Novel iron and albizia gum oral compositions, methods for their preparation and their use in iron deficiency

Abstract

The present invention relates to novel iron pharmaceutical and / or nutritional and / or food compositions and their use in the treatment and / or prevention of absolute iron deficiency or relative iron deficiency in a subject in need thereof. In particular, the present invention relates to novel compositions comprising highly absorbent iron and their use in the treatment and / or prevention of conditions and diseases associated with iron deficiency. The invention also relates to a process for preparing said composition.

Description

[0001] The present invention relates to a new type of iron medicament and / or nutritional and / or food composition and its use in the treatment and / or prevention of absolute or relative iron deficiency in an individual in need thereof. In particular, the present invention relates to a new type of composition comprising a highly absorbable iron and its use in the treatment and / or prevention of iron deficiency related disorders and conditions. The present invention also relates to a process for the preparation of said composition.

[0002] In case of absolute or relative iron deficiency in vivo, iron (iron (II) or iron (III)) can be administered orally or, in the most severe cases, parenterally. Such cases include iron deficiency anemia and, if necessary, iron supplementation during pregnancy.

[0003] While oral administration is preferred, there are significant drawbacks and limitations in the supplementation of iron agents through this route of administration. In fact, traditional oral compositions administering ferrous sulfate or ferrous gluconate (iron (II)) are poorly absorbed due to the low bioavailability of the iron salt. Moreover, oral administration of iron also causes constipation and stomach pain, and in the most severe cases, peptic ulcers, gastritis and ulcerative colitis. Therefore, such complex formulations are usually taken with meals, which inevitably leads to a further significant reduction in the absorption of iron by the gastrointestinal tract.

[0004] Due to these drawbacks, it is necessary to extend the time of treatment with iron salts, even up to 3 to 6 months, until the iron stores in vivo are fully restored.

[0005] Considering the above limitations and side effects, and the fact that the compositions are also accompanied by an unpleasant odor and an unpleasant taste due to the easy degradation of the ferrous salt, it follows that traditional ferrous sulfate or ferrous gluconate therapy is not conducive to patient compliance.

[0006] Iron (III) salts are also known and commercially available, although they have a lower water solubility and bioavailability than iron (II) salts, they have the advantage of being more stable, so that no organoleptic changes occur even when the iron (III) salt is mixed with other components or ingredients to form the final composition.

[0007] Among iron (III) salts, ferric pyrophosphate is commercially available in various compositions and with different degrees of hydration. Some of these compositions sometimes present difficulties in formulation, being prone to the formation of insoluble precipitates, which make dosing and use difficult.

[0008] Patent application CN101455401 describes a multifunctional composition that can enhance the content of iron, zinc and calcium, stabilize the liquid milk system; the composition (embodiment 3) has a total weight of 100 kg, including 4% of iron (III) pyrophosphate, 13.5% of sucrose esters and 6% of sodium pyrophosphate, etc.

[0009] The scientific article XP055661417 by Colin I. Cercamondi et al. shows that sodium pyrophosphate can affect the absorption of iron from bouillon cubes supplemented with iron pyrophosphate. However, in vitro solubility data of iron pyrophosphate (FePP) in the presence of sodium pyrophosphate (NaPP) show that the higher the ratio NaPP:FePP (more than 1 equivalent), the higher the bioavailability of iron, because multiple pyrophosphate ligands can form soluble complexes with iron cations.

[0010] Patent application WO2016 / 037836A1 discloses an aqueous oil emulsion containing iron (III) and other divalent cations, which emulsion is used to prepare artificial cream or mayonnaise. Example 1 Table 1 describes a 1 liter aqueous suspension of iron pyrophosphate (FePP) at a concentration of 8.4 g / liter (37.5 millimoles of iron (III)), and a 1 L solution obtained by adding 10 g of sodium pyrophosphate to 1 liter of water.

[0011] The scientific article XP029527322 by Tian Tian et al. discloses that the solubility of iron pyrophosphate depends on the 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, CAS No. 10058-44-3.

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

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

[0014] Patent application EP 1743530 A1 discloses in examples 3 and 4 the preparation of iron (II) and iron (III) pyrophosphate nanoparticles using gum arabic.

[0015] It is therefore the object of the present application to provide novel oral compositions comprising iron (III) salts, which are simple and convenient to configure and prepare, have improved iron absorption and bioavailability and are therefore even more effective.

[0016] It is the object of the present application to contain oral compositions comprising iron (III) salts having the features of the attached claims and their use in therapy or in a method of treatment for prevention or cure.

[0017] It is another object of the present application to contain oral compositions having the features of the attached claims for the prevention and / or treatment of anemia or iron deficiency (also in pregnant and postpartum phases).

[0018] It is another object of the present application to contain the method described herein for the preparation of said oral compositions.

[0019] First aspect of the application - Aspect A

[0020] According to a first aspect, it is the object of the present application to contain a mixture (physical mixture obtained, for example, by mechanical means or mixing) comprising or consisting of at least one iron salt selected from i) iron (III) pyrophosphate, ii) sodium iron (III) pyrophosphate and / or mixtures thereof, and iii) sodium or potassium pyrophosphate.

[0021] Iron (III) pyrophosphate, sodium iron (III) pyrophosphate, sodium pyrophosphate or potassium pyrophosphate are all salts or compounds known in the state of the art, which are present in solid form, for example as a powder or granules, at a temperature of 25°C and a pressure of 1 atmosphere.

[0022] Preferably, the iron (III) pyrophosphate i) according to the present application is a hydrated salt and preferably has a chemical formula such as [Fe4(P207)3xH20] (CAS RN. 10058-44-3, dry molecular weight 745.22), preferably an iron content of 15% to 30% by weight, preferably 18% to 24% by weight, more preferably 20% to 22% by weight, with respect to the total weight of the molecule.

[0023] Preferably, the sodium iron (III) pyrophosphate ii) is a salt, preferably with a chemical formula such as Fe(III)NaO7P2 (CAS RN. 10045-87-1).

[0024] Preferably, said iii) sodium or potassium pyrophosphate (this description always includes sodium and / or potassium pyrophosphate even if not explicitly stated) is a salt, preferably can be in the form of tetrasodium pyrophosphate, for example, with the chemical formula Na4P2O7 (CAS RN. 1269628-79-6), for example in the form of anhydrous, hemihydrate or hydrated, or with other number of water molecules known to the expert in the field. Tetrasodium pyrophosphate is a colorless, odorless, water-soluble solid at room temperature, 25°C and 1 atm, coded for example E450 in the list of food additives. Sodium pyrophosphate is commonly used in the food industry.

[0025] The Applicant has surprisingly found that the contact of sodium pyrophosphate with iron (III) pyrophosphate and / or sodium iron (III) pyrophosphate, in combination or association, can increase the absorption and bioavailability of iron in vivo. In particular, the Applicant has surprisingly found that a mechanical mixture or mixture, preferably obtained by a series of mechanical processes, of sodium pyrophosphate, for example tetrasodium pyrophosphate, and iron (III) pyrophosphate and / or sodium iron (III) pyrophosphate, is able to completely and unexpectedly significantly increase the absorption of iron in humans.

[0026] According to one embodiment, the object of the present application is a mixture AM-1 comprising or consisting of i) iron (III) pyrophosphate salt and iii) sodium pyrophosphate salt, in a weight ratio of iron (III) pyrophosphate:sodium pyrophosphate, for example preferably in the form of tetrasodium pyrophosphate, from 1 :0.01 to 1 :1, preferably from 1 :0.05 to 1 :0.9, more preferably from 1 :0.1 to 1 :0.8, even more preferably from 1 :0.15 to 1 :0.75, for example 1 :0.20, or 1 :0.25, or 1 :0.30, or 1 :0.35, or 1 :0.40, or 1 :0.45, or 1 :0.50, or 1 :0.55, or 1 :0.60, or 1 :0.65, or 1 :0.70.

[0027] According to one embodiment, the object of the present application is a mixture AM-2 comprising or consisting of i) sodium iron (III) pyrophosphate salt and iii) sodium pyrophosphate salt, in a weight ratio of sodium iron (III) pyrophosphate:sodium pyrophosphate, for example preferably in the form of tetrasodium pyrophosphate, from 1 :0.01 to 1 :1, preferably from 1 :0.05 to 1 :0.9, more preferably from 1 :0.1 to 1 :0.8, even more preferably from 1 :0.15 to 1 :0.75, for example 1 :0.20, or 1 :0.25, or 1 :0.30, or 1 :0.35, or 1 :0.40, or 1 :0.45, or 1 :0.50, or 1 :0.55, or 1 :0.60, or 1 :0.65, or 1 :0.70.

[0028] According to one embodiment, the object of the present application is a mixture AM-3 comprising or consisting of i) an iron (III) pyrophosphate salt and ii) an iron (III) sodium pyrophosphate salt, and iii) a sodium pyrophosphate, in a weight ratio of iron (III) pyrophosphate: iron (III) sodium pyrophosphate: sodium pyrophosphate (e.g. in the form of tetrasodium pyrophosphate) ranging from 1 :0.01 :0.01 to 1 :0.1 :0.1, preferably from 1 :0.05:0.5 to 1 :0.5:1 :0.5:0.5, more preferably from 1 :1 :1.

[0029] By "mechanical mixture" or "mixture obtained preferably by a series of mechanical processes" is understood that the components or salts of the mixture are mixed in solid state, preferably in the form of powders or granules, using techniques and equipment known to the expert in the field.

[0030] The method for preparing the AM-1, AM-2 and AM-3 mixtures consists in mixing the components or salts i) and ii) and / or iii) of the mixture in solid state, preferably in the form of powders or granules.

[0031] According to aspect A, another object of the present application is a method for preparing the mixtures AM-1, AM-2 and AM-3, comprising at least one step consisting in mixing the components of the mixture in solid state, preferably in the form of powders or granules, using a mixing device.

[0032] The object of the present application is a mixture (AM-1, AM-2 or AM-3) comprising or consisting of:

[0033] - at least one iron (III) salt selected from i) iron (III) pyrophosphate and ii) iron (III) sodium pyrophosphate, and mixtures thereof, and

[0034] - iii) sodium or potassium pyrophosphate.

[0035] Preferably, the mixture consists of i) iron (III) pyrophosphate and iii) sodium or potassium pyrophosphate, preferably the iii) sodium pyrophosphate is tetrasodium pyrophosphate.

[0036] Preferably, the weight ratio of the i) iron (III) pyrophosphate and iii) sodium or potassium pyrophosphate in the mixture is iron (III) pyrophosphate: iii) sodium or potassium pyrophosphate ranging from 1 :0.05 to 1 :1, preferably from 1 :0.1 to 1 :0.5, more preferably from 1 :0.2 to 1 :0.4.

[0037] Preferably, the mixture consists of ii) iron (III) sodium pyrophosphate and iii) sodium or potassium pyrophosphate; preferably the iii) sodium pyrophosphate is tetrasodium pyrophosphate.

[0038] Preferably, the weight ratio of the ii) ferric pyrophosphate (sodium and iii) sodium or potassium pyrophosphate in the mixture is ferric sodium pyrophosphate : sodium or potassium pyrophosphate from 1 : 0.05 to 1 : 1, preferably from 1 : 0.1 to 1 : 0.5, more preferably from 1 : 0.2 to 1 : 0.4.

[0039] Preferably, the mixture consists of i) ferric pyrophosphate (III), ii) ferric sodium pyrophosphate and iii) sodium or potassium pyrophosphate; preferably, the iii) sodium pyrophosphate is tetrasodium pyrophosphate.

[0040] Preferably, the mixture is used in therapy; preferably, the mixture is used in a method for the treatment and / or prevention of absolute iron deficiency or relative iron deficiency, in particular for the treatment of a condition or disease related to or caused by iron deficiency.

[0041] An object of the present application is a composition (AC-1, AC-2 or AC-3) comprising the above mixture (AM-1, AM-2 or AM-3) and optionally at least one pharmaceutical or food grade excipient and / or vehicle. Preferably, the composition is in the form of a solid oral dosage unit; more preferably, the composition can further comprise mineral salts and / or vitamins.

[0042] According to aspect A, another object of the present application is a composition, herein referred to as AC-1, AC-2 and AC-3, comprising a mixture selected from AM-1, AM-2 and AM-3, respectively, and optionally at least one pharmaceutical or food grade excipient and / or vehicle.

[0043] The AC-1, AC-2 and AC-3 compositions are prepared and formulated to be suitable for oral administration.

[0044] The oral compositions AC-1, AC-2 and AC-3 of the present application are preferably configured as solid dosage unit compositions. By solid it is meant that the composition can be in the form of granules or microgranules or powder. The granular or powder composition is then mixed with pharmaceutically acceptable additives and excipients, thus providing the final product, such as a supplement product, a medical device composition or a pharmaceutical composition. The final product can be a pharmaceutical dosage unit, such as a sachet of granules, a stick, a tablet or a capsule.

[0045] The tablets can have different shapes, such as cylindrical or spherical, for example, known in the pharmaceutical field. The weight of the tablets can range from 100 · mg to 2000 mg. The tablets can be coated or film-coated with one or more coats or films capable of passing the gastric barrier, according to methods and equipment known to experts in the field.

[0046] For example, the weight of the capsule can be 200 mg to 1200 mg, the weight of the hard capsule can be 500 mg to 1000 mg, and the weight of the chewable tablet can be 500 mg to 2000 mg. The capsule can be made of hard gelatin, soft gelatin, or soft gel.

[0047] As described above, preferably, the oral composition of the present application is a solid composition. However, if necessary or required, the composition of the present application can also be configured in a liquid form, for example, an aqueous suspension, preferably with the addition of a physiologically acceptable acid, for example, citric acid, and other substances or excipients capable of maintaining the stability of the suspension and suitable for the subject to receive.

[0048] As described above, the oral compositions AC-1, AC-2, and AC-3 of the present application can contain physiologically acceptable conventional excipients and carriers, such as diluents, fillers, binders, disintegrants, glidants, lubricants, etc. "Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams & Wilkins" describes non-limiting examples of suitable carriers and excipients. For example, the composition of the present application can include cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The composition can also contain pH buffers, wetting agents, or emulsifiers commonly used in the industry.

[0049] In addition to the above components, if necessary or required, the composition of the present application can also include other active components, for example, components capable of assisting the active ingredients in exerting their effects in the subject receiving treatment, such as vitamins.

[0050] The oral compositions AC-1, AC-2, and AC-3 of the present application in solid or liquid form are used for treatment, in particular for the treatment of absolute iron deficiency or relative iron deficiency, in particular for the treatment of conditions or diseases related to or caused by iron deficiency.

[0051] The solid or liquid oral compositions AC-1, AC-2 and AC-3 of any of the above embodiments are particularly useful for the treatment and prevention of conditions or diseases associated with iron deficiency in children, adolescents, athletes, men, women, pregnant women and the elderly, since they can prevent and combat anemia and help to increase the values of hemoglobin and ferritin. Said compositions are suitable for use in children subjects, adolescents, athletes, men, women, pregnant women and the elderly, for a period of administration of 1 month to 6 months, preferably 2 months to 4 months, at a dose of administration 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, even more preferably 20 mg to 30 mg, for example 25 mg, or 27 mg, or 29 mg of iron (III) per day.

[0052] Another object of the present application is an iron supplement comprising one of the oral compositions AC-1, AC-2 and AC-3 of the present application, optionally comprising further components, for example components selected from minerals and / or vitamins, for example at least one vitamin B, C or D.

[0053] Another object of the present application is a method for the treatment and / or prevention of conditions or diseases associated with iron deficiency, comprising administering to a subject in need thereof an oral composition selected from the compositions AC-1, AC-2 and AC-3 of the present application.

[0054] The compositions AC-1, AC-2 and AC-3 of the present application comprise iron (III) pyrophosphate salts in a content of 10% to 90% by weight, preferably 25% to 75% by weight, more preferably 35% to 65% by weight, even more preferably 40% to 55% by weight, with respect to the total weight of the composition.

[0055] Preferably, in the mixtures AM-1, AM-2 and AM-3 and in the compositions AC-1, AC-2 and AC-3 of the present application, the content of said i) iron (III) pyrophosphate salts in said mixtures is 10% to 90% by weight, more preferably 25% to 75% by weight, more preferably 35% to 65% by weight, even more preferably 40% to 55% by weight, with respect to the total weight of said mixtures.

[0056] Preferably, in the mixtures AM-1, AM-2 and AM-3 and in the compositions AC-1, AC-2 and AC-3 of the present application, the content of said salts i) iron (III) pyrophosphate salts is always greater than 10% by weight and less than 75% by weight, with respect to the total weight.

[0057] Preferably, the mixtures AM-1, AM-2 and AM-3 and the compositions AC-1, AC-2 and AC-3 of the present application are in solid form, such as a powder or granulate, and are administered in the form of tablets, capsules, sachets or sticks. The powders and granulates of the mixtures AM-1, AM-2 and AM-3 and the compositions AC-1, AC-2 and AC-3 of the present application are prepared by means and equipment known to the person skilled in the art, wherein the components i) and / or ii) and / or iii) are mixed and processed in solid state without the use of liquid solutions or water.

[0058] Preferably, in the mixtures AM-1, AM-2 and AM-3 and the compositions AC-1, AC-2 and AC-3 of the present application, the weight ratio of ferric pyrophosphate to sodium pyrophosphate (preferably tetrasodium pyrophosphate) is greater than 1 ((FePP:NaPP) > 1 ); or the molar ratio of ferric pyrophosphate to sodium pyrophosphate (preferably tetrasodium pyrophosphate) is greater than 1 ; or the equivalent ratio of ferric pyrophosphate is greater than 1 ((FePP:NaPP) > 1 equivalent).

[0059] Preferably, the weight ratio of FePP:NaPP is greater than 1 to 15; more preferably, the weight ratio is 2 to 10; even more preferably, the weight ratio is 3 to 6, still even more preferably, the weight ratio can be 3.5; or 4; or 4.5; or 5; or 5.5.

[0060] Preferably, the molar or millimolar ratio of FePP:NaPP is greater than 1 to 15; more preferably, the molar or millimolar ratio is 2 to 10; even more preferably, the molar or millimolar ratio is 3 to 6, still even more preferably, the molar or millimolar ratio can be 3.5; or 4; or 4.5; or 5; or 5.5.

[0061] More preferably, the equivalent ratio of FePP:NaPP is 1 to 15; more preferably, the equivalent ratio is 2 to 10; even more preferably, the equivalent ratio is 3 to 6, still even more preferably, the equivalent ratio can be 3.5; or 4; or 4.5; or 5; or 5.5.

[0062] It is an object of the present application to provide a process for the preparation of the mixtures AM-1, AM-2 and AM-3 and the compositions AC-1, AC-2 and AC-3, wherein the process comprises at least one step of mixing the components i) and / or ii) and / or iii) in solid state to obtain the mixtures and the compositions in solid state, preferably in the form of a powder or granulate.

[0063] Second aspect of the application - Aspect B

[0064] As mentioned above, many iron-containing compositions present difficulties in formulation, are prone to the formation of insoluble precipitates, thus making dosing and use difficult. In addition to this, they often present problems of poor gastrointestinal tolerance and are also very poorly palatable.

[0065] In order to overcome the aforementioned drawbacks, the Applicant has carried out long research activities, developing some compositions containing iron (III) pyrophosphate, and has filed two international patent applications WO2014 / 009806 and WO2015 / 033216. These applications (and the related granted patents) describe and claim compositions containing minerals, in particular iron (III) pyrophosphate, and sucrose esters and lecithin, under the trade name are marketed on the market.

[0066] Compared to the compositions used in the past, the compositions described above improve the absorption of minerals, in particular iron, while at the same time showing good tolerability and organoleptic stability.

[0067] However, the Applicant's in-depth research activities did not stop at the compositions described above, but continued with the aim of further improving the compositions, in particular in terms of iron absorption and bioavailability.

[0068] Therefore, another object of the present application is to provide an oral composition consisting of iron (III) salts, formulated and prepared in such a way as to improve the absorption and bioavailability of iron, thus being even more effective.

[0069] Another object of the present application is to provide an oral composition containing iron (III) salts, which has good tolerability by the human body, so as to be even administered to all subjects (including pregnant women) on an empty stomach; which is well palatable and has long-term chemical and organoleptic stability, i.e. the colour, smell, flavour and taste do not change over time.

[0070] In another aspect of the present application (i.e. B1 aspect), the object of the present application is a mixture BM-1 comprising or consisting of:

[0071] - i) iron (III) pyrophosphate salt;

[0072] - at least one lecithin;

[0073] - at least one sucrose ester; and

[0074] - iii) sodium pyrophosphate salt, preferably tetrasodium pyrophosphate.

[0075] In another aspect of the present application (i.e. B2 aspect), the object of the present application is a mixture BM-2 comprising or consisting of:

[0076] - i) iron (III) pyrophosphate salts;

[0077] - at least one lecithin;

[0078] - at least one sucrose ester;

[0079] - iii) sodium pyrophosphate salts, preferably tetrasodium pyrophosphate; and

[0080] - ii) sodium iron (III) pyrophosphate salts.

[0081] Preferably, the mixtures BM-1 or BM-2 of the present application can further comprise a further component selected from plant starches. Preferably, the plant starches are for example preferably selected from rice starch and / or corn starch and / or sunflower starch and / or soybean starch and mixtures thereof. For example, a preferred starch is rice starch, for example a gelatinized or pregelatinized natural rice starch. For example, a pregelatinized rice starch that can be used is CAS No. 9005-25-8; EINECS 232-679-6, with a moisture content of 10% to 20%, for example about 15%; a particle size (particle size distribution) D10 max 20 pm; D50 max 75 pm; and D90 max 175 pm. A commercially available product that complies with the above-mentioned characteristics is Remyline AX-FG-P by A.D.E.A. Srl.

[0082] Preferably, a further pregelatinized rice starch that can be used in the mixtures BM-1 or BM-2 can have the following physicochemical characteristics: moisture from 1% to 10%; protein content from 0.1% to 1.5%; ash content from 0.1% to 1%; pH value (10% solution) from 5.5 to 7.5; density from 0.40 g / cm 3 to 0.48 g / cm 3 ; starch content from a minimum of 95% to 99%, and fat content from 0.01% to 0.1%.

[0083] Preferably, the gelatinized or pregelatinized plant starch is present in the mixtures BM-1 and BM-2 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, with respect to the total weight of the compositions BC-1 and BC-2.

[0084] Preferably, the i) iron (III) pyrophosphate of the present application is a hydrated salt and preferably has a chemical formula such as [Fe4(P2O7)3xH2O] (CAS RN. 10058-44-3, dry molecular weight 745.22), preferably the iron content can be from 15% to 30% by weight, preferably from 18% to 24% by weight, more preferably from 20% to 22% by weight, with respect to the total weight of the molecule.

[0085] Preferably, said ii) sodium iron (III) pyrophosphate is a salt, preferably of formula for example Fe(III)NaO7P2 (CAS RN. 10045-87-1).

[0086] Preferably, said iii) sodium or potassium pyrophosphate is a salt, preferably in the form of tetrasodium pyrophosphate, of formula for example Na4P2O7 (CAS RN. 1269628-79-6). Tetrasodium pyrophosphate is a colourless, odourless, water-soluble solid at room temperature, 25°C and 1 atm, coded E450 in the list of food additives. Sodium pyrophosphate is commonly used in the food industry.

[0087] Preferably, said i) iron (III) pyrophosphate salt of the application is present in the mixture BM-1 or BM-2 in an amount ranging from 10% to 90% by weight, preferably from 25% to 75% by weight, more preferably from 35% to 65% by weight, even more preferably from 40% to 55% by weight, relative to the total weight of the mixture.

[0088] Preferably, said ii) sodium iron (III) pyrophosphate salt of the application is present in the mixture BM-1 or BM-2 in an amount ranging from 0.1% to 50% by weight, preferably from 1% to 35% by weight, more preferably from 5% to 30% by weight, even more preferably from 10% to 25% by weight, relative to the total weight of the mixture.

[0089] Preferably, said iii) sodium or potassium pyrophosphate salt of the application, preferably in the form of tetrasodium pyrophosphate, is present in the mixture BM-1 or BM-2 in an amount ranging from 0.1% to 50% by weight, preferably from 1% to 35% by weight, more preferably from 5% to 30% by weight, even more preferably from 10% to 25% by weight, relative to the total weight of the mixture.

[0090] The sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium pyrophosphate, present in the oral composition BC-1 or BC-2 of the application is present in an amount ranging from 0.1% to 50% by weight, preferably from 1% to 35% by weight, more preferably from 5% to 30% by weight, even more preferably from 10% to 25% by weight, for example from 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.

[0091] The term "lecithin" is known in the art and, according to Directive 95 / 2 / EC published on 20 February 1995 (published in O.J. No. L61 of 18 September 1995), lecithin is classified as a food additive, for example food additive E322.

[0092] Lecithin, by virtue of its physico-chemical properties, mainly exerts an emulsifying function, in addition to which, since it is also rich in natural antioxidants, it also has a secondary antioxidant function.

[0093] Directive No. 2008 / 84 / EC (published in O.J. of the European Community No. L253) of 27 August 2008 establishes the purity standards that lecithin must meet in order to be certified as food grade (E322): acetone insolubles (actually the active part of the lecithin): minimum 60%; moisture: maximum 2%; acid value: maximum 35; peroxide value: maximum 10; toluene insolubles (actually impurities): maximum 0.3%.

[0094] From a chemical point of view, lecithin is known to be a mixture of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides and phospholipids.

[0095] Phospholipids constitute the main component of lecithin; they derive from a triglyceride structure in which the fatty acids are replaced by a phosphate group, which confers a negative charge and therefore polarity to the molecule; these molecules are collectively known as phospholipids. More complex organic molecules, usually serine, choline, ethanolamine, inositol or a single hydrogen atom, are linked to the phosphate group by an ester bond, thus forming phospholipids known as phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol or phosphatidic acid, respectively. In a narrower sense, phosphatidylcholine is usually referred to as lecithin.

[0096] Phospholipids are characterized by a polar water-soluble head that dissolves well in water, while the two saturated fatty acids represent two non-polar, water-insoluble but lipophilic tails. These molecules are known as amphiphilic molecules, which, in the presence of water and fat, arrange themselves between the fat and water molecules, thus emulsifying them. Lecithin is therefore a natural emulsifier.

[0097] The lecithin used in the present application is any of the commercially available lecithins, including allergen-free grades of lecithin; preferably it can be a non-hydrolysed lecithin, such as lecithin powder. Preferably, the lecithin used can be selected from lecithins of vegetable origin, such as sunflower lecithin and / or corn lecithin and / or soy lecithin and / or rice lecithin and mixtures thereof.

[0098] Preferably, the lecithin used in the present application is lecithin powder, which has a water content of, for example, 0.5% to 10%, preferably 1.5% to 4.5%, more preferably 2% to 4%, even more preferably 2.5% to 3.5%. Preferably, the lecithin used is sunflower lecithin powder.

[0099] Preferably, the content of glucose in the sunflower lecithin or in the corn lecithin or in the soy lecithin or in the rice lecithin or in the mixture thereof is comprised between 20% and 60% by weight, more preferably between 30% and 50% by weight, for example about 45% by weight.

[0100] Preferably, the sunflower lecithin or the corn lecithin or the soy lecithin or the rice lecithin or the mixture thereof usable in the context of the present application can have the following composition by weight (chemico-physical analysis): sunflower lecithin or corn lecithin or soy lecithin between 20% and 80%, preferably between 40% and 50%, carbohydrates between 30% and 60%, preferably between 40% and 50% (for example, about 35% or 45% or 55%), proteins between 6% and 10%, ashes between 3% and 8%, moisture between 2% and 5%, flowing agent between 0.5% and 1.5%.

[0101] Preferably, one of the lecithins usable according to the present application is sunflower lecithin spray-dried on glucose syrup Sunflower lecithin spray-dried on glucose syrup; this lecithin is sold in the form of a composition which comprises glucose syrup, sunflower lecithin, sodium caseinate and tricalcium phosphate. Preferably, another lecithin usable according to the present application is sunflower lecithin spray-dried on rice flour (non-allergenic) This lecithin is sold in the form of a composition which comprises sunflower lecithin, tricalcium phosphate and rice flour.

[0102] Preferably, the content of lecithin in the oral composition according to the present application is comprised between 0.1% and 10% by weight, preferably between 0.5% and 5% by weight, more preferably between 1% and 4% by weight, even more preferably between 1.5% and 3.5% by weight, for example 2% by weight, or 2.5% by weight, or 3% by weight, with respect to the total weight of the composition.

[0103] The term "sucrose esters" according to the present application is known in the art and refers to the products of esterification or interesterification reactions of fatty acid methyl esters with carbohydrates, typically sucrose and other polysaccharides, and are also referred to herein as "sucrose esters of fatty acids" and herein also as "sucrose esters". The chemical and physical properties of these esters depend on the number and type of esterified fatty acids.

[0104] Preferably, according to the present application, the at least one sucrose ester is, for example, of the type E473. As is known, the abbreviation E473 indicates that sucrose esters are food additives approved by European Union legislation and are subject to the regulation of the Italian Ministerial Decree (M.D. 1996). They are mainly emulsifiers, added with the aim of better stabilizing the aqueous and fatty phases.

[0105] Preferably, the sucrose ester of the application is of the type E473, used as emulsifier in the composition of the application, with an HLB of about 14 to 18; advantageously, the HLB is about 15 or 16, wherein HLB stands for "Hydrophilic Lipophilic Balance".

[0106] Preferably, the sucrose ester (of the type E473) contains 50% to 80%, preferably 60% to 70% of monoesters, obtained by esterification reaction with fatty acids of plant origin (stearic acid and palmitic acid).

[0107] Preferably, the sucrose type used in the context of the application can have the following composition by weight: total ester content of 80% to 95%; free fatty acid content (calculated as oleic acid) of 0.1% to 10%, preferably of 0.5% to 5%, more preferably of 1.5% to 4%, for example 2%, or 2.5%, or 3%, or 3.5%; free sucrose content of 0.5% to 5%; moisture content of 0.5% to 10%, preferably of 1% to 5%, more preferably of 2% to 4%; acid value of 1 mg to 10 mg KOH / g, preferably of 2.5 mg to 5 mg KOH / g. According to the application, sucrose esters of the SP70 type from the company Sisterna BV, Netherlands, can be used, for example.

[0108] Preferably, the content of sucrose ester in the oral composition of the application is 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.

[0109] The object of the application is a mixture (BM-1 or BM-2) comprising or consisting of:

[0110] - i) a pyrophosphate iron (III) salt;

[0111] - at least one lecithin;

[0112] - at least one sucrose ester; and

[0113] - iii) a sodium or potassium pyrophosphate salt.

[0114] Preferably, the mixture further comprises ii) a sodium pyrophosphate iron (III) salt; preferably, the content of said ii) sodium pyrophosphate iron (III) salt in the mixture is 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, relative to the total weight of the mixture.

[0115] Preferably, 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 a pregelatinized rice starch.

[0116] Preferably, the content of starch in the mixture is comprised between 1 and 50% by weight, preferably between 10 and 40% by weight, more preferably between 15 and 35% by weight, even more preferably between 20 and 30% by weight, relative to the total weight of the mixture.

[0117] Preferably, the content of i) iron (III) pyrophosphate is comprised between 10 and 90% by weight, preferably between 25 and 75% by weight, more preferably between 35 and 65% by weight, even more preferably between 40 and 55% by weight, relative to the total weight of the mixture.

[0118] Preferably, the at least one lecithin is a plant lecithin, preferably the plant lecithin is selected from the group comprising or consisting of sunflower lecithin, corn lecithin, soybean lecithin or rice lecithin; the content of the at least one lecithin in the mixture is comprised between 0.1 and 10% by weight, preferably between 0.5 and 5% by weight, more preferably between 1 and 4% by weight, even more preferably between 1.5 and 3.5% by weight, relative to the total weight of the mixture.

[0119] Preferably, the content of the at least one sucrose ester in the mixture is comprised between 5 and 75% by weight, preferably between 10 and 60% by weight, more preferably between 12 and 40% by weight, even more preferably between 15 and 30% by weight, relative to the total weight of the mixture.

[0120] Preferably, the content of iii) sodium or potassium pyrophosphate salt in the mixture is comprised between 0.1 and 50% by weight, preferably between 1 and 35% by weight, more preferably between 5 and 30% by weight, even more preferably between 10 and 25% by weight, relative to the total weight of the mixture.

[0121] Preferably, the mixture is for use in therapy; preferably the mixture is for use in a method of treatment and / or prevention of absolute iron deficiency or relative iron deficiency, in particular for use in the treatment of a condition or disease related to or caused by iron deficiency.

[0122] It is an object of the present application a composition (BC-1 or BC-2) comprising the above mixture (BM-1 or BM-2) and optionally at least one pharmaceutical or food grade excipient and / or vehicle; preferably the composition is in solid form of an oral dosage unit.

[0123] Another object of the present application is a composition BC-1 composition comprising or consisting of the mixture BM-1, and at least one pharmaceutical or food grade excipient and / or vehicle.

[0124] Another object of the present application is a composition BC-2 composition comprising or consisting of the mixture BM-2, and at least one pharmaceutical or food grade excipient and / or vehicle.

[0125] The compositions BC-1 and BC-2 are formulated suitable for oral administration.

[0126] The compositions BC-1 and BC-2 of the present application are preferably solid compositions formulated in dosage units. By solid is meant that the composition can be in the form of granules or powder. The granular or powder composition is then mixed with pharmacologically acceptable additives and excipients to make the final product, such as a supplement product, a medical device composition or a pharmaceutical composition. The final product can be a pharmaceutical dosage unit, such as a sachet of granules, a stick, a tablet or a capsule.

[0127] For example, the tablets can have different forms known in the pharmaceutical art, such as cylindrical or spherical. For example, the tablets can have a weight ranging from 100 mg to 2000 mg. The tablets can be coated or film-coated with one or more coats or films capable of passing through the gastric barrier, according to methods and equipment known to experts in the field.

[0128] For example, the weight of the gel capsules can range from 200 mg to 1200 mg, the weight of the hard tablets can range from 500 mg to 1000 mg, and the weight of the chewable tablets can range from 500 mg to 2000 mg. The capsules can be made of hard gelatin, soft gelatin or soft gel.

[0129] As mentioned above, preferably, the oral compositions of the present application are solid compositions. However, if necessary or required, the compositions of the present application can also be configured in liquid form, such as an aqueous suspension, preferably with the addition of a physiologically acceptable acid, such as citric acid, and other substances or excipients capable of maintaining the stability of the suspension and suitable for the subject to receive.

[0130] As mentioned above, the solid compositions of the present application can contain physiologically acceptable conventional excipients as well as pharmaceutical or food grade carriers, such as diluents, fillers, binders, disintegrants, glidants, lubricants, and the like. Non-limiting examples of suitable carriers and excipients are described in "Remington: The Science and Practice of Pharmacy, 21st Edition., Lippincott, Williams & Wilkins". For example, the compositions of the present application can include cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, ethanol, and the like. The compositions can also contain, for example, pH buffering agents and wetting or emulsifying agents.

[0131] In addition to the above-mentioned components, the compositions BC-1 and BC-2 of the present application can also, if desired or necessary, preferably comprise other active components, for example components which are able to assist the active ingredients in exerting their action in the subject being treated, such as vitamins.

[0132] The oral compositions BC-1 and BC-2 of the present application are used for therapy, in particular for the treatment of absolute iron deficiency or relative iron deficiency, in particular for the treatment of conditions or diseases which are associated with or caused by iron deficiency.

[0133] The solid or liquid oral compositions according to any of the above-mentioned embodiments are suitable for use in a method for the treatment, in particular for the treatment and prevention of conditions or diseases which are associated with iron deficiency in child subjects, adolescents, athletes, men, women, pregnant women and elderly people, since they can prevent and counteract anemia and help to increase the values of hemoglobin and ferritin. The compositions are suitable for use in child subjects, adolescents, athletes, men, women, pregnant women and elderly people, for a period of time of 1 month to 12 months, preferably 2 months to 6 months, for example, for a period of time 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, even more preferably 20 mg to 30 mg, for example 25 mg, or 27 mg, or 29 mg of iron (III) per day.

[0134] Another object of the present application is an iron supplement comprising the composition BC-1 or BC-2 of the present application, possibly also comprising other components, for example components selected from minerals and / or vitamins, for example one or more vitamins belonging to group B, group C or group D.

[0135] Another object of the present application is a method for the treatment and / or prevention of conditions or diseases which are associated with iron deficiency, comprising administering to a subject in need thereof the composition BC-1 or BC-2 of the present application.

[0136] The compositions BC-1 and BC-2 of the application comprise a pyrophosphate iron (III) salt in an amount of 10 to 90% by weight, preferably 25 to 75% by weight, more preferably 35 to 65% by weight, even more preferably 40 to 55% by weight, relative to the total weight of the composition.

[0137] The Applicant surprisingly found that the contact of a sodium or potassium pyrophosphate salt, preferably tetrasodium pyrophosphate, with the compositions described in WO2014 / 009806 and WO2015 / 033216, sold under the trade name in a form such as a combination or association, can increase the absorption and bioavailability of iron administered in vivo. In particular, the Applicant surprisingly found that the sodium or potassium pyrophosphate salt, preferably tetrasodium pyrophosphate, with the mechanical mixture or mixture, preferably obtained by mechanical method, of the compositions described in WO2014 / 009806 and WO2015 / 033216, increases the absorption of iron, preferably by increasing the ferritin, completely and totally unexpected.

[0138] This surprising result will be described and demonstrated in detail in the experimental part hereafter.

[0139] Preferably, the sodium or potassium pyrophosphate salt, preferably tetrasodium pyrophosphate, is present in the oral composition BC-1 or BC-2 of the application 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.

[0140] Preferably, the sodium or potassium pyrophosphate salt, preferably tetrasodium pyrophosphate, is present in the oral composition BC-1 or BC-2 of the application 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.

[0141] The oral composition BC-1 of the application thus comprises or consists of the above-mentioned percentages by weight of pyrophosphate iron (III), lecithin, for example sunflower lecithin, sucrose esters or sucrose esters, for example E473, and sodium or potassium salt, preferably tetrasodium pyrophosphate.

[0142] Therefore, the oral composition BC-2 according to the present application comprises or consists of the above-mentioned weight percentages of ferric (III) pyrophosphate, lecithin, e.g. sunflower lecithin, sucrose esters or sucrose esters, e.g. E473, and sodium or potassium salts, preferably in the form of tetrasodium pyrophosphate.

[0143] As mentioned above, the oral composition BC-1 or BC-2 according to the present application can further comprise other conventional, physiologically acceptable components, excipients and carriers.

[0144] Preferably, the oral composition BC-1 or BC-2 according to the present application can further comprise an additional component selected from plant starches. Preferably, the plant starch is, for example, preferably selected from rice starch or corn starch or sunflower starch. For example, a preferred starch is rice starch, e.g. a natural rice starch which is gelled or pregelled. For example, a pregelled rice starch which can be used is CAS No. 9005-25-8; EINECS 232-679-6, with a moisture content of 10% to 20%, e.g. about 15%, a particle size (particle size distribution) D10 max. 20 pm, D50 max. 75 pm and D90 max. 175 pm. A commercially available product which meets the above-mentioned characteristics is Remyline AX-FG-P by A.D.E.A. Srl.

[0145] Preferably, another type of pregelled rice starch which can be used in the scope of the present application can have the following physicochemical characteristics: moisture content of 1% to 10%, protein content of 0.1% to 1.5%, ash content of 0.1% to 1%, pH value (10% solution) of 5.5 to 7.5, density of 0.40 g / cm3to 0.48 g / cm3, starch content of minimum 95% to 99%, and fat content of 0.01% to 0.1%.

[0146] Preferably, the content of gelled or pregelled plant starch contained in the solid composition BC-1 or BC-2 is 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, with respect to the total weight of the composition BC-1 and BC-2.

[0147] The oral composition BC-1 according to the present application comprises or consists of the above-mentioned weight percentages of iron (III) salt, lecithin, e.g. sunflower lecithin, sucrose esters or sucrose esters, e.g. E473, starch, preferably plant starch, e.g. rice starch, and sodium or potassium pyrophosphate salts, preferably in the form of tetrasodium pyrophosphate.

[0148] The oral composition BC-1 according to the present application comprises or consists of the above-mentioned weight percentages of ferric (III) pyrophosphate salt, lecithin, e.g. sunflower lecithin, sucroesters or sucrose esters, e.g. E473, starch, preferably a plant starch, e.g. rice starch, and sodium or potassium pyrophosphate salt, preferably tetrasodium pyrophosphate.

[0149] The oral composition BC-2 according to the present application comprises or consists of the above-mentioned weight percentages of ferric (III) salt, lecithin, e.g. sunflower lecithin, sucroesters or sucrose esters, e.g. E473, starch, preferably a plant starch, e.g. rice starch, and sodium or potassium pyrophosphate salt, preferably tetrasodium pyrophosphate, and sodium ferric (III) pyrophosphate.

[0150] The oral composition BC-2 according to the present application comprises or consists of the above-mentioned weight percentages of ferric (III) salt, lecithin, e.g. sunflower lecithin, sucroesters or sucrose esters, e.g. E473, starch, preferably a plant starch, e.g. rice starch, and sodium or potassium pyrophosphate salt, preferably tetrasodium pyrophosphate, and sodium ferric (III) pyrophosphate.

[0151] Another object of the present application is a first method for the preparation of the mixture BM-1 or BM-2, after which the physiologically acceptable excipient, diluent or carrier is added, thus obtaining the oral composition BC-1 or BC-2 according to the present application, respectively.

[0152] The first method according to the present application involves the preparation of a mixture comprising or consisting of i) ferric (III) pyrophosphate, ii) lecithin, e.g. sunflower lecithin, iii) sucroesters or sucrose esters, e.g. E473, iv) sodium or potassium pyrophosphate salt, preferably tetrasodium pyrophosphate, and optionally v) a plant starch, preferably rice starch, thus obtaining the mixture BM-1. If sodium ferric (III) pyrophosphate is added to the mixture BM-1 in the above-mentioned weight percentages, the mixture BM-2 is obtained.

[0153] Preferably, the i) solid ferric (III) pyrophosphate and iii) sodium or potassium pyrophosphate salt, preferably tetrasodium pyrophosphate, and / or ii) sodium ferric (III) pyrophosphate are mixed in the above-mentioned weight percentages to obtain a mixture, which is then added to the plant lecithin, starch and / or sucroesters. Preferably, the mixing is carried out in a mixer equipped with stirring and mixing devices known in the art. Preferably, a sieving step is provided, using suitable sieves or sieving machines, in order to make the processed solid powder mixture more uniform and consistent. The experimental part of the present application lists further other details of the first method according to the present application.

[0154] Said i) iron (III) pyrophosphate, lecithin, sucroesters, iii) sodium or potassium pyrophosphate (for example tetrasodium pyrophosphate), starch and possibly ii) sodium iron (III) pyrophosphate used in the preparation method of the present application have the characteristics and properties defined above.

[0155] The plant starch (for example in gelled or pregelled form) has a flowability and is flowable, so that an accurate dosing can be achieved without errors or weight deviations. It is also more homogeneously distributed in the mixture during the mixing step. Finally, the plant starch improves the bioavailability of the iron cations and the solubility of the resulting compound is better at 15°C to 30°C (1 atmosphere), preferably 20°C to 25°C, even more preferably 18°C to 23°C.

[0156] After completion of said first preparation method, a mixture BM-1 (and oral solid composition BC-1) of the present application is obtained, which comprises or alternatively consists of the above-mentioned weight percentages of i) iron (III) pyrophosphate, plant lecithin, sucroesters or sucroesters, iii) sodium or potassium pyrophosphate (for example tetrasodium pyrophosphate), and optionally starch, possibly ii) sodium iron (III) pyrophosphate in the mixture BM-2 (and composition BC-2).

[0157] Preferably, by means of said first preparation method, a mixture BM-1 (and oral solid composition BC-1) of the present application is obtained, which comprises or consists of the above-mentioned weight percentages of i) iron (III) pyrophosphate, plant lecithin, for example corn lecithin or soy lecithin or sunflower lecithin E322, sucroesters or sucroesters, for example E473, iii) sodium or potassium pyrophosphate (for example tetrasodium pyrophosphate), and optionally starch (for example rice starch).

[0158] Preferably, by means of said first preparation method, a mixture BM-2 (and oral solid composition BC-2) of the present application is obtained, which comprises or consists of the above-mentioned weight percentages of i) iron (III) pyrophosphate, plant lecithin, for example corn lecithin or soy lecithin or sunflower lecithin E322, sucroesters or sucroesters, for example E473, iii) sodium or potassium pyrophosphate (for example tetrasodium pyrophosphate), ii) sodium iron (III) pyrophosphate, and optionally starch (for example rice starch).

[0159] Preferably, in order to further improve the bioavailability of the iron cations, it is useful to reduce as much as possible the amount of the weight percentage of lecithin in the method for preparing the solid composition of the present application.

[0160] Furthermore, it has been found that in order to further improve the bioavailability of the iron cations, it is preferred to use sucrose esters or sucrose esters in a certain weight ratio, while reducing the weight ratio of lecithin.

[0161] Preferably, the weight ratio of sucrose esters or sucrose esters to lecithin is preferably from 60:1 to 10:1, preferably from 50:1 to 20:1, more preferably from 45:1 to 30:1, for example from 40:1 to 35:1. In one embodiment, the ratio ranges from 45:1 to 35:1.

[0162] Preferably, the content of lecithin in the mixture BM-1 or BM-2 is from 0.01 wt% to 10 wt%, preferably from 0.05 wt% to 5 wt%, more preferably from 0.1 wt% to 3.5 wt%, even more preferably from 0.5 wt% to 2 wt%, for example from 0.8 wt% to 1.5 wt%, for example 0.9 wt%, or 1 wt%, or 1.1 wt%, or 1.2 wt%, or 1.3 wt%, or 1.4 wt%, relative to the total weight of the mixture.

[0163] Said method of the present application is able to form a coating or an encapsulation around the iron (III), which can improve the stability and bioavailability of the cations (III) due to the presence of sodium or potassium pyrophosphate and / or sodium iron (III) pyrophosphate.

[0164] In practice, said method involves forming agglomerates or granules comprising iron (III) pyrophosphate and sodium or potassium pyrophosphate and / or sodium iron (III) pyrophosphate in the presence of lecithin, sucrose esters or sucrose esters and optionally starch.

[0165] Sucrose esters or sucrose esters and lecithin act by facilitating the absorption of the salts, and thus of the iron cations contained in said salts. The mixture with lecithin and starch can form "chimeric" agglomerates, which are able to protect and isolate the iron cations in the pyrophosphate from the absorption by the gastric acid.

[0166] The processing times, for example mixing and sieving, are from 5 minutes to 90 minutes, preferably from 10 minutes to 60 minutes, more preferably from 20 minutes to 40 minutes.

[0167] The particle size distribution of the oral composition obtained by the method of the present application can be of the type D10 of about 1.8 pm, D50 of about 20.5 pm and D90 of about 108 pm.

[0168] The solid composition of the present application has an iron (III) content of from 30 mg / g to 180 mg / g, preferably from 60 mg / g to 120 mg / g, more preferably from 90 mg / g to 1 10 mg / g.

[0169] The oral composition BC-1 or BC-2 of the present application is for use in therapy, in particular for use in absolute iron deficiency or relative iron deficiency, especially for use in the treatment of a condition or disease associated with or caused by iron deficiency.

[0170] The oral composition BC-1 or BC-2 of the present application comprises iron which is readily absorbed and effectively bioavailable, capable of increasing ferritin. Moreover, the oral composition BC-1 or BC-2 has proven to be well tolerated by humans. The composition can be administered to all types of patients, including pregnant women, even in a fasting state. The oral composition BC-1 or BC-2 exhibits good palatability and has proven to be chemically and organoleptically stable in the long term, i.e. no changes in its color, odor, taste and / or flavor have been observed.

[0171] The compositions BC-1 and BC-2 of the present application are solid compositions configured in dosage units. By solid is meant that the composition can be in the form of granules, microparticles or powder or flakes. The granular or microparticulate or powder composition is then mixed with pharmaceutically acceptable additives and pharmaceutical grade or food grade excipients to provide the final product, such as a supplement product, a medical device composition in accordance with reg. EU 745 / 2017 or a pharmaceutical composition. The final product can be a pharmaceutical dosage unit, such as a sachet of granules, a tablet or a capsule.

[0172] The tablets can take different shapes known in the pharmaceutical art, such as cylindrical or spherical. The weight of the tablets can range from 100 · mg to 2000 mg. The tablets can be coated or film-coated with one or more coats or films capable of passing the gastric barrier, according to known methods.

[0173] For example, the weight of the capsules can range from 200 mg to 1200 mg, the weight of the hard capsules can range from 500 mg to 1000 mg, and the weight of the chewable tablets can range from 500 mg to 2000 mg. The capsules can be made of hard gelatin, soft gelatin or soft gel.

[0174] Each dosage unit is from 5 mg to 50 mg of iron (III) per day, preferably from 10 mg to 45 mg of iron (III) per day, more preferably from 15 mg to 40 mg, even more preferably from 20 mg to 30 mg, for example 25 mg, or 27 mg, or 29 mg of iron (III) per day.

[0175] As mentioned above, the oral composition BC-1 or BC-2 of the present application is preferably a solid composition. However, if necessary or required, the composition of the present application can also be configured in liquid form, such as an aqueous suspension, preferably with the addition of a physiologically acceptable acid, such as citric acid.

[0176] As mentioned above, the solid compositions of the present application can contain physiologically acceptable conventional excipients and carriers, such as diluents, fillers, binders, disintegrants, glidants, lubricants, and the like. Non-limiting examples of suitable carriers and excipients are described in "Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams & Wilkins". The compositions of the present application can contain, for example, cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, ethanol, and the like. The compositions can also contain pH buffers and wetting agents or emulsifiers.

[0177] Preferred excipients include hydroxypropyl methylcellulose and magnesium fatty acid salts.

[0178] In addition to the above-mentioned ingredients, the compositions BC-1 and BC-2 of the present application can also contain other active ingredients, if necessary or desirable, such as, for example, components capable of assisting the active ingredients in exerting their action in the subject being treated, such as vitamins.

[0179] Another object of the present application is a liquid oral composition comprising or consisting of the composition BC-1 or BC-2 of the present application, water and citric acid.

[0180] The solid or liquid oral compositions BC-1 or BC-2 according to any of the above-mentioned embodiments are suitable for use in therapy, in particular for use in the treatment and prevention of conditions or diseases associated with iron deficiency in children, adolescents, athletes, men, women, pregnant women and the elderly, since they can prevent and counteract anemia and help to increase the values of hemoglobin and ferritin. The compositions BC-1 or BC-2 are suitable for administration in children, adolescents, athletes, men, women, pregnant women and the elderly for a period of 1 month to 5 months, preferably 2 months to 4 months, at a dose of 10 mg to 40 mg of iron (III) per day, preferably 14 mg to 30 mg of iron (III) per day, even more preferably 28 mg of iron (III) per day.

[0181] The compositions BC-1 and BC-2 can be used throughout pregnancy, in particular from the 12th week until 6 weeks postpartum. The recommended dose of iron (III) is 10 mg to 40 mg per day, preferably 14 mg to 30 mg per day, advantageously 28 mg per day.

[0182] Preferably, in the mixtures BM-1 and BM-2 and compositions BC-1 and BC-2 of the present application, the content of i) iron (III) pyrophosphate is comprised between 10% and 90% by weight, more preferably between 25% and 75% by weight, more preferably between 35% and 65% by weight, even more preferably between 40% and 55% by weight, with respect to the total weight of the composition.

[0183] Preferably, in the mixtures BM-1 and BM-2 and compositions BC-1 and BC-2 of the present application, the content of i) iron (III) pyrophosphate is always greater than 10% by weight and less than 75% by weight with respect to the total weight.

[0184] Preferably, the mixtures BM-1 and BM-2 and compositions BC-1 and BC-2 of the present application are in solid form, such as for example in powder or granule form, and are administered in the form of for example tablets, capsules, sachets or bars. The powders and granules of the mixtures BM-1 and BM-2 and compositions BC-1 and BC-2 of the present application are produced by means of processes using equipment and techniques known to the person skilled in the art, in which the components i)-ii)-iii) in solid state are mixed and dried without the presence of liquid solutions or water.

[0185] Preferably, in the mixtures BM-1 and BM-2 and compositions BC-1 and BC-2 of the present application, iron pyrophosphate is present in a molar ratio with respect to sodium pyrophosphate (preferably tetrasodium pyrophosphate) greater than 1 ((FePP:NaPP) > 1); or iron pyrophosphate is present in a molar ratio with respect to sodium pyrophosphate (preferably tetrasodium pyrophosphate) greater than 1; or the equivalent ratio of iron pyrophosphate is greater than 1 ((FePP:NaPP) > 1 equivalent).

[0186] Preferably, the weight ratio of FePP:NaPP is greater than 1 to 15; more preferably, the weight ratio is 2 to 10; even more preferably, the weight ratio is 3 to 6, still even more preferably, the weight ratio can be 3.5; or 4; or 4.5; or 5; or 5.5.

[0187] Preferably, the molar or millimolar ratio of FePP:NaPP is greater than 1 to 15; more preferably, the molar or millimolar ratio is 2 to 10; even more preferably, the molar or millimolar ratio is 3 to 6, still even more preferably, the molar or millimolar ratio can be 3.5; or 4; or 4.5; or 5; or 5.5.

[0188] More preferably, the equivalent ratio of FePP:NaPP is 1 to 15; more preferably, the equivalent ratio is 2 to 10; even more preferably, the equivalent ratio is 3 to 6, still even more preferably, the equivalent ratio can be 3.5; or 4; or 4.5; or 5; or 5.5.

[0189] It is an object of the present application a process for the preparation of the mixtures BM-1 and BM-2 and of the compositions BC-1 and BC-2, wherein said process comprises at least one step of mixing in the solid state the components i) and / or ii) and / or iii) to obtain said mixtures and said compositions in the solid state (preferably powders or granules).

[0190] Third aspect of the application - Aspect C

[0191] In another aspect of the present application, i.e. aspect C1, it is an object of the present application a mixture CM-1 consisting of:

[0192] i) an iron (III) pyrophosphate salt;

[0193] at least one lecithin;

[0194] at least one gum arabic (or acacia gum); and

[0195] iii) a sodium or potassium pyrophosphate salt, preferably tetrasodium pyrophosphate.

[0196] In another aspect of the present application, i.e. aspect C2, it is an object of the present application a mixture CM-2 consisting of:

[0197] i) an iron (III) pyrophosphate salt;

[0198] at least one lecithin;

[0199] at least one gum arabic (or acacia gum);

[0200] iii) a sodium pyrophosphate salt, preferably tetrasodium pyrophosphate; and

[0201] ii) a sodium iron (III) pyrophosphate salt.

[0202] Preferably, the mixtures CM-1 or CM-2 of the present application can additionally comprise a further component selected from a plant starch. Preferably, the plant starch is for example preferably selected from rice starch or corn starch or sunflower starch or soybean starch or mixtures thereof. For example, a preferred starch is rice starch, for example a gelatinized or pregelatinized natural rice starch. For example, a pregelatinized rice starch that can be used is CAS No. 9005-25-8; EINECS 232-679-6, with a moisture content of 10% to 20%, for example about 15%; a particle size (particle size distribution) D10 maximum of 20 pm; a D50 maximum of 75 pm; and a D90 maximum of 175 pm. A commercially available product that complies with the above mentioned characteristics is Remyline AX-FG-P by A.D.E.A. Srl.

[0203] Preferably, the other pregelatinized rice starch that can be used in the mixture CM-1 or CM-2 can have the following physicochemical properties: moisture content from 1% to 10%; protein content from 0.1% to 1.5%; ash content from 0.1% to 1%; pH value (10% solution) from 5.5 to 7.5; density from 0.40 g / cm3to 0.48 g / cm3; starch content from a minimum of 95% to 99%, and fat content from 0.01% to 0.1%.

[0204] Preferably, the content of the gelling or pregelatinized plant starch contained in the mixture CM-1 and CM-2 is 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 composition CC-1 and CC-2.

[0205] Iron (III) pyrophosphate, sodium iron (III) pyrophosphate and sodium pyrophosphate are all salts or compounds known in the prior art.

[0206] Preferably, the content of the gum arabic or gum acacia in the mixture CM-1 or CM-2 is from 5% to 45% 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.

[0207] Iron (III) pyrophosphate, sodium iron (III) pyrophosphate and sodium pyrophosphate are all salts or compounds known in the prior art, which are in solid form, such as a powder or granules, at a temperature of 25°C.

[0208] Preferably, the i) iron (III) pyrophosphate according to the application is a hydrated salt and preferably has a chemical formula such as [Fe4(P2O7)3xH2O] (CAS RN. 10058-44-3, dry molecular weight of 745.22), the iron content preferably being from 18% to 24% by weight, even more preferably from 20% to 22% by weight, relative to the total weight of the molecule.

[0209] Preferably, the ii) sodium iron (III) pyrophosphate is a salt, preferably of chemical formula such as Fe(III)NaO7P2 (CAS RN. 10045-87-1).

[0210] Preferably, said iii) sodium pyrophosphate is a salt, preferably in the form of tetrasodium pyrophosphate, for example Na4P2O7 (CAS RN. 1269628-79-6), for example in the form of anhydrous, hemihydrated or hydrated, or with other number of water molecules known to the expert in the field. Tetrasodium pyrophosphate is a colourless, odourless, water-soluble solid at room temperature, 25°C and 1 atm, coded E450 in the list of food additives. Tetrasodium pyrophosphate is commonly used in the food industry.

[0211] Preferably, the mixture CM-1 or CM-2 contains said i) iron (III) pyrophosphate salt of the application in an amount ranging from 10% to 90% by weight, preferably from 25% to 75% by weight, more preferably from 35% to 65% by weight, even more preferably from 40% to 55% by weight, with respect to the total weight of the mixture.

[0212] Preferably, the mixture CM-1 or CM-2 contains said ii) sodium iron (III) pyrophosphate salt of the application in an amount ranging from 0.1% to 50% by weight, preferably from 1% to 35% by weight, more preferably from 5% to 30% by weight, even more preferably from 10% to 25% by weight, with respect to the total weight of the mixture.

[0213] Preferably, the mixture CM-1 or CM-2 of the application contains said iii) sodium or potassium pyrophosphate salt, preferably in the form of tetrasodium pyrophosphate, in an amount ranging from 0.1% to 50% by weight, preferably from 1% to 35% by weight, more preferably from 5% to 30% by weight, even more preferably from 10% to 25% by weight, with respect to the total weight of the mixture.

[0214] The term "lecithin" is known in the art and, according to Directive 95 / 2 / EC published on 20 February 1995 (published in O.J. No. L61 of 18 September 1995), lecithin is classified as food additive E322.

[0215] Lecithin, thanks to its physico-chemical properties, mainly exerts an emulsifying function, in addition to which, since it is also rich in natural antioxidants, it also has a secondary antioxidant function.

[0216] Directive No. 2008 / 84 / EC (published in O.J. of the European Community No. L253) of 27 August 2008 sets the purity standards that lecithin must meet in order to be certified as food grade (E322): acetone insolubles (actually the active part of the lecithin): minimum 60%; moisture: maximum 2%; acid value: maximum 35; peroxide value: maximum 10; toluene insolubles (actually impurities): maximum 0.3%.

[0217] From a chemical point of view, lecithin is a mixture of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides and phospholipids.

[0218] Phospholipids constitute the main component of lecithin; they derive from a triglyceride structure in which the fatty acids are replaced by a phosphate group, which confers a negative charge and therefore polarity to the molecule; these molecules are collectively known as phospholipids. More complex organic molecules, usually serine, choline, ethanolamine, inositol or a single hydrogen atom, are linked to the phosphate group by an ester bond, thus forming phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol or phosphatidic acid, respectively. In a narrow sense, phosphatidylcholine is usually referred to as lecithin.

[0219] Phospholipids are characterized by a polar water-soluble head that dissolves well in water, while the two saturated fatty acids represent two non-polar, water-insoluble but lipophilic tails. These molecules are known as amphiphilic molecules, which, in the presence of water and fat, arrange themselves between the fat and water molecules, thus emulsifying them. Lecithin is therefore a natural emulsifier.

[0220] The lecithin used in the present application is an unhydrolysed, powdered lecithin, preferably selected from sunflower lecithin and / or corn lecithin and / or soy lecithin and / or corn lecithin and / or rice lecithin, or mixtures thereof.

[0221] The lecithin used in the present application is a powdered lecithin having a water content of between 1.5% and 4.5%, preferably between 2% and 4%, even more preferably between 2.5% and 3.5%. Preferably, the lecithin used is sunflower lecithin powder.

[0222] In one embodiment, the sunflower lecithin has a glucose content of between 20% and 60% by weight, preferably between 30% and 50% by weight, for example about 45% by weight.

[0223] Soya lecithin that can be used in the context of the application can have the following composition (physicochemical analysis): soya lecithin from 40% to 50%, carbohydrates from 40% to 50% (for example about 42%), proteins from 6% to 10%, ashes from 3% to 8%, moisture from 2% to 5%, flow agent from 0.5% to 1.5%.

[0224] The content of lecithin in the oral composition of the application is from 0.1% to 10% by weight, preferably from 0.5% to 5% by weight, more preferably from 1% to 4% by weight, even more preferably from 1.5% to 3.5% by weight, relative to the total weight of the composition.

[0225] The term "gum arabic" is known in the art and is a natural gum also known as acacia gum, as it is extracted from two species of acacia tree, Acacia senegal and Acacia seyal.

[0226] Gum arabic is commercially available and, in the context of the application, for example, gum type E414 originating from Acacia senegal can be used.

[0227] For example, it can be preferred to use gum arabic type E414 (acacia gum) in the form of a white powder, CAS No. 9000-01-5, EINECS No. 232-519-5, with an average molecular weight of about 350 000, a viscosity of about 60 mPas to 130 mPas (sol. 25%), almost insoluble in ethanol (96%).

[0228] The object of the application is a mixture (CM-1 or CM-2) comprising or consisting of:

[0229] - i) a ferric (III) pyrophosphate salt;

[0230] - at least one lecithin;

[0231] - at least one gum arabic or acacia gum; and

[0232] - iii) a sodium or potassium pyrophosphate salt.

[0233] Preferably, the mixture further comprises ii) a sodium ferric (III) pyrophosphate salt; preferably, the content of said ii) sodium ferric (III) pyrophosphate salt in the mixture is from 0.1% to 50% by weight, preferably from 1% to 35% by weight, more preferably from 5% to 30% by weight, even more preferably from 10% to 25% by weight, relative to the total weight of the mixture.

[0234] Preferably, 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 a pregelatinized rice starch.

[0235] Preferably, the content of starch in the mixture is comprised between 1 and 50% by weight, preferably between 10 and 40% by weight, more preferably between 15 and 35% by weight, even more preferably between 20 and 30% by weight, relative to the total weight of the mixture.

[0236] Preferably, the content of i) iron (III) pyrophosphate is comprised between 10 and 90% by weight, preferably between 25 and 75% by weight, more preferably between 35 and 65% by weight, even more preferably between 40 and 55% by weight, relative to the total weight of the mixture.

[0237] Preferably, the at least one lecithin is a plant lecithin, preferably the plant lecithin is selected from the group comprising or consisting of sunflower lecithin, corn lecithin, soybean lecithin or rice lecithin; the content of the at least one lecithin in the mixture is comprised between 0.1 and 10% by weight, preferably between 0.5 and 5% by weight, more preferably between 1 and 4% by weight, even more preferably between 1.5 and 3.5% by weight, relative to the total weight of the mixture.

[0238] Preferably, the content of gum arabica or gum acacia in the mixture is comprised between 5 and 45% by weight, preferably between 10 and 40% by weight, more preferably between 15 and 35% by weight, even more preferably between 20 and 30% by weight, relative to the total weight of the mixture.

[0239] Preferably, the content of sodium or potassium pyrophosphate salt (preferably in the form of tetrasodium pyrophosphate) in the mixture is comprised between 0.1 and 50% by weight, preferably between 1 and 35% by weight, more preferably between 5 and 30% by weight, even more preferably between 10 and 25% by weight, relative to the total weight of the mixture.

[0240] Preferably, the mixture is for use in therapy; preferably the mixture is for use in a method of treatment and / or prevention of absolute iron deficiency or relative iron deficiency, in particular for use in the treatment of a condition or disease related to or caused by iron deficiency.

[0241] The object of the present application 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 grade excipient and / or vehicle; preferably the composition is in the form of a solid oral dosage unit.

[0242] Another object of the application is a composition CC-1 comprising or consisting of the mixture CM-1, and at least one pharmaceutical or food grade excipient and / or vehicle.

[0243] Another object of the application is a composition CC-2 comprising or consisting of the mixture CM-2, and at least one pharmaceutical or food grade excipient and / or vehicle.

[0244] The compositions CC-1 and CC-2 are suitable for oral administration.

[0245] The oral compositions CC-1 and CC-2 of the application are for use in absolute or relative iron deficiency, in particular for the treatment of a condition or disease associated with or caused by iron deficiency.

[0246] The oral compositions CC-1 and CC-2 of the application are preferably free of diglycerol fatty acid.

[0247] The oral compositions CC-1 and CC-2 of the application are preferably solid compositions formulated in dosage units. By solid is meant that the composition can be in the form of granules or powder. The granular or powder composition is then mixed with pharmacologically acceptable additives and excipients to provide the final product, such as a supplement product, a medical device or a pharmaceutical composition. The final product can be a pharmaceutical dosage unit, such as granules, sachets, tablets or capsules.

[0248] The tablets can take different shapes known in the pharmaceutical art, such as cylindrical or spherical. The weight of the tablets can range from 100 · mg to 2000 mg. The tablets can be coated or film-coated with one or more coats or films capable of passing the gastric barrier, according to known methods.

[0249] For example, the weight of the gel capsules can range from 200 mg to 1200 mg, the weight of the hard capsules can range from 500 mg to 1000 mg, and the weight of the chewable tablets can range from 500 mg to 2000 mg. The capsules can be made of hard gelatin, soft gelatin or soft gel.

[0250] As mentioned above, the oral compositions of the application are preferably solid compositions. However, if necessary or required, the compositions of the application can also be configured in liquid form, such as an aqueous suspension, preferably with the addition of a physiologically acceptable acid, such as citric acid.

[0251] As mentioned above, the solid composition of the application can contain physiologically acceptable conventional excipients and carriers, such as diluents, fillers, binders, disintegrants, glidants, lubricants, etc. Non-limiting examples of suitable excipients and carriers are described in "Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams & Wilkins". For example, the composition of the application can include cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, ethanol, etc. The composition can also contain pH buffers and wetting agents or emulsifiers.

[0252] In addition to the above-mentioned components, the composition of the application can also include other active components, if necessary or desirable, such as components capable of assisting the active ingredient in exerting its effect in the subject being treated, such as vitamins.

[0253] The solid or liquid oral composition according to any of the above-mentioned embodiments is suitable for the treatment and prevention of disorders or diseases related to iron deficiency in children, adolescents, athletes, men, women, pregnant women and the elderly, since it can prevent and combat anemia and help to increase the values of hemoglobin and ferritin. The composition is suitable for children, adolescents, athletes, men, women, pregnant women and the elderly, with an administration time of 1 month to 5 months, preferably 2 months to 4 months, and an administration dose of 10 mg to 40 mg of iron (III) per day, preferably 14 mg to 30 mg of iron (III) per day, even more preferably 28 mg of iron (III) per day.

[0254] Another object of the application is an iron supplement comprising the composition CC-1 or CC-2 of the application, possibly other components such as minerals and / or vitamins.

[0255] Another object of the application is a method for the treatment and / or prevention of disorders or diseases related to iron deficiency, comprising administering to a subject in need thereof the composition CC-1 or CC-2 of the application.

[0256] The composition CC-1 and CC-2 of the application comprises iron (III) pyrophosphate in an amount of 30% to 70% by weight, preferably 35% to 55% by weight, even more preferably 40% to 50% by weight, relative to the total weight of the composition.

[0257] The Applicant has surprisingly found that the compositions described in WO2014 / 009806 and WO2015 / 033216 and marketed under the trade name The addition of a sodium or potassium pyrophosphate salt, such as tetrasodium pyrophosphate, in the composition for sale, completely unexpectedly, significantly increases the amount of iron absorbed by a higher level of ferritin.

[0258] This surprising result will be described and demonstrated in detail in the experimental part hereafter.

[0259] The sodium pyrophosphate contained in the oral composition CC-1 or CC-2 of the application is preferably tetrasodium pyrophosphate, in a content ranging from 0.1 to 30% by weight, preferably from 1 to 20% by weight, even more preferably from 12 to 16% by weight, relative to the total weight of the composition.

[0260] Thus, the oral composition CC-1 of the application comprises or consists of the above-mentioned percentages by weight of iron (III) pyrophosphate, lecithin (e.g. lecithin of type E322), at least one gum arabic (or acacia gum) and sodium pyrophosphate (preferably tetrasodium pyrophosphate).

[0261] Thus, the oral composition CC-2 of the application comprises or consists of the above-mentioned percentages by weight of iron (III) pyrophosphate, lecithin (e.g. lecithin of type E322), at least one gum arabic (or acacia gum), sodium pyrophosphate (preferably tetrasodium pyrophosphate) and sodium iron (III) pyrophosphate.

[0262] As mentioned above, the oral composition CC-1 or CC-2 of the application can also comprise other physiologically acceptable conventional components, excipients and carriers.

[0263] Preferably, the oral composition CC-1 or CC-2 of the application can also comprise an additional component selected from plant starch.

[0264] The plant starch is preferably selected from rice starch or corn starch. Preferably, the starch is rice starch; more preferably, the rice starch is a gelatinized or pregelatinized natural rice starch.

[0265] The pregelatinized rice starch that can be used in the context of the application can have the following physicochemical properties: a moisture content of not more than 7%; a protein content of not more than 1%; an ash content of not more than 1%; a pH value (10% solution) of 5.5 to 7.5; a density of 0.40 g / cm3to 0.48 g / cm3; a starch content of not less than 97%, a fat content of not more than 0.1%. For example, a pregelatinized rice starch can be used.

[0266] The content of the gelatinized or pregelatinized plant starch in the solid composition is 10% to 40%, preferably 15% to 35%, even more preferably 20% to 30%, relative to the total weight of the composition CC-1 and CC-2.

[0267] The oral composition CC-1 of the application comprises or consists of the above-mentioned percentages by weight of iron (III) salt, lecithin (for example of the E322 type), at least one gum arabic (or acacia gum), sodium pyrophosphate (preferably tetrasodium pyrophosphate) and, preferably, a vegetable starch.

[0268] The oral composition CC-2 of the application comprises or consists of the above-mentioned percentages by weight of iron (III) salt, lecithin (for example of the E322 type), at least one gum arabic (or acacia gum), sodium pyrophosphate (preferably tetrasodium pyrophosphate), sodium iron (III) pyrophosphate and, preferably, a vegetable starch

[0269] Another object of the application is a first method for preparing the oral composition CC-1 or CC-2 of the application.

[0270] The first method of the application is a method for preparing an oral composition comprising or consisting of the above-mentioned percentages by weight of iron (III) pyrophosphate, sunflower lecithin, gum arabic, tetrasodium pyrophosphate, a vegetable starch (preferably pregelatinized rice starch) and, possibly, sodium iron (III) pyrophosphate.

[0271] Said first method of the application comprises or consists of a series of processing steps by which the iron (III) pyrophosphate is coated with or encased with or encapsulated with said lecithin and / or said gum arabic and / or said vegetable starch.

[0272] Preferably, the solid iron (III) pyrophosphate is successively brought into contact with said gum arabic, then with said lecithin, then with said tetrasodium pyrophosphate and, finally, with said vegetable starch.

[0273] The iron (III) pyrophosphate, the lecithin, the gum arabic, the tetrasodium pyrophosphate, the possible sodium iron (III) pyrophosphate and the starch used in the method of the application have the characteristics and properties defined above.

[0274] The advantage of the starch in the form of gelatinized starch or pregelatinized starch is that it is more fluid and easy to flow, thus allowing accurate dosing without errors or weight deviations. It is also more uniformly distributed. Finally, the pregelatinized vegetable starch improves the bioavailability of the iron cations, since the resulting compound is better soluble at 15°C to 30°C (1 atmosphere), preferably 20°C to 25°C, even more preferably 18°C to 23°C.

[0275] After completion of said first preparation method, the oral composition CC-1 or CC-2 of the application is obtained, which comprises or consists of the above-mentioned percentages by weight of iron (III) pyrophosphate, sunflower lecithin, gum arabic, tetrasodium pyrophosphate, possibly sodium iron (III) pyrophosphate (CC-2) and pregelatinized rice starch.

[0276] In particular, by said first preparation method, a solid composition CC-1 or CC-2 of the present application is obtained, consisting of or comprising ferric pyrophosphate, sunflower lecithin E322, gum arabic, tetrasodium pyrophosphate, possibly sodium ferric pyrophosphate (CC-2) and pregelatinized rice starch in the above-mentioned percentages by weight.

[0277] The Applicant has found that, in order to further improve the absorption of the iron cations, it is useful to reduce as much as possible the weight percentage of lecithin used in the method for preparing the solid composition of the present application.

[0278] Furthermore, the Applicant has found that, in order to further enhance the absorption of the iron cations, it is important to use gum arabic in a specific weight percentage in combination with a reduced weight of lecithin.

[0279] Advantageously, the weight ratio of gum arabic to lecithin is from 40:1 to 10:1. In one embodiment, said ratio is from 35:1 and 15:1; in each case, the content of lecithin in the composition is from 0.01 to 10% by weight, preferably from 0.1 to 5% by weight, more preferably from 0.5 to 2.5% by weight, even more preferably from 0.8 to 1.2%.

[0280] The experimental part of the present application lists the details of the first method described in the present application.

[0281] The object of the present application is also to provide a second method for preparing the oral composition CC-1 or CC-2 of the present application.

[0282] The second method of the present application relates to the preparation of a solid composition CC-1 or CC-2 consisting of or comprising an iron salt, gum arabic, lecithin, tetrasodium pyrophosphate, possibly sodium ferric pyrophosphate (CC-2) and a gelatinized or pregelatinized starch.

[0283] Said second method of the present application consists of or comprises a technique that forms a coating or a film around the iron to improve the stability and bioavailability of the cations.

[0284] In practice, said second method involves the formation of aggregates or granules comprising ferric pyrophosphate, gum arabic, lecithin, tetrasodium pyrophosphate, possibly sodium ferric pyrophosphate and a gelatinized or pregelatinized starch. All these components have the characteristics described above.

[0285] Gum arabic and lecithin act by facilitating the absorption of the salt, and therefore of the iron cations contained in said salt. The mixture with lecithin and starch can form "chimeric" agglomerates capable of protecting and isolating the iron cations in the pyrophosphate salt from the absorption by the gastric acid.

[0286] The processing time is between 1 minute and 60 minutes, preferably between 10 minutes and 50 minutes, even more preferably between 20 minutes and 40 minutes.

[0287] The particle size, understood as the average particle size, of the oral composition obtained by the process of the application is D50 of about 20.5 pm (pm micrometers, 10 -6 for example, of the type D10 of about 1.8 pm, D50 of about 20.5 pm and D90 of about 108 pm.

[0288] The content of iron (III) in the solid composition of the application is between 60 mg / g and 140 mg / g, preferably between 80 mg / g and 120 mg / g, even more preferably between 90 mg / g and 110 mg / g.

[0289] The oral composition CC-1 or CC-2 of the application is used for absolute or relative iron deficiency, in particular for the treatment of a condition or disease related to or caused by iron deficiency.

[0290] The oral composition CC-1 or CC-2 of the application comprises iron that is easily absorbed and effectively bioavailable, capable of increasing ferritin. In addition, the oral composition CC-1 or CC-2 has proven to be well tolerated by the human body. This composition can be administered to all types of patients, including pregnant women, even in a fasting state. The oral composition CC-1 or CC-2 exhibits good palatability and has proven to have long-term chemical and organoleptic stability, i.e. no changes in its color, odor, taste and / or flavor have been observed.

[0291] The compositions CC-1 and CC-2 of the application are solid-state compositions formulated in dosage units. By solid state it is meant that the composition can be in the form of granules or powder. The granular or powder composition is then mixed with pharmacologically acceptable additives and excipients to provide the final product, such as a supplement product, a medical device or a pharmaceutical composition. The final product can be a pharmaceutical dosage unit, such as granules, sachets, tablets or capsules.

[0292] The tablets can take different shapes known in the pharmaceutical art, such as cylindrical or spherical. The weight of the tablets can range from 200 mg to 2000 mg. The tablets can be coated or film-coated with one or more coats or films capable of passing the gastric barrier, according to known methods.

[0293] For example, the weight of the gel capsules can be 500 mg, the weight of the hard tablets can be 800 mg to 1000 mg, and the weight of the chewable tablets can be 1000 mg to 2000 mg. The capsules can be made of hard gelatin, soft gelatin or soft gel.

[0294] Each dosage unit contains 5 mg to 50 mg of iron (III), preferably 10 mg to 40 mg.

[0295] Preferably, the oral composition CC-1 or CC-2 of the present application is a solid composition as described above. However, if desired or necessary, the composition of the present application can also be configured in liquid form, for example, an aqueous suspension, preferably with the addition of a physiologically acceptable acid, for example, citric acid.

[0296] As mentioned above, the solid composition of the present application can contain physiologically acceptable conventional excipients and carriers, such as diluents, fillers, binders, disintegrants, glidants, lubricants, etc. Non-limiting examples of suitable carriers and excipients are described in "Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams & Wilkins". For example, the composition of the present application can include cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, ethanol, etc. The composition can also contain pH buffers and wetting agents or emulsifiers.

[0297] Preferred excipients include hydroxypropyl methylcellulose and magnesium fatty acid salts.

[0298] In addition to the above-mentioned components, the composition CC-1 and CC-2 of the present application can also contain other active components, if desired or necessary, for example, components capable of assisting the active ingredient in exerting its effect in the subject being treated, for example, vitamins.

[0299] Another object of the present application is to provide a liquid oral composition comprising or consisting of the composition CC-1 or CC-2 of the present application, water and citric acid.

[0300] The solid or liquid oral composition CC-1 or CC-2 according to any of the above embodiments is suitable for the treatment and prevention of disorders or diseases associated with iron deficiency in children, adolescents, athletes, men, women, pregnant women and the elderly, since it can prevent and combat anemia and help to increase the values of hemoglobin and ferritin. The composition CC-1 or CC-2 is suitable for children, adolescents, athletes, men, women, pregnant women and the elderly, with an administration time of 1 month to 5 months, preferably 2 months to 4 months, and an administration dose of 10 mg to 40 mg of iron (III) per day, preferably 14 mg to 30 mg of iron (III) per day, even more preferably 28 mg of iron (III) per day.

[0301] The CC-1 and CC-2 compositions can be used throughout pregnancy, in particular from the 12th week, until 6 weeks postpartum. The recommended dose of iron (III) is from 10 mg to 40 mg per day, preferably from 14 mg to 30 mg per day, advantageously 28 mg per day.

[0302] Another object of the present application is to provide an iron supplement comprising the composition CC-1 or CC-2 of the present application, possibly other components such as minerals and / or vitamins.

[0303] Another object of the present application is to provide a method for the treatment and / or prevention of a condition or disease associated with iron deficiency, comprising administering to a subject in need thereof the composition CC-1 or CC-2 of the present application.

[0304] The Applicant has carried out a number of experimental studies and has found that the mixtures and compositions of the present application show improved performances compared to the commercial compositions, even compared to the composition sold under the trade name Ferromag®.

[0305] The details of the experiments carried out and the results obtained are described below in the "Experimental Part", which illustrates by way of non-limiting example the representative embodiments of the present application.

[0306] Below are listed the preferred embodiments of the present application.

[0307] Preferably, in the mixtures CM-1 and CM-2 and in the compositions CC-1 and CC-2 of the present application, the mixtures contain i) iron (III) pyrophosphate in an amount ranging from 10% to 90% by weight, more preferably from 25% to 75% by weight, more preferably from 35% to 65% by weight, even more preferably from 40% to 55% by weight, with respect to the total weight of the mixture.

[0308] Preferably, in the mixtures CM-1 and CM-2 and in the compositions CC-1 and CC-2 of the present application, the content of i) iron (III) pyrophosphate is always greater than 10% by weight and less than 75% by weight with respect to the total weight.

[0309] Preferably, the mixtures CM-1 and CM-2 and the compositions CC-1 and CC-2 of the present application are in solid form, such as powders or granules, and are administered in the form of, for example, tablets, capsules, sachets or bars. The powders and granules of the mixtures CM-1 and CM-2 and of the compositions CC-1 and CC-2 of the present application are produced by processes using equipment and techniques known to those skilled in the art, in which the individual components i)-ii)-iii) in solid state are mixed and dried without the presence of liquid solutions or water.

[0310] Preferably, in the mixtures CM-1 and CM-2 and compositions CC-1 and CC-2 of the present application, the weight ratio of iron pyrophosphate with respect to sodium pyrophosphate (preferably tetrasodium pyrophosphate) is greater than 1 ((FePP:NaPP) > 1); or the molar ratio of iron pyrophosphate with respect to sodium pyrophosphate (preferably tetrasodium pyrophosphate) is greater than 1; or the equivalent ratio of iron pyrophosphate is greater than 1 ((FePP:NaPP) > 1 equivalent).

[0311] Preferably, the weight ratio of FePP:NaPP is greater than 1 to 15; more preferably, the weight ratio is 2 to 10; even more preferably, the weight ratio is 3 to 6, still even more preferably, the weight ratio can be 3.5; or 4; or 4.5; or 5; or 5.5.

[0312] Preferably, the molar or millimolar ratio of FePP:NaPP is greater than 1 to 15; more preferably, the molar or millimolar ratio is 2 to 10; even more preferably, the molar or millimolar ratio is 3 to 6, still even more preferably, the molar or millimolar ratio can be 3.5; or 4; or 4.5; or 5; or 5.5.

[0313] More preferably, the equivalent ratio of FePP:NaPP is 1 to 15; more preferably, the equivalent ratio is 2 to 10; even more preferably, the equivalent ratio is 3 to 6, still even more preferably, the equivalent ratio can be 3.5; or 4; or 4.5; or 5; or 5.5.

[0314] It is an object of the present application a process for the preparation of the mixtures CM-1 and CM-2 and compositions CC-1 and CC-2, wherein said process comprises at least one step of mixing the components i) and / or ii) and / or iii) in the solid state to obtain said mixtures and said compositions in the solid state (preferably powders or granules). BRIEF DESCRIPTION OF DRAWINGS

[0315] Figure 1 A schematic representation of the static permeation assay is shown.

[0316] Figure 2 Comparison results of solubility tests of iron sulfate, iron pyrophosphate (III), Sideral r.m. (commercial product containing iron pyrophosphate (III), lecithin, sucrose ester and starch), Sideral NaPP (Sideral r.m. of the present application with the addition of tetrasodium pyrophosphate - Example 1) are shown.

[0317] Figure 3Comparison results in simulated gastric digestion test of Sideral r.m. (commercial product containing ferric pyrophosphate, lecithin, sucrose ester and starch), Sideral NaPP (Sideral r.m. of the invention to which tetrasodium pyrophosphate is added - Example 1).

[0318] Figure 4 Comparison results of ferritin accumulation test are shown (Sideral_L ABS = composition of Example 1 of the invention containing lecithin ABS Lecy Spray; Sideral_NaPP_L AF NVH = composition of Example 1 of the invention containing lecithin L AF NVH; Sideral Liquid_NaPP_L AF NVH = composition of Example 2 containing lecithin L AF NVH).

[0319] Figure 5 Comparison results of apparent permeability and ferritin accumulation test of Sideral containing two different lecithins (L063 and LAF NVH) vs. same Sideral to which tetrasodium pyrophosphate is added are shown.

[0320] Figure 6 Comparison results of apparent permeability and ferritin accumulation test of Sideral-like containing two different lecithins (L063 and LAF NVH) vs. same Sideral-like to which tetrasodium pyrophosphate is added (composition containing gum arabic instead of combination of sucrose ester CM1 / CC1 and CM2 / CC2).

[0321] Figure 7 Left side shows A) hematocrit values from T0 to T14; middle shows B) hemoglobin values from T0 to T14; right side shows C) hemoglobin values from T0 to T14, with statistical value p = 0.0073 at T11 and p < 0.0001 at T14: statistical method: two-way ANOVA, multiple comparison correction, Sidak test. T11 and T14: statistically significant 0.5 mg / Kg Sideral NaPP vs. vehicle NaPP. P values are indicated in the graph.

[0322] Figure 8Left side shows A) hemoglobin values at T4-T0, T7-T0, T11-T0 and T14-T0, right side shows B) hematocrit values at T4-T0, T7-T0, T11-T0 and T14-T0: Statistical method: Two-way ANOVA. Multiple comparisons correction, Sidak 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 are indicated in the graph.

[0323] Figure 9 Other hematological parameters analyzed at the end of the experiment are shown, such as A) MCH (mean corpuscular hemoglobin) on the left and B) MCV (mean corpuscular volume) on the right.

[0324] Figure 10 Other hematological parameters analyzed at the end of the experiment are shown, such as A) Ret-He (reticulocyte hemoglobin) on the left and B) RBC (red blood cells) on the right.

[0325] Figure 11 Left side shows A) values of iron in the bone marrow; middle shows B) values of iron in the liver; right side shows C) values of iron in the spleen.

[0326] Figure 12 Left side shows A) liver mFTL values, right side shows B) spleen mFTL values.

[0327] Figure 13 Left side shows A) hepcidin mRNA values; middle shows B) Bmp6 mRNA values; right side shows C) Id1 mRNA values.

[0328] Figure 14 Left side shows A) Saa1 mRNA values, right side shows B) Socs3 mRNA values.

[0329] Figure 15 Left side shows A) serum iron values, right side shows B) TSat values.

[0330] Note:

[0331] - ID = Iron deficiency: amount of iron lower than 9 mg / Kg.

[0332] - Vehicle Sideral RM = is a base containing sucrose ester, lecithin and possibly starch but without iron.

[0333] - Sideral NaPP = Sideral Sodium Pyrophosphate, mixture (or composition) of the invention containing iron (III) pyrophosphate, sucrose ester, lecithin and possibly 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 invention, together with iron (III) pyrophosphate, sucrose ester and lecithin, sodium pyrophosphate replaces all or part of the starch when said Sideral NaPP is prepared.

[0334] - Vehicle NaPP = Sodium pyrophosphate, preferably tetrasodium pyrophosphate.

[0335] - Iron or Sideral RM commercially available mixture (or composition) containing iron (III) pyrophosphate, sucrose ester, lecithin and possibly starch.

[0336] Experimental part

[0337] Example 1

[0338] Preparation of the composition of the first aspect of the application

[0339] Ingredients Content (g) per 100 g Ferric (III) pyrophosphate DRPL DRPL Superfine 44.76g Sucrose ester 17.14g Sodium pyrophosphate 14g Lecithin AF NVH or Lecithin 063 0.58g Rice starch 23.52g Total 100g

[0340] Table 1

[0341] Mixing protocol

[0342] According to the relevant master recipe (per 100 g of finished product), 300 g of prototype are prepared using a NOVINOX mixer.

[0343] 1) the following components are added:

[0344] Iron (III) pyrophosphate

[0345] +

[0346] Sucrose ester

[0347] +

[0348] Lecithin

[0349] +

[0350] Sodium pyrophosphate

[0351] 2) mixing for 30 minutes at 8.7 rpm per hour

[0352] 3) the following is added: rice starch

[0353] 4) mixing for 30 minutes at 8.7 rpm per hour

[0354] 5) automatic sieving for about 10 minutes

[0355] 6) Mix for 30 minutes at 8.7 rpm per hour

[0356] 7) Measure yield at the end of the process

[0357] Example 2

[0358] Composition in liquid form of the first aspect of the application

[0359] Ingredients Content g / 2 ml Composition of Example 1 7.16g Citric acid 4.00g Water 1.984ml

[0360] Table 2

[0361] Example 3

[0362] Preparation of the composition of the third aspect of the application as shown in Example 1

[0363] Ingredients Content (g) per 100 g Ferric (III) pyrophosphate DRPL Superfine 44.76g Gum arabic 17.14g Sodium pyrophosphate 14g Lecithin AF NVH or Lecithin 063 0.58g Rice starch 23.52g Total 100g

[0364] Table 3

[0365] Example 4

[0366] Static permeation test - Transwell system

[0367] Experimental protocol

[0368] Materials

[0369] Cells: Caco-2 (HTB-37 TM ), ATCC.

[0370] Insert: TC insert for 12 well plates, PET, transparent, pore size: 0.4 pm, Sarstedt.

[0371] Plate: 12 well plate.

[0372] Complete medium: Dulbecco's Modified Eagle Medium (DMEM - low glucose content,

[0373] with 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 acids solution (100x) (1%), fetal bovine serum (10%).

[0374] Complete medium without FBS: Dulbecco's Modified Eagle Medium (DMEM - low glucose content,

[0375] Dulbecco's Modified Eagle Medium (DMEM, liquid, with 1000 mg / L glucose and sodium bicarbonate, without L-glutamine and phenol red, cell culture- tested, sterile-filtered) (87%), L-glutamine solution 200 mM (2%), MEM non-essential amino acids solution (100x) (1%).

[0376] DMEM: Dulbecco's Modified Eagle Medium (DMEM, liquid, with 1000 mg / L glucose and sodium bicarbonate, without L-glutamine and phenol red, cell culture- tested, sterile-filtered).

[0377] CelLytic™ MT: Mammalian tissue lysis / extraction reagent, Sigma Aldrich.

[0378] MTT 1 mg / mL: 3,2,5-diphenyltetrazolium bromide, a standard colorimetric assay reagent for determining the activity of enzymes that reduce MTT to formazan, which imparts a blue / purple color to the material. This staining indicates cell viability.

[0379] Alcoholic acid: 19 parts of 2-propanol: 1 part of HCI 2M.

[0380] TEER: Trans epithelial electrical resistance, used to measure the integrity and strength of the intestinal barrier in the confluent state of the cell monolayer.

[0381] Treatment: Ferric (III) pyrophosphate, Sideral® r.m., composition of example 1 (Sideral NaPP), blank.

[0382] Supernatant of simulated gastrointestinal digestion.

[0383] Cell proliferation:

[0384] - 12 inserts of 0.4 pm were placed in a 12-well plate. The experiment was repeated on 2 plates.

[0385] - 1 ml of complete medium with Caco-2 cells at a density of 0.5 x 10 5 Cells per insert. The passage number at cell seeding should be over 25.

[0386] - 1.5 mL of complete medium were added to the basal compartment.

[0387] - The cells were placed in an incubator at 37°C, 5% CO2.

[0388] - The medium was changed every other day for 21 days.

[0389] - On day 21, the cells were ready for the experiment.

[0390] Simulation of the gastrointestinal digestion:

[0391] The following samples were subjected to a simulated gastrointestinal digestion protocol: Blank (B), Ferric Pyrophosphate (FeP), Sideral® r.m. (SID), Sideral® with sodium pyrophosphate (SID NaPP).

[0392] Oral compartment: 3.5 mL of an aqueous solution of elemental iron at 2 mg / mL (3.5 mL of water for the blank) were incubated at 37°C under stirring for 5 minutes.

[0393] Gastric compartment: 6.5 mL of SGF (Simulated Gastric Fluid: 0.2 g of NaCl dissolved in 100 mL of water, adjusted to pH 1.2 with concentrated HC1) were added. The solution was left at 37°C under stirring for 2 hours.

[0394] Intestinal compartment: 10 mL of gastric digest were added to 1 mL of NaHC03 1 M and 4 mL of SIF (Simulated Intestinal Fluid: 0.68 g of anhydrous KH2P04 dissolved in 100 mL of H20, adjusted to pH 7.5 with 1 M NaOH). The solution was left at 37°C under stirring for 2 hours.

[0395] After the completion of the simulated gastrointestinal digestion, the samples were centrifuged at 8000 rpm for 5 minutes and the supernatant was collected. The supernatant was quantified using the ICP-OES instrument.

[0396] Experiment

[0397] Preparation of treatment: the supernatant of the gastrointestinal digestion was diluted with complete medium without FBS to reach a final concentration of 1 mg / mL.

[0398] 1. The inserts were moved to a clean 12-well plate and the medium of the apical compartment was removed. 2 complete plates with 24 inserts each were needed for each experiment.

[0399] 2. The cells were washed 2 times with 500 ml of PBS.

[0400] 3. 400 mL of treatment were added to the apical compartment and 1600 mL of complete medium without FBS were added to the basal compartment.

[0401] 4. The TEER of the 24 inserts was measured at T0 (i.e. immediately after the treatment).

[0402] 5. The treatment was waited for 3 hours in an incubator at 37°C.

[0403] 6. After the completion of the 3 hours treatment, the TEER of all the 24 inserts was measured and then the apical and basal were taken.

[0404] 7. The cells of both plates were washed 2 times with 500 ml of PBS.

[0405] 8. Add 400 uL of CelLytic™ Mt to the top side of each well of plate 1 (12 inserts) and shake for 10 minutes.

[0406] 9. At the end of 10 minutes, collect the CelLytic™ Mt from each well and centrifuge at 8000 rpm for 5 minutes. Remove the supernatant and collect the cell pellet.

[0407] Take the top side, base, pellet and cell supernatant from the inserts of plate 1. Take the top side and base from plate 2.

[0408] 10. To assess barrier integrity, i.e. another parameter than TEER, in plate 2, add 400 uL of DMEM containing the phenol red indicator to the top side compartment of each well. Add 1600 uL of complete medium without FBS to the base compartment. Wait for 1 hour in the incubator at 37°C. Do the same for three groups of untreated inserts (positive control) and three groups of empty inserts without cells (negative control).

[0409] 11. At the end of 1 hour, take the base and analyze the staining with a spectrophotometer at a wavelength of 479 nm. Compare the results with the positive and negative controls.

[0410] 12. Remove the top side and wash the cells twice with 500 ml of PBS.

[0411] 13. Add 400 mL of MTT to the top side compartment and 1600 mL of complete medium without FBS to the base compartment. Wait for 2 hours in the incubator at 37°C.

[0412] 14. At the end of 2 hours, remove the liquid from both compartments, add 400 mL of acid alcohol to the top side compartment and 1600 mL of acid alcohol to the base compartment. Leave for 24 hours in the incubator at 37°C.

[0413] 15. At the end of 24 hours, read the staining values obtained at a wavelength of 570 nm and 650 nm on a spectrophotometer and compare them with the positive control (viable cells that have not received treatment on the inserts).

[0414] Through plate 2, it is possible to obtain the cell monolayer integrity value and its viability, and to correlate it with the TEER values at T0 and T3h.

[0415] Figure 1 A static permeation system is shown. The results of the tests are shown in Figure 2 and Figure 3 .

[0416] As can be seen from the results shown in the figures, the compositions of any aspect of the application all show an improved bioavailability of the iron contained therein, as well as an unexpected increase in ferritin. For these reasons, the compositions of any aspect of the application all represent a significant technical progress over known iron-based compositions.

[0417] Experimental part

[0418] Animals

[0419] To induce iron deficiency anemia, 4-week-old C57BL / J6 mice were fed with an iron- balanced diet or an iron-deficient diet containing < 9 mg / Kg carbonyl iron (code PF4418, purchased from Mucedola s.r.l.) for at least 8 weeks. The basal Hb levels of the mice were monitored by collecting a drop of blood every week with the instrument Hemo_Vet (InfraTec, Dresden, Germany) for hemoglobin and hematocrit. The treatment was started when Hb decreased below 12.5-13.0 g / dL, from a basal level of 15.5-17 g / dL. The treatment consisted of the oral administration daily of the vehicle (Vehicle Sideral RM, but without ferric pyrophosphate), Iron (Sideral RM), vehicle NaPP (vehicle NaPP) and Sideral NaPP, with a concentration of elemental iron of 0.5 mg / Kg, for a duration of 2 weeks. The mice were sacrificed after two weeks of treatment. Blood and different tissues were collected for further analysis.

[0420] NOTE:

[0421] ID = Iron deficiency: iron content lower than 9 mg / Kg.

[0422] - Vehicle Sideral RM = is a base containing sucrose esters, lecithin and possibly starch, but without iron.

[0423] - Sideral NaPP = Sideral sodium pyrophosphate, is a mixture (or composition) of the application containing ferric pyrophosphate, sucrose esters, lecithin and possibly starch, and also containing sodium pyrophosphate, preferably in the form of tetrasodium pyrophosphate. Preferably, when the mixture (or composition) of the application contains starch, ferric pyrophosphate, sucrose esters and lecithin, in the preparation of said Sideral NaPP, the sodium pyrophosphate replaces all or part of said starch.

[0424] - Vehicle NaPP = sodium pyrophosphate, preferably tetrasodium pyrophosphate.

[0425] - Iron or Sideral RM commercially available mixture (or composition) containing ferric pyrophosphate, sucrose ester, lecithin and possibly starch.

[0426] Analysis

[0427] Hematological analysis: Hemoglobin and hematocrit were monitored at time 0 (TO) and at 4-7-11-14 days of treatment using the instrument Hemo Vet (InfraTec, Dresden, Germany). At the end of the trial, blood was collected and analyzed for red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MHC) and reticulocyte hemoglobin content (Ret-He) (analysis performed by the IZLER Institute of Brescia, Italy).

[0428] Serum hepcidin and serum iron. Quantitative analysis of mouse serum hepcidin was performed using a validated commercial Elisa kit by Intrinsic Lifesciences (Cod. HMC-001). Iron and transferrin saturation in serum were determined by spectrophotometry using commercial kits (Cod. MAK025 by Sigma-Aldrich and Cod. TI1010 by Randox Laboratories) according to the manufacturer’s instructions.

[0429] Iron quantification. Tissue iron content was determined by spectrophotometry. Briefly, 50 mg of wet tissue were incubated in 0.5 mL of 3 M HC1 and 0.6 M trichloroacetic acid at 65 °C for 18 hours. After centrifugation, 10 pL of sample were added to 240 pL of working chromogenic reagent in a 96-well plate, containing 1 vol. of 0.1% o-phenanthroline sulfonate / 1% mercaptoacetic acid solution, 5 vol. of water and 5 vol. of saturated sodium acetate. The sample was then incubated at room temperature for 30 minutes and the absorbance at 535 nm was measured with a microplate reader. A standard curve was drawn using a previously calibrated FeCl3solution (Sigma-Aldrich). The values obtained were normalized to the mg of wet tissue initially used for this analysis.

[0430] ELISA of mouse L-ferritin.L-ferritin was quantitatively analyzed by an internal ELISA assay. Rabbit anti-mouse FtL antisera were added to 96-well microplates, 100 μL of 10 μg / mL sodium carbonate (50 mM, pH 9.6) was added, and incubated for 18 h at 4°C or 2 h at 37°C. After washing 3 times with 200 μL of phosphate-buffered saline (PBS) containing 0.1% Tween (PBST), 100 μL of a 3% bovine serum albumin (BSA) solution in PBS was added to the wells and incubated for 1 h at 37°C to block the plates. After washing, 100 μL of 50 μg of liver and spleen protein extracts in PBST was added and incubated for 2 h at 37°C. After washing, 100 μL of a 1:500 dilution of HRP-conjugated anti-FtL antibody was added and incubated for 1 h at 37°C. HRP activity was detected by using tetramethylbenzidine (TMB) in dimethyl sulfoxide (DMSO) at a concentration of 1 mg / mL, diluted 1:10 with phosphate-citrate buffer at pH 5, adding fresh hydrogen peroxide to a final concentration of 0.006%, and reading the absorbance at 620 nm using a Multiskan Ex microplate reader (Thermo). The reaction was stopped by adding 1 N sulfuric acid, and the absorbance was measured at 405 nm. The test was calibrated using different dilutions of purified recombinant mouse L-ferritin.

[0431] Ferritin evaluation. Liver and spleen homogenates were heated at 70°C for 10 min to enrich ferritin. Samples (equivalent to 100 μg of liver and spleen in pre-warmed proteins) were loaded on a 7.5% non-denaturing PAGE and run at 160 V for 3 h. After washing the gel with water, it was incubated in 2% ferrocyanide (Sigma-Aldrich) and 2% HC1 for 1 h. To enhance the signal, the gel was incubated in TBE IX containing 0.025% 3,30-diaminobenzidine (Sigma-Aldrich) and 0.05% H2O2 for 15-60 min. The reaction was stopped by rinsing the gel with tap water.

[0432] Quantitative QRT-PCR. Total RNA was isolated from tissues using TRIzol reagent (Ambion) according to the manufacturer’s instructions. cDNA was generated from 1 μg of RNA and Improm-II reverse transcriptase (Promega) in 20 μL according to the manufacturer’s instructions and analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using SensiFAST SYBR Lo-ROX (Bioline). All data were normalized to the expression of Hprt1 and expressed as relative quantification (2nd-ΔΔΔCt method).

[0433] The primers used were:

[0434] Hprt1:

[0435] For 5-CTGGTTAAGCAGTACAGCCAA-3,Rev 5-CAGGAGGTCCTTTTCACCAGC-3;

[0436] Hepcidin:

[0437] For 5-AAGCAGGCAGACATTGCGAT-3,Rev 5-CAGGATGTGGCTCTAGGCTATGT-3;

[0438] Socs3:For 5-TTAAATGCCCTCTGTCCCAGG-3,Rev 5-TGTTTGGCTCCTTGTGCC-3;

[0439] Saa1 For 5-AGAGGACATGAGGACACCAT-3; Rev 5-CAGGAGGTCTGTAGTAATTGG-3;

[0440] Id1:

[0441] For 5-ACCCTGAACGGCGAGATCA-3,Rev 5-TCGTCGGCTGGAACACATG-3.

[0442] Bmp6:

[0443] For 5-ATGGCAGGACTGGATCATTGC-3,Rev 5-CCATCACAGTAGTTGGCAGCGT-3.

[0444] Statistical methods. For various treatment groups, comparisons between vehicle and iron formulation groups were made by two-way ANOVA, with Sidak’s test for multiple comparisons correction; or regular one-way ANOVA, with Tukey’s test for multiple comparisons correction.

[0445] In vivo experimental plan (EXP3-2023)

[0446] Experimental groups: Two-week treatment

[0447] Male C57BL / 6J mice were fed with iron-deficient chow (<10 mg / Kg Fe). When mice hemoglobin levels reached <12.5-13.0 g / dL (T0), mice were randomly divided into 6 groups:

[0448] (a) ID mice without any treatment (N=9 mice).

[0449] (b) Mice (N=8 mice) administered Sideral RM vehicle (150 uL daily for 2 weeks) by gavage

[0450] (c) Mice (N=9 mice) orally administered 0.5 mg / Kg Sideral RM (150 uL daily for 2 weeks)

[0451] (d) Mice (N=8 mice) orally administered NaPP vehicle (150 uL daily for 2 weeks)

[0452] (e) Mice (N=9 mice) orally administered 0.5 mg / Kg Sideral NaPP (150 uL daily for 2 weeks)

[0453] Note that 6 male mice remained on normal diet as healthy controls.

[0454] Analysis: Hemoglobin, hematocrit, Ret-He and other blood parameters (analyzed by IZLER Institute at the end of the experiment) at time points 0 (TO) and T4-T7-T11-T14 days of treatment. Iron content in liver, spleen and bone marrow. Serum iron and transferrin saturation (TSat).

Claims

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

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

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

4. The mixture of claim 3, wherein, The presence of said starch in the mixture is between 1 and 50% by weight, preferably between 10 and 40% by weight, more preferably between 15 and 35% by weight, even more preferably between 20 and 30% by weight, relative to the total weight of the mixture.

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

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

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

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

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

10. The mixture according to any one of claims 1 to 9, wherein, The presence of said i) pyrophosphate iron (III) salt is always 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 powder form or granule form.

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 bar.

13. The mixture according to any one of claims 1 to 12, wherein, In the mixture, the weight ratio FePP:NaPP of the iron (III) pyrophosphate present relative to sodium pyrophosphate, preferably tetrasodium pyrophosphate, is greater than 1 to 5, preferably 2 to 3.

14. The mixture according to any one of claims 1 to 12, wherein, In the mixture, the molar ratio FePP:NaPP of the iron (III) pyrophosphate present relative to sodium pyrophosphate, preferably tetrasodium pyrophosphate, is greater than 1 to 5, preferably 2 to 3.

15. The mixture according to any one of claims 1 to 12, wherein, In the mixture, the equivalent ratio FePP:NaPP of the iron (III) pyrophosphate relative to sodium pyrophosphate, preferably tetrasodium pyrophosphate, is greater than 1 to 5, preferably 2 to 3.

16. The mixture according to any one of claims 1 to 15, wherein, The mixture is used as a medicament for treatment.

17. The mixture of claim 16, wherein, The mixture is used in a method for the treatment and / or prevention of absolute iron deficiency or relative iron deficiency, in particular for the treatment of a condition or disease related to or caused by iron deficiency.

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

19. The composition of claim 18, wherein, The composition is used as a medicament for treatment.

20. The mixture of claim 18 or 19, wherein, The composition is used in a method for the treatment and / or prevention of absolute iron deficiency or relative iron deficiency, in particular for the treatment of a condition or disease related to or caused by iron deficiency.

21. A process for the preparation of a mixture as claimed in at least one of claims 1 to 17 or a composition as claimed in at least one of claims 18 to 20, wherein, The method comprises at least one step of mixing the individual components i) and / or ii) and / or iii) in solid state to obtain the mixture and the composition in solid form, preferably as a powder or granule. The mixture is in solid form; preferably, the mixture is in powder form or granule form. The mixture is administered in the form of a tablet, capsule, sachet or bar. In the mixture, the weight ratio FePP:NaPP of the iron (III) pyrophosphate present relative to sodium pyrophosphate, preferably tetrasodium pyrophosphate, is greater than 1 to 5, preferably 2 to 3. In the mixture, the molar ratio FePP:NaPP of the iron (III) pyrophosphate present relative to sodium pyrophosphate, preferably tetrasodium pyrophosphate, is greater than 1 to 5, preferably 2 to 3. In the mixture, the equivalent ratio FePP:NaPP of the iron (III) pyrophosphate relative to sodium pyrophosphate, preferably tetrasodium pyrophosphate, is greater than 1 to 5, preferably 2 to 3. The mixture is used as a medicament for treatment. The mixture is used in a method for the treatment and / or prevention of absolute iron deficiency or relative iron deficiency, in particular for the treatment of a condition or disease related to or caused by iron deficiency. The mixture of any one of claims 1 to 15 and optionally at least one pharmaceutical or food grade excipient and / or carrier; preferably, the composition is in solid form of an oral dosage unit. The composition is used as a medicament for treatment. The composition is used in a method for the treatment and / or prevention of absolute iron deficiency or relative iron deficiency, in particular for the treatment of a condition or disease related to or caused by iron deficiency. The method comprises at least one step of mixing the individual components i) and / or ii) and / or iii) in solid state to obtain the mixture and the composition in solid form, preferably as a powder or granule.

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