Novel iron and sodium pyrophosphate 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] This invention relates to novel iron pharmaceutical and / or nutritional and / or food compositions and their use in the treatment and / or prevention of absolute or relative iron deficiency in subjects of need. Specifically, this invention relates to novel compositions comprising highly absorbable iron and their use in the treatment and / or prevention of iron deficiency-related conditions and diseases. The invention also relates to methods for preparing said compositions.

[0002] In cases of absolute or relative iron deficiency, iron can be administered orally, or in the most severe cases, via parenteral administration (iron (II) or iron (III)). These conditions include iron deficiency anemia, and iron supplementation during pregnancy if necessary.

[0003] While oral administration is preferred, this route of iron supplementation has significant drawbacks and limitations. In fact, conventional oral combinations of ferrous sulfate or ferrous gluconate (iron(II)) are poorly absorbed due to the low bioavailability of the iron salts. Furthermore, oral iron administration can cause constipation and stomach pain, and in severe cases, peptic ulcers, gastritis, and ulcerative colitis. Therefore, such compound preparations are usually taken with meals, which inevitably leads to a further significant decrease in gastrointestinal iron absorption.

[0004] Because of these drawbacks, it is necessary to extend the duration of iron salt therapy, even up to 3 to 6 months, until the body's iron stores are fully restored.

[0005] Considering the aforementioned limitations and side effects, and the fact that the composition also has an unpleasant odor and unpleasant taste due to the easy degradation of the ferrous salt, it is clear 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 their water solubility and bioavailability are lower than those of iron (II) salts, their advantage is that they are more stable and therefore do not cause sensory changes even when said iron (III) salts are mixed with other components or ingredients to form a final composition.

[0007] Among iron (III) salts, ferric pyrophosphate (III) is commercially available in various compositional forms with varying degrees of hydration. Some of these compositions can be difficult to formulate, often resulting in insoluble precipitates, which can complicate dosage and administration.

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

[0009] The scientific article XP055661417 by Colin I. Cercamondi et al. indicates that sodium pyrophosphate may affect the absorption of iron from broth cubes containing added ferric pyrophosphate. However, in vitro dissolution data of ferric pyrophosphate (FePP) in the presence of sodium pyrophosphate (NaPP) show that the higher the NaPP:FePP ratio (above 1 equivalent), the higher the iron bioavailability, 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 is used to prepare margarine or mayonnaise. Example 1, Table 1, describes a 1-liter aqueous suspension of ferric pyrophosphate (FePP) with a concentration of 8.4 g / L (37.5 mmol / L 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 ferric pyrophosphate depends on pH and the amount of pyrophosphate ions. Tetrasodium pyrophosphate (NaPP) Na4P2O7, molar mass 265.9 g / mol, CAS No. 13472-36-1. Ferric 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% ferric pyrophosphate (III), 10% to 30% sucrose ester E473, 0.1% to 1.5% lecithin E322, wherein the weight ratio of sucrose ester to lecithin is 25:1 to 20:1, and optionally 15% to 40% starch.

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

[0014] Patent application EP1743530 A1 discloses the preparation of iron pyrophosphate (II) and iron pyrophosphate (III) nanoparticles using gum arabic in Examples 3 and 4.

[0015] Therefore, the object of the present invention is to provide novel oral compositions containing iron (III) salts that are simple and convenient to formulate and prepare, and have improved iron absorption and bioavailability, and are therefore even more effective.

[0016] The object of the present invention is an oral composition comprising an iron (III) salt having the features described in the appended claims, and its use in a therapy or in a treatment method for prevention or cure.

[0017] Another object of the present invention is an oral composition having the features described in the appended claims for the prevention and / or treatment of anemia or iron deficiency (also for use in pregnant women and postpartum periods).

[0018] Another object of the present invention is the method for preparing the oral composition described herein.

[0019] First aspect of the present invention - Aspect A

[0020] According to a first aspect, the object of the present invention is a mixture (e.g., a physical mixture obtained 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 pyrophosphate or potassium pyrophosphate.

[0021] Ferric pyrophosphate (III), sodium ferric pyrophosphate (III), sodium pyrophosphate, or potassium pyrophosphate are all salts or compounds known in the art that exist in solid form, such as powder or granules, at a temperature of 25°C and a pressure of 1 atmosphere.

[0022] Preferably, the i) ferric pyrophosphate (III) of the present invention 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), and the iron content is preferably 15% to 30% by weight, more preferably 18% to 24% by weight, and more preferably 20% to 22% by weight relative to the total weight of the molecule.

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

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

[0025] The applicant unexpectedly discovered that contacting sodium pyrophosphate with ferric (III) pyrophosphate and / or sodium ferric (III) pyrophosphate in combination or in combination can improve the absorption and bioavailability of iron administered in vivo. In particular, the applicant unexpectedly discovered that mechanical mixtures or mixtures of sodium pyrophosphate (e.g., tetrasodium pyrophosphate) and ferric (III) pyrophosphate and / or sodium ferric (III) pyrophosphate (preferably obtained by, for example, a series of mechanical processes) can significantly and unexpectedly enhance the absorption of iron in the human body.

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

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

[0028] According to one embodiment, the object of the present invention is a mixture AM-3 comprising or composed of: i) ferric(III) pyrophosphate salt and ii) sodium ferric(III) pyrophosphate salt, and iii) sodium pyrophosphate, wherein the weight ratio of ferric(III) pyrophosphate:sodium ferric(III) pyrophosphate:sodium pyrophosphate (e.g., in the form of tetrasodium pyrophosphate) is 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, and more preferably 1:1:1.

[0029] "Mechanical mixture" or "preferably a mixture obtained by, for example, a series of mechanical processes" should be understood as the components or salts of the mixture being mixed in a solid state using techniques and equipment known to those skilled in the art.

[0030] The method for preparing the AM-1, AM-2 and AM-3 mixture is to mix the components or salts i) and ii) and / or iii) of the mixture in a solid state, preferably in the form of powder or granules.

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

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

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

[0034] -iii) Sodium pyrophosphate or potassium pyrophosphate.

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

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

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

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

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

[0040] Preferably, the mixture is used for treatment; preferably, the mixture is used in methods for treating and / or preventing absolute or relative iron deficiency, particularly for treating symptoms or diseases related to or caused by iron deficiency.

[0041] The object of this invention is a composition comprising the above-described mixture (AM-1, AM2, or AM-3) and optionally at least one pharmaceutical-grade or food-grade excipient and / or carrier (AC-1, AC-2, or AC-3). Preferably, the composition is in solid form for oral dosage units; more preferably, the composition may further comprise mineral salts and / or vitamins.

[0042] According to aspect A, another object of the present invention is a composition referred to herein as AC-1, AC-2 and AC-3, the composition 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 carrier.

[0043] The AC-1, AC-2 and AC-3 compositions were prepared and formulated for oral administration.

[0044] The oral compositions AC-1, AC-2, and AC-3 of the present invention are preferably formulated as solid compositions in dosage units. Solid means that the composition may exist in the form of granules, microparticles, or powder. This granular or powder composition is then mixed with pharmaceutically acceptable additives and excipients to provide a final product, such as a supplement product, a medical device composition, or a pharmaceutical composition. The final product may be a pharmaceutical dosage unit, such as sachets, sticks, tablets, or capsules.

[0045] Tablets can have various shapes, such as cylindrical or spherical, as known in the pharmaceutical field. The weight of a tablet can range from 100 mg to 2000 mg. Tablets can be coated or covered with one or more layers of a coating or film capable of passing through the gastric barrier, using methods and equipment known to those skilled in the art.

[0046] For example, capsules can weigh from 200 mg to 1200 mg, hard capsules can weigh from 500 mg to 1000 mg, and chewable tablets can weigh from 500 mg to 2000 mg. Capsules can be made of hard gelatin, soft gelatin, or soft gel.

[0047] As described above, preferably, the oral composition of the present invention is a solid composition. However, if desired or necessary, the composition of the present invention may also be formulated in liquid form, such as an aqueous suspension, preferably with the addition of physiologically acceptable acids, such as citric acid, and other substances or excipients that can maintain the stability of the suspension and are suitable for the subject's acceptance.

[0048] As described above, the oral compositions AC-1, AC-2, and AC-3 of the present invention may contain physiologically acceptable conventional excipients and carriers, such as diluents, fillers, binders, disintegrants, flow aids, 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 compositions of the present invention may include cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, ethanol, etc. The compositions may also contain industry-standard pH buffers, wetting agents, or emulsifiers.

[0049] In addition to the components described above, the compositions of the present invention may also include other active components, such as components that can assist the active ingredients in exerting their effects in the body of the treated subject, for example, vitamins.

[0050] The oral compositions AC-1, AC-2, and AC-3 of the present invention, in solid or liquid form, are for the treatment of, particularly, absolute or relative iron deficiency, and especially for the treatment of symptoms 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 intended for the treatment and prevention of conditions or diseases associated with iron deficiency in children, adolescents, athletes, men, women, pregnant women, and the elderly, because they can prevent and combat anemia and help increase hemoglobin and ferritin levels. The compositions are suitable for use in pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly for a duration of 1 to 6 months, preferably 2 to 4 months, at a dose 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, and even more preferably 20 mg to 30 mg, such as 25 mg, 27 mg, or 29 mg of iron (III) per day.

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

[0053] Another object of the present invention is a method for treating and / or preventing iron deficiency-related conditions or diseases, comprising administering to a subject in need an oral composition selected from the compositions AC-1, AC-2 and AC-3 of the present invention.

[0054] The compositions AC-1, AC-2 and AC-3 of the present invention contain ferric(III) pyrophosphate salt, wherein the content of ferric(III) pyrophosphate salt is from 10% to 90% by weight, preferably from 25% to 75% by weight, more preferably from 35% to 65% by weight, and even more preferably from 40% to 55% by weight, relative to the total weight of the composition.

[0055] Preferably, in the mixtures AM-1, AM-2 and AM-3 of the present invention and the compositions AC-1, AC-2 and AC3, the content of the i) ferric pyrophosphate (III) salt in the mixture is 10% to 90% by weight, more preferably 25% to 75% by weight, more preferably 35% to 65% by weight, and even more preferably 40% to 55% by weight, relative to the total weight of the mixture.

[0056] Preferably, in the mixtures AM-1, AM-2 and AM-3 of the present invention and the compositions AC-1, AC-2 and AC3, the content of the salt i) ferric pyrophosphate (III) salt is always greater than 10% by weight and less than 75% by weight relative to the total weight.

[0057] Preferably, the mixtures AM-1, AM-2, and AM-3 of the present invention, as well as the compositions AC-1, AC-2, and AC3, are all in solid form, such as powder or granules, and are administered in tablet, capsule, sachet, or stick form. The powders and granules of the mixtures AM-1, AM-2, and AM-3 of the present invention, as well as the compositions AC-1, AC-2, and AC3, are prepared by equipment and methods known to those skilled in the art, wherein the solid components i)-ii)-iii) are dry-mixed and processed without the use of liquid solutions or water.

[0058] Preferably, in the mixtures AM-1, AM-2, and AM-3 of the present invention and the compositions AC-1, AC-2, and AC3, 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; and even more preferably, the weight ratio can be 3.5; or 4; or 4.5; or 5; or 5.5.

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

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

[0062] The object of the present invention is a method for preparing mixtures AM-1, AM-2 and AM-3 and compositions AC-1, AC-2 and AC3, wherein the method includes at least one step of mixing each component i) and / or ii) and / or iii) in a solid state to obtain the mixtures and compositions in a solid state, preferably powders or granules.

[0063] Second aspect of the invention - Aspect B

[0064] As mentioned above, many iron-containing compositions are difficult to formulate and prone to producing insoluble precipitates, thus posing challenges to dosage and administration. Furthermore, they often suffer from poor gastrointestinal tolerance and are also very unpalatable.

[0065] To overcome the aforementioned shortcomings, the applicant conducted extensive research and developed several compositions containing ferric pyrophosphate (III), and filed two international patent applications, WO2014 / 009806 and WO2015 / 033216. These applications (and related granted patents) describe and claim protection for compositions containing minerals (particularly ferric pyrophosphate (III)) as well as sucrose esters and lecithin, under the trade name... Sold on the market.

[0066] Compared to previously used compositions, the composition improves the absorption of minerals, particularly iron, while exhibiting good tolerance and sensory stability.

[0067] However, the applicant's in-depth research activities did not stop at the above-mentioned composition, but continued to focus on further improving the composition, especially in terms of iron absorption and bioavailability.

[0068] Therefore, another object of the present invention is to provide an oral composition consisting of iron (III) salts, which is formulated and prepared in a manner that improves iron absorption and bioavailability, thereby making it more effective.

[0069] Another object of the present invention is to provide an oral composition comprising an iron (III) salt that is well tolerated in humans and can therefore be administered to all subjects (including pregnant women) even on an empty stomach; the composition is palatable and has long-term chemical and sensory stability, i.e., its color, odor, flavor and taste do not change over time.

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

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

[0072] -At least one type of lecithin;

[0073] - at least one sucrose ester; and

[0074] -iii) Sodium pyrophosphate, preferably tetrasodium pyrophosphate.

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

[0076] -i) Ferric (III) pyrophosphate salt;

[0077] -At least one type of lecithin;

[0078] -At least one sucrose ester;

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

[0080] -ii) Sodium ferric pyrophosphate (III).

[0081] Preferably, the mixture BM-1 or BM-2 of the present invention may further comprise another component selected from plant starches. Preferably, the plant starch is selected, for example, 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, such as gelatinized or pregelatinized natural rice starch. For example, a usable pregelatinized rice starch is CAS No. 9005-25-8; EINECS232-679-6, with a moisture content of 10% to 20%, for example, about 15%; a particle size (particle size distribution) D10 maximum of 20 μm; D50 maximum of 75 μm; and D90 maximum of 175 μm. A commercially available product meeting the above characteristics is ADEASrl's Remyline AX-FG-P.

[0082] Preferably, another pregelatinized rice starch that can be used in mixture BM-1 or BM-2 may have the following physicochemical properties: 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; and density of 0.40 g / cm³. 3 Up to 0.48 g / cm 3 The starch content is a minimum of 95% to 99%, and the fat content is 0.01% to 0.1%.

[0083] Preferably, the mixture BM-1 and BM-2 contain gelatinized or pregelatinized plant starch in an amount of 1% to 50% by weight relative to the total weight of the composition BC-1 and BC-2, preferably 10% to 40% by weight, more preferably 15% to 35% by weight, and even more preferably 20% to 30% by weight.

[0084] Preferably, the i) ferric pyrophosphate (III) of the present invention 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), and the iron content is preferably 15% to 30% by weight, more preferably 18% to 24% by weight, and more preferably 20% to 22% by weight relative to the total weight of the molecule.

[0085] Preferably, the ii) sodium ferric(III) pyrophosphate is a salt, preferably with the chemical formula, for example, Fe(III)NaO7P2 (CAS RN.10045-87-1).

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

[0087] Preferably, the mixture BM-1 or BM-2 contains the i) ferric pyrophosphate (III) salt of the present invention in an amount of 10% to 90% by weight relative to the total weight of the mixture; preferably 25% to 75% by weight, more preferably 35% to 65% by weight, and even more preferably 40% to 55% by weight.

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

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

[0090] The sodium or potassium pyrophosphate salt contained in the oral compositions BC-1 or BC-2 of the present invention, preferably in the form of tetrasodium phosphate, is present in a content of 0.1% to 50% by weight, preferably 1% to 35% by weight, more preferably 5% to 30% by weight, and even more preferably 10% to 25% by weight, 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.

[0091] The term "lecithin" is technically known, and according to Directive 95 / 2 / EC issued on 20 February 1995 (published in OJ No. L61 on 18 September 1995), lecithin is classified as a food additive, such as food additive E322.

[0092] Lecithin, due to its physicochemical properties, mainly functions as an emulsifier. In addition, because it is rich in natural antioxidants, it also has a secondary antioxidant function.

[0093] Directive No. 2008 / 84 / EC (published in OJ of the European Community No. L253) of August 27, 2008, specifies the purity standards that lecithin must meet. Only lecithin that meets these standards can be classified as food grade (E322): Acetone-insoluble matter (actually the active fraction of lecithin): minimum 60%; Moisture: maximum 2%; Acid value: maximum 35; Peroxide value: maximum 10; Toluene-insoluble matter (actually impurities): maximum 0.3%.

[0094] From a chemical perspective, 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 originate from triglyceride structures where fatty acids are replaced by phosphate groups. These phosphate groups impart a negative charge to the molecule, thus giving it polarity; such molecules are collectively called phospholipids. More complex organic molecules, typically serine, choline, ethanolamine, inositol, or a single hydrogen atom, are linked to phosphate groups via ester bonds, forming phospholipids called 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 is readily soluble in water, while the two saturated fatty acids represent two nonpolar, water-insoluble, but lipophilic tails. These molecules are called amphoteric molecules, and when water and fat are present, they arrange themselves between fat and water molecules, thus emulsifying them. Therefore, lecithin is a natural emulsifier.

[0097] The lecithin used in this invention is any commercially available lecithin, including allergen-free lecithin; preferably, it can be non-hydrolyzed lecithin, such as lecithin powder. Preferably, lecithin selected from plant-derived lecithin, such as sunflower lecithin and / or corn lecithin and / or soybean lecithin and / or rice lecithin and mixtures thereof, can be used.

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

[0099] Preferably, the glucose content in sunflower lecithin, corn lecithin, soybean lecithin, rice lecithin, or mixtures thereof is 20% to 60% by weight, more preferably 30% to 50% by weight, for example about 45% by weight.

[0100] Preferably, the sunflower lecithin, corn lecithin, soybean lecithin, rice lecithin, or mixtures thereof available in the context of this invention may have the following weight composition (chemical and physical analysis): 20% to 80% sunflower lecithin, corn lecithin, or soybean lecithin, preferably 40% to 50%; 30% to 60% carbohydrates, preferably 40% to 50% (e.g., about 35%, 45%, or 55%); 6% to 10% protein; 3% to 8% ash; 2% to 5% moisture; and 0.5% to 1.5% flow agent.

[0101] Preferably, the lecithin used in this invention is preferably in glucose syrup. Sunflower lecithin is spray-dried on rice flour; this lecithin is sold in the form of a composition comprising glucose syrup, sunflower lecithin, sodium caseinate, and tricalcium phosphate. Preferably, another type of lecithin used in this invention is sunflower lecithin spray-dried on rice flour (allergen-free). This lecithin is sold in the form of a composition comprising sunflower lecithin, tricalcium phosphate, and rice flour.

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

[0103] The term "sucrose ester" as used in this invention is known in the art and refers to the product obtained by esterification or transesterification of fatty acid methyl esters with carbohydrates (typically sucrose and other polysaccharides), and is therefore also referred to herein as "fatty acid-containing sucrose esters" and "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 invention, at least one sucrose ester is, for example, a sucrose ester of type E473. It is well known that the abbreviation E473 indicates that sucrose esters are food additives approved by EU legislation and regulated by the Italian Ministerial Decree (MD1996). They are primarily emulsifiers, added to better stabilize the aqueous and fatty phases.

[0105] Preferably, the sucrose ester of the present invention is, for example, a type E473 sucrose ester, which is used as an emulsifier in the compositions of the present invention, and has 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 (e.g., type E473) contains 50% to 80%, more preferably 60% to 70% monoesters, which are obtained by esterification with plant-derived fatty acids (stearic acid and palmitic acid).

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

[0108] Preferably, the content of sucrose ester in the oral composition of the present invention is 5% to 75% by weight, more preferably 10% to 60% by weight, more preferably 12% to 40% by weight, and 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 present invention is a mixture (BM-1 or BM-2) comprising or consisting of the following:

[0110] -i) Ferric (III) pyrophosphate salt;

[0111] -At least one type of lecithin;

[0112] - at least one sucrose ester; and

[0113] -iii) Sodium pyrophosphate or potassium pyrophosphate.

[0114] Preferably, the mixture further comprises ii) sodium ferric(III) pyrophosphate; preferably, the content of sodium ferric(III) pyrophosphate in the mixture is 0.1% to 50% by weight, preferably 1% to 35% by weight, more preferably 5% to 30% by weight, and even more preferably 10% to 25% by weight, relative to the total weight of the mixture.

[0115] Preferably, the mixture further comprises starch, preferably, the starch is a plant starch selected from the group consisting of or selected from rice starch, corn starch, sunflower starch or soybean starch, more preferably, the plant starch is pregelatinized rice starch.

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

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

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

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

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

[0121] Preferably, the mixture is used for treatment; more preferably, the mixture is used for methods of treating and / or preventing absolute or relative iron deficiency, particularly for treating symptoms or diseases related to or caused by iron deficiency.

[0122] The object of the present invention is a composition comprising the above-mentioned mixture (BM-1 or BM-2) and optionally at least one pharmaceutical-grade or food-grade excipient and / or carrier (BC-1 or BC-2); preferably the composition is in solid form for oral dose units.

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

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

[0125] Compositions BC-1 and BC-2 are formulated for oral administration.

[0126] The compositions BC-1 and BC-2 of the present invention are preferably solid compositions formulated in dosage units. Solid means that the composition may exist in granular or powder form. The granular or powder composition is then mixed with pharmacologically acceptable additives and excipients to prepare a final product, such as a supplement product, a medical device composition, or a pharmaceutical composition. The final product may be a pharmaceutical dosage unit, such as sachets of granules, sticks, tablets, or capsules.

[0127] For example, tablets can have different forms known in the pharmaceutical field, such as cylindrical or spherical. For example, the weight of a tablet can range from 100 mg to 2000 mg. Tablets can be coated or covered with one or more layers of coatings or films capable of passing through the gastric barrier, according to methods and equipment known to those skilled in the art.

[0128] For example, gel capsules can weigh from 200 mg to 1200 mg, hard tablets can weigh from 500 mg to 1000 mg, and chewable tablets can weigh from 500 mg to 2000 mg. Capsules can be made from hard gelatin, soft gelatin, or soft gel.

[0129] As described above, preferably, the oral composition of the present invention is a solid composition. However, if desired or necessary, the composition of the present invention may also be formulated in liquid form, such as an aqueous suspension, preferably with the addition of physiologically acceptable acids, such as citric acid, and other substances or excipients that can maintain the stability of the suspension and are suitable for the subject's acceptance.

[0130] As described above, the solid compositions of the present invention may contain physiologically acceptable conventional excipients and pharmaceutical-grade or food-grade carriers, such as diluents, fillers, binders, disintegrants, flow aids, 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 compositions of the present invention may include cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, ethanol, etc. The compositions may also contain, for example, pH buffers and wetting agents or emulsifiers.

[0131] In addition to the components described above, if needed or necessary, the compositions BC-1 and BC-2 of the present invention may preferably contain other active components, such as components that can assist the active ingredients in exerting their effects in the body of the treated subject, such as vitamins.

[0132] The oral compositions BC-1 and BC-2 of the present invention are used for treatment, particularly for absolute or relative iron deficiency, especially for the treatment of symptoms or diseases related to or caused by iron deficiency.

[0133] The solid or liquid oral compositions according to any of the above embodiments are suitable for treating, and particularly for treating and preventing, iron-deficiency-related conditions or diseases in pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly, because they can prevent and combat anemia and help increase hemoglobin and ferritin levels. The compositions are suitable for pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly for administration for 1 to 12 months, preferably 2 to 6 months, for example, at a dose 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, and even more preferably 20 mg to 30 mg, such as 25 mg, 27 mg, or 29 mg of iron (III) per day.

[0134] Another object of the present invention is an iron supplement comprising the composition BC-1 or BC-2 of the present invention, and may also contain other components, such as components selected from minerals and / or vitamins, such as one or more vitamins belonging to the B, C or D groups.

[0135] Another object of the present invention is a method for treating and / or preventing symptoms or diseases related to iron deficiency, comprising administering the composition BC-1 or BC-2 of the present invention to a subject in need.

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

[0137] The applicant unexpectedly discovered that sodium pyrophosphate or potassium pyrophosphate (preferably tetrasodium pyrophosphate) is similar to the product described in WO2014 / 009806 and WO2015 / 033216 under the trade name... The compositions sold, in combination or in combination, can improve the absorption and bioavailability of iron applied in vivo. Specifically, the applicant has unexpectedly discovered that sodium or potassium pyrophosphate (preferably tetrasodium pyrophosphate) in combination with the compositions described in WO2014 / 009806 and WO2015 / 033216, preferably mechanically obtained by mechanical means, significantly and unexpectedly increases iron absorption, preferably through an increase in ferritin.

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

[0139] Preferably, the sodium pyrophosphate or potassium pyrophosphate, preferably in the form of tetrasodium pyrophosphate, is present in the oral composition BC-1 or BC-2 of the present invention in an amount of 0.1% to 50% by weight relative to the total weight of the composition, 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.

[0140] Preferably, the oral composition BC-1 or BC-2 of the present invention contains sodium ferric(III) pyrophosphate in a content of 0.1% to 50% by weight relative to the total weight of the composition, 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.

[0141] Therefore, the target oral composition BC-1 of the present invention comprises or consists of the following: iron (III) pyrophosphate, lecithin, such as sunflower lecithin, sucrose esters or sucrose esters, such as E473, in the weight percentages mentioned above, and sodium or potassium salts, preferably in the form of tetrasodium pyrophosphate.

[0142] Therefore, the target oral composition BC-2 of the present invention comprises or consists of the following: iron (III) pyrophosphate, lecithin, such as sunflower lecithin, sucrose esters or sucrose esters, such as E473, in the weight percentages mentioned above, and a sodium or potassium salt, preferably in the form of tetrasodium pyrophosphate.

[0143] As described above, the oral compositions BC-1 or BC-2 of the present invention may also contain other conventional, physiologically acceptable components, excipients, and carriers.

[0144] Preferably, the oral compositions BC-1 or BC-2 of the present invention may further comprise additional components selected from plant starches. Preferably, the plant starch is selected, for example, from rice starch, corn starch, or sunflower starch. For example, a preferred starch is rice starch, such as gelatinized or pregelatinized natural rice starch. For example, a usable pregelatinized rice starch 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 μm; a D50 maximum of 75 μm; and a D90 maximum of 175 μm. A commercially available product meeting the above characteristics is ADEASrl's Remyline AX-FG-P.

[0145] Preferably, another type of pregelatinized rice starch that can be used within the scope of this invention may have the following physicochemical properties: 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 / cm3 to 0.48 g / cm3; starch content of at least 95% to 99%; and fat content of 0.01% to 0.1%.

[0146] Preferably, the content of gelatinized or pregelatinized plant starch 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, and even more preferably from 20% to 30% by weight, relative to the total weight of compositions BC-1 and BC-2.

[0147] The target oral composition BC-1 of the present invention comprises or consists of the following: iron (III) salt, lecithin, such as sunflower lecithin, sucrose esters or sucrose esters, such as E473, starch, preferably plant starch, such as rice starch, and sodium pyrophosphate or potassium pyrophosphate, preferably in the form of tetrasodium pyrophosphate, in the weight percentages mentioned above.

[0148] The target oral composition BC-1 of the present invention comprises or consists of the following: iron(III) pyrophosphate salt, lecithin, such as sunflower lecithin, sucrose esters or sucrose esters, such as E473, starch, preferably plant starch, such as rice starch, and sodium pyrophosphate salt or potassium pyrophosphate salt, preferably in the form of tetrasodium pyrophosphate, in the weight percentages mentioned above.

[0149] The target oral composition BC-2 of the present invention comprises or consists of the following: iron (III) salt, lecithin, such as sunflower lecithin, sucrose esters or sucrose esters, such as E473, starch, preferably plant starch, such as rice starch, and sodium pyrophosphate or potassium pyrophosphate (preferably in the form of tetrasodium pyrophosphate) and sodium iron (III) pyrophosphate in the above weight percentages.

[0150] The oral composition BC-2 of the present invention comprises or consists of the following: iron(III) pyrophosphate salt, lecithin, such as sunflower lecithin, sucrose esters or sucrose esters, such as E473, starch, preferably plant starch, such as rice starch, and sodium or potassium pyrophosphate salt (preferably in the form of tetrasodium pyrophosphate) and sodium iron(III) pyrophosphate in the above weight percentages.

[0151] Another object of the present invention is a first method for preparing mixtures BM-1 or BM-2, wherein physiologically acceptable excipients, diluents or carriers are added after preparation to obtain oral compositions BC-1 or BC-2 of the present invention, respectively.

[0152] The first method of the present invention relates to preparing a mixture comprising or consisting of: i) ferric (III) pyrophosphate, lecithin (e.g., sunflower lecithin), sucrose esters or sucrose esters (e.g., E473), iii) sodium or potassium pyrophosphate (preferably tetrasodium pyrophosphate), and optionally plant starch (preferably rice starch), thereby obtaining mixture BM-1. If sodium ferric (III) pyrophosphate is optionally added to mixture BM-1 in the above weight percentages, mixture BM-2 is obtained.

[0153] Preferably, the i) solid ferric pyrophosphate (III) is mixed with iii) sodium pyrophosphate or potassium pyrophosphate (preferably in the form of tetrasodium pyrophosphate) and / or ii) sodium ferric pyrophosphate (III) in the aforementioned weight percentages to obtain a mixture, and then plant lecithin, starch, and / or sucrose esters are added. Preferably, the mixing is carried out in a mixer equipped with stirring and mixing devices known in the art. Preferably, a sieving step is included, using a suitable sieve or sieving machine to make the processed solid powder mixture more uniform. The experimental section of the invention lists further details of the first method of the invention.

[0154] The i) ferric pyrophosphate (III), lecithin, sucrose ester, iii) sodium pyrophosphate or potassium pyrophosphate (e.g., tetrasodium pyrophosphate), starch, and possibly ii) sodium ferric pyrophosphate (III) used in the preparation method of the present invention have the characteristics and properties defined above.

[0155] Plant starch (e.g., in gelatinized or pregelatinized forms) has fluidity and easy flowability, enabling accurate dosing without errors or weight deviations. It also distributes more uniformly and homogeneously throughout the mixture during the mixing process. Finally, plant starch improves the bioavailability of iron cations, resulting in compounds with better solubility at 15°C to 30°C (1 atm), preferably 20°C to 25°C, and even more preferably 18°C ​​to 23°C.

[0156] After completing the first preparation method, the mixture BM-1 (and oral solid composition BC-1) of the present invention is obtained, which comprises or optionally consists of the following: i) ferric pyrophosphate (III), vegetative lecithin, sucrose esters or sucrose esters in the weight percentages mentioned above, iii) sodium pyrophosphate or potassium pyrophosphate (e.g., tetrasodium pyrophosphate), and optionally starch, and ii) sodium ferric pyrophosphate (III) possibly in the mixture BM-2 (and composition BC-2).

[0157] Preferably, the mixture BM-1 (and oral solid composition BC-1) of the present invention is obtained by the first preparation method, the mixture comprising or consisting of: i) ferric pyrophosphate (III), plant lecithin, such as corn lecithin or soybean lecithin or sunflower lecithin E322, sucrose esters or sucrose esters, such as E473, iii) sodium pyrophosphate or potassium pyrophosphate (e.g. tetrasodium pyrophosphate), and optionally starch (e.g. rice starch).

[0158] Preferably, the mixture BM-2 (and oral solid composition BC-2) of the present invention is obtained by the first preparation method, the mixture comprising or consisting of: i) ferric pyrophosphate (III), plant lecithin, such as corn lecithin or soybean lecithin or sunflower lecithin E322, sucrose esters or sucrose esters, such as E473, iii) sodium pyrophosphate or potassium pyrophosphate (e.g. tetrasodium pyrophosphate), ii) sodium ferric pyrophosphate (III), and optionally starch (e.g. rice starch).

[0159] Preferably, in order to further improve the bioavailability of iron cations, it is useful to minimize the amount of lecithin by weight percentage in the method for preparing the solid composition of the present invention.

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

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

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

[0163] The method of the present invention is capable of forming a coating or encapsulation around iron (III), which can improve the stability and bioavailability of cation (III) due to the presence of sodium pyrophosphate or potassium pyrophosphate and / or sodium ferric (III) pyrophosphate.

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

[0165] Sucrose esters or sucrose lipids and lecithin function by promoting the absorption of salt, thereby promoting the absorption of iron cations contained in the salt. A mixture with lecithin and starch can form "chimeric" aggregates that can protect and isolate the iron cations in pyrophosphate from absorption by gastric acid.

[0166] Processing time, such as mixing and sieving, is 5 to 90 minutes, preferably 10 to 60 minutes, and more preferably 20 to 40 minutes.

[0167] The particle size distribution of the oral composition obtained by the method of the present invention can be: D10 approximately 1.8 μm, D50 approximately 20.5 μm, and D90 approximately 108 μm.

[0168] The iron(III) content of the solid composition of the present invention is from 30 mg / g to 180 mg / g, preferably from 60 mg / g to 120 mg / g, and more preferably from 90 mg / g to 110 mg / g.

[0169] The oral compositions BC-1 or BC-2 of the present invention are used for treatment, particularly for absolute or relative iron deficiency, especially for the treatment of symptoms or diseases related to or caused by iron deficiency.

[0170] The oral compositions BC-1 or BC-2 of the present invention contain readily absorbed and efficiently bioavailable iron, which can increase ferritin levels. Furthermore, the oral compositions BC-1 or BC-2 have been shown to have good human tolerability. The compositions can be administered to all types of patients, including pregnant women, even on an empty stomach. The oral compositions BC-1 or BC-2 exhibit good palatability and have been shown to possess long-term chemical and sensory stability, i.e., no changes in color, odor, taste, and / or flavor have been observed.

[0171] The compositions BC-1 and BC-2 of the present invention are solid compositions formulated in dosage units. Solid means that the composition may exist in the form of granules, microparticles, powders, or flakes. The granular or microparticle or powder composition is then mixed with pharmaceutically acceptable additives and pharmaceutical-grade or food-grade excipients to provide a final product, such as a supplement product, a medical device composition conforming to reg. EU 745 / 2017, or a pharmaceutical composition. The final product may be a pharmaceutical dosage unit, such as sachets of granules, tablets, or capsules.

[0172] Tablets can take on various shapes known in the pharmaceutical field, such as cylindrical or spherical. The weight of a tablet can range from 100 mg to 2000 mg. Tablets can be coated or coated with one or more layers of a coating or film capable of passing through the gastric barrier, according to known methods.

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

[0174] The dosage units are 5 mg to 50 mg iron (III) / day, preferably 10 mg to 45 mg iron (III) / day, more preferably 15 mg to 40 mg, and even more preferably 20 mg to 30 mg, such as 25 mg, or 27 mg, or 29 mg iron (III) / day.

[0175] As described above, the oral compositions BC-1 or BC-2 of the present invention are preferably solid compositions. However, if desired or necessary, the compositions of the present invention may also be formulated in liquid form, such as an aqueous suspension, preferably with the addition of a physiologically acceptable acid, such as citric acid.

[0176] As described above, the solid compositions of the present invention may contain physiologically acceptable conventional excipients and carriers, such as diluents, fillers, binders, disintegrants, flow aids, lubricants, etc. "Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott, Williams & Wilkins" describes non-limiting examples of suitable carriers and excipients. The compositions of the present invention may contain, for example, cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, ethanol, etc. The compositions may also contain pH buffers and wetting agents or emulsifiers.

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

[0178] In addition to the above-mentioned components, if desired or necessary, the compositions BC-1 and BC-2 of the present invention may also contain other active ingredients, such as components that can assist the active ingredients in exerting their effects in the body of the treated subject, such as vitamins.

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

[0180] The solid or liquid oral compositions BC-1 or BC-2 according to any of the above embodiments are suitable for the treatment, particularly for the treatment and prevention of iron deficiency-related conditions or diseases in pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly, because they can prevent and combat anemia and help increase hemoglobin and ferritin levels. The compositions BC-1 or BC-2 are suitable for administration in pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly for a period of 1 to 5 months, preferably 2 to 4 months, at a dose of 10 mg to 40 mg iron (III) / day, preferably 14 mg to 30 mg iron (III) / day, and even more preferably 28 mg iron (III) / day.

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

[0182] Preferably, in the mixtures BM-1 and BM-2 and the compositions BC-1 and BC-2 of the present invention, the mixture contains 10% to 90% by weight, more preferably 25% to 75% by weight, more preferably 35% to 65% by weight, and even more preferably 40% to 55% by weight, relative to the total weight of the compositions.

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

[0184] Preferably, the mixtures BM-1 and BM-2 and the compositions BC-1 and BC-2 of the present invention are in solid form, such as powder or granules, and are administered in, for example, tablets, capsules, sachets, or sticks. The powders and granules in the mixtures BM-1 and BM-2 and the compositions BC-1 and BC-2 of the present invention are produced using methods and equipment known to those skilled in the art, wherein the solid components i)-ii)-iii) are mixed and dried in the absence of a liquid solution or water.

[0185] Preferably, in the mixtures BM-1 and BM-2 and the compositions BC-1 and BC-2 of the present invention, ferric pyrophosphate is present in a molar ratio of more than 1 relative to sodium pyrophosphate (preferably tetrasodium pyrophosphate) ((FePP:NaPP)>1); or ferric pyrophosphate is present in a molar ratio of more than 1 relative to sodium pyrophosphate (preferably tetrasodium pyrophosphate); or ferric pyrophosphate has an equivalent ratio of more 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; and even more preferably, the weight ratio can be 3.5; or 4; or 4.5; or 5; or 5.5.

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

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

[0189] The object of the present invention is a method for preparing mixtures BM-1 and BM-2 and compositions BC-1 and BC-2, wherein the method includes at least one step of mixing the components i) and / or ii) and / or iii) in a solid state to obtain the mixture and the composition (preferably powder or granules) in a solid state.

[0190] Third aspect of the invention - aspect C

[0191] In another aspect of the invention, namely aspect C1, the object of the invention is a mixture CM-1 composed of the following:

[0192] i) Ferric (III) pyrophosphate salt;

[0193] At least one lecithin;

[0194] At least one type of gum arabic (or acacia gum); and

[0195] iii) Sodium or potassium pyrophosphate, preferably tetrasodium pyrophosphate.

[0196] In another aspect of the invention, namely aspect C2, the object of the invention is a mixture CM-2 composed of the following:

[0197] i) Ferric (III) pyrophosphate salt;

[0198] At least one lecithin;

[0199] At least one type of gum arabic (or acacia gum);

[0200] iii) Sodium pyrophosphate, preferably tetrasodium pyrophosphate; and

[0201] ii) Sodium ferric pyrophosphate (III).

[0202] Preferably, the mixture CM-1 or CM-2 of the present invention may further comprise another component selected from plant starches. Preferably, the plant starch is selected, for example, from rice starch, corn starch, sunflower starch, soybean starch, or mixtures thereof. For example, a preferred starch is rice starch, such as gelatinized or pregelatinized natural rice starch. For example, a usable pregelatinized rice starch is CAS No. 9005-25-8; EINECS232-679-6, with a moisture content of 10% to 20%, for example, about 15%; a particle size (particle size distribution) D10 maximum of 20 μm; a D50 maximum of 75 μm; and a D90 maximum of 175 μm. A commercially available product meeting the above characteristics is ADEASrl's Remyline AX-FG-P.

[0203] Preferably, another pregelatinized rice starch that can be used in mixture CM-1 or CM-2 may have the following physicochemical properties: 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 / cm3 to 0.48 g / cm3; starch content of at least 95% to 99%; and fat content of 0.01% to 0.1%.

[0204] Preferably, relative to the total weight of compositions CC-1 and CC-2, the content of gelatinized or pregelatinized plant starch in mixtures 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, and even more preferably from 20% to 30% by weight.

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

[0206] Preferably, the content of gum arabic or acacia gum in mixture CM-1 or CM-2 is 5% to 45% by weight, more preferably 10% to 40% by weight, more preferably 15% to 35% by weight, and even more preferably 20% to 30% by weight, relative to the total weight of the mixture.

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

[0208] Preferably, the i) ferric pyrophosphate (III) of the present invention 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), and the iron content is preferably 18% to 24% by weight, or even more preferably 20% to 22% by weight, relative to the total weight of the molecule.

[0209] Preferably, the ii) sodium ferric(III) pyrophosphate is a salt, preferably with the chemical formula, for example, Fe(III)NaO7P2 (CAS RN.10045-87-1).

[0210] Preferably, the sodium pyrophosphate (iii) is a salt, preferably in the form of tetrasodium pyrophosphate, with the chemical formula, for example, Na4P2O7 (CAS RN. 1269628-79-6), in anhydrous, hemihydrated, or hydrated form, or in other forms with a number of water molecules known to those skilled in the art. Tetrasodium pyrophosphate is a colorless, odorless, water-soluble solid at room temperature, 25°C, and 1 atm, and is coded as 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 the i) ferric pyrophosphate (III) salt of the present invention, in a content of 10% to 90% by weight relative to the total weight of the mixture; preferably 25% to 75% by weight, more preferably 35% to 65% by weight, and even more preferably 40% to 55% by weight.

[0212] Preferably, the mixture CM-1 or CM-2 contains the sodium ferric pyrophosphate (III) salt of the present invention in a content of 0.1% to 50% by weight, preferably 1% to 35% by weight, more preferably 5% to 30% by weight, and even more preferably 10% to 25% by weight, relative to the total weight of the mixture.

[0213] Preferably, the mixture CM-1 or CM-2 of the present invention contains the sodium pyrophosphate or potassium pyrophosphate salt of (iii), preferably in the form of tetrasodium phosphate, in a content of 0.1% to 50% by weight, preferably 1% to 35% by weight, more preferably 5% to 30% by weight, and even more preferably 10% to 25% by weight, relative to the total weight of the mixture.

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

[0215] Lecithin, due to its physicochemical properties, mainly functions as an emulsifier. In addition, because it is rich in natural antioxidants, it also has a secondary antioxidant function.

[0216] Directive No. 2008 / 84 / EC (published in OJ of the European Community No. L253) of August 27, 2008, specifies the purity standards that lecithin must meet. Only lecithin that meets these standards can be classified as food grade (E322): Acetone-insoluble matter (actually the active fraction of lecithin): minimum 60%; Moisture: maximum 2%; Acid value: maximum 35; Peroxide value: maximum 10; Toluene-insoluble matter (actually impurities): maximum 0.3%.

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

[0218] Phospholipids constitute the main component of lecithin; they originate from triglyceride structures where fatty acids are replaced by phosphate groups. These phosphate groups impart a negative charge to the molecule, thus giving it polarity; such molecules are collectively called phospholipids. More complex organic molecules, typically serine, choline, ethanolamine, inositol, or a single hydrogen atom, are linked to phosphate groups via ester bonds, forming phospholipids called phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, or phosphatidic acid, respectively. In a narrower sense, phosphatidylcholine is usually referred to as lecithin.

[0219] Phospholipids are characterized by a polar, water-soluble head that is readily soluble in water, while the two saturated fatty acids represent two nonpolar, water-insoluble, but lipophilic tails. These molecules are called amphoteric molecules, and when water and fat are present, they arrange themselves between fat and water molecules, thus emulsifying them. Therefore, lecithin is a natural emulsifier.

[0220] The lecithin used in this invention is an unhydrolyzed powdered lecithin, preferably selected from sunflower lecithin and / or corn lecithin and / or soybean lecithin and / or rice lecithin, or a mixture thereof.

[0221] The lecithin used in this invention is a powdered lecithin with a water content of 1.5% to 4.5%, preferably 2% to 4%, and even more preferably 2.5% to 3.5%. Preferably, the lecithin used is sunflower lecithin powder.

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

[0223] The sunflower lecithin used in the context of this invention may have the following composition (physicochemical analysis): 40% to 50% sunflower lecithin, 40% to 50% carbohydrates (e.g., about 42%), 6% to 10% protein, 3% to 8% ash, 2% to 5% moisture, and 0.5% to 1.5% flow aid.

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

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

[0226] Gum arabic is commercially available. In the context of this invention, for example, E414 type gum derived from Senegalese acacia wood can be used.

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

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

[0229] -i) Ferric (III) pyrophosphate salt;

[0230] -At least one type of lecithin;

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

[0232] -iii) Sodium pyrophosphate or potassium pyrophosphate.

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

[0234] Preferably, the mixture further comprises starch, preferably, the starch is a plant starch selected from the group consisting of or selected from rice starch, corn starch, sunflower starch or soybean starch, more preferably, the plant starch is pregelatinized rice starch.

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

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

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

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

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

[0240] Preferably, the mixture is used for treatment; more preferably, the mixture is used for methods of treating and / or preventing absolute or relative iron deficiency, particularly for treating symptoms or diseases related to or caused by iron deficiency.

[0241] The object of the present invention is a composition (CC-1 or CC-2) comprising the above mixture (CM-1 or CM-2) and optionally at least one pharmaceutical grade or food grade excipient and / or carrier; preferably the composition is in solid form for oral dose units.

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

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

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

[0245] The oral compositions CC-1 and CC-2 of the present invention are used for absolute or relative iron deficiency, and are particularly used to treat symptoms or diseases related to or caused by iron deficiency.

[0246] The oral compositions CC-1 and CC-2 of the present invention are preferably free of diglycerides.

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

[0248] Tablets can take on various shapes known in the pharmaceutical field, such as cylindrical or spherical. The weight of a tablet can range from 100 mg to 2000 mg. Tablets can be coated or coated with one or more layers of a coating or film capable of passing through the gastric barrier, according to known methods.

[0249] For example, gel capsules can weigh from 200 mg to 1200 mg, hard capsules can weigh from 500 mg to 1000 mg, and chewable tablets can weigh from 500 mg to 2000 mg. Capsules can be made from hard gelatin, soft gelatin, or soft gel.

[0250] As described above, the oral composition of the present invention is preferably a solid composition. However, if desired or necessary, the composition of the present invention may also be formulated in liquid form, such as an aqueous suspension, preferably with the addition of a physiologically acceptable acid, such as citric acid.

[0251] As described above, the solid compositions of the present invention may contain physiologically acceptable conventional excipients and carriers, such as diluents, fillers, binders, disintegrants, flow aids, lubricants, etc. "Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott, Williams & Wilkins" describes non-limiting examples of suitable excipients and carriers. For example, the compositions of the present invention may include cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, ethanol, etc. The compositions may also contain pH buffers and wetting agents or emulsifiers.

[0252] In addition to the components described above, the compositions of the present invention may also include other active components, such as components that can assist the active ingredients in exerting their effects in the body of the treated subject, for example, vitamins.

[0253] The solid or liquid oral compositions according to any of the above embodiments are suitable for the treatment and prevention of iron deficiency-related conditions or diseases in pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly, because they can prevent and combat anemia and help increase hemoglobin and ferritin levels. The compositions are suitable for pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly, for administration for 1 to 5 months, preferably 2 to 4 months, at a dose of 10 mg to 40 mg iron (III) / day, preferably 14 mg to 30 mg iron (III) / day, and even more preferably 28 mg iron (III) / day.

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

[0255] Another object of the present invention is a method for treating and / or preventing symptoms or diseases associated with iron deficiency, comprising administering the composition CC-1 or CC-2 of the present invention to a subject in need.

[0256] The compositions CC-1 and CC-2 of the present invention contain ferric pyrophosphate (III) in a content of 30% to 70% by weight, preferably 35% to 55% by weight, and even more preferably 40% to 50% by weight, relative to the total weight of the composition.

[0257] The applicant unexpectedly discovered that the product described in WO2014 / 009806 and WO2015 / 033216 and named as a product... Adding sodium or potassium pyrophosphate salts, such as tetrasodium pyrophosphate, to commercially available compositions unexpectedly and significantly increases iron absorption through higher levels of ferritin.

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

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

[0260] Therefore, the oral composition CC-1 of the present invention comprises or consists of the following: ferric pyrophosphate (III), lecithin (e.g., E322 type lecithin), at least one gum arabic (or acacia gum), and sodium pyrophosphate (preferably tetrasodium pyrophosphate) in the above weight percentages.

[0261] Therefore, the oral composition CC-2 of the present invention comprises or consists of the following: ferric pyrophosphate (III), lecithin (e.g., E322 type lecithin), at least one gum arabic (or acacia gum), and sodium pyrophosphate (preferably tetrasodium pyrophosphate) and sodium ferric pyrophosphate (III) in the above weight percentages.

[0262] As described above, the oral compositions CC-1 or CC-2 of the present invention may also contain other physiologically acceptable conventional components, excipients, and carriers.

[0263] Preferably, the oral compositions CC-1 or CC-2 of the present invention may further contain additional components selected from plant starches.

[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 gelatinized or pregelatinized natural rice starch.

[0265] The pregelatinized rice starch that can be used within the scope of this invention may have the following physicochemical properties: moisture content not exceeding 7%; protein content not exceeding 1%; ash content not exceeding 1%; pH value (10% solution) of 5.5 to 7.5; density of 0.40 g / cm3 to 0.48 g / cm3; starch content not less than 97%; and fat content not exceeding 0.1%. For example, pregelatinized rice starch can be used.

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

[0267] The oral composition CC-1 of the present invention comprises or consists of the following: iron (III) salt, lecithin (e.g., E322 type lecithin), at least one gum arabic (or acacia gum), sodium pyrophosphate (preferably tetrasodium pyrophosphate), and preferred plant starch in the above weight percentages.

[0268] The oral composition CC-2 of the present invention comprises or consists of: iron (III) salt, lecithin (e.g., E322 type lecithin), at least one gum arabic (or acacia gum), sodium pyrophosphate (preferably tetrasodium pyrophosphate), sodium iron (III) pyrophosphate, and preferably plant starch in the above weight percentages.

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

[0270] The first method of the present invention is to prepare an oral composition comprising or consisting of: ferric pyrophosphate (III), sunflower lecithin, gum arabic, tetrasodium pyrophosphate, plant starch (preferably pregelatinized rice starch) and possibly sodium ferric pyrophosphate (III) in the above weight percentages.

[0271] The first method of the present invention comprises or consists of a series of processing steps in which ferric pyrophosphate (III) is coated, encapsulated, or occluded with the lecithin and / or the gum arabic and / or the plant starch.

[0272] Preferably, solid ferric pyrophosphate (III) is sequentially contacted with the gum arabic, then with the lecithin, then with the tetrasodium pyrophosphate, and finally with the plant starch.

[0273] The ferric pyrophosphate (III), lecithin, gum arabic, tetrasodium pyrophosphate, possibly sodium ferric pyrophosphate (III), and starch used in the method of the present invention have the characteristics and properties defined above.

[0274] The advantages of gelatinized or pregelatinized starch are its greater fluidity and ease of flow, enabling accurate dosing without errors or weight deviations. Its distribution is also more uniform. Finally, pregelatinized plant starch improves the bioavailability of iron cations because the resulting compounds dissolve better at 15°C to 30°C (1 atmosphere), preferably 20°C to 25°C, and even more preferably 18°C ​​to 23°C.

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

[0276] Specifically, the solid composition CC-1 or CC-2 of the present invention was obtained by the first preparation method, which comprises or consists of the above-mentioned weight percentages of ferric pyrophosphate (III), sunflower lecithin E322, gum arabic, tetrasodium pyrophosphate, possibly sodium ferric pyrophosphate (III) (CC-2) and pregelatinized rice starch.

[0277] The applicant has found that, in order to further improve the absorption of iron cations, it is useful to minimize the weight percentage of lecithin used in the method for preparing the solid composition of the present invention.

[0278] In addition, the applicant found that, in order to further enhance the absorption of iron ions, it is important to use a combination of gum arabic in a specific weight ratio with lecithin in reduced weight.

[0279] Advantageously, the weight ratio of gum arabic to lecithin is from 40:1 to 10:1. In one embodiment, the ratio is 35:1 and 15:1; in various cases, the lecithin content 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, and even more preferably from 0.8% to 1.2% by weight.

[0280] The experimental section of this invention details the first method of this invention.

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

[0282] The second method of the present invention relates to the preparation of a solid composition CC-1 or CC-2, which comprises or consists of an iron salt, gum arabic, lecithin, tetrasodium pyrophosphate, possibly sodium iron(III) pyrophosphate (CC-2), and gelled or pregelled starch.

[0283] The second method of the present invention includes or comprises a technique for forming a coating or membrane around iron to improve the stability and bioavailability of cations.

[0284] In practice, the second method involves forming aggregates or granules comprising ferric (III) pyrophosphate, gum arabic, lecithin, tetrasodium pyrophosphate, possibly sodium ferric (III) pyrophosphate, and gelatinized or pregelatinized starch. All of these components possess the properties described above.

[0285] Gum arabic and lecithin work by promoting the absorption of salt, thereby promoting the absorption of iron cations contained in the salt. A mixture with lecithin and starch can form "chimeric" aggregates that can protect and isolate the iron cations in pyrophosphate from absorption by gastric acid.

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

[0287] The oral compositions obtained by the method of the present invention have a particle size (understood as the average particle size measured by available equipment and techniques) D50 of about 20.5 μm (μm micrometers, 10 μm). -6 (meters); for example, its average particle size distribution is D10 of about 1.8 μm, D50 of about 20.5 μm, and D90 of about 108 μm.

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

[0289] The oral compositions CC-1 or CC-2 of the present invention are used for absolute or relative iron deficiency, and are particularly used to treat symptoms or diseases related to or caused by iron deficiency.

[0290] The oral compositions CC-1 or CC-2 of the present invention contain readily absorbed and efficiently bioavailable iron, which can increase ferritin. Furthermore, the oral compositions CC-1 or CC-2 have been shown to have good human tolerability. The compositions can be administered to all types of patients, including pregnant women, even on an empty stomach. The oral compositions CC-1 or CC-2 exhibit good palatability and have been shown to possess long-term chemical and sensory stability, i.e., no changes in color, odor, taste, and / or flavor have been observed.

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

[0292] Tablets can take on various shapes known in the pharmaceutical field, such as cylindrical or spherical. The weight range of tablets can be from 200 mg to 2000 mg. Tablets can be coated or coated with one or more layers of a coating or film capable of passing through the gastric barrier, according to known methods.

[0293] For example, gel capsules may weigh 500 mg, hard tablets may weigh 800 mg to 1000 mg, and chewable tablets may weigh 1000 mg to 2000 mg. Capsules may be made of hard gelatin, soft gelatin, or soft gel.

[0294] Each dose 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 invention is the above-described solid composition. However, if desired or necessary, the composition of the present invention may also be formulated in liquid form, such as an aqueous suspension, preferably with the addition of a physiologically acceptable acid, such as citric acid.

[0296] As described above, the solid compositions of the present invention may contain physiologically acceptable conventional excipients and carriers, such as diluents, fillers, binders, disintegrants, flow aids, 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 compositions of the present invention may include cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, ethanol, etc. The compositions may also contain pH buffers and wetting agents or emulsifiers.

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

[0298] In addition to the components described above, if desired or necessary, the compositions CC-1 and CC-2 of the present invention may also contain other active components, such as components that can assist the active ingredients in exerting their effects in the body of the treated subject, such as vitamins.

[0299] Another object of the present invention is to provide a liquid oral composition comprising or composed of the composition CC-1 or CC-2 of the present invention, 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 iron deficiency-related conditions or diseases in pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly, because it can prevent and combat anemia and help increase hemoglobin and ferritin levels. The composition CC-1 or CC-2 is suitable for pediatric subjects, adolescents, athletes, men, women, pregnant women, and the elderly for administration for 1 to 5 months, preferably 2 to 4 months, at a dose of 10 mg to 40 mg iron (III) / day, preferably 14 mg to 30 mg iron (III) / day, and even more preferably 28 mg iron (III) / day.

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

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

[0303] Another object of the present invention is to provide a method for treating and / or preventing iron deficiency-related conditions or diseases, comprising administering the composition CC-1 or CC-2 of the present invention to a subject in need.

[0304] The applicant has conducted numerous experimental studies and has found that the mixtures and compositions of the present invention are superior to commercially available compositions, and even to those marketed under trade names. All the compositions sold exhibited improved performance.

[0305] Detailed information about the experiments conducted and the results obtained are provided in the “Experimental Section” below, which illustrates representative embodiments of the invention in a non-limiting manner.

[0306] Preferred embodiments of the present invention are listed below.

[0307] Preferably, in the mixtures CM-1 and CM-2 and the compositions CC-1 and CC-2 of the present invention, the content of i) ferric pyrophosphate (III) contained in the mixture is 10% to 90% by weight, more preferably 25% to 75% by weight, more preferably 35% to 65% by weight, and even more preferably 40% to 55% by weight, relative to the total weight of the mixture.

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

[0309] Preferably, the mixtures CM-1 and CM-2 and the compositions CC-1 and CC-2 of the present invention are in solid form, such as powder or granules, and are administered in, for example, tablets, capsules, sachets, or sticks. The powders and granules in the mixtures CM-1 and CM-2 and the compositions CC-1 and CC-2 of the present invention are produced using methods and techniques known to those skilled in the art, wherein the individual solid components i)-ii)-iii) are mixed and dried in the absence of a liquid solution or water.

[0310] Preferably, in the mixtures CM-1 and CM-2 and the compositions CC-1 and CC-2 of the present invention, 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)).

[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; and even more preferably, the weight ratio can be 3.5; or 4; or 4.5; or 5; or 5.5.

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

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

[0314] The object of the present invention is a method for preparing mixtures CM-1 and CM-2 and compositions CC-1 and CC-2, wherein the method includes at least one step of mixing the components i) and / or ii) and / or iii) in a solid state to obtain the mixture and the composition (preferably powder or granules) in a solid state. Attached Figure Description

[0315] Figure 1 A schematic diagram of static permeability measurement is shown.

[0316] Figure 2 The results of solubility tests for ferric sulfate, ferric pyrophosphate (III), Sider.m. (a commercially available product containing ferric pyrophosphate (III), lecithin, sucrose ester and starch), and Sider. NaPP (Sideral rm of the present invention with added tetrasodium pyrophosphate - Example 1) are shown.

[0317] Figure 3Comparative results in simulated gastric digestion tests are shown for Sideral rm (a commercially available product containing ferric pyrophosphate (III), lecithin, sucrose ester and starch) and Sideral NaPP (Sideral rm of the present invention with added tetrasodium pyrophosphate - Example 1).

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

[0319] Figure 5 The results of the apparent permeability and ferritin accumulation assays of Sideral containing two different lecithin (L063 and LAFNVH) are shown to be compared with those of the same Sideral containing tetrasodium pyrophosphate.

[0320] Figure 6 The results of the apparent permeability and ferritin accumulation assays of sideeral-like products containing two different lecithin (L063 and LAFNVH) (compositions containing gum arabic, but not sucrose esters CM1 / CC1 and CM2 / CC2) are shown to be compared with those of the same sideeral-like products with added tetrasodium pyrophosphate.

[0321] Figure 7 The left side shows A) hematocrit values ​​from T0 to T14; the middle shows B) hemoglobin values ​​from T0 to T14; the right side shows C) hemoglobin values ​​from T0 to T14. The statistical value at T11 is p = 0.0073, and the statistical value at T14 is p < 0.0001. Statistical methods: two-way ANOVA, multiple comparison correction, Sidak test. T11 and T14: statistically significant difference between 0.5 mg / Kg Sideral NaPP and carrier NaPP. P-values ​​are marked in the figure.

[0322] Figure 8The left side shows A) hemoglobin values ​​at T4-T0, T7-T0, T11-T0, and T14-T0, and the right side shows B) hematocrit values ​​at T4-T0, T7-T0, T11-T0, and T14-T0. Statistical methods: Two-way ANOVA. Multiple comparisons corrected, 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. Loaded NaPP; T14-T0: Statistically significant 0.5 mg / Kg Sideral NaPP vs. Loaded NaPP. P-values ​​are labeled in the figure.

[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 The left side shows A) the iron value in the bone marrow; the middle shows B) the iron value in the liver; and the right side shows C) the iron value in the spleen.

[0326] Figure 12 The left side shows A) liver mFTL value, and the right side shows B) spleen mFTL value.

[0327] Figure 13 The left side shows A) hepcidin mRNA value; the middle shows B) Bmp6 mRNA value; and the right side shows C) Id1 mRNA value.

[0328] Figure 14 The left side shows the value of A) Saa1 mRNA, and the right side shows the value of B) Socs3 mRNA.

[0329] Figure 15 The left side displays A) serum iron levels, and the right side displays B) TSat levels.

[0330] Notice:

[0331] -ID = Iron deficiency: Iron levels are below 9 mg / kg.

[0332] - The carrier Sideral RM is a matrix containing sucrose esters, lecithin, and possibly starch, but without iron.

[0333] -Sideral NaPP = Sideral sodium pyrophosphate, is a mixture (or composition) of the present invention containing ferric pyrophosphate (III), sucrose ester, lecithin, and possibly starch, and further containing sodium pyrophosphate (preferably in the form of tetrasodium pyrophosphate). Preferably, when starch, ferric pyrophosphate, sucrose ester, and lecithin are present in the mixture (or composition) of the present invention, sodium pyrophosphate replaces all or part of the starch in the preparation of said Sideral NaPP.

[0334] - The carrier NaPP = sodium pyrophosphate, preferably tetrasodium pyrophosphate.

[0335] - Iron or Sideral RM are commercially available mixtures (or compositions) containing iron(III) pyrophosphate, sucrose esters, lecithin, and possibly starch.

[0336] Experimental Section

[0337] Example 1

[0338] Preparation of the composition of the first aspect of the present invention

[0339] Element Content per 100g (g) Ferric pyrophosphate (III) DRPL DRPL Superfine 44.76g sucrose esters 17.14g Sodium pyrophosphate 14g Lecithin AF NVH or lecithin 063 0.58g Rice starch 23.52g total 100g

[0340] Table 1

[0341] Hybrid scheme

[0342] Based on the relevant master formulation (per 100g of finished product), prepare 300g of prototype using a NOVINOX mixer.

[0343] 1) Add the following components:

[0344] Ferric pyrophosphate (III)

[0345] +

[0346] sucrose esters

[0347] +

[0348] Lecithin

[0349] +

[0350] Sodium pyrophosphate

[0351] 2) Mix at 8.7 rpm for 30 minutes.

[0352] 3) Add: Rice starch

[0353] 4) Mix at 8.7 rpm for 30 minutes.

[0354] 5) Automatic sieving takes approximately 10 minutes.

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

[0356] 7) Measure the yield at the end of the method.

[0357] Example 2

[0358] The liquid composition of the first aspect of the present invention

[0359] Element Content g / 2ml The composition of Example 1 7.16g Citric acid 4.00g water 1.984ml

[0360] Table 2

[0361] Example 3

[0362] As shown in Example 1, the preparation of the composition of the third aspect of the present invention

[0363] Element Content per 100g (g) Ferric pyrophosphate (III) 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] Material

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

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

[0371] Plate: 12-hole plate.

[0372] Complete culture medium: Duchenne modified Eagle medium (DMEM - low glucose content),

[0373] Contains 1000 mg / L glucose and sodium bicarbonate, free of L-glutamine and phenol red, liquid, sterile filtered, suitable for cell culture (87%), L-glutamine solution 200 mM (2%), MEM non-essential amino acid solution (100×) (1%), fetal bovine serum (10%).

[0374] Complete culture medium without FBS: Duchenne modified Eagle medium (DMEM - low glucose content)

[0375] Contains 1000 mg / L glucose and sodium bicarbonate, free of L-glutamine and phenol red, liquid, sterile filtered, suitable for cell culture (87%), L-glutamine solution 200 mM (2%), MEM non-essential amino acid solution (100×) (1%).

[0376] DMEM: Duchenne Modified Eagle Medium containing phenol red pH indicator (DMEM, containing 1000 mg / L glucose and sodium bicarbonate, free of L-glutamine and phenol red, liquid, sterile filtered, suitable for cell culture).

[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 used to determine the activity of enzymes that reduce MTT to formazan, giving the substance a blue / purple color. This staining indicates cell viability.

[0379] Alkyd: 19 parts; 2-propanol: 1 part; HCl 2M.

[0380] TEER: Transepithelial resistance, used to measure the integrity and strength of the intestinal barrier in a fused monolayer state.

[0381] Treatment: Ferric pyrophosphate (III), Sider.m., the composition of Example 1 (Sideral NaPP), blank.

[0382] Supernatant that simulates the digestive contents of the gastrointestinal tract.

[0383] Cell proliferation:

[0384] - Place 12 0.4 μm inserts into a 12-well plate. Repeat the experiment on two plates.

[0385] - Inoculate 1 ml of complete culture medium containing Caco-2 cells into the top side compartment at a density of 0.5 x 10⁻⁶ cells / mL. 5 Cells / insertions. Cells should be passaged more than 25 times during seeding.

[0386] --Add 1.5 mL of complete culture medium to the basal compartment.

[0387] - Place the cells in an incubator at 37°C and 5% CO2.

[0388] - Change the culture medium every other day for 21 days.

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

[0390] Simulated gastrointestinal digestion:

[0391] Simulated gastrointestinal digestion protocols were applied to the following samples: blank (B), ferric pyrophosphate (III) (FeP), Sideral r.m. (SID), and Sideral containing sodium pyrophosphate (SID NaPP).

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

[0393] Stomach compartment: Add 6.5 mL SGF (simulated gastric juice: dissolve 0.2 g NaCl in 100 mL of water and adjust the pH to 1.2 with concentrated HCl). Place the solution at 37 °C and stir for 2 hours.

[0394] Intestinal compartment: Add 10 mL of gastric digestive fluid to 1 mL of 1 M NaHCO3 and 4 mL of SIF (simulated intestinal fluid: dissolve 0.68 g of anhydrous KH2PO4 in 100 mL of H2O and adjust the pH to 7.5 with 1 M NaOH). Place the solution at 37 °C and stir for 2 hours.

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

[0396] experiment

[0397] Preparation: Dilute the supernatant of gastrointestinal digestive fluid with FBS-free complete culture medium to achieve a final concentration of 1 mg / mL.

[0398] 1. Transfer the inserts to a clean 12-well plate and remove the culture medium from the top compartment. Two complete plates containing 24 inserts are required for each experiment.

[0399] 2. Wash the cells twice with 500ml PBS.

[0400] 3. Add 400 mL of treatment solution to the top compartment and 1600 mL of FBS-free complete culture medium to the base compartment.

[0401] 4. Measure the TEER of 24 inserts at T0 (i.e., immediately after processing).

[0402] 5. Wait for 3 hours in an incubator at 37°C.

[0403] 6. After completing the 3-hour processing, measure the TEER of all 24 inserts, and then obtain the top side and base.

[0404] 7. Wash the cells in both plates twice with 500ml PBS.

[0405] 8. Add 400 μL of CelLytic TMMT to plate 1 (12 inserts) and oscillate for 10 minutes.

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

[0407] Obtain the top side, base, precipitate, and cell supernatant of the insert from plate 1. Obtain the top side and base from plate 2.

[0408] 10. To assess barrier integrity, i.e., in addition to another TEER parameter, 400 μL of DMEM containing phenol red indicator was added to the top compartment of each insert in plate 2. 1600 μL of FBS-free complete culture medium was added to the base compartment. The plates were incubated at 37°C for 1 hour. The same procedure was performed on three untreated insert groups (positive control) and three cell-free empty insert groups (negative control).

[0409] 11.1 hours later, the substrate was harvested and the staining was analyzed at a wavelength of 479 nm using a spectrophotometer. The results were compared with the positive and negative controls.

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

[0411] 13. Add 400 mL of MTT to the top compartment and 1600 mL of FBS-free complete culture medium to the base compartment. Incubate at 37°C for 2 hours.

[0412] At the end of 14.2 hours, remove the liquid from both compartments, add 400 mL of acidic alcohol to the top compartment and 1600 mL of acidic alcohol to the base compartment. Incubate at 37°C for 24 hours.

[0413] At the end of 15.24 hours, the staining values ​​obtained at wavelengths of 570 nm and 650 nm were read on a spectrophotometer and compared with the positive control (untreated live cells on the insert).

[0414] Plate 2 allows us to obtain cell monolayer integrity values ​​and their viability, which are then correlated with TEER values ​​at T0 and T3h.

[0415] Figure 1 A schematic diagram of the static permeation system is shown. The test results are as follows: Figure 2 and Figure 3 As shown.

[0416] As can be seen from the results shown in the figures, the compositions of any aspect of the present invention exhibit improved bioavailability of the iron contained therein, and an unexpected increase in ferritin. For these reasons, the compositions of any aspect of the present invention demonstrate significant technological advancements compared to known iron-based compositions.

[0417] Experimental Section

[0418] animal

[0419] To induce iron deficiency anemia, 4-week-old C57BL / J6 mice were fed an iron-balanced diet or an iron-deficient diet containing <9 mg / kg iron carbonyl (PF4418, purchased from Mucedola srl) for at least 8 weeks. One drop of blood was collected weekly using the Hemo_Vet instrument (InfraTec, Dresden, Germany) to monitor hemoglobin and hematocrit. The mice's basal Hb level was maintained at 15.5 g / dL to 17 g / dL. Iron treatment was initiated when Hb decreased to below 12.5 g / dL to 13.0 g / dL. Treatment consisted of daily oral administration of a carrier (Vehicle Sideral RM, but without ferric pyrophosphate). Iron (Sideral RM), NaPP (loador NaPP), and Sideral NaPP were administered at a concentration of 0.5 mg / kg for two weeks. Mice were sacrificed two weeks after treatment. Blood and various tissues were collected for further analysis.

[0420] Notice:

[0421] ID = Iron deficiency: Iron content is less than 9 mg / Kg.

[0422] - The carrier Sideral RM is a matrix containing sucrose esters, lecithin, and possibly starch, but without iron.

[0423] -Sideral NaPP = Sideral sodium pyrophosphate, is a mixture (or composition) of the present invention containing ferric pyrophosphate (III), sucrose ester, lecithin, and possibly starch, and further containing sodium pyrophosphate (preferably in the form of tetrasodium pyrophosphate). Preferably, when starch, ferric pyrophosphate (III), sucrose ester, and lecithin are present in the mixture (or composition) of the present invention, sodium pyrophosphate replaces all or part of the starch in the preparation of said Sideral NaPP.

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

[0425] - Iron or Sideral RM are commercially available mixtures (or compositions) containing iron(III) pyrophosphate, sucrose esters, lecithin, and possibly starch.

[0426] analyze

[0427] Hematological analysis: Hemoglobin and hematocrit were monitored at time 0 (T0) and on treatment days 4-7-11-14 using the Hemo Vet instrument (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) (analyzed by the IZLER Institute in Brescia, Italy).

[0428] Serum hepcidin and serum iron. Mouse serum hepcidin was quantified using an empirically validated commercial ELISA kit (Cod. HMC-001) from Intrinsic Lifesciences. Serum iron and transferrin saturation were determined spectrophotometrically using commercial kits (Sigma-Aldrich Cod. MAK025 and Randox Laboratories Cod. TI1010) according to the manufacturer's instructions.

[0429] Quantitative analysis of iron. The iron content of tissues was determined spectrophotometrically. Briefly, 50 mg of wet tissue was incubated in 0.5 mL of 3 M HCl and 0.6 M trichloroacetic acid at 65 °C for 18 h. After centrifugation, 10 μL of sample was added to 240 μL of working chromogenic reagent in a 96-well plate containing 1 vol. 0.1% o-phenanthroline sulfonate / 1% mercaptoacetic acid solution, 5 vol. water, and 5 vol. saturated sodium acetate. The sample was then incubated at room temperature for 30 min, and the absorbance at 535 nm was measured using a microplate reader. A standard curve was plotted using a pre-calibrated FeCl3 solution (Sigma-Aldrich). The obtained values ​​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 internal ELISA. Rabbit anti-mouse FtL antiserum was added to 96-well microplates, followed by 100 μL of 10 μg / mL sodium carbonate (50 mM, pH 9.6), and incubated at 4°C for 18 hours or at 37°C for 2 hours. After washing three times with 200 μL of phosphate-buffered saline (PBS) containing 0.1% Tween, 100 μL of PBS solution containing 3% bovine serum albumin (BSA) was added to the wells, and the plates were incubated at 37°C for 1 hour to block the wells. After washing, 100 μL of 50 μg of liver and spleen protein extract in PBST was added to the wells, and the plates were incubated at 37°C for 2 hours. After washing, 100 μL of HRP-conjugated anti-FtL antibody diluted 1:500 was added, and the plates were incubated at 37°C for 1 hour. HRP activity was detected as follows: Dimethyl sulfoxide (DMSO) containing tetramethylbenzene (TMB) at a concentration of 1 mg / mL was diluted 1:10 with phosphate-citrate buffer at pH 5, and fresh hydrogen peroxide was added to achieve a final concentration of 0.006%. Absorbance was read at 620 ns / m using a MultiskanEx microplate reader (Thermo). The reaction was terminated by adding 1N sulfuric acid, and absorbance was measured at 405 nm. This assay was calibrated using different dilutions of purified recombinant mouse L-ferritin.

[0431] Ferritin assessment. Liver and spleen homogenates were heated at 70°C for 10 minutes to enrich ferritin. Samples (equivalent to 100 μg of pre-warmed liver and spleen protein) were loaded onto a 7.5% non-denaturing PAGE gel and electrophoresed at 160 V for 3 hours. After washing the gel with water, it was incubated in 2% ferrocyanide (Sigma-Aldrich) and 2% HCl for 1 hour. To enhance the signal, incubation was performed for 15 to 60 minutes in TBE 1X containing 0.025% 3,30-diaminobenzidine (Sigma-Aldrich) and 0.05% H₂O₂. The reaction was terminated 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 by reverse transcription using 1 μg RNA and Improm-II reverse transcriptase (Promega) in 20 μL, as per the manufacturer's instructions. The cDNA was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using SensiFAST SYBR Lo-ROX (Bioline). All data were normalized to Hprt1 expression and expressed as relative quantification (2nd-ΔΔΔCt method).

[0433] The primers used are:

[0434] Hprt1:

[0435] For 5-CTGGTTAAGCAGTACAGCCAA-3,Rev 5-CAGGAGGTCCTTTTCACC AGC-3;

[0436] Iron supplement:

[0437] For 5-AAGCAGGCAGACATTGCGAT-3,Rev 5-CAGGATTGTGGCTCTAGGCT ATGT-3;

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

[0439] Saa1 For 5-AGAGGACATGAGGACACCAT-3; Rev 5-CAGGAGGTCTGTAGT AATTGG-3;

[0440] Id1:

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

[0442] Bmp6:

[0443] For 5-ATGGCAGGACTGGATCATTGC-3,Rev 5-CCATCACAGTAGTTGGC AGCGT-3.

[0444] Statistical methods. For each treatment group, comparisons between the carrier and iron supplement groups were made using either two-way ANOVA with correction for multiple comparisons using the Sidak test, or conventional one-way ANOVA with correction for multiple comparisons using the Tukey test.

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

[0446] Experimental group: two weeks of treatment

[0447] Male C57BL / 6J mice were fed an iron-deficient diet (<10 mg / kg Fe). When the hemoglobin level of the mice reached <12.5-13.0 g / dL (T0), the mice were randomly divided into 6 groups:

[0448] (a) ID mice that have not undergone any treatment (N=9 mice).

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

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

[0451] (d) Mice (N=8 mice) were given NaPP carrier (150 uL) orally daily for 2 weeks.

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

[0453] Please note that 6 male mice were kept on a normal diet as a healthy control.

[0454] analyze: Hemoglobin and hematocrit at time points 0 (T0) and during treatment days T4-T7-T11-T14. Ret-He and other blood parameters (analyzed by the IZLER Institute at the end of the experiment). Iron content in the liver, spleen, and bone marrow. Serum iron and transferrin saturation (TSat).

Claims

1. A mixture comprising or consisting of: -i) Ferric (III) pyrophosphate salt; -At least one type of lecithin; - at least one sucrose ester; and -iii) Sodium pyrophosphate or potassium pyrophosphate.

2. The mixture according to claim 1, wherein, The mixture also contains ii) sodium ferric(III) pyrophosphate; preferably, the amount of sodium ferric(III) pyrophosphate in the mixture is 0.1% to 50% by weight, more preferably 1% to 35% by weight, more preferably 5% to 30% by weight, and even more preferably 10% to 25% by weight, relative to the total weight of the mixture.

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

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

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

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

7. The mixture according to any one of claims 1 to 6, wherein, The presence of at least one sucrose ester in the mixture is from 5% to 75% by weight, preferably from 10% to 60% by weight, more preferably from 12% to 40% by weight, and even more preferably from 15% to 30% by weight, relative to the total weight of the mixture.

8. The mixture according to any one of claims 1 to 7, wherein, The amount of sodium pyrophosphate or potassium pyrophosphate in the mixture relative to the total weight of 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, and even more preferably from 10% to 25% by weight, wherein the sodium pyrophosphate or potassium pyrophosphate is preferably in the form of tetrasodium pyrophosphate.

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

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

12. The mixture according to any one of claims 1 to 11, wherein, The mixture is administered in the form of tablets, capsules, sachets, or sticks.

13. The mixture according to any one of claims 1 to 12, wherein, In the mixture, the weight ratio of ferric pyrophosphate (III) to sodium pyrophosphate, preferably tetrasodium pyrophosphate (FePP:NaPP) 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 of ferric pyrophosphate (III) to sodium pyrophosphate, preferably tetrasodium pyrophosphate (FePP:NaPP), 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 equivalence ratio of ferric pyrophosphate to sodium pyrophosphate, preferably tetrasodium pyrophosphate (FePP:NaPP), 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 medicine for treatment.

17. The mixture according to claim 16, wherein, The mixture is used in methods for treating and / or preventing absolute or relative iron deficiency, particularly for treating conditions or diseases related to or caused by iron deficiency.

18. A composition comprising a mixture, said 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 for oral dose units.

19. The composition according to claim 18, wherein, The composition is used as a medicine for treatment.

20. The mixture according to claim 18 or 19, wherein, The composition is used for the treatment and / or prevention of absolute or relative iron deficiency, particularly for the treatment of conditions or diseases related to or caused by iron deficiency.

21. A method for preparing a mixture according to at least one of claims 1 to 17 or a composition according to at least one of claims 18 to 20, wherein, The method includes at least one step of mixing individual components i) and / or ii) and / or iii) in a solid state to obtain the mixture and the composition in solid form, preferably as powder or granules.

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