; peroxide number: maximum 10; insoluble in toluene (substantially impurities): maximum 0.3%.

[0191] Chemically, lecithin is a mixture of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides and phospholipids.

[0192] Phospholipids constitute the main components of lecithin; they are derived from the triglyceride structure in which fatty acids are replaced by phosphate groups, giving the molecule a negative charge and polarity; the collective term for such molecules is phosphatide. More complex organic molecules, usually serine, choline, ethanolamine, inositol, or a single hydrogen atom, are attached to the phosphate group via an ester bond to produce phospholipids called phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, or phosphatidic acid, respectively. In the narrower sense, phosphatidylcholine is often referred to as lecithin.

[0193] Phospholipids are characterized by a water-soluble polar head, which dissolves well in water, and two saturated fatty acids, which dissolve in water but have two non-polar tails that are lipophilic. These molecules are called amphiphilic, and in the presence of water and fat, they place themselves between the fat and water molecules to emulsify. Therefore, lecithin is a natural emulsifier.

[0194] The lecithin used according to the invention is a non-hydrolyzed powdered lecithin, preferably chosen from sunflower lecithin and / or corn lecithin and / or soybean lecithin and / or maize lecithin and / or rice lecithin, or mixtures thereof.

[0195] The lecithin used according to the present invention is a powdered lecithin having a moisture content of 1.5% to 4.5%, preferably 2 to 4%, and even more preferably 2.5% to 3.5%. Preferably, the lecithin used is sunflower lecithin powder.

[0196] In an embodiment, the sunflower lecithin has a glucose content of 20% to 60% by weight, preferably 30% to 50% by weight, for example about 45% by weight.

[0197] Sunflower lecithin that can be used in connection with the present invention can have the following composition by weight (chemical-physical analysis): 40% to 50% sunflower lecithin, 40% to 50% carbohydrates (e.g., about 42%), 6% to 10% protein, 3% to 8% ash, 2% to 5% moisture, and 0.5% to 1.5% flow agent.

[0198] Lecithin is present in the oral composition of the present invention in an amount of 0.1% to 10% by weight, preferably 0.5% to 5% by weight, more preferably 1% to 4% by weight, and even more preferably 1.5% to 3.5% by weight, relative to the total weight of the composition.

[0199] The term "gum arabic" is known in the art and refers to a natural gum that is also known as gum acacia because it is extracted from two types of acacia, Acacia senegal and Acacia seyal.

[0200] Gum arabic is commercially available and in the context of the present invention, for example, gum from Acacia senegal of type E414 may be used.

[0201] Preferably, for example, gum arabic (gum acacia) of type E414 can be used, which exists as a white powder, has CAS No. 9000-01-5 and EINECS No. 232-519-5, an average molecular weight of about 350,000, a viscosity of about 60 to 130 mPa (sol. 25%), and is substantially insoluble in ethanol (96%).

[0202] The subject of the present invention is - i) iron(III) pyrophosphate salts; - at least one type of lecithin; - at least one type of gum arabic or gum acacia; and - iii) sodium pyrophosphate or potassium pyrophosphate and mixtures (CM-1 or CM-2) comprising or consisting of:

[0203] Preferably, the mixture also comprises ii) iron(III) pyrophosphate sodium salt; preferably, the ii) iron(III) pyrophosphate sodium salt is present in the mixture in an amount of 0.1 wt % to 50 wt %, preferably 1 wt % to 35 wt %, more preferably 5 wt % to 30 wt %, and even more preferably 10 wt % to 25 wt %, based on the total weight of the mixture.

[0204] Preferably, the mixture also comprises a starch, preferably the starch is a vegetable starch selected from the group comprising or consisting of rice starch, corn starch, sunflower starch or soybean starch, more preferably the vegetable starch is pregelatinized rice starch.

[0205] Preferably, the starch is present in the mixture in an amount of from 1% to 50% by weight, preferably from 10% to 40% by weight, more preferably from 15% to 35% by weight, even more preferably from 20% to 30% by weight, relative to the total weight of the mixture.

[0206] Preferably, the i) iron(III) pyrophosphate salt is present in the mixture in an amount of 10% by weight to 90% by weight, preferably 25% by weight to 75% by weight, more preferably 35% by weight to 65% by weight, and even more preferably 40% by weight to 55% by weight, based on the total weight of the mixture.

[0207] Preferably, the at least one lecithin is a vegetable lecithin, preferably the vegetable lecithin is selected from the group comprising or consisting of sunflower lecithin, corn lecithin, soybean lecithin or rice lecithin; preferably, the at least one lecithin is present in the mixture in an amount of 0.1% to 10% by weight, preferably 0.5% to 5% by weight, more preferably 1% to 4% by weight, even more preferably 1.5% to 3.5% by weight, relative to the total weight of the mixture.

[0208] Preferably, the gum arabic or gum acacia is present in the mixture in an amount ranging from 5% to 45% by weight, preferably from 10% to 40% by weight, more preferably from 15% to 35% by weight, and even more preferably from 20% to 30% by weight, relative to the total weight of the mixture.

[0209] Preferably, the iii) sodium or potassium pyrophosphate, preferably in the form of tetrasodium pyrophosphate, is present in the mixture in an amount of 0.1% to 50% by weight, preferably 1% to 35% by weight, more preferably 5% to 30% by weight, and even more preferably 10% to 25% by weight, based on the total weight of the mixture.

[0210] Preferably, the mixture is for use in therapy; preferably, the mixture is for use in a method for the treatment and / or prevention of conditions of total or relative iron deficiency, in particular for use in the treatment of disorders or diseases associated with or caused by iron deficiency.

[0211] The subject of the present invention is a composition (CC-1 or CC-2) comprising the above mixture (CM-1 or CM-2) and, optionally, at least one pharmaceutical or food excipient and / or vehicle; preferably, said composition is in the solid form of an oral dosage unit.

[0212] The subject of the present invention is also a composition CC-1 comprising or consisting of the mixture CM-1 together with at least one pharmaceutical or food excipient and / or vehicle.

[0213] The subject of the present invention is also a composition CC-2, which comprises or consists of the mixture CM-2 together with at least one pharmaceutical or food excipient and / or vehicle.

[0214] Compositions CC-1 and CC-2 are suitable for oral administration.

[0215] Oral compositions CC-1 and CC-2 according to the present invention are for use in conditions of total or relative iron deficiency, and in particular for use in the treatment of disorders or diseases associated with or caused by iron deficiency.

[0216] Oral compositions CC-1 and CC-2 of the present invention preferably do not contain diglycerol fatty acids.

[0217] Oral compositions CC-1 and CC-2 according to the present invention are preferably solid compositions formulated in dosage units.Solid state means that the composition can be in the form of granules, fine granules, or powder.The granular or powdered composition is then mixed with pharmacologically acceptable additives and excipients to provide a final product, such as a supplement product, a medical device, or a pharmaceutical composition.The final product can be, for example, a pharmaceutical dosage unit, such as a granule sachet, a tablet, or a capsule.

[0218] Tablets can have a variety of shapes, including cylindrical or spherical, known in the art of pharmaceutical dosage forms. Tablets range in weight from 100 to 2000 mg. Tablets can be coated or filmed with one or more coating or film layers capable of passing through the gastric barrier, according to known methods.

[0219] For example, gel capsules may weigh from 200 mg to 1200 mg, hard capsules may weigh from 500 mg to 1000 mg, and chewable tablets may weigh from 500 mg to 2000 mg. Capsules can be made from hard gelatin or soft gelatin or soft gel.

[0220] Preferably, the oral compositions of the present invention are solid compositions as described above, however, if desired or necessary, the compositions can be formulated in liquid form, such as a suspension in water, for example, with the addition of a physiologically acceptable acid, such as citric acid.

[0221] The solid composition of the present invention may contain conventional physiologically acceptable excipients and vehicles, such as diluents, fillers, binders, disaggregants, flow aids, lubricants, etc., as described above. Non-limiting examples of suitable vehicles and excipients are described in "Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins." For example, the composition of the present invention may contain cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat powdered milk, glycerol, propylene, glycol, water, ethanol, etc. The composition may also contain a pH buffering agent and a wetting agent or emulsifier.

[0222] In addition to the above components, if desired or necessary, the compositions of the present invention may contain further active components, such as vitamins, which can assist the active ingredient in exerting its action in the body of the treated subject.

[0223] Oral compositions (solid or liquid) according to any of the above embodiments are useful for preventing and counteracting anemia and increasing hemoglobin and ferritin levels, and are therefore useful for treating and / or preventing disorders or diseases associated with iron deficiency in pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly. The compositions are suitable for administration to pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly at doses of 10-40 mg of iron(III) / day, preferably 14-30 mg of iron(III) / day, and even more preferably 28 mg of iron(III) / day, for a period of 1-5 months, preferably 2-4 months.

[0224] The subject of the present invention is also an iron supplement comprising the composition CC-1 or CC-2 of the present invention, optionally together with other components, such as minerals and / or vitamins.

[0225] A subject of the present invention is also a method for the treatment and / or prevention of disorders or diseases associated with iron deficiency, comprising administering composition CC-1 or CC-2 according to the present invention to a subject in need thereof.

[0226] Compositions CC-1 and CC-2 of the present invention contain iron(III) pyrophosphate in an amount of 30 to 70% by weight, preferably 35 to 55% by weight, and even more preferably 40 to 50% by weight, based on the total weight of the composition.

[0227] The applicant has surprisingly found that adding sodium or potassium pyrophosphate, for example tetrasodium pyrophosphate, to the compositions described in WO2014 / 009806 and WO2015 / 033216 and sold under the trade name "Sideral®" significantly increases iron uptake via an increase in ferritin, quite unexpectedly.

[0228] This surprising result is described and demonstrated in detail in the experimental section below.

[0229] Sodium pyrophosphate is preferably present as tetrasodium pyrophosphate and is present in oral composition CC-1 or CC-2 of the present invention in an amount of 0.1 to 30% by weight, preferably 1 to 20% by weight, and even more preferably 12 to 16% by weight, based on the total weight of the composition.

[0230] The oral composition CC-1 of the present invention therefore comprises or consists of, in the weight percentages indicated above, iron(III) pyrophosphate, lecithin, for example of the E322 type, at least one type of gum arabic (or gum acacia) and sodium pyrophosphate, preferably tetrasodium pyrophosphate.

[0231] Oral composition CC-2 of the present invention therefore comprises or consists of, in the weight percentages indicated above, iron(III) pyrophosphate, lecithin, such as lecithin of the E322 type, at least one type of gum arabic (or gum acacia), sodium pyrophosphate, preferably tetrasodium pyrophosphate, and sodium iron(III) pyrophosphate.

[0232] As mentioned above, oral composition CC-1 or CC-2 of the present invention may also contain other physiologically acceptable conventional components, excipients and vehicles.

[0233] Preferably, the oral composition CC-1 or CC-2 of the present invention may further comprise a further component selected from plant starches.

[0234] The plant starch is preferably selected from rice starch or corn starch. Preferably, the starch is rice starch; more preferably, the rice starch is gelatinized native rice starch or pregelatinized native rice starch.

[0235] The pregelatinized rice starch that can be used within the scope of the present invention can have the following physicochemical properties: moisture content of 7% or less; protein content of 1% or less; ash content of 1% or less; pH (10% solution) of 5.5 to 7.5; density of 0.40 to 0.48 g / cm 3 a starch content of 97% or more and a fat content of 0.1% or less. For example, pregelatinized rice starch can be used.

[0236] The gelatinized or pregelatinized vegetable starch is present in the solid compositions in an amount of 10 to 40% by weight, preferably 15 to 35% by weight, and even more preferably 20 to 30% by weight, relative to the total weight of compositions CC-1 and CC-2.

[0237] The oral composition CC-1 of the present invention comprises or consists of, in the weight percentages given above, an iron(III) salt, a lecithin, such as E322 type lecithin, at least one type of gum arabic (or one type of acacia gum), sodium pyrophosphate, preferably tetrasodium pyrophosphate, and preferably vegetable starch.

[0238] The oral composition CC-2 of the present invention comprises or consists of, in the weight percentages given above, a salt of iron(III), lecithin, for example of the E322 type, at least one type of gum arabic (or one type of gum acacia), sodium pyrophosphate, preferably tetrasodium pyrophosphate, sodium iron(III) pyrophosphate, and preferably vegetable starch.

[0239] The subject of the present invention is also a first method for preparing the oral compositions CC-1 or CC-2 of the invention.

[0240] A first method of the present invention is directed to the preparation of an oral composition comprising or consisting of iron(III) pyrophosphate, sunflower lecithin, gum arabic, tetrasodium pyrophosphate, vegetable starch, preferably pregelatinized rice starch, and optionally sodium iron(III) pyrophosphate, in the weight percentages described above.

[0241] The first method of the present invention comprises or consists of a series of process steps of coating or wrapping or encapsulating iron(III) pyrophosphate with the lecithin and / or the gum arabic and / or the vegetable starch.

[0242] Preferably, solid iron(III) pyrophosphate is contacted in the following order: with the gum arabic, then with the lecithin, then with the tetrasodium pyrophosphate, and finally with the vegetable starch.

[0243] The iron(III) pyrophosphate, lecithin, gum arabic, tetrasodium pyrophosphate, optionally sodium iron(III) pyrophosphate and starch used in the method of the present invention have the above-mentioned properties and characteristics.

[0244] Starch in the form of gelatinized or pregelatinized starch has the advantage of being more fluid and free-flowing, allowing for accurate dosing without introducing errors or weight variations. It is also more evenly and homogeneously distributed. Finally, pregelatinized starch improves the bioavailability of iron cations, as the resulting compound is better soluble at temperatures ranging from 15 to 30°C (1 atmosphere pressure), preferably 20 to 25°C, and even more preferably 18 to 23°C.

[0245] Upon completion of the first preparation method, oral composition CC-1 or CC-2 of the present invention is obtained, comprising or consisting of iron(III) pyrophosphate, sunflower lecithin, gum arabic, tetrasodium pyrophosphate, optionally sodium iron(III) pyrophosphate (CC-2), and pregelatinized rice starch in the weight percentages described above.

[0246] Specifically, the first preparation method results in a solid composition CC-1 or CC-2 of the present invention comprising or consisting of iron(III) pyrophosphate, sunflower lecithin E322, gum arabic, tetrasodium pyrophosphate, optionally sodium iron(III) pyrophosphate (CC-2), and pregelatinized rice starch in the weight percentages described above.

[0247] Applicant has found that to further improve the absorption of iron cations, it is useful to use as little lecithin by weight as possible in the process for preparing the solid composition of the present invention.

[0248] Additionally, applicants have discovered that it is important to use a specific weight of gum arabic in combination with a reduced weight of lecithin to further enhance iron cation absorption.

[0249] Advantageously, the weight ratio of gum arabic to lecithin is between 40:1 and 10:1. In an embodiment, said ratio is between 35:1 and 15:1; in each case, lecithin is present in the composition in an amount of between 0.01% and 10% by weight, preferably between 0.1% and 5% by weight, more preferably between 0.5% and 2.5% by weight, and even more preferably between 0.8% and 1.2% by weight.

[0250] Details of the first method of the present invention are described in the experimental section of the present invention.

[0251] The subject of the present invention is also a second method for preparing the oral compositions CC-1 or CC-2 of the invention.

[0252] A second method of the present invention is directed to the preparation of a solid composition CC-1 or CC-2 comprising or consisting of an iron salt, gum arabic, lecithin, tetrasodium pyrophosphate, optionally sodium iron(III) pyrophosphate (CC-2), and gelatinized or pregelatinized starch.

[0253] The second method of the present invention comprises or consists of techniques developed to enable the creation of a coating or encapsulation around iron to improve the stability and bioavailability of the cation.

[0254] In practice, the second method involves the formation of agglomerates or granules comprising iron(III) pyrophosphate, gum arabic, lecithin, tetrasodium pyrophosphate, optionally sodium iron(III) pyrophosphate, and gelatinized or pregelatinized starch, all of which components have the properties described above.

[0255] Gum arabic and lecithin act by facilitating the absorption of the salt and, consequently, the iron cations contained in said salt. The mixture with lecithin and starch forms "chimeric" aggregates that are able to protect and shield the iron cations contained in the pyrophosphate salt from stomach acid.

[0256] The treatment time is 1 to 60 minutes, preferably 10 to 50 minutes, and even more preferably 20 to 40 minutes.

[0257] The oral composition obtained by the method of the present invention has a D50 of about 20.5 μm (μm micrometers, 10 -6 It may have a particle size (understood to be the average particle size measured by available equipment and techniques) of a type in which D10 is about 1.8 μm, D50 is about 20.5 μm and D90 is about 108 μm.

[0258] The solid composition of the present invention has an iron(III) content of 60 mg / g to 140 mg / g, preferably 80 mg / g to 120 mg / g, and even more preferably 90 to 110 mg / g.

[0259] Oral compositions CC-1 or CC-2 according to the present invention are for use in conditions of total or relative iron deficiency, and in particular for use in the treatment of disorders or diseases associated with or caused by iron deficiency.

[0260] The oral composition CC-1 or CC-2 of the present invention contains iron, which is easily absorbed, effectively bioavailable, and can increase ferritin. Furthermore, oral composition CC-1 or CC-2 has been shown to be well tolerated by the body. The composition can be administered to all categories of patients, including pregnant women, even on an empty stomach. Oral composition CC-1 or CC-2 has been shown to be palatable and chemically and organoleptically stable over time, i.e., no changes in color, odor, taste, and / or flavor have been observed.

[0261] Compositions CC-1 and CC-2 according to the present invention are solid compositions formulated in dosage units.Solid state means that the composition can be in the form of granules or powder.The granular or powdered composition is then mixed with pharmacologically acceptable additives and excipients to provide a final product such as a supplement product, medical device, or pharmaceutical composition.The final product can be, for example, a pharmaceutical dosage unit such as a granule sachet, tablet, or capsule.

[0262] Tablets can have a variety of shapes, such as cylindrical or spherical, known in the art of pharmaceutical dosage forms. Tablets can range in weight from 200 mg to 2000 mg. Tablets can be coated or filmed with one or more coating or film layers capable of passing through the gastric barrier, according to known methods.

[0263] For example, a gel capsule may weigh 500 mg, a hard capsule may weigh 800-1000 mg, and a chewable tablet may weigh 1000-2000 mg. Capsules can be made from hard gelatin or soft gelatin or soft gel.

[0264] Each dosage unit contains 5 to 50 mg, preferably 10 to 40 mg, of iron(III).

[0265] Preferably, the oral composition CC-1 or CC-2 of the present invention is a solid composition as described above. However, if desired or necessary, the composition can be formulated in liquid form, for example, as a suspension in water, preferably with the addition of a physiologically acceptable acid, such as citric acid.

[0266] The solid composition of the present invention may contain conventional physiologically acceptable excipients and vehicles, such as diluents, fillers, binders, disaggregants, 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." For example, the composition of the present invention may contain cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat powdered milk, glycerol, propylene, glycol, water, ethanol, etc. The composition may also contain a pH buffer and a wetting agent or emulsifier.

[0267] Preferred excipients include hydroxypropyl methylcellulose and magnesium salts of fatty acids.

[0268] In addition to the above components, if desired or necessary, compositions CC-1 and CC-2 of the present invention may contain further active components, e.g., components such as vitamins, which can assist the active ingredient in exerting its action in the body of the treated subject.

[0269] A subject of the present invention is a liquid oral composition comprising or consisting of composition CC-1 or CC-2 according to the invention, water and citric acid.

[0270] Oral compositions CC-1 or CC-2 (solid or liquid) according to any of the above embodiments are useful for preventing and counteracting anemia and increasing hemoglobin and ferritin levels, and are therefore useful for treating and / or preventing disorders or diseases associated with iron deficiency in pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly. Compositions CC-1 or CC-2 are suitable for administration at doses of 10-40 mg of iron(III) / day, preferably 14-30 mg of iron(III) / day, and even more preferably 28 mg of iron(III) / day, to pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly, for a period of 1-5 months, preferably 2-4 months.

[0271] Compositions CC-1 and CC-2 can be administered throughout pregnancy, in particular from the 12th week until the 6th week after delivery. The recommended dose of iron(III) is 10-40 mg / day, preferably 14-30 mg / day, advantageously 28 mg / day.

[0272] The subject of the present invention is also an iron supplement comprising the composition CC-1 or CC-2 of the present invention, optionally together with other components, such as minerals and / or vitamins.

[0273] A subject of the present invention is also a method for the treatment and / or prevention of disorders or diseases associated with iron deficiency, comprising administering composition CC-1 or CC-2 according to the present invention to a subject in need thereof.

[0274] The applicant has conducted numerous experimental studies and has been able to observe that the mixtures and compositions of the present invention exhibit improved performance compared to commercially available compositions, and even compared to compositions marketed under the trade name "Sideral®".

[0275] Details of the assays performed and the results obtained are set forth in the experimental section below, which describes in a non-limiting manner representative embodiments of the present invention.

[0276] Embodiments of the present invention are described below.

[0277] Preferably, in the mixtures CM-1 and CM-2 and compositions CC-1 and CC-2 of the present invention, the i) iron(III) pyrophosphate salt is present in the mixture in an amount of 10% by weight to 90% by weight, more preferably 25% by weight to 75% by weight, more preferably 35% by weight to 65% by weight, and even more preferably 40% by weight to 55% by weight, based on the total weight of the mixture.

[0278] Preferably, in the mixtures CM-1 and CM-2 and compositions CC-1 and CC-2 of the invention, the salt i) iron(III) pyrophosphate salt is always present in an amount greater than 10% by weight and less than 75% by weight, relative to the total weight.

[0279] Preferably, the mixtures CM-1 and CM-2 and compositions CC-1 and CC-2 of the present invention are both administered in solid form, for example as powders or granules, for example in the form of tablets, capsules, sachets or sticks. The powders and granules of the mixtures CM-1 and CM-2 and compositions CC-1 and CC-2 of the present invention are produced by a method using equipment and techniques known to those skilled in the art in that the individual components i)-ii)-iii) in solid state are mixed and dried without the use of liquid solutions or water.

[0280] Preferably, in mixtures CM-1 and CM-2 and compositions CC-1 and CC-2 of the present invention, iron pyrophosphate is present in a weight ratio relative to sodium pyrophosphate, preferably tetrasodium pyrophosphate, of greater than 1 ((FePP:NaPP)>1); or iron pyrophosphate is present in a molar ratio relative to sodium pyrophosphate, preferably tetrasodium pyrophosphate, of greater than 1; or iron pyrophosphate is present in an equivalent ratio greater than 1 ((FePP:NaPP)>1 equivalent)).

[0281] Preferably, the FePP:NaPP weight ratio is greater than 1 and not greater than 15; more preferably, the weight ratio is 2 to 10; even more preferably, the weight ratio is 3 to 6, and even more preferably, the weight ratio may be 3.5; or 4; or 4.5; or 5; or 5.5.

[0282] Preferably, the FePP:NaPP molar or millimolar ratio is greater than 1 and not greater than 15; more preferably, the molar or millimolar ratio is 2 to 10; even more preferably, the molar or millimolar ratio is 3 to 6, and even more preferably, the molar or millimolar ratio may be 3.5; or 4; or 4.5; or 5; or 5.5.

[0283] Preferably, the FePP:NaPP equivalent ratio is greater than 1 and not greater than 15; more preferably, the equivalent ratio is 2 to 10; even more preferably, the equivalent ratio is 3 to 6, and even more preferably, the equivalent ratio may be 3.5; or 4; or 4.5; or 5; or 5.5.

[0284] The subject of the present invention is a process for preparing mixtures CM-1 and CM-2 and compositions CC-1 and CC-2, which process comprises at least one step of mixing the individual components i) and / or ii) and / or iii) in solid state to provide said mixtures and said compositions in solid state, preferably as powders or granules. [Brief explanation of the drawings]

[0285] [Figure 1] FIG. 1 shows the scheme of the static permeation assay.

[0286] [Figure 2]FIG. 2 shows the comparative results of solubility testing of ferrous sulfate, ferrous pyrophosphate, Sideral rm (a commercial product containing ferrous pyrophosphate, lecithin, sucroesters, and starch), and Sideral NaPP (Sideral rm with added tetrasodium pyrophosphate in accordance with the present invention - Example 1).

[0287] [Figure 3] FIG. 3 shows the comparative results of a simulated gastric digestion study of Sideral rm (a commercial product containing iron(III) pyrophosphate, lecithin, sucroesters, and starch) and Sideral NaPP (Sideral rm with added tetrasodium pyrophosphate in accordance with the present invention - Example 1).

[0288] [Figure 4] FIG. 4 shows comparative results of ferritin accumulation tests (Sideral_L ABS = Inventive Example 1 composition with lecithin ABS LecySpray; Sideral_NaPP_L AF NVH = Inventive Example 1 composition with lecithin L AF NVH; Sideral Liquid_NaPP_L AF NVH = Inventive Example 2 composition with lecithin L AF NVH).

[0289] [Figure 5] FIG. 5 shows the results of a comparison of apparent permeability and ferritin accumulation assays of Sideral supplemented with two types of lecithin (L063 and LAFNVH) compared to the same Sideral supplemented with tetrasodium pyrophosphate.

[0290] [Figure 6] FIG. 6 shows the results of a comparison of apparent permeability and ferritin accumulation assays of Sideral-like compositions (compositions containing gum arabic instead of the sucroesters CM1 / CC1 and CM2 / CC2) supplemented with two lecithins (L063 and LAFNVH) compared with the same Sideral-like compositions supplemented with tetrasodium pyrophosphate.

[0291] [Figure 7] Figure 7 shows A) hematocrit values ​​from T0 to T14 on the left, B) hemoglobin values ​​from T0 to T14 in the middle, and C) hemoglobin values ​​from T0 to T14 on the right, with statistics of p=0.0073 for T11 and p<0.0001 for T14: Statistics: Two-way ANOVA with multiple comparison correction, Sidak test. T11 and T14: 0.5 mg / Kg Sideral NaPP vs. Vehicle NaPP. P values ​​reported on the graph.

[0292] [Figure 8] Figure 8 shows A) hemoglobin values ​​at T4-T0; T7-T0; T11-T0, and T14-T0 on the left, and B) hematocrit values ​​at T4-T0; T7-T0; T11-T0, and T14-T0 on the right. Statistics: Two-way ANOVA. Multiple comparisons correction, Sidak's test. T4-T0: Statistically significant 0.5 mg / Kg Sideral NaPP vs. Sideral RM; T7-T0; T11-T0: Statistically significant 0.5 mg / Kg Sideral NaPP vs. Vehicle NaPP; T14-T0: Statistically significant 0.5 mg / Kg Sideral NaPP vs. Vehicle NaPP. P values ​​reported on the graph.

[0293] [Figure 9] Figure 9 shows other hematological parameters analyzed at the end of the experiment such as A) MCH (mean corpuscular hemoglobin) on the left and B) MCV (mean corpuscular value) on the right.

[0294] [Figure 10] FIG. 10 shows other hematological parameters analyzed at the end of the experiment such as A) Ret-He (reticulocyte hemoglobin) on the left and B) RBC (red blood cells) on the right.

[0295] [Figure 11]FIG. 11 shows, on the left side, A) iron levels in the bone marrow; in the middle, B) iron levels in the liver; and on the right side, C) iron levels in the spleen.

[0296] [Figure 12] Figure 12 shows A) liver mFTL levels on the left and B) spleen mFTL levels on the right.

[0297] [Figure 13] FIG. 13 shows A) hepcidin mRNA levels on the left; B) Bmp6 mRNA levels in the middle; and C) Id1 mRNA levels on the right.

[0298] [Figure 14] FIG. 14 shows A) Saa1 mRNA levels on the left side and B) Socs3 mRNA levels on the right side.

[0299] [Figure 15] FIG. 15 shows A) serum iron levels on the left and B) TSat levels on the right.

[0300] Notes: - ID = Iron deficiency: iron levels less than 9 mg / Kg. - Vehicle Sideral RM = It is a matrix containing sucroesters, lecithin and possibly starch but no iron. - Sideral NaPP = Sideral sodium pyrophosphate is a mixture (or composition) of the present invention containing iron(III) pyrophosphate, sucroester, lecithin, and optionally starch, and also containing sodium pyrophosphate (preferably in the form of tetrasodium pyrophosphate). Preferably, when starch is present in the mixture (or composition) of the present invention together with iron(III) pyrophosphate, sucroester and lecithin, sodium pyrophosphate replaces all or part of the starch in the preparation of said Sideral NaPP. - Vehicle NaPP = sodium pyrophosphate, preferably tetrasodium pyrophosphate. - Sucrosomial® Iron or Sideral RM is a commercially available mixture (or composition) containing iron(III) pyrophosphate, sucroesters, lecithin, and optionally starch. [Example]

[0301] Experimental Section Example 1 Preparation of the composition of the first aspect of the invention. [Table 1]

[0302] Mixed Protocol Prepare 300g of prototype per 100g of finished product according to the relevant Master Formula using a NOVINOX mixer.

[0303] 1) Addition of the following components: Iron(III) pyrophosphate + sucrose + Lecithin + Sodium pyrophosphate 2) Mix for 30 minutes at 8.7 rpm per hour 3) Add rice starch 4) Mix for 30 minutes at 8.7 rpm per hour 5) Automatically sift for approximately 10 minutes 6) Mix for 30 minutes at 8.7 rpm per hour 7) Measure the yield at the end of the process

[0304] Example 2 The composition of the first aspect of the present invention in liquid form [Table 2]

[0305] Example 3 Preparation of the composition of the third aspect of the present invention, similar to Example 1. [Table 3]

[0306] Example 4 Static permeability assay - Transwell system Experimental protocol material Cell: Caco-2(HTB-37 TM ), ATCC. Insert: TC insert, 12-well plate, PET, transparent, pore size: 0.4 μm, Sarstedt. Plate: 12 wells. Complete Medium: Dulbecco's Modified Eagle Medium (DMEM - reduced glucose content, containing 1000 mg / L glucose and sodium bicarbonate, without L-glutamine and phenol red, liquid, sterile filtered, suitable for cell culture) (87%), L-glutamine solution 200 mM (2%), MEM non-essential amino acid solution (100x) (1%), fetal bovine serum (10%). Complete medium without FBS: Dulbecco's Modified Eagle Medium (DMEM - reduced glucose content, containing 1000 mg / L glucose and sodium bicarbonate, without L-glutamine and phenol red, liquid, sterile filtered, suitable for cell culture) (87%), L-glutamine solution 200 mM (2%), MEM non-essential amino acid solution (100x) (1%). DMEM: Dulbecco's Modified Eagle's Medium with Phenol Red pH indicator (DMEM - contains 1000mg / L glucose and sodium bicarbonate, does not contain L-glutamine and does not contain phenol red, is liquid, is sterile filtered, and is suitable for cell culture). CelLyticTM MT: Mammalian tissue lysis / extraction reagent, Sigma Aldrich. MTT 1mg / mL: 3,2,5-diphenyltetrazolium bromide, a standard colorimetric assay for measuring the activity of the enzyme that reduces MTT to formazan, rendering the material blue / purple in color. This stain indicates cell viability. Alcoholic acid: 19 parts 2 propanol: 1 part 2M HCl. TEER: Transepithelial electrical resistance, a measure of intestinal barrier integrity and strength at cell monolayer confluence. Treatments: iron(III) pyrophosphate, Sideral rm, composition of Example 1 (Sideral NaPP), blank. Supernatant of simulated gastrointestinal digest.

[0307] Cell proliferation: - 12 inserts of 0.4 μm in 12-well plates. Duplicate plates. - 1 mL of Caco-2 cells in complete medium, 0.5 x 10 per insert 5 Plate cells into the apical compartment at a density of 1000 x g. Cells should be seeded at passage 25 or greater. - Add 1.5 mL of complete medium to the basal compartment. -Cells are cultured at 37°C and 5% CO2. - Change the medium every other day for 21 days. - On day 21, the cells are ready for experiments.

[0308] Simulated gastrointestinal digestion: Apply the simulated gastrointestinal digestion protocol to the following samples: blank (B), iron(III) pyrophosphate (FeP), Sideral rm (SID), Sideral supplemented with sodium pyrophosphate (SID NaPP). Oral compartment: 3.5 mL of 2 mg / mL elemental iron solution in water (3.5 mL water for blank) is kept at 37° C. for 5 minutes with stirring. Gastric compartment: 6.5 mL of SGF is added (simulated gastric fluid: 0.2 g of NaCl dissolved in 100 mL of water and brought to pH 1.2 with concentrated HCl). The solution is kept under stirring at 37° C. for 2 hours. Intestinal compartment: 10 mL of gastric digest is added to 1 mL of 1 M NaHCO3 and 4 mL of SIF (simulated intestinal fluid: 0.68 g anhydrous KH2PO4 in 100 mL of H2O, pH 7.5, NaOH). The solution is kept at 37°C for 2 hours with stirring. Once the simulated gastrointestinal digestion is complete, the sample is centrifuged at 8000 rpm for 5 minutes and the supernatant is collected and quantified using an ICP-OES instrument.

[0309] experiment Preparation: Dilute the supernatant of the digesta in the gut to a final concentration of 1 mg / mL in complete medium without FBS.

[0310] 1. Transfer the inserts to a clean 12-well plate and remove the medium from the apical compartment. Two full plates of 24 inserts each are required per experiment. 2. Wash the cells twice with 500 ml of PBS. 3. Add 400 mL of treatment solution to the apical compartment and 1600 mL of complete medium without FBS to the basal compartment. 4. The TEER of the 24 inserts is measured at TO, i.e. immediately after treatment. 5. Place in a 37℃ incubator for 3 hours. 6. At the completion of the 3 hour treatment, measure the TEER of all 24 inserts, then measure apical and basal. 7. Wash cells twice with 500 ml PBS for both plates. 8. Add 400 uL of CelLytic™ MT to plate 1 (12 inserts) and shake for 10 minutes. 9. After 10 minutes, remove the CelLytic™ MT from each insert and centrifuge at 8000 rpm for 5 minutes. Remove the supernatant and save the cell pellet. From plate 1, obtain the apical, basal, pellet, and cell supernatant of each insert. From plate 2, obtain the apical and basal inserts. 10. To assess barrier integrity, an additional parameter of TEER, in plate 2, add 400 uL of DMEM containing phenol red indicator to the apical compartment of each insert. Add 1600 uL of complete medium without FBS to the basal compartment. Wait 1 hour in a 37°C incubator. The same procedure is applied to triplicate inserts that were not treated (positive control) and to triplicate empty inserts without cells (negative control). 11. After 1 hour, the basal tissue is collected and analyzed for staining by spectrophotometry at a wavelength of 479 nm. The results are compared with the positive and negative controls. 12. Remove the apical cavity and wash the cells twice with 500 ml of PBS. 13. Add 400 mL of MTT to the apical compartment and 1600 mL of complete medium without FBS to the basal compartment. Place in a 37°C incubator for 2 hours. After 14.2 hours, remove the fluid from the two compartments and add 400 mL of acidic alcohol to the apical compartment and 1600 mL of acidic alcohol to the basal compartment. Place in a 37°C incubator for 24 hours. At the end of 15.24 hours, the resulting staining is read in a spectrophotometer at wavelengths of 570 nm and 650 nm and compared to a positive control (viable cells on an insert that received no treatment).

[0311] Through plate 2, values ​​of cell monolayer integrity and its viability are obtained and correlated with TEER values ​​at T0 and T3h.

[0312] A schematic of the static permeation system is shown in Figure 1. The results of the assay are shown in Figures 2 and 3.

[0313] From the results shown in the figures, it can be seen that the compositions according to any one of the embodiments of the present invention exhibit improved bioavailability of the iron contained therein and a surprising increase in ferritin. For these reasons, the compositions according to any one of the embodiments of the present invention represent a significant technological advance over known iron-based compositions.

[0314] Experimental Part animal To induce iron deficiency anemia, 4-week-old male C57BL / J6 mice were placed on an iron-balanced diet or a low-iron diet containing <9 mg / kg carbonyl iron (code PF4418, from Mucedola srl) for at least 8 weeks. Hemoglobin and hematocrit were monitored weekly by collecting a single drop of blood using a Hemo_Vet (InfraTec, Dresden, Germany) device. Mice had basal Hb levels of 15.5-17 g / dL, and iron treatment was initiated when Hb levels fell below 12.5-13.0 g / dL. Treatment consisted of daily oral administration of vehicle (Vehicle Sideral RM, but without iron pyrophosphate), Sucrosomial® Iron (Sideral RM), vehicle NaPP (Vehicle NaPP), and Sideral NaPP at an elemental iron concentration of 0.5 mg / kg for 2 weeks. The mice were sacrificed two weeks after administration, and blood and various tissues were collected for further analysis.

[0315] Notes: ID = Iron deficiency: iron levels less than 9 mg / Kg. - Vehicle Sideral RM = It is a matrix containing sucroesters, lecithin and possibly starch but no iron. - Sideral NaPP = Sideral sodium pyrophosphate is a mixture (or composition) of the present invention containing iron(III) pyrophosphate, sucroester, lecithin, and optionally starch, and also containing sodium pyrophosphate (preferably in the form of tetrasodium pyrophosphate). Preferably, when starch is present in the mixture (or composition) of the present invention together with iron(III) pyrophosphate, sucroester and lecithin, sodium pyrophosphate replaces all or part of the starch in the preparation of said Sideral NaPP. - Vehicle NaPP = sodium pyrophosphate, preferably tetrasodium pyrophosphate. - Sucrosomial® Iron or Sideral RM is a commercially available mixture (or composition) containing iron(III) pyrophosphate, sucroesters, lecithin, and optionally starch.

[0316] analysis Hematological analysis. Hemoglobin and hematocrit were monitored using HemoVet (InfraTec, Dresden, Germany) at time point 0 (T0) and on days 4, 7, 11, and 14 of treatment. At the end of the study, blood was collected and analyzed for red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MHC), and reticulocyte hemoglobin (Ret-He) (analysis performed by the IZLER Institute, Brescia, Italy).

[0317] Serum hepcidin and iron. Mouse serum hepcidin was quantified using a certified commercial Elisa kit (Code. HMC-001) from Intrinsic Lifesciences. Serum iron and transferrin saturation were measured spectrophotometrically using commercial kits (Code. MAK025 from Sigma-Aldrich and Code. TI1010 from Randox Laboratories) according to the manufacturer's instructions.

[0318] Iron quantification. Tissue iron content was measured spectrophotometrically. Briefly, 50 mg of wet tissue was incubated in 0.5 mL of 3 M HCl and 0.6 M trichloroacetic acid at 65°C for 18 h. After centrifugation, 10 μL of sample was added to 240 μL of working color reagent containing 1 volume of 0.1% bathophenanthroline sulfonic acid / 1% thioglycolic acid solution, 5 volumes of water, and 5 volumes of saturated sodium acetate in a 96-well plate. The sample was then incubated at room temperature for 30 min, and the absorbance was measured at 535 nm on a plate reader. A standard curve was generated using a calibrated FeCl3 solution (Sigma-Aldrich). The values ​​obtained were normalized to mg of wet tissue initially used in this analysis.

[0319] Mouse L-ferritin ELISA. L-ferritin was quantified using an in-house ELISA assay. Rabbit anti-mouse FtL antiserum was loaded onto a 96-well microplate by adding 100 μL of 10 μg / mL in 50 mM sodium carbonate, pH 9.6, for 18 hours at 4°C or 2 hours at 37°C. After washing three times with 200 μL of phosphate-buffered saline (PBS) containing 0.1% Tween (PBST), the wells were covered by adding 100 μL of 3% bovine serum albumin (BSA) in PBS for 1 hour at 37°C. After washing, 100 μL of 50 μg liver and spleen protein extracts in PBST was added to the wells and incubated for 2 hours at 37°C. After washing, 100 μL of a 1:500 dilution of HRP-conjugated anti-FtL antibody was added and incubated for 1 hour at 37°C. HRP activity was detected using 1 mg / mL tetramethylbenzene (TMB) in dimethyl sulfoxide (DMSO) diluted 1:10 in phosphate-citrate buffer (pH 5) and freshly added hydrogen peroxide to a final concentration of 0.006%, and absorbance was read at 620 nm using a MultiskanEx plate reader (Thermo). The reaction was stopped by adding 1 N sulfuric acid, and absorbance was measured at 405 nm. The assay was calibrated using various dilutions of purified recombinant mouse L-ferritin.

[0320] Ferritin assessment. Liver and spleen homogenates were heated at 70°C for 10 min to enrich for ferritin. Samples (equivalent to 100 μg of prewarmed protein for liver and spleen) were loaded onto a 7.5% non-denaturing PAGE and run at 160 V for 3 h. The gel was washed with water and then incubated in 2% ferrocyanide (Sigma-Aldrich) and 2% HCl for 1 h. To increase the signal, the gel was incubated in 0.025% 3,30-diaminobenzidine (Sigma-Aldrich) and 0.05% hydrogen peroxide in TBE 1X for 15–60 min. The reaction was stopped by washing with tap water.

[0321] Quantitative qRT-PCR. Total RNA was isolated from tissues using TRIzol Reagent (Ambion) according to the manufacturer's instructions. cDNA was generated by reverse transcription using 1 μg of RNA in 20 μL and Improm-II reverse transcriptase (Promega) and analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using SensiFAST SYBR Lo-ROX (Bioline) according to the manufacturer's instructions. All data were normalized to Hprt1 expression and expressed as relative quantification (2nd-ΔΔΔCt method).

[0322] The primers used were: Hprt1: For 5-CTGGTTAAGCAGTACAGCCAA-3, Rev 5-CAGGAGGTCCTTTTCACCAGC-3; Hepcidin: For 5-AAGCAGGCAGACATTGCGAT-3, Rev 5-CAGGATGTGGCTCTAGGCTATGT-3; Socs3: For 5-TTAAATGCCCTCTGTCCCAGG-3, Rev 5-TGTTTGGCTCCTTGTGCC-3; Saa1 For 5-AGAGGACATGAGGACACCAT-3;Rev 5-CAGGAGGTCTGTAGTAATTGG-3; Id1: For 5-ACCCTGAACGGCGAGATCA-3, Rev 5-TCGTCGGCTGGAACACATG-3. Bmp6: For 5-ATGGCAGGACTGGATCATTGC-3, Rev 5-CCATCACAGTAGTTGGCAGCGT-3.

[0323] Statistics. Treatment comparisons between vehicle and iron preparations were performed by two-way ANOVA with multiple comparisons adjusted by Sidak's test or by ordinary one-way ANOVA with multiple comparisons adjusted by Tukey's test.

[0324] In vivo Experimental Design (EXP3-2023) Experimental group: 2-week treatment Male C57BL / 6J mice were fed an iron-deficient diet (Fe<10mg / kg). When the mice reached a hemoglobin concentration of <12.5-13.0g / dL (T0), they were randomly divided into six groups: (a) Untreated ID mice (N=9 mice). (b) Mice treated daily (2 weeks) by oral gavage with Sideral RM vehicle (150 uL) (N=8 mice). (c) Mice treated orally with 0.5 mg / kg Sideral RM (15 μL) daily (2 weeks) (N=9 mice). (d) Mice treated orally with NaPP vehicle (150 uL) daily (2 weeks) (N=8 mice). (e) Mice treated orally with 0.5 mg / kg Sideral NaPP (150 μL) daily (2 weeks) (N=9 mice). Six male mice were kept on a normal diet as healthy controls.

[0325] Analyses: hemoglobin, hematocrit on day 0 (T0) and days T4-T7-T11-T14 of treatment. Re-He and other blood parameters (analysis performed by the IZLER Institute at the end of the study). Iron content in the liver, spleen and bone marrow. Serum iron and transferrin saturation (TSat).

Claims

1. i) iron(III) pyrophosphate; at least one lecithin; at least one gum arabic or gum acacia; and - iii) sodium pyrophosphate or potassium pyrophosphate A mixture comprising or consisting of:

2. 2. The mixture of claim 1, wherein the mixture further comprises ii) iron(III) pyrophosphate sodium salt; preferably, the ii) iron(III) pyrophosphate sodium salt is present in the mixture in an amount of 0.1 wt. % to 50 wt. %, preferably 1 wt. % to 35 wt. %, more preferably 5 wt. % to 30 wt. %, and even more preferably 10 wt. % to 25 wt. %, relative to the total weight of the mixture.

3. 3. The mixture according to claim 1 or 2, wherein the mixture further comprises starch, preferably the starch is a plant starch selected from the group comprising or consisting of rice starch, corn starch, sunflower starch or soybean starch, more preferably the plant starch is pregelatinized rice starch.

4. 4. The mixture according to claim 3, wherein the starch is present in the mixture in an amount of from 1% to 50% by weight, preferably from 10% to 40% by weight, more preferably from 15% to 35% by weight, and even more preferably from 20% to 30% by weight, relative to the total weight of the mixture.

5. 5. The mixture according to any one of claims 1 to 4, wherein the i) iron(III) pyrophosphate salt is present in the mixture in an amount of 10% to 90% by weight, preferably 25% to 75% by weight, more preferably 35% to 65% by weight, and even more preferably 40% to 55% by weight, relative to the total weight of the mixture.

6. 6. The mixture according to any one of claims 1 to 5, wherein the at least one lecithin is a vegetable lecithin, preferably selected from the group comprising or consisting of sunflower lecithin, corn lecithin, soybean lecithin or rice lecithin; preferably the at least one lecithin is present in the mixture in an amount of 0.1% to 10% by weight, preferably 0.5% to 5% by weight, more preferably 1% to 4% by weight, even more preferably 1.5% to 3.5% by weight, relative to the total weight of the mixture.

7. 7. The mixture according to any one of claims 1 to 6, wherein the gum arabic or gum acacia is present in the mixture in an amount of from 5% to 45% by weight, preferably from 10% to 40% by weight, more preferably from 15% to 35% by weight, and even more preferably from 20% to 30% by weight, relative to the total weight of the mixture.

8. 8. The mixture according to any one of claims 1 to 7, wherein the iii) sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium pyrophosphate, is present in the mixture in an amount of 0.1% to 50% by weight, preferably 1% to 35% by weight, more preferably 5% to 30% by weight, and even more preferably 10% to 25% by weight, relative to the total weight of the mixture.

9. 9. The mixture according to any one of claims 1 to 8, wherein the i) iron(III) pyrophosphate salt is present in the mixture in an amount of 10 wt. % to 90 wt. %, more preferably 25 wt. % to 75 wt. %, more preferably 35 wt. % to 65 wt. %, and even more preferably 40 wt. % to 55 wt. %, relative to the total weight of the mixture.

10. 10. The mixture according to any one of claims 1 to 9, wherein the salt i) iron(III) pyrophosphate is always present in an amount greater than 10% by weight, relative to the total weight.

11. The mixture according to any one of claims 1 to 10, wherein the mixture is in solid form; preferably, the mixture is in the form of a powder or granules.

12. The mixture according to any one of claims 1 to 11, wherein the mixture is administered in the form of a tablet, capsule, sachet or stick.

13. 13. The mixture according to any one of claims 1 to 12, wherein the FePP:NaPP weight ratio of iron(III) pyrophosphate to sodium pyrophosphate, preferably tetrasodium pyrophosphate, is in the range of from above 1 to 5, preferably in the range of 2 to 3.

14. 13. The mixture according to any one of claims 1 to 12, wherein the FePP:NaPP molar ratio of iron(III) pyrophosphate to sodium pyrophosphate, preferably tetrasodium pyrophosphate, is in the range of from above 1 to 5, preferably in the range of 2 to 3.

15. 13. The mixture according to any one of claims 1 to 12, wherein the FePP:NaPP equivalent ratio of iron pyrophosphate to sodium pyrophosphate, preferably tetrasodium pyrophosphate, is in the range of from above 1 to 5, preferably in the range of 2 to 3.

16. 16. The mixture of any one of claims 1 to 15, wherein the mixture is for therapeutic use as a medicine.

17. 17. The mixture for use according to claim 16, wherein the mixture is for use in a method for the treatment and / or prevention of conditions of total or relative iron deficiency, in particular for use in the treatment of disorders or diseases associated with or caused by iron deficiency.

18. A composition comprising a mixture according to any one of claims 1 to 15, and optionally comprising or consisting of at least one pharmaceutical or food grade excipient and / or vehicle, preferably in the form of a solid oral dosage unit.

19. 19. The composition of claim 18, wherein the composition is for therapeutic use as a medicine.

20. 20. The mixture according to claim 18 or 19, wherein the composition is for use in a method for the treatment and / or prevention of conditions of total or relative iron deficiency, in particular for use in the treatment of disorders or diseases associated with or caused by iron deficiency.

21. 21. A process for the preparation of a mixture according to at least one of claims 1 to 17 or a composition according to at least one of claims 18 to 20, comprising at least one step of mixing the individual components i) and / or ii) and / or iii) in the solid state to obtain said mixture and said composition in the solid state, preferably as a powder or granules.

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