Formulations comprising at least one vitamin and at least one phosphate salt, their compositions, and their use in supplementing said at least one vitamin

Abstract

The present invention relates to a formulation in solid form based on a nutrient (such as at least one vitamin) consisting of: (a) at least one vitamin, (b) at least one phospholipid, (c) at least one polysaccharide and / or (d) at least one sucrester, (z) at least one phosphate salt as a stabilizing agent for said at least one vitamin selected from tricalcium phosphate salts and, optionally, (e) at least one starch of plant origin.

Description

[0001] FORMULATIONS COMPRISING AT LEAST ONE VITAMIN AND AT LEAST ONE PHOSPHATE SALT, THEIR COMPOSITIONS, AND THEIR USE IN SUPPLEMENTING SAID AT LEAST ONE VITAMIN

[0002] DESCRIPTION

[0003] The present invention relates to a formulation in solid form based on a nutrient (such as at least one vitamin) consisting of: (a) at least one vitamin, (b) at least one phospholipid, (c) at least one polysaccharide and / or (d) at least one sucrester, (z) at least one phosphate salt as a stabilizing agent for said at least one vitamin selected from tricalcium phosphate salts and, optionally, (e) at least one starch of plant origin.

[0004] In particular, the present invention relates to a formulation in solid form based on a vitamin (referred to as cyclosome vitamin or cyclosomal vitamin) comprising or, alternatively, consisting of: (a) at least one vitamin, such as a vitamin A, a vitamin of the B group (preferably B12), a vitamin C, a vitamin D (preferably D3) and / or a vitamin E, (b) at least one phospholipid, (c) at least one first agent (polysaccharide) selected from (c-i) at least one carrageenan, (c-ii) at least one acacia gum, and mixtures thereof, and / or (d) at least one sucrester, (z) at least one phosphate salt as a stabilizing agent for said at least one vitamin selected from tricalcium phosphate salts and, optionally, (e) at least one starch of plant origin.

[0005] Furthermore, the present invention relates to a composition, preferably in solid form, comprising at least one additive and at least one formulation in solid form comprising at least one nutrient (i.e., at least one vitamin) and to the use of said composition or formulation in the (therapeutic or non-therapeutic) treatment of a deficiency of said at least one nutrient, and of pathologies, symptoms, and / or disorders associated with or resulting from said deficiency.

[0006] Furthermore, the present invention relates to a composition, preferably in solid form, comprising additives, and said formulation in solid form comprising at least one vitamin (cyclosomal vitamin), and to the use of said composition or formulation in the (therapeutic or non-therapeutic) treatment of a deficiency of said at least one vitamin, and of pathologies, symptoms, or disorders connected with or resulting from said deficiency.

[0007] Finally, the present invention relates to a method for the preparation of said formulation in solid form comprising a vitamin (cyclosome vitamin or cyclosomal vitamin).

[0008] In addition, the present invention relates to a further method for the preparation of said composition comprising said formulation comprising a vitamin (cyclosomal vitamin) (in short, the composition method of the invention).

[0009] Each of the vitamins that may be present in the compositions or formulations of the present invention (e.g., vitamins A, of the B group, C, D and E) plays fundamental roles in the metabolism and functioning and homeostasis mechanisms of cells and organs in subjects, particularly in human subjects. However, when said vitamins (such as vitamin A, of the B group (e.g., B12), C, D e.g., D3), and / or E) are administered orally (in short, PO) to a subject, preferably a human subject, their gastrointestinal or intestinal absorption and their blood bioavailability may vary from subject to subject and / or not be particularly high, thus causing significant differences in the response of subjects, with cases of poor efficacy.

[0010] Therefore, there is a high need to provide new formulations of said vitamins (such as vitamin A, of the B group (e.g., B12), C, D (e.g., D3), and / or E) and compositions comprising said formulations that are both highly absorbable in the gastrointestinal tract and bioavailable in the bloodstream and highly effective in supplementing said vitamin, in the treatment of a deficiency or insufficiency of said vitamin, and in the treatment of pathologies, symptoms, or disorders associated with or resulting from said deficiency, for all categories of subjects.

[0011] For example, pathologies or symptoms associated with or resulting from a deficiency of said vitamins (such as vitamin A, of the B group (e.g., B12), C, D (e.g., D3), and / or E) may be selected from: cognitive problems, motor problems, lowered immune defenses, and others as exemplified in this description.

[0012] Vitamin B12 (cobalamin) is a crucial water-soluble vitamin that is essential for several physiological processes that are vital to human health. A key function of vitamin B12 is its role in converting homocysteine to methionine, an amino acid that is essential for protein synthesis, gene expression regulation, and numerous other bodily functions. Vitamin B12 is also essential for maintaining the integrity of the myelin sheath, which protects nerve cells and ensures efficient transmission of nerve signals. Vitamin B12 works closely with vitamin B9 (folate or folic acid) to support red blood cell production and synthesize S-adenosylmethionine, a compound that is critical for immune regulation and mood stabilization. Despite its importance, the body cannot produce sufficient amounts of vitamin B12 on its own.

[0013] Vitamin B12 deficiency, defined as a circulating level below 150-200 pg / mL (borderline 200-300 pg / mL), is a significant global health concern, particularly affecting the elderly, pregnant women, and young children, especially in regions with limited dietary options.

[0014] Deficiency is also common among people with gastrointestinal (Gl) disorders and those who adhere to restrictive diets such as vegetarianism or veganism. This deficiency can lead to a wide range of serious health problems, including megaloblastic anemia and irreversible neurological damage. Symptoms of vitamin B12 deficiency often first manifest as hematological problems, such as pernicious anemia and megaloblastic anemia, which involve enlarged red blood cells due to impaired DNA synthesis during erythropoiesis. In children, vitamin B12 deficiency can cause anemia, stunted growth, reduced cognitive abilities, and developmental delays, with potentially irreversible consequences.

[0015] For people at risk of B12 deficiency, treatment is often necessary to maintain adequate circulating levels, and oral supplementation is a common approach. However, conventional oral B12 supplements, such as cyanocobalamin and methylcobalamin, face significant challenges during transit through the gastrointestinal tract.

[0016] To be absorbed, B12 must bind to intrinsic factor (IF), a glycoprotein produced by the parietal cells of the stomach, so only the B12-intrinsic factor complex is then absorbed in the terminal ileum.

[0017] Therefore, altered IF production due to various conditions such as autoimmune diseases (pernicious anemia), chronic inflammatory bowel diseases such as Crohn's disease or celiac disease, or surgical resection of the ileum, can severely compromise B12 absorption. In addition, the acidic environment of the stomach and / or dysfunctions of the R proteins (aptocorrins) that protect B12 in the stomach and its potential degradation by gastric enzymes can compromise the stability and bioavailability of oral B12 supplements. Furthermore, deficiencies or dysfunctions in transcobalamin II, which is essential for transporting B12 into the bloodstream, may further impact its bioavailability. As a result, the absorption of supplemental oral B12 can be variable and often suboptimal, especially in individuals with compromised gastrointestinal function. On the other hand, intramuscular injection of vitamin B12 is often used as an alternative. Although this method bypasses the gastrointestinal tract and generally ensures more reliable absorption, it is not without drawbacks.

[0018] Metformin (1 , 1-dimethylbiguanide; CAS RN 657-24-9 or 1115-70-4 for metformin* HOI) is a drug commonly used as a first-line treatment for type 2 diabetes, and is also used for polycystic ovary syndrome (POOS) and certain forms of metabolic syndrome.

[0019] Prolonged use of metformin can reduce the intestinal absorption of vitamin B12. This effect is not directly dependent on metformin, but indirectly, as it appears to interfere with the binding of the VitB12-IF complex to the CUBAM receptor on the surface of ileal enterocytes.

[0020] Therefore, vitamin B12 deficiency is a serious problem in patients being treated with metformin, such as those with type 2 diabetes, polycystic ovary syndrome (POOS), and certain forms of metabolic syndrome, who may develop serious consequences over time, such as megaloblastic anemia and peripheral neuropathy. This vitamin B12 deficiency can also occur in the presence of normal intrinsic factor (IF), because the problem lies in the ileal absorption of the B12-IF complex.

[0021] In cases of vitamin B12 deficiency, patients being treated with metformin, such as those with type 2 diabetes, polycystic ovary syndrome (PCOS), and certain forms of metabolic syndrome, are forced to take high-dose oral vitamin B12 supplements or intramuscular injections of vitamin B12.

[0022] Therefore, an optimized support system is essential to improving the bioavailability of supplemental oral B12. A well-designed support system can protect B12 from degradation, facilitate its transport through the gastrointestinal tract, control its release at the appropriate site in the small intestine (the ileum), and promote efficient absorption. Without such a system, B12 absorption may be inconsistent and inadequate, particularly in individuals with compromised gastrointestinal function or conditions that compromise IF production. Said optimized support system is also essential for improving the absorption of supplemental oral vitamin B12 in patients undergoing treatment with a drug that, even in the absence of intrinsic factor IF alteration, impairs ileal absorption of the vitamin B12-IF complex, without the need for high-dose oral vitamin B12 supplements or intramuscular vitamin B12 injections.

[0023] Said system, for example, is also essential for improving the absorption of supplemental oral vitamin B12 in patients undergoing treatment with metformin, such as patients with type 2 diabetes, polycystic ovary syndrome (PCOS), and certain forms of metabolic syndrome.

[0024] Finally, there is a need for these new solid formulations of at least one vitamin and their compositions to be stable over time, well tolerated by all categories of subjects, and easy to prepare.

[0025] PCT application WO2021 / 111404 A1 , filed by the Applicant itself, discloses a formulation in solid form consisting of (a) a nutrient (a mineral or a vitamin), (b) a phospholipid, (c) a first agent selected from (c-i) carrageenan or (c- II) acacia gum and which, optionally, may comprise a sucrester and a starch of plant origin.

[0026] The Applicant, following extensive research and development, addresses and solves the above needs by providing new formulations in solid comprising at least one vitamin (such as vitamin A, of the B group (e.g., B12), C, D (e.g., D3), and / or E) and compositions, preferably in solid form, comprising additives and said formulations comprising said at least one vitamin.

[0027] Said formulations based on at least one vitamin of the present invention and compositions thereof are effective in the treatment of a partial or almost total deficiency or insufficiency of said at least one vitamin, and in the treatment of pathologies, symptoms, or disorders related to or resulting from said deficiency.

[0028] One purpose of the present invention is to provide a new formulation of said at least one vitamin (such as vitamin A, of the B group (e.g., B12), C, D (e.g., D3) and / or E), and compositions thereof that is capable of rendering effective the supplementation of said at least one vitamin administered orally, for example following an increase in gastrointestinal absorption and its bioavailability.

[0029] In the context of the present invention, the terms gastrointestinal absorption and intestinal absorption are used interchangeably.

[0030] A good level of efficacy and / or increase in efficacy, even of slight extent, of the formulation based on at least one vitamin according to the present invention compared to the vitamin as such in the treatment of a deficiency of said vitamin, or in the treatment of pathologies / disorders resulting from said deficiency and illustrated in the present invention, results in a reduction in the effective dose to be administered to a subject in need compared to the vitamin as such, and therefore also presents an economic advantage. Said good level or increase in efficacy, even of slight extent, in the aforementioned treatments with vitamins formulated according to the invention or their compositions, compared to treatments with the vitamin as such, could be due to an increase in the blood bioavailability of the vitamin, which in turn is due to an increase in the intestinal or gastrointestinal absorption of the formulations based on the vitamin that is the object of the present invention compared to the vitamin as such, when administered orally. However, there may be other mechanisms and reasons for this increase in efficacy.

[0031] It can be hypothesized that the increase in intestinal absorption of the formulations or compositions based on the vitamin that is the object of the present invention compared to the vitamin as such is due to the internalization of said formulations in microvesicles that allow their transport through the intestinal membrane.

[0032] Said good level or increase in efficacy in the treatment of a deficiency of said vitamin or in the treatment of pathologies / disorders resulting from said deficiency by the use of formulations or compositions based on a vitamin that is the object of the present invention, compared to the vitamin as such, results in a greater effect being achieved with the same amount or concentration of vitamin administered to a subject in need.

[0033] In addition, the formulations and compositions comprising at least one vitamin object of the present invention are stable over time from a chemical, physical, and organoleptic point of view.

[0034] Finally, the formulations and compositions comprising said at least one vitamin object of the present invention have no significant side effects, are well tolerated and can therefore be administered, even on an empty stomach, to all categories of subjects, including children, adolescents, pregnant or breastfeeding women and the elderly.

[0035] Furthermore, the method for the preparation of said formulations in solid form comprising at least one vitamin (such as vitamin A, of the B group (e.g., B12), C, D (e.g., D3), and / or E) and their compositions is easy to implement or prepare and economically advantageous in proportion to the treatment potential.

[0036] For example, the formulation in solid form based on at least one vitamin object of the present invention (cyclosome vitamin or cyclosomal vitamin) is easily workable to provide the compositions of the present invention, preferably in solid form for oral use.

[0037] These purposes, and others that will become clear from the detailed description below, are achieved by the formulation in solid form of at least one vitamin (such as vitamin A, of the B group (e.g., B12), C, D (e.g., D3), and / or E) of the present invention (cyclosome vitamin or cyclosomal vitamin) and their compositions thanks to the technical characteristics claimed in the attached claims and reported in the present description. FIGURES

[0038] Figures 1A-1C refer to the effect of Sucrosomial® B12 supplementation compared to the conventional oral formulation Mecogen SL B12 on circulating (serum) levels of vitamin B12 in healthy adults with vitamin B12 deficiency (serum level < 200 pg / ml) and borderline deficiency (serum level between 200 and 300 pg / ml) (B12 supplementation dosage, one 1000 pig tablet per day for 7 days).

[0039] Figure 1A: the connected scatter plot shows the serum B12 levels of the participants (expressed as mean ± SEM) before supplementation (baseline) and subsequently each day, with levels recorded every two days for one week. Sucrosomial® B12, n = 12; Mecogen SL B12, n = 12. The dotted horizontal lines indicate the B12 deficiency and borderline thresholds (200 and 300 pg / mL, respectively).

[0040] Figures 1 B-1C: boxplots show daily vitamin B12 levels recorded for each formulation, with significant differences over time (Figure 1 B) and between groups (Figure 1C). Statistical analysis was performed using the Wilcoxon test with FDR correction; only significant differences are indicated, * p < 0.05, ** p < 0.01 , *** p < 0.001 , **** p < 0.0001. Sample collection and analysis were performed by Chughtai Lab PK (https: / / chughtailab.com / ).

[0041] Figures 2A-2C refer to the effect of Sucrosomial® Ultra B12 supplementation compared to the conventional B- SUB B12 formulation on serum vitamin B12 levels in healthy adults with vitamin B12 deficiency (serum level < 200 pg / ml) and borderline deficiency (serum level between 200 and 300 pg / ml) (B12 supplementation dosage, one 1000 pig tablet per day for 7 days).

[0042] Figure 2A: the connected scatter plot shows the serum B12 levels of the participants (expressed as mean ± SEM) before supplementation (baseline) and subsequently each day, with levels recorded every two days for one week. Sucrosomial® Ultra B12, n = 10; B-SUB B12, n = 12. The dotted horizontal lines indicate B12 deficiency and borderline thresholds (200 and 300 pg / mL, respectively).

[0043] Figures 2B-2C: boxplots show daily circulating vitamin B12 levels recorded for each formulation, with significant differences over time (Figure 2B) and between groups (Figure 2C). Statistical analysis was performed using the Wilcoxon test with FDR correction; only significant differences are indicated, * p < 0.05, ** p < 0.01 , *** p < 0.001. Blood samples were collected and analyzed by Chughtai Lab PK (https: / / chughtailab.com / ).

[0044] Figures 3A-3C refer to the effect of Sucrosomial® Ultra B12 supplementation compared to conventional Evermin B12 and Neuromax B12 formulations on serum vitamin B12 levels in healthy adults with vitamin B12 deficiency (serum level < 200 pg / ml) and borderline deficiency (serum level between 200 and 300 pg / ml) (B12 supplementation dosage, one 1000 pig tablet per day for 7 days).

[0045] Figure 3A: the connected scatter plot shows circulating vitamin B12 levels (expressed as mean ± SEM) before supplementation (baseline) and subsequently each day, with levels recorded every two days for one week. Sucrosomial® Ultra B12, n = 10; Evermin B12, n = 10, Neuromax B12, n = 10. The dotted horizontal lines indicate B12 deficiency and borderline thresholds (200 and 300 pg / mL, respectively).

[0046] Figures 3B-3C: boxplots show daily vitamin B12 levels for each B12 formulation, with significant differences over time (Figure 3B) and between groups (Figure 3C). Statistical analysis was performed using the Wilcoxon test with FDR correction; only significant differences are indicated, * p < 0.05, ** p < 0.01 , *** p < 0.001 . Blood samples were collected and analyzed by Diagnostic and Research Laboratory, LUMHS, PK (https: / / drlab.lu hs.edu.pk / ).

[0047] Figures 4A-4C refer to the results obtained in an in vitro model using UltraB12 (sucrosomial vitamin B12) in comparison to free cyanocobalamin (vitamin B12) in the absence or presence of IF (intrinsic factor) and / or MET (metformin).

[0048] Figure 4A: the graphs show the results of an MTT assay of Epilntestinal tissue viability treated for 24 hours (left) or 48 hours (right) with UB12 (UltraBI 2, Sucrosomial Vitamin B12) or with B12 (free cyanocobalamin) and in the absence or presence of IF (intrinsic factor) and / or MET (metformin).

[0049] Figure 4B: the graphs show the results of the quantification of apparent permeability (Papp) following treatment of Epilntestinal tissues for 24 hours with UB12 (UltraBI 2, Sucrosomial Vitamin B12) or with B12 (free cyanocobalamin) and in the absence or presence of IF (intrinsic factor) and / or MET (metformin).

[0050] Figure 4C: the graphs show the results of the quantification of apparent permeability (Papp) following treatment of Epilntestinal tissues for 48 hours with UB12 (UltraBI 2, Sucrosomial Vitamin B12) or with B12 (free cyanocobalamin) and in the absence or presence of IF (intrinsic factor) and / or MET (metformin).

[0051] SUMMARY OF THE INVENTION

[0052] One purpose of the present invention is to provide a formulation in solid form of at least one vitamin consisting of, in addition to said (a) at least one vitamin, (b) at least one phospholipid, (c) at least one polysaccharide and / or (d) at least one sucrester, (z) at least one phosphate salt as a stabilizing agent for said at least one vitamin and, optionally, (e) at least one starch of plant origin (in short, formulation of the present invention).

[0053] One purpose of the present invention is to provide a composition, preferably in solid form, comprising at least one formulation of the present invention based on a vitamin and pharmaceutical or food grade additives and / or excipients (in short, composition of the present invention).

[0054] One purpose of the present invention is to provide said formulations or compositions of the present invention for use as a medicament.

[0055] One purpose of the present invention is to provide said formulations or compositions of the present invention for use in a method of treatment of a deficiency or insufficiency of said at least one vitamin in a subject in need.

[0056] One purpose of the present invention is to provide a method of treatment of a deficiency or insufficiency of said at least one vitamin by administering a therapeutically effective amount of said formulations or compositions of the present invention to a subject in need. One purpose of the present invention is to provide a non-therapeutic (or cosmetic) use of said formulations or compositions of the present invention for supplementing said at least one vitamin to a healthy subject in order to enhance his or her physical and / or mental performance.

[0057] DETAILED DESCRIPTION OF THE INVENTION

[0058] It is an object of the present invention a formulation in solid form of at least one vitamin (in short, formulation of at least one vitamin of the invention or formulation of the invention or, alternatively, cyclosome vitamin or cyclosomal vitamin) consisting of:

[0059] (a) at least one vitamin, wherein said vitamin is selected from the group comprising or, alternatively, consisting of: (a-l) at least one vitamin of the B group (e.g., B12, B9, B6, B3, or B2), preferably vitamin B12, (a-ll) a vitamin C, (a- III) a vitamin D, preferably D3, (a-IV) a vitamin E, and (a-V) a vitamin A; and

[0060] (b) at least one phospholipid, preferably a phosphoglyceride, more preferably a phosphatidylcholine or a lecithin; and

[0061] (c) at least one first agent (a polysaccharide) selected from (c-i) at least one carrageenan and / or (c-ii) at least one acacia gum; and / or

[0062] (d) at least one carbohydrate ester of fatty acids (alternatively referred to as sucrester); and

[0063] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin; and, optionally,

[0064] (e) at least one starch of plant origin, preferably gelatinized or pregelatinized, for example rice starch.

[0065] Said (z) at least one phosphate salt as a stabilizing agent for said at least one vitamin, said (z) is selected from tricalcium phosphate salts such as, for example, without in any way limiting the choice of possible phosphate salts that can be used, that of the type, for example:

[0066] Formula: Ca3(PO4)2

[0067] Molar mass: 310.18 g / mol

[0068] Density: 3.14 g / cm3

[0069] CAS number: 7758-87-4

[0070] Melting temperature: 1 ,391 °C (1 ,664 K)

[0071] Density (g / cm3, at s.t.p.): 3.14

[0072] Molecular formula: Ca3(PO4)2.

[0073] Preferably, said (z) at least one phosphate salt, such as, for example, tricalcium phosphate, is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%, preferably from 0.1 % to 2%, more preferably from 0.3% to 1.5%, even more preferably from 0.5% to 1 %, for example, from 0.35% to 0.85%.

[0074] Preferably, said (z) at least one phosphate salt such as, for example, tricalcium phosphate is present in a weight ratio (expressed as a mass ratio) relative to the weight of said (b) at least one phospholipid, preferably a phosphatidylcholine or a lecithin, for example a lecithin (E322) selected from sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof (preferably, sunflower lecithin) comprised from 1 :5 to 5:1; preferably, from 1 :4 to 4:1; more preferably, from 1 :3 to 3:1; even more preferably, from 1 :2 to 2:1, for example, 1 :1.

[0075] Preferably, said formulation in solid form of at least one vitamin consists of:

[0076] (a) at least one vitamin selected from: (a-l) vitamin B12, (a-ll) vitamin C, (a-lll) vitamin D, preferably D3, (a-IV) vitamin E; and

[0077] (b) at least one lecithin, preferably a sunflower, corn, or soy lecithin (e.g., sunflower lecithin (E322)); and (c-i) at least one carrageenan (e.g., E407) or (c-ii) at least one acacia gum (e.g., E414); and / or

[0078] (d) at least one sucrester (e.g., sucrester E473); and

[0079] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin; and, optionally, (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0080] Preferably, said formulation in solid form of at least one vitamin consists of:

[0081] (a) at least one vitamin selected from: (a-l) vitamin B12, (a-ll) vitamin C, (a-lll) vitamin D, preferably D3, (a-IV) vitamin E; and

[0082] (b) at least one lecithin, preferably a sunflower, corn, or soy lecithin (e.g., sunflower lecithin (E322)); and (c-i) at least one carrageenan (e.g., E407) or (c-ii) at least one acacia gum (e.g., E414); and

[0083] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin; and, optionally, (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0084] Preferably, said formulation in solid form of at least one vitamin consists of:

[0085] (a) at least one vitamin selected from: (a-l) vitamin B12, (a-ll) vitamin C, (a-lll) vitamin D, preferably D3, (a-IV) vitamin E; and

[0086] (b) at least one lecithin, preferably a sunflower, corn, or soy lecithin (e.g., sunflower lecithin (E322)); and

[0087] (d) at least one sucrester (e.g., sucrester E473); and

[0088] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin; and, optionally, (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0089] Preferably, said formulation in solid form of at least one vitamin consists of:

[0090] (a) at least one vitamin selected from: (a-l) vitamin B12; and

[0091] (b) at least one lecithin, preferably a sunflower, corn, or soy lecithin (e.g., sunflower lecithin (E322)); and (c-i) at least one carrageenan (e.g., E407) or (c-ii) at least one acacia gum (e.g., E414); and / or (d) at least one sucrester (e.g., sucrester E473); and

[0092] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin B12; and, optionally, (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0093] Preferably, said formulation in solid form of at least one vitamin consists of:

[0094] (a) at least one vitamin selected from: (a-l) vitamin B12, (a-ll) vitamin C, (a-lll) vitamin D, preferably D3, (a-IV) vitamin E; and

[0095] (b) at least one lecithin, preferably a sunflower, corn, or soy lecithin (e.g., sunflower lecithin (E322)); and

[0096] (c-i) at least one carrageenan (e.g., E407) or (c-ii) at least one acacia gum {e.g., E414); and / or

[0097] (d) at least one sucrester (e.g., sucrester E473); and

[0098] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin; and

[0099] (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0100] Preferably, said formulation in solid form of at least one vitamin consists of:

[0101] (a) at least one vitamin selected from: (a-l) vitamin B12, (a-ll) vitamin C, (a-lll) vitamin D, preferably D3, (a-IV) vitamin E; and

[0102] (b) at least one lecithin, preferably a sunflower, corn, or soy lecithin (preferably sunflower lecithin (E322)); and

[0103] (c-i) at least one carrageenan (e.g., E407) or (c-ii) at least one acacia gum (e.g., E414); and

[0104] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin; and

[0105] (e) a gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0106] Preferably, said formulation in solid form of at least one vitamin consists of:

[0107] (a) at least one vitamin selected from: (a-l) vitamin B12, (a-ll) vitamin C, (a-lll) vitamin D, preferably D3, (a-IV) vitamin E; and

[0108] (b) at least one lecithin, preferably a sunflower, corn, or soy lecithin (preferably sunflower lecithin (E322)); and

[0109] (d) a sucrester (e.g., sucrester E473); and

[0110] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin;

[0111] (e) a gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0112] Preferably, said formulation in solid form of at least one vitamin consists of:

[0113] (a) at least one vitamin selected from: (a-l) vitamin B12; and

[0114] (b) at least one lecithin, preferably a sunflower, corn, or soy lecithin (e.g., sunflower lecithin (E322)); and

[0115] (c-i) at least one carrageenan (e.g., E407) or (c-ii) at least one acacia gum (e.g., E414); and / or

[0116] (d) at least one sucrester (e.g., sucrester E473); and

[0117] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin B12; and (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0118] Preferably, said formulation in solid form of at least one vitamin consists of:

[0119] (a) at least one vitamin selected from: (a-l) vitamin B12; and

[0120] (b) at least one lecithin, preferably a sunflower, corn, or soy lecithin (e.g., sunflower lecithin (E322)); and

[0121] (d) at least one sucrester (e.g., sucrester E473); and

[0122] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin B12; and optionally, (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0123] Preferably, said formulation in solid form of at least one vitamin consists of:

[0124] (a) at least one vitamin selected from: (a-l) vitamin B12; and

[0125] (b) at least one lecithin, preferably a sunflower, corn, or soy lecithin (e.g., sunflower lecithin (E322)); and

[0126] (d) at least one sucrester (e.g., sucrester E473); and

[0127] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin B12; and

[0128] (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0129] Said (z) at least one phosphate salt as a stabilizing agent for said at least one vitamin, said (z) is selected from tricalcium phosphate salts such as, for example, without in any way limiting the choice of possible phosphate salts that can be used, that of the type, for example:

[0130] Formula: Ca3(PO4)2

[0131] Molar mass: 310.18 g / mol

[0132] Density: 3.14 g / cm3

[0133] CAS number: 7758-87-4

[0134] Melting temperature: 1 ,391 °C (1 ,664 K)

[0135] Density (g / cm3, at s.t.p.): 3.14

[0136] Molecular formula: Ca3(PO4)2.

[0137] Preferably, said (z) at least one phosphate salt, such as, for example, tricalcium phosphate, is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%, preferably comprised from 0.1 % to 2%, more preferably comprised from 0.3% to 1.5%, even more preferably comprised from 0.5% to 1 %, for example, comprised from 0.35% to 0.85%.

[0138] Preferably, said (z) at least one phosphate salt such as, for example, tricalcium phosphate is present in a weight ratio (expressed as a mass ratio) relative to the weight of said (b) at least one phospholipid, preferably a phosphatidylcholine or lecithin, for example a lecithin (E322) selected from sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof (preferably, sunflower lecithin) comprised from 1 :5 to 5:1 ; preferably, comprised from 1 :4 to 4: 1 ; more preferably, comprised from 1 :3 to 3: 1 ; even more preferably, comprised from 1 :2 to 2: 1 , for example, 1 : 1. The following embodiments (EM) of the formulation in solid form of vitamin B12 (in short, vit B12) of the invention (vitamin B12 cyclosome or vitamin B 12 cyclosomal) are comprised in the present invention:

[0139] - EMa-vit B12: vit B12, (b) and (c), such as (c-i) or (c-ii), and (z); for example, vit B12, (b) and (c-i) and (z) or vit B12, (b) and (c-ii) and (z);

[0140] - EMb-vit B12: vit B12, (b), (c) (such as (c-i) or (c-ii)) and (d) and (z); for example, vit B12, (b), (c-i) and (d) and (z) or vit B12, (b), (c-ii) and (d) and (z);

[0141] - EMc-vit B12: vit B12, (b), (c) (such as (c-i) or (c-ii)) and (z) and (e); for example, vit B12, (b), (c-i) and (z) and (e) or vit B12, (b), (c-ii) and (z) and (e);

[0142] - EMd-vit B12: vit B12, (b), (c) (such as (c-i) or (c-ii)), (d) and (z) and (e); for example, vit B12, (b), (c-i), (d) and (z) and (e) or vit B12, (b), (c-ii), (d) and (z) and (e); wherein the components designated (a), (b), (c-i), (c-ii), (d) and (z) and (e) are as defined in the present invention.

[0143] Preferably, said formulation in solid form of vitamin B12 (referred to as vitamin B12 cyclosome or vitamin B12 cyclosomal) consists of:

[0144] (a-i) vitamin B12 (cobalamin) (e.g., CAS No. 68-19-9);

[0145] (b) at least one phospholipid, preferably a phosphatidylcholine or lecithin, for example a lecithin (E322) selected from sunflower lecithin, corn lecithin, soy lecithin and mixtures thereof (preferably sunflower lecithin);

[0146] (c) a polysaccharide selected from (c-i) at least one carrageenan (e.g., E407) or (c-ii) at least one acacia gum (e.g., E414) and mixtures thereof; and / or

[0147] (d) at least one sucrester (e.g., E473);

[0148] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin B12; and, optionally, (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0149] Said (z) at least one phosphate salt as a stabilizing agent for said at least one vitamin, said (z) is selected from tricalcium phosphate salts such as, for example, without in any way limiting the choice of possible phosphate salts that can be used, that of the type, for example:

[0150] Formula: Ca3(PO4)2

[0151] Molar mass: 310.18 g / mol

[0152] Density: 3.14 g / cm3

[0153] CAS number: 7758-87-4

[0154] Melting temperature: 1 ,391 °C (1 ,664 K)

[0155] Density (g / cm3, at s.t.p.): 3.14

[0156] Molecular formula: Ca3(PO4)2.

[0157] Preferably, said (z) at least one phosphate salt, such as, for example, tricalcium phosphate, is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%, preferably comprised from 0.1 % to 2%, more preferably comprised from 0.3% to 1.5%, even more preferably comprised from 0.5% to 1 %, for example, comprised from 0.35% to 0.85%.

[0158] Preferably, said (z) at least one phosphate salt such as, for example, tricalcium phosphate is present in a weight ratio (expressed as a mass ratio) relative to the weight of said (b) at least one phospholipid, preferably a phosphatidylcholine or lecithin, for example a lecithin (E322) selected from sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof (preferably, sunflower lecithin) comprised from 1 :5 to 5:1 ; preferably, comprised from 1 :4 to 4: 1 ; more preferably, comprised from 1 :3 to 3: 1 ; even more preferably, comprised from 1 :2 to 2: 1 , for example, 1 : 1.

[0159] The following embodiments (EM) of the formulation in solid form of vitamin C (in short, vit C) of the invention (vitamin C cyclosome or vitamin C cyclosomal) are comprised in the present invention:

[0160] - EMa-vit C: vit C, (b) and (c), such as (c-i) or (c-ii), and (z); for example, vit C, (b) and (c-i) and (z) or vit C, (b) and (c-ii) and (z);

[0161] - EMb-vit C: vit C, (b), (c) (such as (c-i) or (c-ii)) and (d) and (z); for example, vit C, (b), (c-i) and (d) and (z) or vit C,

[0162] (b), (c-ii) and (d) and (z);

[0163] - EMc-vit C: vit C, (b), (c) (such as (c-i) or (c-ii)) and (z) and (e); for example, vit C, (b), (c-i) and (z) and (e) or vit C, (b), (c-ii) and (z) and (e);

[0164] - EMd-vit C: vit C, (b), (c) (such as (c-i) or (c-ii)), (d) and (z) and (e); for example, vit C, (b), (c-i), (d) and (z) and (e) or vit C, (b), (c-ii), (d) and (z) and (e); wherein the components designated (a), (b), (c-i), (c-ii), (d) and (z) and (e) are as defined in the present invention.

[0165] Preferably, said formulation in solid form of vitamin C (referred to as vitamin C cyclosome or vitamin C cyclosomal) comprises or, alternatively, consists of:

[0166] (a-i) vitamin C (ascorbic acid or ascorbate) (e.g., CAS No. 50-81-7 or 134-03-2);

[0167] (b) at least one phospholipid, preferably a phosphatidylcholine or lecithin, for example a lecithin (E322) selected from sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof (preferably sunflower lecithin);

[0168] (c) a polysaccharide selected from (c-i) at least one carrageenan (e.g., E407) or (c-ii) at least one acacia gum (e.g., E414) and mixtures thereof; and / or

[0169] (d) at least one sucrester (e.g., E473);

[0170] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin C; and, optionally, (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch. Said (z) at least one phosphate salt as a stabilizing agent for said at least one vitamin, said (z) is selected from tricalcium phosphate salts such as, for example, without in any way limiting the choice of possible phosphate salts that can be used, that of the type, for example:

[0171] Formula: Ca3(PO4)2

[0172] Molar mass: 310.18 g / mol

[0173] Density: 3.14 g / cm3

[0174] CAS number: 7758-87-4

[0175] Melting temperature: 1 ,391 °C (1 ,664 K)

[0176] Density (g / cm3, at s.t.p.): 3.14

[0177] Molecular formula: Ca3(PO4)2.

[0178] Preferably, said (z) at least one phosphate salt, such as, for example, tricalcium phosphate, is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%, preferably comprised from 0.1 % to 2%, more preferably comprised from 0.3% to 1.5%, even more preferably comprised from 0.5% to 1 %, for example, comprised from 0.35% to 0.85%.

[0179] Preferably, said (z) at least one phosphate salt such as, for example, tricalcium phosphate is present in a weight ratio (expressed as a mass ratio) relative to the weight of said (b) at least one phospholipid, preferably a phosphatidylcholine or lecithin, for example a lecithin (E322) selected from sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof (preferably, sunflower lecithin) comprised from 1 :5 to 5:1 ; preferably, comprised from 1 :4 to 4: 1 ; more preferably, comprised from 1 :3 to 3: 1 ; even more preferably, comprised from 1 :2 to 2: 1 , for example, 1 : 1.

[0180] The following embodiments (EM) of the formulation in solid form of vitamin D (in short, vit D) of the invention (vitamin D cyclosome or vitamin D cyclosomal) are comprised in the present invention:

[0181] - EMa-vit D: vit D, (b) and (c), such as (c-i) or (c-ii), and (z); for example, vit D, (b) and (c-i) and (z) or vit D, (b) and (c-ii) and (z);

[0182] - EMb-vit D: vit D, (b), (c) (such as (c-i) or (c-ii)) and (d) and (z); for example, vit D, (b), (c-i) and (d) and (z) or vit D, (b), (c-ii) and (d) and (z);

[0183] - EMc-vit D: vit D, (b), (c) (such as (c-i) or (c-ii)) and (z) and (e); for example, vit D, (b), (c-i) and (z) and (e) or vit D, (b), (c-ii) and (z) and (e);

[0184] - EMd-vit D: vit D, (b), (c) (such as (c-i) or (c-ii)), (d) and (z) and (e); for example, vit D, (b), (c-i), (d) and (z) and (e) or vit D, (b), (c-ii), (d) and (z) and (e); wherein the components designated (a), (b), (c-i), (c-ii), (d) and (z) and (e) are as defined in the present invention.

[0185] Preferably, said formulation in solid form of vitamin D (referred to as vitamin D cyclosome or vitamin D cyclosomal) comprises or, alternatively, consists of:

[0186] (a-i) vitamin D (cholecalciferol) (e.g., CAS No. 67-97-0); (b) at least one phospholipid, preferably a phosphatidylcholine or lecithin, for example a lecithin (E322) selected from sunflower lecithin, corn lecithin, soy lecithin and mixtures thereof (preferably sunflower lecithin);

[0187] (c) a polysaccharide selected from (c-i) at least one carrageenan (e.g., E407) or (c-ii) at least one acacia gum (e.g., E414) and mixtures thereof; and / or

[0188] (d) at least one sucrester (e.g., E473);

[0189] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin D; and, optionally, (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0190] Said (z) at least one phosphate salt as a stabilizing agent for said at least one vitamin, said (z) is selected from tricalcium phosphate salts such as, for example, without in any way limiting the choice of possible phosphate salts that can be used, that of the type, for example:

[0191] Formula: Ca3(PO4)2

[0192] Molar mass: 310.18 g / mol

[0193] Density: 3.14 g / cm3

[0194] CAS number: 7758-87-4

[0195] Melting point: 1 ,391 °C (1 ,664 K)

[0196] Density (g / cm3, at s.t.p.): 3.14

[0197] Molecular formula: Ca3(PO4)2.

[0198] Preferably, said (z) at least one phosphate salt, such as, for example, tricalcium phosphate, is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%, preferably comprised from 0.1 % to 2%, more preferably comprised from 0.3% to 1.5%, even more preferably comprised from 0.5% to 1 %, for example, comprised from 0.35% to 0.85%.

[0199] Preferably, said (z) at least one phosphate salt such as, for example, tricalcium phosphate is present in a weight ratio (expressed as a mass ratio) relative to the weight of said (b) at least one phospholipid, preferably a phosphatidylcholine or lecithin, for example a lecithin (E322) selected from sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof (preferably, sunflower lecithin) comprised from 1 :5 to 5:1 ; preferably, comprised from 1 :4 to 4: 1 ; more preferably, comprised from 1 :3 to 3: 1 ; even more preferably, comprised from 1 :2 to 2: 1 , for example, 1 : 1.

[0200] The following embodiments (EM) of the formulation in solid form of vitamin E (in short, vit E) of the invention (vitamin E cyclosome or vitamin E cyclosomal) are comprised in the present invention:

[0201] - EMa-vit E: vit E, (b) and (c), such as (c-i) or (c-ii), and (z); for example, vit E, (b) and (c-i) and (z) or vit E, (b) and (c-ii) and (z);

[0202] - EMb-vit E: vit E, (b), (c) (such as (c-i) or (c-ii)) and (d) and (z); for example, vit E, (b), (c-i) and (d) and (z) or vit E, (b), (c-ii) and (d) and (z); - EMc-vit E: vit E, (b), (c) (such as (c-i) or (c-ii)) and (z) and (e); for example, vit E, (b), (c-i) and (z) and (e) or vit E,

[0203] (b), (c-ii) and (z) and (e);

[0204] - EMd-vit E: vit E, (b), (c) (such as (c-i) or (c-ii)), (d) and (z) and (e); for example, vit E, (b), (c-i), (d) and (z) and (e) or vit E, (b), (c-ii), (d) and (z) and (e); wherein the components designated (a), (b), (c-i), (c-ii), (d), and (z) and (e) are as defined in the present invention.

[0205] Preferably, said formulation in solid form of vitamin E (referred to as vitamin E cyclosome or vitamin E cyclosomal) comprises or, alternatively, consists of:

[0206] (a-i) vitamin E (tocopherol) (e.g., CAS No. 59-02-9);

[0207] (b) at least one phospholipid, preferably a phosphatidylcholine or lecithin, for example a lecithin (E322) selected from sunflower lecithin, corn lecithin, soy lecithin and mixtures thereof (preferably sunflower lecithin);

[0208] (c) a polysaccharide selected from (c-i) at least one carrageenan (e.g., E407) or (c-ii) at least one acacia gum (e.g., E414) and mixtures thereof; and / or

[0209] (d) at least one sucrester (e.g., E473);

[0210] (z) at least one phosphate salt as a stabilizing agent for said (a) at least one vitamin E; and, optionally, (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0211] Said (z) at least one phosphate salt as a stabilizing agent for said at least one vitamin, said (z) is selected from tricalcium phosphate salts such as, for example, without in any way limiting the choice of possible phosphate salts that can be used, that of the type, for example:

[0212] Formula: Ca3(PO4)2

[0213] Molar mass: 310.18 g / mol

[0214] Density: 3.14 g / cm3

[0215] CAS number: 7758-87-4

[0216] Melting temperature: 1 ,391 °C (1 ,664 K)

[0217] Density (g / cm3, at s.t.p.): 3.14

[0218] Molecular formula: Ca3(PO4)2.

[0219] Preferably, said (z) at least one phosphate salt, such as, for example, tricalcium phosphate, is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%, preferably comprised from 0.1 % to 2%, more preferably comprised from 0.3% to 1.5%, even more preferably comprised from 0.5% to 1 %, for example, comprised from 0.35% to 0.85%.

[0220] Preferably, said (z) at least one phosphate salt such as, for example, tricalcium phosphate is present in a weight ratio (expressed as a mass ratio) relative to the weight of said (b) at least one phospholipid, preferably a phosphatidylcholine or lecithin, for example a lecithin (E322) selected from sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof (preferably, sunflower lecithin) comprised from 1 :5 to 5:1 ; preferably, comprised from 1 :4 to 4: 1 ; more preferably, comprised from 1 :3 to 3: 1 ; even more preferably, comprised from 1 :2 to 2: 1 , for example, 1 : 1.

[0221] Phospholipids are phosphate-containing lipids. Molecules of this class of organic compounds have a water-soluble polar head (i.e., soluble in water and insoluble in nonpolar solvents) based on phosphate and a nonpolar hydrophobic tail that is not water-soluble (i.e., insoluble in water and soluble in nonpolar solvents), which is why they are called amphipathic molecules.

[0222] Phosphoglycerides (also called glycerophospholipids) represent the most important class of phospholipids.

[0223] Glycerophospholipids (or phosphoglycerides) are all derived from sn-glycerol-3-phosphate, in which glycerol (CH2OH-CHOH-CH2OH) is esterified in position 3 with orthophosphoric acid (H3PO4). In glycerophospholipids, glycerol is esterified in position 2 with a fatty acid, while different classes of compounds can be bound in position 1 ; since carbon 2 is asymmetric, there are two possible stereoisomers: L and D. In nature, glycerophospholipids all belong to the L series.

[0224] Depending on the nature of the molecule that binds to position 1 of glycerol, three subclasses of phosphoglycerides can be distinguished: 1 ,2-di-acyl-phospholipids, 1-alkyl-2-acyl-phospholipids, and 1-alkenyl-2-acyl-phospholipids.

[0225] Di-acyl-phospholipids (phosphoglycerides) derive from the structure of triglycerides, where a fatty acid is replaced by a phosphate group that gives the molecule a negative charge and therefore polarity; this molecule has the generic name of phosphatide. A more complex organic molecule, generally serine, choline, ethanolamine, inositol, or a single hydrogen atom, is linked to the phosphate group via an ester bond, giving rise to a phospholipid called, respectively, phosphatidylserine, phosphatidylcholine (or lecithin), phosphatidylethanolamine, phosphatidylinositol, or phosphatidic acid.

[0226] Di-acyl-phospholipids are characterized by a water-soluble polar head, which dissolves well in water, while the two saturated fatty acids represent the two non-polar tails, which are not water-soluble but lipophilic.

[0227] The term lecithin refers to a class of chemical compounds found in animal and plant tissues (particularly in egg yolk). From a chemical point of view, a lecithin is a phosphatidylcholine ((R)-1-oleoyl-2-palmitoyl- phosphatidylcholine) or, alternatively, a lecithin comprises phosphatidylcholine as its main component.

[0228] A phosphatidylcholine is a phosphoglyceride in which phosphatidic acid is esterified with choline. Phosphatidic acids are the simplest phosphoglycerides, formally produced by the esterification of glycerol in positions 1 and 2 with fatty acids and in position 3 with orthophosphoric acid.

[0229] Lecithin is a natural emulsifier thanks to its chemical and physical properties, and has a secondary antioxidant function, being rich in natural antioxidants.

[0230] A lecithin E322 is a food additive (emulsifier). The term "E322" defines lecithin as a food additive permitted by European legislation and regulated by Italian Ministerial Decree D.M.1996. Directive 2008 / 84 / EC of August 27, 2008 (published in the Official Journal of the European Union No. L253) establishes the purity requirements that a lecithin must meet in order to be considered of food grade (lecithin E322): insoluble in acetone (practically the active part of lecithin): 60% min.; moisture: 2% max.; acid value: 35 max.; peroxide value: 10 max.; insoluble in toluene (basically the impurities): 0.3% max.

[0231] Advantageously, the (b) phospholipids of the present invention, included in the formulation of at least one vitamin of the present invention together with (a), (c) such as (c-i) or (c-ii), and / or (d), (z) and / or (e), are phosphoglycerides selected from 1 ,2-diacyl-phospholipids, 1-alkyl-2-acyl-phospholipids, 1 -alkenyl-2-acyl-phospholipids, preferably di- acyl-phospholipids.

[0232] Preferably, said at least one phospholipid (b), included in the formulation of a vitamin of the invention together with (a), (c) such as (c-i) or (c-ii), and / or (d), (z) and / or (e), is a phosphoglyceride, preferably a di-acyl-phospholipid, more preferably selected from the group of di-acyl-phospholipids comprising or, alternatively, consisting of: phosphatidylcholine or lecithin, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid and mixtures thereof; preferably phosphatidylcholine or lecithin (e.g., E322); more preferably sunflower lecithin (e.g., E322), corn lecithin (e.g., E322) or soy lecithin (e.g., E322); even more preferably allergen-free lecithin (e.g., E322), for example allergen-free sunflower lecithin (e.g., E322).

[0233] Advantageously, said lecithin (e.g., E322) is a lecithin (e.g., E322) in powder or granule form, preferably a sunflower lecithin (e.g., E322), corn lecithin (e.g., E322) or soy lecithin (e.g., E322) in powder or granule form, even more preferably an allergen-free sunflower lecithin (e.g., E322), corn lecithin (e.g., E322) or soy lecithin (e.g., E322) in powder or granule form. The term "allergen-free" means that it has no allergen residues.

[0234] In the case wherein said (b) phosphatidylcholine or lecithin (e.g., E322) is a lecithin in powder or granule form, the lecithin may have, for example, a water content by weight% in the range from 1.5% to 4.5% relative to the weight of the lecithin, preferably from 2% to 4%, and more preferably from 2.5% to 3.5%.

[0235] In the case where said (b) phosphatidylcholine or lecithin is a sunflower lecithin, e.g., E322, preferably in powder or granule form, the lecithin may have, for example, a glucose content in % by weight in the range from 20% to 60% relative to the weight of the lecithin, preferably from 30% to 50%, for example approximately 45%. A (b) sunflower lecithin, e.g., E322, preferably in powder or granule form, usable in the context of the present invention may have the following composition in % by weight (chemical-physical analysis): sunflower lecithin from 40% to 50%, carbohydrates from 40% to 50% (e.g., approximately 42%), proteins from 6% to 10%, ash from 3% to 8%, moisture from 2% to 5%, and a flow agent from 0.5% to 1 .5%.

[0236] For example, said (b) lecithin, included in the formulation at least one vitamin of the invention together with (a), (c) such as (c-i) or (c-ii) and / or (d), (z) and / or (e), does not comprise or, alternatively, does not consist of a decomposed or hydrolyzed lecithin, and does not comprise or, alternatively, does not consist of an enzymatically decomposed or hydrolyzed lecithin.

[0237] For example, said (b) lecithin, included in the formulation of at least one vitamin of the invention together with (a), (c) such as (c-i) or (c-ii) and / or (d), (z) and / or (e), may preferably be a lecithin (e.g., E322) that is not enzymatically decomposed or hydrolyzed.

[0238] Preferably, in the formulation according to the present invention (comprising (a) a vitamin, (b), (c) such as (c-i) or (c-ii), and / or (d), (z) and / or (e)), the weight ratio [(c) and / or (d)] : (b) (i.e., the total weight of a polysaccharide (i.e., carrageenan or acacia gum) and sucrester: a phospholipid (preferably a lecithin, more preferably sunflower lecithin)) is comprised from 50: 1 to 10:1 (e.g., 45: 1 , 40:1 , 35: 1 , 30: 1 , 25:1 , 20: 1 , or 15:1), preferably from 40:1 to 10: 1 , more preferably from 30:1 to 15:1 (e.g., approximately 17:1 or 17:0.6-0.5).

[0239] Preferably, in the formulation in solid form of a vitamin according to the present invention, components (a), (b), (c) such as (c-i) or (c-ii), and / or (d), (z) and / or (e) are comprised in said formulations in the following amounts expressed as a percentage by weight relative to 100 of the total weight of the formulation:

[0240] - said (b) phospholipid, preferably lecithin or sunflower lecithin (e.g., E322), is comprised from 0.05% to 15%, preferably from 0.1 % to 5%, more preferably from 0.1 % to 2%, for example about 0.5-1 .0%;

[0241] - the sum of (c) first agent (a polysaccharide, such as (c-i) carrageenan or (c-ii) acacia gum) and / or (d) sucrester (sucrester optionally present in the formulation) is comprised from 1% to 50% (e.g., 10%, 20%, 30%, or 40%), preferably from 5% to 35%, more preferably from 10% to 25%, for example 15%-20% (such as 16%, 17%, or 18%); and

[0242] - said (a) at least one vitamin varies with its weight;

[0243] - said (e) starch, optional, varies with said percentage of vitamin;

[0244] - said (z) at least one phosphate salt, preferably a tricalcium phosphate, is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%; preferably, it is comprised from 0.1 % to 2%; more preferably, it is comprised from 0.3% to 1.5%; even more preferably, it is comprised from 0.5% to 1 %, for example, comprised from 0.35% to 0.85%, or

[0245] - said (z) at least one phosphate salt, preferably a tricalcium phosphate, is present in a weight ratio, relative to the weight of said (b) at least one phospholipid, comprised from 1 :5 to 5:1 ; preferably, comprised from 1 :4 to 4:1 ; more preferably, comprised from 1 :3 to 3:1 ; even more preferably, comprised from 1 :2 to 2:1.

[0246] Preferably, the formulation in solid form of a vitamin of the invention, comprising (a), (b), (c) such as (c-i) or (c-ii), and / or (d), (z) and / or (e), comprises the following amounts expressed as a percentage by weight relative to 100 of the total weight of the formulation:

[0247] - said (b) phospholipid, preferably lecithin or sunflower lecithin (e.g., E322), from about 0.5-1 .0%; - the sum of (c) first agent (a polysaccharide, such as (c-i) carrageenan or (c-ii) acacia gum) and / or (d) sucrester (sucrester optionally present) from 15% to 20% (such as 16%, 17%, or 18%); and

[0248] - said (a) at least one vitamin varies with its weight;

[0249] - said (e) starch, optional, varies with said percentage of vitamin.

[0250] In 100 parts by weight of said sum of (c) first agent (a polysaccharide, such as (c-i) carrageenan or (c-ii) acacia gum) and / or (d) sucrester, said (c) first agent may be present at 100% and said (d) at zero%, or, alternatively, said (c) first agent may be present at zero% and said (d) at 100%, or said (c) first agent and / or (d) may be present in all variable combinations between them expressed as % (percentage to 100); or said (c) first agent is comprised in a percentage by weight from 1 % to 100% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) and said (d) sucrester ranges from 0% (absent) to 99% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%); preferably said (c) first agent from 50% to 95% and said (d) sucrester from 5% to 50% (e.g., (c) about 50% and (d) about 50%), or said (c) first agent from 70% to 95% and said (d) sucrester from 5% to 30% (e.g., (c) 70% - 80% and (d) 20% - 30%, or (c) about 75% and (d) about 25%), or said (c) first agent from 5% to 30% and said (d) sucrester from 70% to 95% (e.g., (c) 20% - 30% and (d) 70% - 80%, or (c) about 25% and (d) about 75%). Advantageously, in formulations of a vitamin according to the present invention, in 100 parts by weight of said sum of (c) first agent (a polysaccharide, such as (c-i) carrageenan or (c-ii) acacia gum) and (d) sucrester, said (c) first agent is zero% and said (d) is 100%, or said (c) first agent is about 75% and said (d) sucrester is about 25%, or vice versa.

[0251] Preferably, in the formulation in solid form of a vitamin of the invention (vitamin C, B12, or E), components (a), (b), (c) (such as (c-i) or (c-ii)), and / or (d), (z) and / or (e) are present in said formulation in the following amounts expressed as a percentage by weight relative to the total weight of the formulation:

[0252] - said (a) vitamin C or vitamin B12 or vitamin E is in the range from 20% to 80% (e.g., 25%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%), preferably from 45% to 60% (e.g., approximately 50-55%);

[0253] - said (b) phospholipid, preferably phosphoglyceride, more preferably phosphatidylcholine or lecithin, even more preferably solid lecithin (E322) or solid sunflower lecithin (E322), is comprised from 0.05% to 10% (e.g., 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1 %, 2%, 3%, 4%, 5%, or 8%), preferably approximately from 0.1 % to 2% (e.g., approximately 1 ,0±0.1%);

[0254] - said (c) first agent (a polysaccharide), such as (c-i) carrageenan or (c-ii) acacia gum, or, alternatively, the sum of said (c) first agent and said (d) sucrester (E473), is included in a range from 1 % to 50% (e.g., 3%, 5%, 7%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, or 40%), preferably about 10% to 25% (e.g., about 15±1 to 20±1 %); and

[0255] - if present, said (e) starch, preferably pregelatinized rice starch, is comprised in a range from 5% to 60% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55%), preferably about from 20% to 40% (e.g., about 30±0.1 %); - said (z) at least one phosphate salt, preferably a tricalcium phosphate, is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%; preferably, it is comprised from 0.1 % to 2%; more preferably, it is comprised from 0.3% to 1 .5%; more preferably, it is comprised from 0.5% to 1 %, for example, comprised from 0.35% to 0.85%, or

[0256] - said (z) at least one phosphate salt, preferably a tricalcium phosphate, is present in a weight ratio, relative to the weight of said (b) at least one phospholipid, comprised from 1 :5 to 5:1 ; preferably, comprised from 1 :4 to 4:1 ; more preferably, comprised from 1 :3 to 3:1 ; even more preferably, comprised from 1 :2 to 2:1.

[0257] Preferably, in the formulation in solid form of vitamin D3 of the invention, components (a), (b), (c) (such as (c-i) or (c-ii)), and / or (d), (z) and / or (e) are present in said formulation in the following amounts expressed as a percentage by weight relative to the total weight of the formulation:

[0258] - said (a) vitamin D3 (commercial) is in a range from 50% to 95% (e.g., 60%, 70%, 75%, 80%, 85%, or 90%), preferably about from 80% to 90% (e.g., 85%), wherein the amount of pure vitamin D3 (or vitamin D3 as such) is about 0.10% - 0.25% (e.g., 0.12%, 0.14%, 0.16%, 0.18%, 0.20%, 0.22%, or 0.24%), preferably about 0.20±1 %;

[0259] - said (b) phospholipid, preferably phosphoglyceride, more preferably phosphatidylcholine or lecithin, even more preferably solid lecithin (E322) or solid sunflower lecithin (E322), is comprised in a range from 0.05% to 10% (e.g., 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, or 8%), preferably approximately from 0.1 % to 2% (e.g., approximately from 0.5±0.1 to 1 ,0±0.1 %);

[0260] - said (c) first agent (a polysaccharide), such as (c-i) carrageenan or (c-ii) acacia gum, or, alternatively, the sum of said (c) first agent and (d) sucrester (E473), is comprised in a range from 1 % to 50% (e.g., 3%, 5%, 7%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, or 40%), preferably about from 5% to 20% (e.g., about from 10±1 to 15±1 %); and

[0261] - if present, said (e) starch, preferably pregelatinized rice starch, is comprised in a range from 0.05% to 10% (e.g., 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, or 8%), preferably approximately from 0.1 % to 2% (e.g., approximately 1 ,0±0.1 %).

[0262] It is understood that, in the formulation in solid form of vitamin D3 according to the present invention, the amount of commercial vitamin D3 may vary depending on the amount of pure vitamin D3 (or vitamin D3 as such) included in said commercial vitamin D3, in order to have in the formulation of the invention a percentage by weight of pure vitamin D3 of approximately 0.10%-0.25%, preferably approximately 0.20±1 %, relative to the weight of the formulation.

[0263] Carrageenan is a food additive (thickener, stabilizer, gelling agent, emulsifier) permitted by European and Italian legislation and classified according to European regulations as food additive "E407."

[0264] Carrageenan or carraghenin (INCI Name: Carrageenan EU INCI Name: Chrondrus Chrispus Powder) is a product derived from carragheen, whose name derives from the town of Carragheen in Ireland. Carrageenans are a complex group of linear polysaccharides, often sulfates, extracted from red algae. They are high molecular weight compounds, i.e., very large molecules, characterized by repeating units of galactose and 3,6-anhydrogalactose (3,6-AG), both sulfated and non-sulfated. The units alternate with alpha 1-3 and beta 1-4 glycosidic bonds. Given their structure, carrageenans behave like highly flexible molecules that curl up to form helical structures. The spatial arrangement of the molecule generally gives it the ability to form a wide variety of different gels at room temperature. There are mainly three commercial classes of carrageenan: lambda, kappa, and iota.

[0265] Carrageenan consists essentially of calcium, potassium, sodium, and magnesium salts of sulfuric esters of polysaccharides which, upon hydrolysis, yield galactose and 3,6-anhydrogalactose. Carrageenan must not be hydrolyzed or otherwise chemically degraded. It comes in the form of a coarse to fine powder, yellowish to colorless in color and practically odorless.

[0266] Carrageenan is a gelatin widely used in food, medicine, and industry (used to clarify honey and beer, in paper manufacturing, finishing agents, and more), especially in Ireland and Great Britain; it is obtained by boiling two red algae from the rocky coast of the North Atlantic (Chondrus crispus and Gigartina mamitiosa), known as Irish moss, sea lichen, or carragheen.

[0267] An example of (c-i) carrageenan that can be used in the present invention is a CSW-2 type carrageenan (Genuvisco®, registered trademark, CP Kelco) standardized with sucrose; CAS 9000-07-1 , 57-50-1 ; according to European standard E407; pH (0.5% solution) 7.0-10.0; loss on drying <=12.0, instant viscosity-high salts <=12; instant viscosity-low salts >=50.

[0268] Said (c-i) carrageenan can be obtained according to methods known to those skilled in the art, for example by extraction from marine algae with water and Ca(OH)2 at high temperature (e.g. slightly >100°C), neutralization and precipitation with ethanol or isopropanol.

[0269] Acacia gum or gum arabic is a food additive (thickener, stabilizer, emulsifier) permitted by European and Italian legislation and classified according to European regulations as food additive "E414."

[0270] Acacia gum is a natural gum of plant origin called acacia gum because it is extracted from two species of sub- Saharan acacia: Acacia Senegal (L) and Acacia seyal. In particular, acacia gum is a dry exudate obtained from the trunks and branches of natural acacia and related trees.

[0271] Gum arabic is a complex mixture of high molecular weight polysaccharides (Mw 250,000-400,000), their calcium, magnesium, and potassium salts, and glycoproteins, which give it one of its most important properties: complete edibility. It is composed of several components: arabinose, D-galactopyranose, rhamnopyranose, D-glucuronic acid, calcium, magnesium, potassium, sodium, and mucilage.

[0272] Like almost all gums and resins of plant origin, it is produced by the plant following a natural "gumming" process, which is activated spontaneously to heal a vulnus (wound) to its surface integrity. It is an excipient used mainly in the food industry as a "stabilizer," but it also has viscosity control functions in certain inks. An example of (c-ii) acacia gum that can be used in the present invention is acacia gum having CAS No. 232-519- 5, EINECS 232-519-5, compliant with E414, purity min. 99.9%, loss on drying max. 10%, total ash max. 4%, viscosity (20°C) min. 60 cps., specific optical rotation 30-60° (commercial example gum arabic 386° from Chimab, code 306045).

[0273] Acacia gums are obtained using methods known to those skilled in the art, which include the steps of centrifugation, filtration, heating, and drying.

[0274] The code "E473" indicates that sucresters or saccharide esters of fatty acids are food additives (emulsifiers) permitted by European legislation and regulated by Italian Ministerial Decree D.M.1996.

[0275] "Sucresters" are generally obtained from the esterification of fatty acids or from the trans-esterification of methyl esters of fatty acids with carbohydrates (also known as saccharides). The carbohydrates used are generally sucrose (monosaccharide) and polysaccharides, which is why sucresters are also called "sucrose esters of fatty acids." The chemical and physical properties of these compounds depend on the number and type of esterified fatty acids.

[0276] They are essentially emulsifiers and are added to compositions in order to improve the stabilization of an aqueous phase with a fatty phase.

[0277] For example, a (d) sucrester (E473) that can be used in the context of the present invention may be a sucrester having an HLB (hydrophilic-lipophilic balance) value in the range from 14 to 18, preferably an HLB value of about 15 or 16.

[0278] A sucrester (E473) that can be used in the context of the present invention may have the following composition by total ester content of at least 90%, of which at least 70% by weight, relative to the total weight of the sucrester, of monoesters obtained by esterification of sucrose with one or more fatty acids of plant origin, preferably stearic acid and / or palmitic acid; free fatty acid content (as oleic acid) not exceeding 3%; free sucrose content not exceeding 2%; moisture not exceeding 4%; acidity value not exceeding 5. An example of commercial sucrester (d) that can be used in the context of the present invention is: sucrose esters SP70 from Chimab S.p.A. - Italy.

[0279] Preferably, said (d) sucrester, comprised in the formulation of at least one vitamin of the invention together with (a), (b), (c) such as (c-i) or (c-ii) and / or (d), (z) and, optionally, (e), does not comprise or, alternatively, does not consist of, for example, of a polyglycerol fatty acid ester.

[0280] Preferably, the formulation of at least one vitamin of the invention comprises, together with (a), (b), (c) such as (c- i) or (c-ii), and / or (d), (z), also a (e) starch of plant origin, preferably gelatinized or pregelatinized; preferably, said (e) starch of plant origin is selected from rice starch and / or corn starch; preferably, said (e) starch of plant origin is rice starch (Oryza sativa) or native rice starch, preferably gelatinized or pregelatinized; more preferably, said (e) starch of plant origin is pregelatinized rice starch. A pregelatinized rice starch (e) that can be used in the context of the present invention may have, for example, the following chemical-physical characteristics: moisture content not exceeding 7%; protein content not exceeding 1 %; ash content not exceeding 1 %; pH (10% solution) comprised from 5.5 to 7.5, density 0.40-0.48 g / cm3; minimum starch content of 97% and fat content not exceeding 0.1 %. An example of commercial pregelatinized rice starch is AX-FG-P from Reire Sri, Italy.

[0281] It is an object of the present invention a composition (in short, the composition of the invention), preferably in solid form, which comprises or, alternatively, consists of: at least one solid formulation of a vitamin (vitamin formulation of the invention) comprising or, alternatively, consisting of (a), (b), (c) such as (c-i) or (c-ii), and / or (d), (z) and / or (e) according to any one of the embodiments described in the present invention (e.g., EM-vit B12 from (a) to (d), EM- vit C from (a) to (d), EM-vit D from (a) to (d), EM-vit E from (a) to (d),) and, optionally, said composition comprises at least one acceptable pharmaceutical or food grade additive and / or excipient.

[0282] Said at least one additive and / or excipient of acceptable pharmaceutical or food grade may be selected from all substances known to those skilled in the art of pharmaceutical technology or food preparation, such as preservatives, emulsifiers and / or thickeners, such as hydroxymethylcellulose, sweeteners, colorants such as colorant E171, natural and artificial flavorings, antioxidants, stabilizers, fillers, anti-caking agents, such as vegetable magnesium stearate, magnesium salts of fatty acids, and silicon dioxide, bulking agents, such as microcrystalline cellulose, and mixtures thereof.

[0283] Preferably, said composition of the invention may comprise a single formulation in solid form of a vitamin (e.g., vitamin B12, C, D3, or E).

[0284] Preferably, said composition of the invention may comprise two, three, or four formulations in solid form of said vitamins (e.g., vitamin B12, C, D3, and / or E).

[0285] Preferably, the vitamin (or vitamins), such as vitamin B12, C, D3, and / or E, is present in the composition of the invention in the form of a formulation according to the invention, wherein said formulation comprises (a) said at least one vitamin, (b) a phospholipid (preferably lecithin), (c) a first agent (preferably (c-i) carrageenan or (c-ii) acacia gum) and / or (d) a sucrester, (z) and / or (e) a starch; or comprises (a) said at least one vitamin, (b) a phospholipid (preferably lecithin), (d) a sucrester, (z) and / or (e) a starch.

[0286] Preferably, the compositions of the invention are in solid form, for example in solid form as such or in solid orosoluble form (or orodispersible, which dissolve in the oral cavity) or in solid hydrodispersible form.

[0287] Alternatively, the compositions of the invention may be in liquid form, for example as a solution, dispersion, or suspension of a solid in a liquid, or in semi-solid form, for example as creams, gels, or soft gels. Preferably, the compositions of the invention are formulated for oral administration (in short, PO).

[0288] Advantageously, the compositions of the invention are in solid form as such or orosoluble or hydrodispersible for oral administration, such as, for example, powder, granules, microgranules, flakes, tablets, or capsules.

[0289] If the compositions of the invention are in tablet form, said tablet may have a weight in a range comprised from 100 mg to 1500 mg, for example a hard tablet of 200 mg, or 500 mg, or from 800 mg to 1000 mg.

[0290] Said tablets may be coated or film-coated with one or more layers or coating films capable of passing through the gastric barrier. Said coating may comprise beeswax or a sugar-based solution.

[0291] If the compositions of the invention are in capsule form, said capsule may be made of hard gelatin or soft gelatin or soft-gel; preferably, a gelatin capsule may have a weight in a range comprised from 100 mg to 1500 mg, more preferably about 200 mg, or 500 mg, or 800 mg.

[0292] The composition of the invention, comprising said formulation in solid form of at least one vitamin, may be a pharmaceutical composition, a composition for a medical device, a dietary supplement, a food or novel food or nutraceutical composition, or a food for special medical purposes (FSMP).

[0293] The term "medical device" in the context of the present invention is used in the meaning according to Italian Legislative Decree No. 46 of February 24, 1997, or according to the new Medical Devices Regulation (EU) 2017 / 745 (MDR).

[0294] It is an object of the present invention a formulation in solid from of at least one vitamin of the invention, comprising or, alternatively, consisting of (a), (b), (c) such as (c-i) or (c-ii), and / or (d), (z) and / or (e) according to any one of the described embodiments, and the compositions of the invention comprising said formulations of at least one vitamin of the invention, according to any one of the described embodiments, for use as a medicament, either as a main medicament or as a medicament supporting other medicaments (adjuvant).

[0295] It is an object of the present invention the compositions and formulations of at least one vitamin of the present invention (such as vitamin A, of the B group (e.g., B12), C, D (e.g. D3) and / or E), according to any one of the embodiments described, for use in a method of preventive and / or curative treatment of a deficiency or insufficiency of said at least one vitamin, and of pathologies, symptoms and / or disorders associated with said deficiency, or for use for the supplementation of said at least one vitamin in subjects in need.

[0296] Pathologies, symptoms, and / or disorders associated with said deficiency or insufficiency of at least one vitamin (such as vitamin A, of the B group (e.g., B12), C, D (e.g. D3) and / or E), which can be treated preventively and / or curatively and / or supportively by administering to a subject said compositions or formulations of at least one vitamin of the present invention, may be selected from:

[0297] - alterations in carbohydrate metabolism and / or pathologies and disorders associated with them, such as, for example, diabetes, preferably type II diabetes mellitus, hyperglycemia, insulin resistance, high carbohydrate absorption, dysregulation of blood glucose levels, and / or metabolic syndrome;

[0298] - alterations in muscle energy metabolism and / or disorders associated with them, such as, for example, reduction in muscle mass, reduction in muscle strength, reduction in physical resistance to muscular effort, poor absorption of amino acids;

[0299] - dyslipidemia or alterations in lipid metabolism and associated pathologies and disorders, such as, for example, cholesterolemia, high triglyceride levels, and obesity or overweight;

[0300] - cognitive disorders or alterations in the cognitive-emotional sphere;

[0301] - cardiometabolic disorders: - alterations in the immune system; - states of stress associated with anxiety and depression, fatigue, chronic fatigue, and / or asthenia in individuals in need.

[0302] The compositions and formulations comprising at least one vitamin of the present invention can be administered to any category of subjects, including pediatric subjects, the elderly, athletes, pregnant women, preferably women both during pregnancy and in the period after pregnancy, and women before, during, and after their menstrual cycle.

[0303] In addition, it is an object of the present invention said composition and formulation of at least one vitamin of the invention (such as vitamin A, of the B group (e.g., B12), C, D (e.g. D3) and / or E), according to any one of the described embodiments, for use in a preventive and / or curative and / or supportive method of treatment (both therapeutic and non-therapeutic) to increase muscle energy metabolism (both for therapeutic and non-therapeutic purposes) and, thereby, increase muscle mass, increase muscle strength, increase physical endurance to muscular effort, and reduce recovery times after physical effort, in a subject in need or in a healthy subject; and / or to increase the physical or mental performance of a subject, preferably a healthy subject, for example a subject who exercises and / or studies.

[0304] Advantageously, the compositions or formulations comprising vitamin B12 (according to any one of the embodiments described in the present invention) find valid use in preventing, reducing, or treating a vitamin B12 deficiency. Pathologies or symptoms associated with vitamin B12 deficiency are, for example: weakness and physical fatigue, shortness of breath, tingling in the extremities, memory loss or cognitive difficulties, difficulty walking due to balance problems, hallucinations, anemia, and paleness. Said formulation is called "Vitamin B12 cyclosome or Vitamin B12 cyclosomal".

[0305] Advantageously, the compositions or formulations comprising vitamin C (according to any one of the embodiments described in this invention) find valid use in preventing, reducing, or treating a vitamin C deficiency. Pathologies or symptoms associated with vitamin C deficiency are, for example: fatigue, depression, connective tissue defects (e.g., collagen, gingivitis, petechiae, skin rashes, internal bleeding, and delayed wound healing), brittle nails, skin, and hair following inflammation or medical treatment, impaired bone growth in children, immune system alterations, and oxidative stress. Said formulation is called "Vitamin C cyclosome or Vitamin C cyclosomal".

[0306] Advantageously, the compositions or formulations comprising vitamin D (according to any one of the embodiments described in the present invention) find valid use in preventing, reducing, or treating a vitamin D deficiency. Pathologies or symptoms associated with vitamin D deficiency are, for example: rachitis in children and osteomalacia in adults (due to impaired bone mineralization), osteoporosis, and hyperparathyroidism, immune system alterations. Said formulation is called "Vitamin D cyclosome or Vitamin D cyclosomal".

[0307] Advantageously, the compositions or formulations comprising vitamin E (according to any one of the embodiments described in the present invention) find valid use in preventing, reducing, or treating a vitamin E deficiency. Pathologies or symptoms associated with vitamin E deficiency (especially in pediatric subjects) are, for example: impaired reflexes and coordination, difficulty walking, muscle weakness, a form of anemia in which red blood cells break down (hemolytic anemia), hair loss, skin diseases, weak immune system, fatigue, difficulty concentrating, vision problems, loss of muscle tone, and oxidative stress. Said formulation is called "Vitamin E cyclosome or Vitamin E cyclosomal."

[0308] In order to treat a vitamin C deficiency (for both therapeutic and non-therapeutic or cosmetic purposes), and pathologies or symptoms associated with said deficiency, daily oral administration of a therapeutically effective amount known to the technician in the field of vitamin C formulation of the present invention (vitamin C cyclosomal) or compositions thereof is indicated, for example, an amount of pure (or as such) vitamin C in the range form 100 mg to 1500 mg (e.g., 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg), preferably from 500 mg to 1000 mg, for example approximately 1000 mg (currently, the maximum daily dose allowed is 1000 mg).

[0309] In order to treat a vitamin B12 deficiency (both for therapeutic and non-therapeutic or cosmetic purposes), and pathologies or symptoms associated with said deficiency, daily oral administration of a therapeutically effective amount known to the technician in the field of vitamin B12 formulation of the present invention (vitamin B12 cyclosomal) or compositions thereof is indicated, for example, an amount of pure (or as such) vitamin B12 in the range from 0.5 pig to 1000 pig (e.g., 1 pig, 1.5 pig, 2 pig, 2.5 pig, 5 pig, 10 pig, 50 pig, 100 pig, 200 pig, 300 pig, 400 pig, 500 pig, 600 pig, 700 pig, 800 pig, or 900 pig) preferably from 1 pig to 5 pig, for example approximately 2-2.5 pig (currently, the maximum daily dose allowed is 1000 pig).

[0310] In order to treat a vitamin E deficiency (for both therapeutic and non-therapeutic or cosmetic purposes), and pathologies or symptoms associated with said deficiency, daily oral administration of a therapeutically effective amount known to the technician in the field of vitamin E formulation of the present invention (vitamin E cyclosomal) or compositions thereof is indicated, for example, an amount of pure (or as such) vitamin E in the range from 0.5 mg to 80 mg (for example, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 70 mg), preferably from 5 mg to 15 mg, for example approximately 10 mg (currently, the maximum daily dose allowed is 60 mg).

[0311] In order to treat a vitamin D3 deficiency (for both therapeutic and non-therapeutic or cosmetic purposes), and diseases or symptoms associated with said deficiency, daily oral administration of a therapeutically effective amount known to those skilled in the art of vitamin D3 formulation of the present invention (vitamin D3 cyclosomal) or compositions thereof is indicated, for example, an amount of pure (or as such) vitamin D3 in the range from 1 pg to 100 pg (e.g., 5 pg, 10 pg, 15 pg, 20 pg, 25 pg, 30 pg, 50 pg, 100 pg, 150 pg, 200 pg, 250 pg, 300 pg, 350 pg, 400 pg, or 450 pg) preferably from 10 pg to 100 pg, for example approximately 25-50 pg.

[0312] The intake of the compositions or formulations of the present invention, comprising said at least one vitamin, shows significant changes in subjects after intake (efficacy). In particular, continuous intake of the compositions or formulations of the invention in the doses described above significantly improves the relative vitamin levels in treated individuals (symptomatic or healthy individuals), both in the blood and in the organs.

[0313] Furthermore, continuous intake of the compositions or formulations of the present invention in the doses described has no side effects and can be taken by all types of subjects, including pregnant women, either on a full or empty stomach.

[0314] Finally, the compositions or formulations of the present invention are easy to take, particularly if they are in solid form, and do not present problems of unpleasant palatability.

[0315] In addition, the compositions or formulations of the present invention exhibit chemical-physical and organoleptic stability over time.

[0316] The term "subject(s)" in the context of the present invention refers to human subjects or animal subjects, preferably mammals (e.g., pets such as dogs, cats, horses, sheep, or cattle).

[0317] Preferably, the formulations and compositions of the invention are for use in methods otreatment on human subjects.

[0318] The compositions of the invention or the formulations of at least one vitamin of the invention (vitamin cyclosome or vitamin cyclosomal) can be administered for a period ranging from 3 days to 60 days or 90 days.

[0319] It is an object of present invention a method for the preventive and / or curative and / or supportive treatment of a deficiency or insufficiency of at least one vitamin (such as vitamin A, of the B group (e.g., B12), C, D (e.g. D3) and / or E) or a pathology, symptom, and / or disorder associated with said deficiency, wherein said method involves administering an effective amount (therapeutically effective amount) of the composition of the invention or the formulation of at least one vitamin of the invention to a subject in need.

[0320] The term "therapeutically effective amount" refers to the amount of formulation or compound that elicits the biological or medicinal response in a tissue, system, or subject that is sought and defined by an expert in the field. Furthermore, it is an object of present invention the (non-therapeutic) use of compositions and formulations of at least one vitamin (such as vitamin A, of the B group (e.g., B12), C, D (e.g. D3) and / or E) according to any one of the described embodiments, to increase muscle energy metabolism and, therefore, increase muscle mass, increase muscle strength, increase physical resistance to muscular effort, and reduce recovery times after physical effort in a healthy subject; and / or to increase the physical or mental performance of a healthy subject; and / or to support or strengthen the immune defenses in a healthy subject.

[0321] It is an object of present invention a method (in short, method of the invention) for the preparation of formulations in solid form of at least one vitamin (such as vitamin A, of the B group (e.g., B12), C, D (e.g. D3) and / or E) (vitamin cyclosome or vitamin cyclosomal).

[0322] In a first embodiment of the invention, said method of the invention (in short, first method of the invention) is described in patent document WO 2014 / 009806 A1 from page 7 line 1 to page 8 line 20, incorporated in the present application by reference.

[0323] In a second embodiment of the invention, said method of the invention (in short, second method of the invention) is described in patent document WO 2014 / 009806 A1 from page 8 line 22 to page 10 line 21 , incorporated in the present application by reference.

[0324] According to the present invention, said first method of the invention and second method of the invention are applied as described in patent document WO 2014 / 009806 A1 considering that (c-i) and / or (c-ii), if present, may be used in place of or in addition to (d) and in amounts appropriate to obtain the formulations of the present invention, and that the term (b) lecithin should be read as representing the class of phospholipids (where (c-i) is carrageenan and (c-ii) is acacia gum, and (d) is sucrester). The method of the present invention also provides for the necessary addition of (z) at least one phosphate salt as a stabilizing agent for said at least one vitamin, said (z) being selected from tricalcium phosphate salts such as, for example, without in any way limiting the choice of possible phosphate salts that can be used, that of the type:

[0325] Formula: Ca3(PO4)2

[0326] Molar mass: 310.18 g / mol

[0327] Density: 3.14 g / cm3

[0328] CAS number: 7758-87-4

[0329] Melting temperature: 1 ,391 °C (1 ,664 K)

[0330] Density (g / cm3, at s.t.p.): 3.14

[0331] Molecular formula: Ca3(PO4)2.

[0332] Preferably, said (z) at least one phosphate salt, such as tricalcium phosphate, is added in the preparation method of the present invention in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%, preferably comprised from 0.1 % to 2%, more preferably comprised from 0.3% to 1.5%, even more preferably comprised from 0.5% to 1 %, for example, comprised from 0.35% to 0.85%.

[0333] Preferably, said (z) at least one phosphate salt, such as, for example, tricalcium phosphate, is added in the preparation method of the present invention in a weight ratio (expressed as a weight mass) relative to the weight of said (b) at least one phospholipid, preferably a phosphatidylcholine or lecithin, for example, a lecithin (E322) selected from sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof (preferably, sunflower lecithin) comprised from 1 :5 to 5: 1 ; preferably, comprised from 1 :4 to 4: 1 ; more preferably, comprised from 1 :3 to 3:1 ; even more preferably, comprised from 1 :2 to 2: 1 , for example 1 : 1.

[0334] In the context of the present invention, the term " vitamin cyclosome or cyclosomal vitamin" refers to a formulation of said at least one vitamin obtainable by processing a vitamin (a) together with a phospholipid or a phosphatidylcholine or lecithin (b), a first agent (c) (such as carrageenan (c-i) or acacia gum (c-ii)) and / or a sucrester

[0335] (d), (z) and / or a starch (e), according to said first method or said second method, described in WO 2014 / 009806 A1 , or as described in the present description.

[0336] Said method according to the invention is carried out by mixing components (a), (b), (c) and, and / or (d), (z) and / or

[0337] (e) according to the percentages by weight defined in the context of the present invention in order to obtain the formulations according to the invention comprising at least one vitamin, preferably the formulations according to the invention comprising one vitamin.

[0338] Preferably, said method of the invention for the preparation of a formulation according to the invention comprising a vitamin (preferably, only one vitamin), for example according to an embodiment described in WO 2014 / 009806 A1 , comprises the steps of:

[0339] - step 1 : providing a vitamin in powder or granule form (preferably only one vitamin);

[0340] - step 2: mixing said vitamin with a phospholipid (b) and (z), preferably lecithin (e.g., sunflower lecithin) and (z) said (z) at least one phosphate salt such as, for example, tricalcium phosphate, to give a step 2 mixture; preferably, said lecithin is not a hydrolyzed lecithin or an enzymatically hydrolyzed lecithin;

[0341] - step 3: mixing said step 2 mixture with a polysaccharide (c) (e.g. (c-i) carrageenan or acacia gum) and / or with a sucrester (d), to give a step 3 mixture; or, preferably, said step 3 involves mixing said step 2 mixture only with a sucrester (d), without polysaccharide (c), to give a step 3 mixture;

[0342] - step 4 (optional): mixing said step 3 mixture with a gelatinized or pregelatinized starch of plat origin (e), preferably pregelatinized, for example pregelatinized rice starch;

[0343] - Sstep 5 (optional after step 3 and / or after step 4): sieving, preferably with at least one sieve having a size (or nominal sieve opening) comprised in the range from 150 pm to 1400 pm (e.g., 180 pm, 212 pm, 250 pm, 300 pm, 355 pm, 425 pm, 500 pm, 600 pm, 710 pm, 850 pm, 1000 pm, , or 1180 pm), preferably from 600 pm to 850 pm, e.g., 710 pm (25 US Mesh).

[0344] Advantageously, said mixing steps 2, 3, and / or 4 are performed at room temperature (from 15°C to 30°C, preferably at about 25°C) for a time ranging from 10 minutes to 120 minutes, preferably from 15 minutes to 60 minutes, for example about 30 minutes.

[0345] Advantageously, said mixing steps 2, 3, and / or 4 are performed in the absence of solvent (dry mixing).

[0346] In the embodiment in which said sucrester (d) is present in the formulation of the invention, said step 3 of the method of the invention may involve mixing said step 2 mixture first with the polysaccharide and then with the sucrester, or, alternatively, mixing said step 2 mixture first with the sucrester and then with the polysaccharide, or, alternatively and preferably, mixing said step 2 mixture simultaneously with the sucrester and the polysaccharide, or, alternatively, when only sucrester (d) is used, said step 3 involves mixing said step 2 mixture only with a sucrester (d), without polysaccharide (c), to give a step 3 mixture;

[0347] Said method for the preparation of the formulation of the invention (based on a vitamin) may provide that step 2 and step 3 are carried out simultaneously, i.e., the vitamin(s) are mixed with the phospholipid, the sucrester in a single step (step 2+3).

[0348] According to one example of the method of the invention for preparing a formulation comprising a vitamin, said method does not include a spray-dry step.

[0349] In a preferred embodiment, said method of the invention for the preparation of a formulation according to the invention comprising vitamin B12 comprises the steps of:

[0350] - step 1 : providing a vitamin B12 in powder or granule form (preferably cyanocobalamin);

[0351] - step 2: mixing said vitamin with a phospholipid (b) and (z), preferably lecithin (e.g., sunflower lecithin) and (z), said (z) being at least one phosphate salt selected from tricalcium phosphate salts, to give a step 2 mixture; preferably, said lecithin is not a hydrolyzed lecithin or an enzymatically hydrolyzed lecithin;

[0352] - step 3: mixing said step 2 mixture with a polysaccharide (c) (e.g. (c-i) carrageenan or acacia gum) and / or with a sucrester (d), to give a step 3 mixture; or, preferably, said step 3 involves mixing said step 2 mixture only with a sucrester (d), without polysaccharide (c), to give a step 3 mixture;

[0353] - step 4 (optional): mixing said step 3 mixture with a gelatinized or pregelatinized starch of plant origin (e), preferably pregelatinized, for example pregelatinized rice starch;

[0354] - step 5 (optional after step 3 and / or after step 4): sieving, preferably with at least one sieve having a size (or nominal sieve opening) comprised in the range from 150 pm to 1400 pm (e.g., 180 pm, 212 pm, 250 pm, 300 pm, 355 pm, 425 pm, 500 pm, 600 pm, 710 pm, 850 pm, 1000 pm, or 1180 pm), preferably from 600 pm to 850 pm, for example 710 pm (25 US Mesh).

[0355] Advantageously, said mixing steps 2, 3, and / or 4 are performed at room temperature (from 15°C to 30°C, preferably at about 25°C) for a time ranging from 10 minutes to 120 minutes, preferably from 15 minutes to 60 minutes, for example about 30 minutes.

[0356] Advantageously, said mixing steps 2, 3, and / or 4 are performed in the absence of solvent (dry mixing).

[0357] Without wishing to go into specific details, the structure of the product obtained by the above method can be described as follows: a vitamin core coated with a first layer comprising a phospholipid matrix (lecithin) and tricalcium phosphate and a with second layer comprising the sucrester matrix (and, if present, carrageenan and / or acacia gum).

[0358] More preferably, said vitamin is vitamin B12, and even more preferably, it is cyanocobalamin.

[0359] Without wishing to go into specific details, the structure of the product obtained by the above method can be described as follows: a vitamin B12 core coated with a first layer comprising a phospholipid matrix (lecithin) and tricalcium phosphate and with a second layer comprising the sucrester matrix (and, if present, carrageenan and / or acacia gum).

[0360] Unless otherwise specified, the expression composition or other comprising a component in an amount "comprised in a range from x to y” means that said component may be present in the composition or formulation or other in all amounts within said range, even if not explicitly stated, including the extremes of the range.

[0361] Unless otherwise specified, the content of a component in a composition or formulation refers to the percentage by weight of that component relative to the total weight of the composition or formulation.

[0362] Unless otherwise specified, the indication that a composition "comprises" one or more components means that other components may be present in addition to the one or more specifically indicated, and the indication that a composition "consists" of certain components means that the presence of other components is excluded.

[0363] Further examples of embodiments (EMb-nr) of the present invention are provided below:

[0364] EMb-1. A formulation in solid form comprising or, alternatively, consisting of:

[0365] - (a) a nutrient, wherein said nutrient is at least one vitamin, wherein said at least one vitamin is selected from the group comprising or, alternatively, consisting of: vitamin B12, vitamin C, vitamin D3, vitamin E;

[0366] - (b) a phospholipid;

[0367] - (c) a first agent selected from (c-i) a carrageenan or (c-ii) an acacia gum and / or (d) at least one sucrester or carbohydrate ester of fatty acids; preferably sucrester E473; more preferably sucrester (e.g., E473) comprising from 70% to 90% by weight, relative to the total weight of the sucrester, of monoesters obtained by esterification of sucrose with one or more fatty acids of vegetable origin, preferably said fatty acids are selected from stearic acid and / or palmitic acid.

[0368] EMb-2. The formulation according to EMb-1 , wherein said (c) first agent consists of said (c-i) carrageenan; preferably carrageenan, e.g., E407.

[0369] EMb-3. The formulation according to EMb-1 , wherein said (c) first agent consists of said (c-ii) acacia gum; preferably an acacia gum, e.g., E414; more preferably an acacia gum E414 having an average molecular weight comprised in the range from 250,000 to 400,000.

[0370] EMb-4. The formulation according to any one of EMb-1 - EMb-3, wherein said formulation further comprises (e) a gelatinized or pregelatinized starch of plant origin; preferably, wherein said (e) starch is selected from rice starch or corn starch; preferably, wherein said starch is pregelatinized rice starch.

[0371] EMb-5. The formulation according to any one of EMb-1 - EMb-4, wherein said (b) phospholipid is a phosphatidylcholine or a lecithin; preferably, wherein said (b) phospholipid is a lecithin (e.g., E322) selected from the group omprising or, alternatively, consisting of: sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof.

[0372] EMb-6. The formulation according to any one of EMb-1 - EMb-5, wherein a weight ratio between said first agent (c) and said phospholipid (b) [(c): (b)], or, alternatively, a weight ratio between the weight of the sum of said first agent (c) and / or said sucrester (d), and the weight of said phospholipid [[(c) and / or (d)]:(b)] is comprised from 50:1 to 10: 1 , preferably from 40:1 to 10: 1 , more preferably from 30: 1 to 15:1 ; preferably wherein said (b) phospholipid is a lecithin.

[0373] EMb-7. The formulation according to any one of EMb-1 - EMb-6, wherein with respect to 100 parts by weight of a sum of said first agent (c) and said sucrester (d), said (c) first agent is 100% or zero% and said sucrester (d) is zero% or 100%, or is comprised in a percentage by weight from 1 % to 100% and said sucrester (d) is comprised from 0% (absent) to 99%; preferably said first agent (c) is from 50% to 95% and said sucrester (d) is from 5% to 50%; more preferably, said (c) first agent is from 70% to 80% and said (d) sucrester is from 20% to 30%.

[0374] EMb-8. A composition comprising:

[0375] - at least one formulation in solid form of a vitamin according to any one of EMb-1 - EMb-8; and at least one acceptable pharmaceutical or food grade additive and / or excipient.

[0376] EMb-9. The formulation or composition according to any one of EMb-1 - EMb-8 for use as a medicament.

[0377] EMb-10. The formulation or composition according to any one of EMb-1 - EMb-9 for use in a preventive and / or curative and / or supportive method of treatment of a deficiency of said (a) a vitamin, and of pathologies, symptoms or disorders connected with or resulting from said deficiency, in a subject in need.

[0378] EMb-11. The formulation or composition for use according to EMb-10, wherein said pathologies or symptoms associated with or resulting from said deficiency are selected from the group comprising or, alternatively, consisting of:

[0379] - alterations in carbohydrate metabolism and associated pathologies and disorders, diabetes, type II diabetes mellitus, hyperglycemia, insulin resistance, elevated carbohydrate absorption, blood glucose dysregulation, metabolic syndrome;

[0380] - alterations in muscle energy metabolism and / or associated disorders, reduction in muscle mass, reduction in muscle strength, reduction in physical resistance to muscular effort, poor absorption of amino acids;

[0381] - dyslipidemia or alterations in lipid metabolism and associated pathologies and disorders, cholesterolemia, high triglyceride levels, and obesity or overweight;

[0382] - cognitive disorders or alterations in the cognitive-emotional sphere;

[0383] - cardiometabolic disorders:

[0384] - alterations in the immune system;

[0385] - states of stress associated with anxiety and depression, fatigue, chronic fatigue, asthenia, impaired reflexes and coordination;

[0386] - rachitis or delayed bone growth in children, osteomalacia in adults, osteoporosis, and hyperparathyroidism.

[0387] - gingivitis; brittle nails, hair, and / or skin as a result of inflammation or medical treatment.

[0388] EMb-12. Non-therapeutic use of the formulation or composition according to any one of EMb-1 - EMb-11 for the supplementation of said (a) vitamin in a healthy subject.

[0389] EMb-13. Non-therapeutic use according to EMb-12, wherein said use is selected from: increasing muscle mass, increasing muscle strength, increasing physical endurance to muscular effort, reducing recovery time after physical effort, increasing mental performance, strengthening nails and hair.

[0390] EMb-14. A method for the preparation of the formulation according to any one of EMb-1 - EMb-11 comprising the steps of:

[0391] - (1) providing a vitamin (a) in powder or granule form, to obtain a step 1 vitamin;

[0392] - (2) mixing said step 1 vitamin with a phospholipid (b), preferably lecithin, in the absence of a solvent, to give a step 2 mixture;

[0393] - (3) mixing said step 2 mixture with a polysaccharide (c) selected from (c-i) carrageenan or (c-ii) acacia gum, and / or with a sucrester (d), in the absence of solvent, to obtain a step 3 mixture or the formulation;

[0394] - (4), optionally, mixing said step 3 mixture with a gelatinized or pregelatinized starch of plant origin (e), preferably pregelatinized rice starch, to give the formulation.

[0395] EMb-15. A method for the preparation of the composition according to claim 8 comprising the steps of:

[0396] - (i) providing at least one formulation in solid form of a vitamin;

[0397] - (ii) mixing said at least one formulation in solid form of said at least one formulation in solid form of a vitamin to give a step (ii) mixture.

[0398] - (iii) mixing said step (ii) mixture with at least one additive and / or excipient to give the composition.

[0399] It is a further object of the present invention a formulation in solid form of a vitamin B12 (e.g., cobalamin, methylcobalamin, cyanocobalamin, preferably cyanocobalamin) comprising or, alternatively, consisting of:

[0400] (a) at least one vitamin B12;

[0401] (b) at least one phospholipid; and at least one agent selected from:

[0402] (c) at least one polysaccharide selected from (c-i) at least one carrageenan and / or (c-ii) at least one acacia gum; (d) at least one sucrester or carbohydrate ester of fatty acids; and mixtures of (c) and (d); and which, optionally, also comprises one or more of:

[0403] (e) at least one starch of plant origin and (z) at least one phosphate salt selected from tricalcium phosphate salts; for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient undergoing treatment with a drug which, optionally in the absence of intrinsic factor IF alteration, impairs ileal absorption of the vitamin B12-IF complex.

[0404] Preferably, said drug is metformin. Therefore, it is a further object of the present invention a formulation in solid form of a vitamin B12 (e.g., cobalamin, methylcobalamin, cyanocobalamin, preferably cyanocobalamin) comprising or, alternatively, consisting of:

[0405] (a) at least one vitamin B12;

[0406] (b) at least one phospholipid; and at least one agent selected from:

[0407] (c) at least one polysaccharide selected from (c-i) at least one carrageenan and / or (c-ii) at least one acacia gum;

[0408] (d) at least one sucrester or carbohydrate ester of fatty acids; and mixtures of (c) and (d); and which, optionally, also comprises one or more of:

[0409] (e) at least one starch of plant origin and (z) at least one phosphate salt selected from tricalcium phosphate salts; for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient undergoing treatment with metformin.

[0410] Preferably, said patient suffers from one or more pathologies selected from the group comprising or, alternatively, consisting of: diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS), and metabolic syndrome. Therefore, it is a further object of the present invention a formulation in solid form of a vitamin B12 (e.g., cobalamin, methylcobalamin, cyanocobalamin, preferably cyanocobalamin) comprising or, alternatively, consisting of:

[0411] (a) at least one vitamin B12;

[0412] (b) at least one phospholipid; and at least one agent selected from:

[0413] (c) at least one polysaccharide selected from (c-i) at least one carrageenan and / or (c-ii) at least one acacia gum;

[0414] (d) at least one sucrester or carbohydrate ester of fatty acids; and mixtures of (c) and (d); and which, optionally, also comprises one or more of:

[0415] (e) at least one starch of plant origin and (z) at least one phosphate salt selected from tricalcium phosphate salts; for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient undergoing treatment with a drug (preferably metformin) that impairs ileal absorption of the vitamin B12-IF complex, wherein the patient suffers from one or more pathologies selected from the group comprising or, alternatively, consisting of: diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS), and metabolic syndrome.

[0416] More preferably, said vitamin B12 deficiency occurs in the presence of normal intrinsic factor. Therefore, it is a further object of the present invention a formulation in solid form of a vitamin B12 (e.g., cobalamin, methylcobalamin, cyanocobalamin, preferably cyanocobalamin) comprising or, alternatively, consisting of: (a) at least one vitamin B12;

[0417] (b) at least one phospholipid; and at least one agent selected from:

[0418] (c) at least one polysaccharide selected from (c-i) at least one carrageenan and / or (c-ii) at least one acacia gum;

[0419] (d) at least one sucrester or carbohydrate ester of fatty acids; and mixtures of (c) and (d); and which, optionally, also comprises one or more of:

[0420] (e) at least one starch of plant origin and (z) at least one phosphate salt selected from tricalcium phosphate salts; for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient (e.g., suffering from one or more pathologies selected from the group comprising or, alternatively, consisting of: diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS) and metabolic syndrome) undergoing treatment with a drug (preferably metformin) that impairs ileal absorption of the vitamin B12-IF complex, wherein the vitamin B12 deficiency occurs in the presence of normal intrinsic factor.

[0421] Preferably, said vitamin B12 deficiency occurs in the presence of altered intrinsic factor. Therefore, it is a further object of the present invention a formulation in solid form of a vitamin B12 (e.g., cobalamin, methylcobalamin, cyanocobalamin, preferably cyanocobalamin) comprising or, alternatively, consisting of:

[0422] (a) at least one vitamin B12;

[0423] (b) at least one phospholipid; and at least one agent selected from:

[0424] (c) at least one polysaccharide selected from (c-i) at least one carrageenan and / or (c-ii) at least one acacia gum;

[0425] (d) at least one sucrester or carbohydrate ester of fatty acids; and mixtures of (c) and (d); and which, optionally, also comprises one or more of:

[0426] (e) at least one starch of plant origin and (z) at least one phosphate salt selected from tricalcium phosphate salts; for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient (e.g., suffering from one or more pathologies selected from the group comprising or, alternatively, consisting of: diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS) and metabolic syndrome) undergoing treatment with a drug (preferably metformin) that impairs ileal absorption of the vitamin B12-IF complex, wherein the vitamin B12 deficiency occurs in the presence of an altered intrinsic factor.

[0427] Preferably, the formulation described in the present invention is for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient undergoing treatment with metformin and suffering from type 2 diabetes.

[0428] Preferably, the formulation for one or more of the above uses consists of:

[0429] - (a) a nutrient, wherein said nutrient is at least one vitamin B12;

[0430] - (b) a phospholipid, preferably a phosphoglyceride, more preferably a phosphatidylcholine or a lecithin; and an agent selected from:

[0431] (c) at least one polysaccharide selected from (c-i) at least one carrageenan and / or (c-ii) at least one acacia gum;

[0432] (d) at least one sucrester or one carbohydrate ester of fatty acids; or mixtures of (c) and (d); and which, optionally, also comprises one or more of:

[0433] (e) at least one starch of plant origin and (z) at least one phosphate salt selected from tricalcium phosphate salts. Preferably, said at least one phospholipid (b), included in the formulation of a vitamin B12 for the uses of the invention, is a phosphoglyceride, preferably a di-acyl-phospholipid, more preferably selected from the group of di- acyl-phospholipids comprising or, alternatively, consisting of: phosphatidylcholine or lecithin, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, and mixtures thereof; preferably phosphatidylcholine or lecithin (e.g., E322); even more preferably sunflower lecithin (e.g., E322), corn lecithin (e.g., E322) or soy lecithin (e.g., E322); even more preferably allergen-free lecithin (e.g., E322), for example allergen- free sunflower lecithin (e.g., E322).

[0434] Advantageously, said lecithin (e.g., E322) is a lecithin (e.g., E322) in powder or granule form, preferably a sunflower lecithin (e.g., E322), corn lecithin (e.g., E322) or soy lecithin (e.g., E322) in powder or granule form, even more preferably an allergen-free sunflower lecithin (e.g., E322), corn lecithin (e.g., E322) or soy lecithin (e.g., E322) in powder or granule form. The term "allergen-free" means that it has no allergen residues.

[0435] In the case wherein said (b) phosphatidylcholine or lecithin (e.g., E322) is a lecithin in powder or granule form, the lecithin may have, for example, a water content by weight% in the range from 1.5% to 4.5% relative to the weight of the lecithin, preferably from 2% to 4%, and more preferably from 2.5% to 3.5%.

[0436] For example, said (b) lecithin, included in the formulation of at least one vitamin B12 for the uses of the invention, does not comprise or, alternatively, does not consist of a decomposed or hydrolyzed lecithin, and does not comprise or, alternatively, does not consist of an enzymatically decomposed or hydrolyzed lecithin.

[0437] For example, a (c-i) carrageenan that can be used in the formulation of at least one vitamin B12 for the uses of the invention is a CSW-2 type carrageenan (Genuvisco®, registered trademark, CP Kelco) standardized with sucrose; CAS 9000-07-1 , 57-50-1 ; according to European standard E407; pH (0.5% solution) 7.0-10.0; loss on drying <=12.0, instant viscosity-high salts <=12; instant viscosity-low salts >=50.

[0438] Said (c-i) carrageenan can be obtained according to methods known to those skilled in the art, for example by extraction from marine algae with water and Ca(OH)2 at high temperature (e.g. slightly >100°C), neutralization and precipitation with ethanol or isopropanol.

[0439] For example, a (c-ii) acacia gum that can be used in the formulation of at least one vitamin B12 for the uses of the invention is an acacia gum having CAS No. 232-519-5, EINECS 232-519-5, compliant with E414, purity min. 99.9%, loss on drying max. 10%, total ash max. 4%, viscosity (20°C) min. 60 cps., specific optical rotation 30-60° (commercial example gum arable 386° from Chimab, code 306045).

[0440] Acacia gums are obtained according to methods known to those skilled in the art, which include the steps of centrifugation, filtration, heating, and drying.

[0441] For example, a (d) sucrester (E473), that can be used in the formulation of at least one vitamin B12 for the uses of the invention, can be a sucrester having an HLB (hydrophilic-lipophilic balance) value in the range from 14 to 18, preferably an HLB value of about 15 or 16. A (d) sucrester (E473), that can be used in the formulation of at least one vitamin B12 for the uses of the invention, may have the following composition by weight: total ester content of at least 90%, of which at least 70% by weight, relative to the total weight of the sucrester, of monoesters obtained by esterification of sucrose with one or more fatty acids of plant origin, preferably stearic acid and / or palmitic acid; free fatty acid content (as oleic acid) not exceeding 3%; free sucrose content not exceeding 2%; moisture not exceeding 4%; acidity value not exceeding 5. An example of commercial sucrester (d) that can be used in the context of the present invention is: sucrose esters SP70 from Chimab S.p.A. - Italy.

[0442] Preferably, said (d) sucrester, included in the formulation of at least one vitamin B12 for the uses of the invention, does not comprise or, alternatively, does not consist of, for example, a polyglycerol fatty acid ester.

[0443] Optionally, the formulation of at least one vitamin B12 for the uses of the invention also comprises a (e) starch of plant origin, preferably gelatinized or pregelatinized; preferably, said (e) starch of plant origin is selected from rice starch and / or corn starch; preferably, said (e) starch of plant origin is rice starch (Oryza sativa) or native rice starch, preferably gelatinized or pregelatinized; more preferably, said (e) starch of plant origin is pregelatinized rice starch. A pregelatinized rice starch (e) that can be used in the formulation of at least one vitamin B12 for the uses of the invention can have, for example, the following chemical-physical characteristics: moisture content not exceeding 7%; protein content not exceeding 1 %; ash content not exceeding 1%; pH (10% solution) comprised from 5.5 to 7.5, density 0.40-0.48 g / cm3; minimum starch content of 97% and fat content not exceeding 0.1 %. An example of commercial pregelatinized rice starch is AX-FG-P from Reire Sri, Italy.

[0444] Optionally, the formulation of at least one vitamin B12 for the uses of the invention also comprises (z) at least one phosphate salt selected from tricalcium phosphate salts. Said (z) at least one phosphate salt selected from tricalcium phosphate salts is, for example:

[0445] Formula: Ca3(PO4)2

[0446] Molar mass: 310.18 g / mol

[0447] Density: 3.14 g / cm3

[0448] CAS number: 7758-87-4

[0449] Melting temperature: 1 ,391 °C (1 ,664 K)

[0450] Density (g / cm3, at s.t.p.): 3.14

[0451] Molecular formula: Ca3(PO4)2.

[0452] Preferably, said (z) at least one phosphate salt selected from tricalcium phosphate salts is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%, preferably comprised from 0.1% to 2%, more preferably comprised from 0.3% to 1.5%, even more preferably comprised from 0.5% to 1 %, for example comprised from 0.35% to 0.85%.

[0453] Preferably, said formulation in solid form of vitamin B12 for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient (e.g., suffering from diabetes (preferably type 2 diabetes), polycystic ovary syndrome (POOS), and metabolic syndrome) undergoing treatment with a drug (preferably metformin) which, optionally in the absence of intrinsic factor IF alteration, impairs ileal absorption of the vitamin B12-IF complex, consists of: (a) vitamin B12 (e.g., cobalamin, methylcobalamin, cyanocobalamin, preferably cyanocobalamin, example of CAS No. 68-19-9);

[0454] (b) at least one phospholipid, preferably a phosphatidylcholine or a lecithin, e.g., a lecithin (E322) selected from sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof (preferably sunflower lecithin); at least one agent selected from:

[0455] (c) at least one polysaccharide selected from (c-i) at least one carrageenan (e.g., E407) and / or (c-ii) at least one acacia gum (e.g., E414); (d) at least one sucrester (e.g., E473) or a carbohydrate ester of fatty acids; and mixtures of (c) and (d); and, optionally, one or more of

[0456] (z) at least one tricalcium phosphate salt; and / or

[0457] (e) at least one gelatinized or pregelatinized starch of plant origin, preferably pregelatinized rice starch.

[0458] Preferably, in the formulation in solid form of a vitamin B12 for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient (e.g., suffering from diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS), and metabolic syndrome) undergoing treatment with a drug (preferably metformin) which, optionally in the absence of intrinsic factor IF alteration, impairs ileal absorption of the vitamin B12-IF complex, the components (b), the agent selected from (c-i), (c-ii), (d) or a mixture thereof, and, optionally, (z) are included in said formulations in the following amounts expressed as a percentage by weight relative to 100 of the total weight of the formulation:

[0459] - said (b) phospholipid, preferably lecithin or sunflower lecithin (e.g., E322), is comprised from 0.05% to 15%, preferably from 0.1 % to 5%, more preferably from 0.1 % to 2%, for example about 0.5-1 .0%;

[0460] - the sum of (c) (a polysaccharide, such as (c-i) carrageenan or (c-ii) acacia gum) and / or (d) sucrester is comprised from 1 % to 50% (e.g., 10%, 20%, 30%, or 40%), preferably from 5% to 35%, more preferably from 10% to 25%, for example 15%-20% (such as 16%, 17%, or 18%); and

[0461] - said (z) at least one phosphate salt, preferably a tricalcium phosphate, is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%; preferably, it is comprised from 0.1 % to 2%; more preferably, it is comprised from 0.3% to 1.5%; even more preferably, it is comprised from 0.5% to 1 %, for example, from 0.35% to 0.85%, or

[0462] - said (z) at least one phosphate salt, preferably a tricalcium phosphate, when present, is in a weight ratio, relative to the weight of said (b) at least one phospholipid, comprised from 1 :5 to 5: 1 ; preferably, comprised from 1 :4 to 4: 1; more preferably, comprised from 1 :3 to 3:1 ; more preferably, comprised from 1 :2 to 2:1.

[0463] Preferably, in the formulation in solid form of a vitamin B12 for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient (e.g., suffering from diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS), and metabolic syndrome) undergoing treatment with a drug (preferably metformin) which, optionally in the absence of intrinsic factor IF alteration, impairs ileal absorption of the vitamin B12-IF complex, the components (a), (b), the agent selected from (c-i), (c-ii), (d) or a mixture thereof, and, optionally, one or more of (z) and (e) are present in said formulation in the following amounts expressed as a percentage by weight relative to the total weight of the formulation: - said (a) vitamin B12 (e.g., cobalamin, methylcobalamin, cyanocobalamin, preferably cyanocobalamin, example of CAS No. 68-19-9) is comprised in a range from 20% to 80% (e.g., 25%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%), preferably from 45% to 60% (e.g., about 50-55%);

[0464] - said (b) phospholipid, preferably phosphoglyceride, more preferably phosphatidylcholine or lecithin, even more preferably solid lecithin (E322) or solid sunflower lecithin (E322), is comprised in a range from 0.05% to 10% (e.g., 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, or 8%), preferably approximately from 0.1 % to 2% (e.g., about 1 ,0±0.1 %);

[0465] - said agent (c) (a polysaccharide), such as (c-i) carrageenan and / or (c-ii) acacia gum, or, alternatively, the sum of said agent (c) and said (d) sucrester (E473), is comprised in a range from 1 % to 50% (e.g., 3%, 5%, 7%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, or 40%), preferably approximately from 10% to 25% (e.g., about from 15±1 to 20±1 %); and

[0466] - if present, said (e) starch, preferably pregelatinized rice starch, is comprised in a range from 5% to 60% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55%), preferably approximately from 20% to 40% (e.g., about 30±0.1 %);

[0467] - if present, said (z) at least one phosphate salt, preferably a tricalcium phosphate, is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%; preferably, it is comprised from 0.1 % to 2%; more preferably, it is comprised from 0.3% to 1.5%; even more preferably, it is comprised from 0.5% to 1 %, for example, from 0.35% to 0.85%, or

[0468] - said (z) at least one phosphate salt, preferably a tricalcium phosphate, is present in a weight ratio, relative to the weight of said (b) at least one phospholipid, comprised from 1 :5 to 5:1 ; preferably, comprised from 1 :4 to 4:1 ; more preferably, comprised from 1 :3 to 3:1 ; even more preferably, comprised from 1 :2 to 2:1.

[0469] Preferably, the formulation in solid form of a vitamin B12 for the uses of the invention, comprising (a), (b), the agent selected from (c-i), (c-ii), (d) or a mixture thereof, and, optionally, at least one of (z) and (e), comprises the following amounts expressed as a percentage by weight relative to 100 of the total weight of the formulation:

[0470] - said (b) phospholipid, preferably lecithin or sunflower lecithin (e.g., E322), from about 0.5-1 .0%;

[0471] - the sum of (c) (a polysaccharide, such as (c-i) carrageenan and / or (c-ii) acacia gum) and / or (d) sucrester from 15%-20% (such as 16%, 17%, or 18%).

[0472] In 100 parts by weight of said sum of (c) (a polysaccharide, such as (c-i) carrageenan or (c-ii) acacia gum) and / or (d) sucrester, said (c) first agent may be present at 100% and said (d) at zero%, or, alternatively, said (c) may be present at zero% and said (d) at 100%, or said (c) and / or (d) may be present in all variable combinations between them expressed as % (percentage to 100); or said (c) is comprised in a percentage by weight from 1% to 100% (for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) and said (d) sucrester ranges from 0% (absent) to 99% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%); preferably said (c) from 50% to 95% and said (d) sucrester from 5% to 50% (e.g., (c) about 50% and (d) about 50%), or said (c) from 70% to 95% and said (d) sucrester from 5% to 30% (e.g., (c) 70% - 80% and (d) 20% - 30%, or (c) approximately 75% and (d) approximately 25%), or said (c) from 5% to 30% and said (d) sucrester from 70% to 95% (e.g., (c) 20% - 30% and (d) 70% - 80%, or (c) about 25% and (d) about 75%).

[0473] Advantageously, in formulations of a vitamin B12 for the uses of the invention, in 100 parts by weight of said sum of (c) (a polysaccharide, such as (c-i) carrageenan or (c-ii) acacia gum) and (d) sucrester, said (c) is zero% and said (d) is 100%, or said (c) first agent is about 75% and said (d) sucrester is about 25%, or vice versa.

[0474] It is an object of the present invention a method for the preparation of formulations in solid form of at least one vitamin B12 for the uses of the invention.

[0475] In a first embodiment of the invention, said method of the invention (in short, first method of the invention) is described in patent document WO 2014 / 009806 A1 from page 7 line 1 to page 8 line 20, incorporated in the present application by reference.

[0476] In a second embodiment of the invention, said method of the invention (in short, second method of the invention) is described in patent document WO 2014 / 009806 A1 from page 8 line 22 to page 10 line 21 , incorporated in the present application by reference.

[0477] According to the present invention, said first method of the invention and second method of the invention are applied as described in patent document WO 2014 / 009806 A1 considering that (c-i) and / or (c-ii), if present, may be used in place of or in addition to (d) and in amounts appropriate to obtain the formulations of the present invention, and that the term (b) lecithin should be read as representing the class of phospholipids (where (c-i) is carrageenan and (c-ii) is acacia gum, and (d) is sucrester).

[0478] Said method according to the invention is carried out by mixing components (a), (b), the agent selected from (c-i), (c-ii), (d) or a mixture thereof, and, optionally, one or more of (z) and (e) in the percentages by weight defined in the context of the present invention in order to obtain the formulations according to the invention comprising at least one vitamin B12.

[0479] Preferably, said method of the invention for the preparation of a formulation comprising a vitamin B12 for the uses of the invention, for example according to an embodiment described in WO 2014 / 009806 A1 , comprises the steps of:

[0480] - step 1 : providing a vitamin B12 (preferably cyanocobalamin) in powder or granule form;

[0481] - step 2: mixing said vitamin B12 with a phospholipid (b), preferably lecithin (e.g., sunflower lecithin) and, optionally, (z), said (z) being a tricalcium phosphate salt, to give a step 2 mixture; preferably, said lecithin is not a hydrolyzed lecithin or an enzymatically hydrolyzed lecithin;

[0482] - step 3: mixing said step 2 mixture with an agent selected from: a polysaccharide (c) (e.g. (c-i) carrageenan or acacia gum), a sucrester (d) or a mixture of (c) and (d), to give a step 3 mixture;

[0483] - step 4 (optional): mixing said step 3 mixture with (e) a gelatinized or pregelatinized starch of plant origin, preferably pregelatinized, for example pregelatinized rice starch;

[0484] - step 5 (optional after step 3 and / or after step 4): sieving, preferably with at least one sieve having a size (or nominal sieve opening) comprised in the range from 150 pm to 1400 pm (e.g., 180 pm, 212 pm, 250 pm, 300 pm, 355 pm, 425 pm, 500 pm, 600 pm, 710 pm, 850 pm, 1000 pm, or 1180 pm), preferably from 600 pm to 850 pm, for example 710 m (25 US Mesh).

[0485] Advantageously, said mixing steps 2, 3, and / or 4 are performed at room temperature (from 15°C to 30°C, preferably at about 25°C) for a time ranging from 10 minutes to 120 minutes, preferably from 15 minutes to 60 minutes, for example about 30 minutes.

[0486] Advantageously, said mixing steps 2, 3, and / or 4 are performed in the absence of solvent (dry mixing).

[0487] In the embodiment in which both said polysaccharide (c) and said sucrester (d) are present in the formulation of the invention, said step 3 of the method of the invention may involve mixing said step 2 mixture first with the polysaccharide and then with the sucrester, or, alternatively, mixing said step 2 mixture first with the sucrester and then with the polysaccharide, or, alternatively and preferably, mixing said step 2 mixture simultaneously with the sucrester and the polysaccharide, or, alternatively, when only sucrester (d) is used, said step 3 involves mixing said step 2 mixture only with a sucrester (d), without polysaccharide (c), to give a step 3 mixture.

[0488] Said method for the preparation of the vitamin B12-based formulation for the uses of the invention may provide that step 2 and step 3 are carried out simultaneously.

[0489] According to one example of the method of the invention for preparing a formulation comprising a vitamin B12 for the uses of the invention, said method does not comprise a spray-dry step.

[0490] Without wishing to go into specific details, the structure of the product obtained by the above method can be described as follows: a vitamin B12 core coated with a first layer comprising the phospholipid matrix (lecithin) and, if present, tricalcium phosphate, and with a second layer comprising the sucrester matrix (and, if present, carrageenan and / or acacia gum).

[0491] Unless otherwise specified, the expression composition or other comprising a component in an amount "comprised in a range from x to y” means that said component may be present in the composition or formulation or other in all amounts within said range, even if not explicitly stated, including the extremes of the range.

[0492] Unless otherwise specified, the content of a component in a composition or formulation refers to the percentage by weight of that component relative to the total weight of the composition or formulation.

[0493] Unless otherwise specified, the indication that a composition "comprises" one or more components means that other components may be present in addition to the one or more specifically indicated, and the indication that a composition "consists" of certain components means that the presence of other components is excluded.

[0494] The following embodiments (EM) of the formulation in solid form of vitamin B12 for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient (e.g., suffering from diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS), and metabolic syndrome) undergoing treatment with a drug (preferably metformin) which, optionally in the absence of intrinsic factor IF alteration, impairs ileal absorption of the vitamin B12-IF complex, are comprised in the present invention:

[0495] - EMe-vit B12: vit B12, (b) and (c), such as (c-i) and / or (c-ii), and (z); for example, vit B12, (b) and (c-i) and (z) or vit B12, (b) and (c-ii) and (z);

[0496] - EMf-vit B12: vit B12, (b), (c) (such as (c-i) and / or (c-ii)) and (d) and (z); for example, vit B12, (b), (c-i) and (d) and (z) or vit B12, (b), (c-ii) and (d) and (z); - EMg-vit B12: vit B12, (b), (c) (such as (c-i) and / or (c-ii)) and (z) and (e); for example, vit B12, (b), (c-i) and (z) and (e) or vit B12, (b), (c-ii) and (z) and (e);

[0497] - EMh-vit B12: vit B12, (b), (c) (such as (c-i) and / or (c-ii)), (d) and (e) and (z); for example, vit B12, (b), (c-i), (d) and (z) and (e) or vit B12, (b), (c-ii), (d) and (z) and (e);

[0498] - EMi-vit B12: vit B12, (b) and (c), such as (c-i) and / or (c-ii); for example, vit B12, (b) and (c-i) or vit B12, (b) and (c-

[0499] - EMI-vit B12: vit B12, (b) and (d);

[0500] - EMm-vit B12: vit B12, (b) and (c), such as (c-i) and / or (c-ii) and (e); for example, vit B12, (b) and (c-i) and (e) or vit B12, (b) and (c-ii) and (e);

[0501] - EMn-vit B12: vit B12, (b) and (c), such as (c-i) and / or (c-ii) and (d) and (e); e.g. vit B12, (b) and (c-i) and (d) and

[0502] (e) or vit B12, (b) and (c-ii) and (d) and (e);

[0503] - EMo-vit B12: vit B12, (b) and (d) and (e);

[0504] - EMp-vit B12: vit B12, (b) and (d) and (z);

[0505] - EMq-vit B12: vit B12, (b) and (d) and (z) and (e); wherein the components designated (a), (b), (c-i), (c-ii), (d), (z), and (e) are as defined in the present invention.

[0506] Is is an object of the present invention also a composition, preferably in solid form, comprising:

[0507] - at least one formulation in solid form of vitamin B12 for uses according to the invention; and, optionally,

[0508] - at least one acceptable pharmaceutical or food grade additive and / or excipient.

[0509] Is is a further object of the present invention a composition, preferably in solid form, comprising at least one formulation of the present invention in solid form of at least one vitamin B12 for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient (e.g., suffering from diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS) and metabolic syndrome) undergoing treatment with a drug (preferably metformin) which, optionally in the absence of intrinsic factor IF alteration, impairs ileal absorption of the vitamin B12-IF complex, and pharmaceutical or food grade additives and / or excipients.

[0510] Advantageously, compositions or formulations comprising vitamin B 12 (according to any of the above embodiments EMe-vit B12-EMq-vit B12) find valid use in preventing, reducing, or treating a vitamin B12 deficiency in a patient (e.g., suffering from diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS), and metabolic syndrome) undergoing treatment with a drug (preferably metformin) which, optionally in the absence of intrinsic factor IF alteration, impairs ileal absorption of the vitamin B12-IF complex.

[0511] Advantageously, compositions or formulations comprising vitamin B12 (according to any of the above embodiments EMe-vit B12-EMq-vit B12) find valid use in preventing, reducing, or treating a vitamin B12 deficiency in a patient (e.g., suffering from diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS), and metabolic syndrome) undergoing treatment with a drug (preferably metformin) that impairs ileal absorption of the vitamin B12— IF complex, in which vitamin B12 deficiency occurs in the presence of a normal intrinsic factor.

[0512] Advantageously, compositions or formulations comprising vitamin B 12 (according to any of the above embodiments EMe-vit B12-EMq-vit B12) find valid use in preventing, reducing, or treating vitamin B12 deficiency in a patient (e.g., suffering from diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS), and metabolic syndrome) undergoing treatment with a drug (preferably metformin) that impairs ileal absorption of the vitamin B12— I F complex, wherein the vitamin B12 deficiency occurs in the presence of an altered intrinsic factor.

[0513] The composition of the invention, comprising said formulation in solid form of at least one vitamin B12 for uses according to the invention, may be a pharmaceutical composition, a composition for a medical device, a dietary supplement, a food or novel food or a nutraceutical composition, or a food for special medical purposes (FSMP). The term "medical device" in the context of the present invention is used in the meaning according to Italian Legislative Decree No. 46 of February 24, 1997, or according to the new Medical Devices Regulation (EU) 2017 / 745 (MDR).

[0514] EXPERIMENTAL PART

[0515] 1. Study

[0516] Comparative study of the bioavailability of oral Sucrosomial® compared to conventional oral vitamin B12 interventions in improving circulating B12 levels in healthy deficient adults: A randomized, double-blind, multicenter clinical study.

[0517] 2. Materials and methods

[0518] 2.1 Study design

[0519] This study was a multicenter, prospective, double-blind, randomized clinical trial designed to evaluate the absorption rate and therefore the bioavailability of an innovative oral Sucrosomial® B12 (Sidevit® B12 developed by Pharmanutra S.p.A, Pisa, Italy; the formulation comrises: cyanocobalamin 1000 pig, sunflower lecithin, sucrester, pregelatinized rice starch, and tricalcium phosphate) in increasing circulating B12 levels in healthy deficient adults, compared to various conventional formulations of oral B12 supplements, randomly selected from local pharmacies in each participating center.

[0520] The study was conducted at three centers in Pakistan:

[0521] - At Mayo Hospital, King Edward Medical University (KEMU), Lahore (Punjab Province), the efficacy of Sucrosomial® B12 was compared with the conventional formulation of Mecogen SL B12 (Mecobalamin 1000 pig, manufactured by Genetics Pharmaceuticals, Lahore, Pakistan; the formulation comprises: Methylcobalamin; Folic acid; Alpha-lipoic acid; Pyridoxine (Vitamin B6); Mannitol (sweetener and stabilizer); Microcrystalline cellulose; Magnesium stearate; Natural flavors; Colloidal silica). - At Lady Reading Hospital (LRH) in Peshawar (Khyber Pakhtunkhwa province), the efficacy of the Sucrosomial® B12 formula was compared with the conventional formulation B-SUB B12 (methylcobalamin 1000, manufactured by Bio Life® Enterprises Nutraceuticals and marketed by Honing Pharmaceutical Laboratories, Rawalpindi, Pakistan).

[0522] - At Liaquat University of Medical & Health Sciences (LUMHS), Jamshoro (Sindh province), the efficacy of Sucrosomial® B12 was compared with the conventional formulation of Evermin B12 (Methylcobalamin 1000 pig, manufactured by Global Laboratories and marketed by Reliance Pharma, Islamabad, Pakistan; the formulation comprises: Methylcobalamin; Maltodextrin; Glycerol (E422) - humectant; Sorbitol (E420) - humectant; Water; Raspberry flavoring; Polyvinylpyrrolidone vinyl acetate copolymer (E1208) - resistance agent; Mono- and diglycerides of fatty acids (E471) - emulsifiers; Polyoxyethylene sorbitan monooleate (E433) - emulsifier; Sucralose (E955) - sweetener) and Neuromax B12 (Mecobalamin 1000 pig, manufactured by Bio Fine Pharmaceuticals, Multan, Pakistan; the formulation comprises: Methylcobalamin; L-Carnitine - 125 mg; L-Taurine - 125 mg; Cognizin® (CDP-Citicoline) - 75 mg; Phosphatidylserine (from soybeans) - 62.5 mg; Ginkgo Biloba (dry extract 50:1) - 50 mg; Bacopa monnieri (BacoMind®) - 25 mg; Phosphatidylcholine (Epikuron®) - 25 mg; L- Glutamine - 25 mg; Alpha-lipoic acid - 12.5 mg; Vitamin B5 - 3 mg; Hypromellose - vegetable capsule shell; Microcrystalline cellulose - bulking agent; Magnesium salts of fatty acids - anti-caking agent; Silicon dioxide - anticaking agent).

[0523] The rationale for using a different conventional B12 supplement in each center, for comparison with Sucrosomial® B12, was to ensure the reproducibility of the study results amid the variability of B12 formulations. The use of participants from different ethnic origin in the three centers was intended to ensure a robust comparison and significantly improve the generalizability of the study results. This approach allowed for a comprehensive assessment of the efficacy and safety of Sucrosomial® vitamin B12 across all centers.

[0524] 2.2 Study participants

[0525] Participants were enrolled from April 2024 to July 2024. The study population included healthcare professionals, including physicians, medical students, nurses, and other support staff working at the participating hospitals. Study participants had to meet the following specific criteria to be included in the study.

[0526] Inclusion criteria

[0527] • Healthy adults, male or female, aged 18 to 65 years

[0528] • Stable medical conditions, including stable liver, kidney, and hematological status, confirmed by laboratory tests

[0529] • Normal vital signs (blood pressure, heart rate, respiratory rate, temperature) and body mass index (BMI) between 18 and 30 kg / m2

[0530] • Suboptimal vitamin B12 status (deficient to borderline 200-300 pg / mL), defined as serum B12 levels within the lower end of the reference range (234-894 pg / mL)

[0531] • Able to provide written informed consent

[0532] • Able to comply with study procedures and follow-up visits as specified in the protocol. Exclusion criteria

[0533] • Known hypersensitivity or allergy to oral vitamin B12 supplements or any of its components.

[0534] • Known history of allergy or sensitivity to cobalt.

[0535] • Severe malabsorption syndromes, including pernicious anemia or intestinal disorders affecting vitamin B12 absorption

[0536] • Current use of acetaminophen, nonsteroidal anti-inflammatory drugs, antibiotics, antacids, proton pump inhibitors (PPIs), multivitamins, or dietary supplements containing vitamin B12

[0537] • History of gastric bypass surgery or other procedures that significantly alter gastrointestinal anatomy or function.

[0538] • Significant renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL / min / 1.73m2) or hepatic impairment

[0539] • Uncontrolled or significant cardiovascular disease, including recent myocardial infarction, unstable angina, or heart failure.

[0540] • History of psychiatric illness or cognitive impairment that could compromise the ability to comply with study procedures or provide informed consent.

[0541] • Currently enrolled in another clinical trial involving investigational products or interventions.

[0542] • Pregnant or breastfeeding women.

[0543] • Any other medical condition or circumstance that, in the investigator's judgment, would compromise the safety of the participant or the integrity of the study.

[0544] 2.2.1 Randomization and blinding

[0545] Participants were randomly assigned, in a 1 :1 ratio, to receive oral B12 Sucrosomial® or one of the conventional oral B12 supplements specific to each center. Both participants and investigators were assigned to the groups in a blind manner to ensure data integrity and minimize bias. Randomization was conducted using a sequence of random numbers generated by computer by an independent statistician not involved in the study. The assignment of participants to their respective B12 groups was performed via a centralized, off-site allocation mechanism to preserve concealment of group allocation.

[0546] 2.2.2 B12 supplementation

[0547] Participants in both the Sucrosomial® B12 and conventional B12 supplement groups received a single dose of 1 tablet of 1000 pig of B12 per day for 7 days. All participants were instructed to take the oral B12 supplement at the same time each day, specifically at 10 a.m. Blood samples were collected by a phlebotomist from an independent diagnostic laboratory at specific intervals, to monitor circulating (serum) levels of B12. These intervals were: day 0 (baseline, i.e., before the first dose), day 1 (24 hours), day 3 (72 hours), day 5 (120 hours), and day 7 (168 hours). Serum B12 levels were measured using standardized laboratory techniques. To maintain consistency, all follow-up blood samples were collected shortly before taking the daily B12 supplement and were promptly analyzed in the diagnostic laboratory within 30 minutes of collection to ensure the accuracy and reliability of serum B12 level measurements. To ensure compliance with the study protocol, participants were required to keep a daily log of B12 supplement intake with the study team. In addition, participants received a daily reminder from the study team via phone call or text message to take the supplement at the scheduled time. Compliance was further assessed by counting the remaining tablets at each follow-up blood draw to verify that participants had taken the supplement as instructed.

[0548] To assess the safety profile of B12 supplements, participants' liver and kidney function tests, complete blood count, and vital signs (including blood pressure, heart rate, respiratory rate, and body temperature) were evaluated and recorded at baseline and after completing 7 days of B12 supplementation.

[0549] 2.3 Outcome measures

[0550] The primary outcome of the study was the bioavailability of B12 supplements, assessed by the increase in circulating B12 levels. Secondary outcomes included the safety and tolerability of B12 supplements, assessed by any significant adverse effects on vital signs, liver function enzymes, renal function, and complete blood count, as well as the incidence of side effects, treatment-emergent effects, and serious adverse events.

[0551] 2.4 Statistical analysis

[0552] The Wilcoxon rank-sum test was used to compare the absorption (bioavailability) of the Sucrosomial® B12 formulation with the local B12 formulations used in the study hospitals and the effect on the increase in blood B12 levels. The homogeneity of sex, age, weight, and body mass index (BMI) was assessed using Pearson's Chi-square test with Yates' continuity correction for the dichotomous variable (sex), and the Wilcoxon test or t-test for continuous variables (age, weight, BMI), depending on the data distribution determined by the Shapiro-Wilk test. P values were adjusted for multiple comparisons using the Benjamini-Hochberg correction (False Discovery Rate - FDR) (CIT). All consolidated values are presented as mean ± standard error of the mean (SEM). The Wilcoxon test or two-sample t-test was also used to assess the safety and tolerability of the vitamin B12 formulations. Statistical analyses were performed using R version 4.4.0 (CIT), with the "ggplot2" package (CIT) used for graphical representations. Based on previous studies, a sample size of > 20 subjects in each cohort was considered sufficient for this exploratory descriptive study.

[0553] 3. Results

[0554] A total of 91 individuals were screened for eligibility in the three cohort studies. Of these, 15 individuals were excluded based on study exclusion criteria, resulting in a final study population of 76 participants— 24 in the KEMU study cohort, 22 in the LRH cohort, and 30 in the LUMHS cohort. All participants completed the study, and no dropouts were reported. The demographic and anthropometric characteristics of the participants and baseline circulating vitamin B12 levels in the study cohorts are shown in Table 1. In the KEMU cohort, the mean age was 38.2 ± 9.4 years, and it consisted of 16 males and 8 females. The LRH study had a mean age of 32.7 ± 7.4 years, with 15 females and 7 males. In the LUMHS cohort, the mean age was 35.7 ± 6.9 years, with 20 males and 10 females. In each study cohort, the groups were well balanced with regard to age, anthropometric characteristics (age, weight, BMI), and baseline circulating vitamin B12 levels (p > 0.05). Among the three cohorts, only the LUMHS cohort demonstrated a balanced gender distribution across groups (Pearson's Chi-square test; KEMU, p = 0.025; LRH, p = 0.004; LUHMS, P=0.22). Table 1. Demographic data of study participants, anthropometric characteristics, and baseline circulating (serum) vitamin B12.

[0555] Table 1

[0556] Data are presented as mean and standard error of the mean (SEM) or numbers. No statistically significant differences in any variable were observed between the Sucrosomial® vitamin B12 and conventional oral vitamin B12 treatment groups within each cohort study.

[0557] 3.1 Bioavailability of Sucrosomial® B12 compared to conventional B12 from Moecogen SL B12

[0558] Vitamin B12 levels were monitored for one week after treatment with the Sucrosomial® B12 formulation or the conventional Mecogen SL B12 formulation. As shown by the connected scatter plot in Figure 1A, the Sucrosomial® B12 formulation rapidly increased circulating vitamin B12 levels above the deficiency threshold, exceeding 300 pg / mL (borderline level) within 24 hours. Specifically, the Sucrosomial® B12 formulation resulted in a significant increase in circulating vitamin B12 levels from day 1 compared to baseline (p < 0.012), with levels continuing to increase through day 5 (Figure 1 B). In contrast, circulating vitamin B12 levels did not exceed the threshold at any time after the conventional Mecogen SL B12 formulation, despite a significant increase from day 3 to day 7 compared to baseline (p < 0.038) (Figure 1 B). Significant differences between the two formulations were observed on days 5 and 7 (p < 0.0036), with a maximum circulating B12 concentration of 454 ± 3.9 pg / mL measured in the Sucrosomial® B12 group compared to 274 ± 11.1 pg / mL in the conventional Mecogen SL B12 group on day 5 (Figure 1C).

[0559] 3.2 Bioavailability of Sucrosomial® B12 compared to the conventional B-SUB B12 formulation (LRH study) Vitamin B12 levels were monitored for one week after treatment with the Sucrosomial® B12 formulation or the conventional oral B-SUB B12 formulation. As shown by the connected scatter plot in Figure 2A, the Sucrosomial® B12 formulation rapidly increased circulating vitamin B12 levels above the deficiency threshold, exceeding 300 pg / mL (borderline level) from day one. It should be noted that baseline vitamin B12 levels in this cohort were significantly higher than in the KEMU cohort (p = 0.006), which may explain the faster exceeding of the vitamin B12 threshold. Similar to the KEMU study cohort, the Sucrosomial® B12 formulation resulted in a significant increase in circulating vitamin B12 levels starting on day 1 compared to baseline (p < 0.015), with levels continuing to increase through day 5. In contrast, circulating vitamin B12 levels did not exceed the threshold level at any time after the conventional B-SUB B12 formulation, and no significant differences were found over time (Figure 2B). Comparing the two formulations, the Sucrosomial® B12 group showed higher circulating levels of vitamin B12 at every time point after treatment (p < 0.029) (Figure 2C). On day 5, a maximum serum B12 concentration of 496 ± 34.4 pg / mL was recorded in the Sucrosomial® B12 group compared to 304 ± 49.4 pg / mL in the conventional B- SUB B12 group (Figure 2C).

[0560] 3.3 Bioavailability of Sucrosomial® B12 compared to conventional Evermin B12 and Neuromax B12

[0561] Vitamin B12 levels were monitored for one week after treatment with the Sucrosomial® B12 formulation or with the conventional formulations Evermin B12 and Neuromax B12. As shown in the connected scatter plot in Figure 3A, the Sucrosomial® B12 formulation rapidly increased circulating vitamin B12 levels above the deficiency threshold, exceeding 300 pg / mL (borderline level) from day 1 , and demonstrated a similar pattern of increase in circulating vitamin B12 levels over time, as observed in the KEMU and LRH study cohorts, reaching a peak value of 592.7 ±

[0562] 74.3 on day 7, with all measurements during the week significantly higher than baseline (p < 0.012). The conventional Evermin B12 formulation showed a similar trend, with a significant overall increase in circulating vitamin B12 levels starting on day 3, reaching a peak value of 407.2 ± 41.6 on day 7 compared to baseline (p < 0.004). Of the three formulations, conventional Neuromax B12 was the least effective in increasing circulating vitamin B12 levels, with a significant increase only on day 5 (275.5 ± 23.8 mg / mL) (p = 0.018) and never exceeding the threshold limit (Figure 3B). Compared to Evermin B12, the Sucrosomial® B12 formulation showed a significant increase in circulating vitamin B12 levels only on day 7 (p = 0.045), suggesting a similar short-term effect but a more sustained effect over time for Sucrosomial® B12. Compared to Neuromax B12, Sucrosomial® B12 resulted in significantly higher circulating levels of vitamin B12 at every time point after treatment (p < 0.023). In particular, Evermin B12 showed a generally better effect in increasing vitamin B12 levels than Neuromax B12, with significant differences starting on day 3 (p < 0.029).

[0563] 3.4 Safety and tolerability of B12 supplements

[0564] All B12 supplements were generally well tolerated by all participants in the three studies. No serious adverse events, side effects, or emergency effects of treatment were reported. Furthermore, there were no significant negative impacts on liver function, kidney function, hematology, or vital signs, either during or after the supplementation period. The only exception was the conventional Neuromax B12 formulation, which led to significant changes in some parameters of renal function, such as serum sodium, potassium, chloride, and bicarbonate levels, as well as in some hematological parameters, including relative monocyte and basophil abundance.

[0565] 4. Discussion

[0566] In this multicenter, randomized, double-blind clinical study, we evaluated the efficacy and bioavailability of an innovative oral Sucrosomial® B12 supplement, administered as a single daily dose of 1000 pig for a period of 7 days. The study compared Sucrosomial® B12 with several conventional oral B12 supplements (Mecogen SL B12, B-SUB B12, Evermin B12, Neuromax B12, randomly selected from local pharmacies) in three cohorts of healthy adults with deficient to borderline B12 levels. The primary outcome was the change in serum B12 levels after taking supplemental B12, allowing a comparative assessment of the effectiveness of different formulations in increasing and maintaining B12 concentrations in the bloodstream. Our results reveal that Sucrosomial® B12 was significantly more effective in increasing and maintaining higher circulating levels of B12 than all four conventional B12 formulations at all time points (day 1 , day 3, day 5, and day 7). In the KEMU study cohort, Sucrosomial® B12 reached a peak circulating B12 concentration of 454 ± 3.9 pg / mL on day 5, compared to 274 ± 11.1 pg / mL with conventional Mecogen SL B12. In the LRH cohort, it reached a peak concentration of 496 ± 34.4 pg / ml on day 5, compared to 304 ± 49.4 pg / ml for B-SUB B12. In the LUMHS cohort, Sucrosomial® B12 also demonstrated superior efficacy, reaching a peak value of 592.7 ± 74.3 pg / ml on day 7, compared to 407.2 ± 41.6 pg / ml for Evermin B12 and 263.8 ± 23.8 pg / ml for Neuromax B12. In particular, Sucrosomial® B12 was the only formulation to rapidly increase circulating B12 levels from day 1 (within 24 hours), consistently exceeding the deficiency threshold (200- 300 pg / mL), while conventional formulations did not achieve similar efficacy. Furthermore, Sucrosomial® B12 was well tolerated, with no reported side effects, serious adverse events, or treatment-emergent effects, nor any negative effects on vital signs, confirming its excellent safety and tolerability. These results underscore the superior efficacy of Sucrosomial® B12 in rapidly and consistently increasing and maintaining higher circulating levels of vitamin B12 compared to conventional B12 formulations.

[0567] Conventional oral B12 formulations often face significant potential challenges, including primary dependence on IF for absorption in the ileum and potential degradation by the acidic environment of the stomach and gastric enzymes. The absorption process is significantly impeded in conditions such as pernicious anemia, Crohn's disease, celiac disease, and following ileal surgical resection, all of which can compromise B12 absorption and contribute to suboptimal supplementation outcomes.

[0568] The Sucrosomial® B12 formulation, which is the object of the present invention, overcomes these obstacles by trapping vitamin B12 within a protective matrix composed of phospholipids, mainly derived from sunflower lecithin, and a sucrester (sucrose ester) in the presence of at least one phosphate salt, such as a tricalcium phosphate, as a stabilizing agent for vitamin B12. The protective matrix, combined with starch and tricalcium phosphate (vitamin B12 stabilizing agent), forms a robust, stable "sucrosome" transport system capable of releasing the vitamin B12 present within it. It has been found that said phosphate salt, such as tricalcium phosphate, is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%, preferably comprised from 0.1% to 2%, more preferably comprised from 0.3% to 1 .5%, even more preferably comprised from 0.5% to 1 %, for example, comprised from 0.35% to 0.85%. For example, it has been found that said phosphate salt, such as tricalcium phosphate, is present in a weight ratio (expressed as a mass ratio) relative to the weight of lecithin, for example a lecithin (e.g., E322) selected from sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof (preferably, sunflower lecithin) comprised from 1 :5 to 5: 1 ; preferably, comprised from 1 :4 to 4:1 ; more preferably, comprised from 1 :3 to 3: 1 ; even more preferably, comprised from 1 :2 to 2:1 , for example, 1 :1.

[0569] Thanks to this specific protective matrix, the gastro-resistant properties of the sucrosome are enhanced, protecting the vitamin from premature release, degradation, and minimized interactions with food during its passage through the stomach, ensuring that B12 reaches the intestinal mucosa intact. Once in the ileum, Sucrosomial® B12 can bypass the traditional IF-dependent absorption pathway. The intact sucrosome vesicles facilitate absorption through paracellular and transcellular pathways, potentially involving absorption by enterocytes and M cells. The unique structure of the formulation allows passive diffusion through the intestinal epithelium, which can occur in both the jejunum and ileum. After being absorbed, B12 is gradually released from the sucrosomal vesicles within the enterocytes and then transported into the bloodstream, leading to elevated circulating levels of B12. This mechanism ensures that Sucrosomial® B12 is absorbed efficiently, even in the presence of compromised IF function or damage to the ileum. As a result, this approach improves the bioavailability of oral supplemental B12, providing a more reliable source of the nutrient.

[0570] However, it is worth noting that there is a possibility that some Sucrosomial® B12 may enter the bloodstream in its intact form and potentially be released into hepatocytes; this aspect of its absorption and metabolism requires further investigation.

[0571] The clinical importance of Sucrosomial® B12 is substantial, as it offers an innovative and effective solution for managing vitamin B12 deficiency in diverse populations. This advanced formulation is particularly beneficial for people at increased risk of deficiency, including the elderly, vegetarians, vegans, and people with gastrointestinal conditions that hinder B12 absorption, such as pernicious anemia, celiac disease, Crohn's disease, and irritable bowel syndrome (IBS), among others. The Sucrosomial® delivery system significantly improves bioavailability, allowing B12 to be absorbed more efficiently, possibly bypassing the intrinsic factor pathway. This makes the Sucrosomial® delivery system an attractive option for maintaining optimal B12 levels, thereby supporting overall health and preventing a wide range of health conditions related to B12 deficiency. These conditions include, among others, megaloblastic anemia, neurological disorders, cognitive decline, cardiovascular problems, and complications during pregnancy. By providing a more reliable and effective means of supplementation, Sucrosomial® B12 could play a crucial role in improving patient outcomes and quality of life. In this randomized, double-blind clinical study, the innovative Sucrosomial® B12 formulation was shown to rapidly achieve significantly higher and sustained circulating B12 levels, exceeding the deficiency threshold (200-300 pg / mL) within 24 hours of a single 1000 pig dose. This was observed in different population cohorts with multiple ethnic backgrounds, improving the generalizability of the results.

[0572] 5. Conclusions

[0573] In conclusion, the Sucrosomial® B12 formulation represents a significant advance in oral vitamin B12 supplementation. This innovative delivery system rapidly increases circulating levels of B12 and achieves optimal circulating vitamin B12 status without causing gastrointestinal or other side effects. The formulation offers a reliable and efficient solution for maintaining adequate vitamin B12 intake and supporting the health of various populations at risk of deficiency. Its unique benefits underscore its role as an effective therapeutic strategy for managing vitamin B12 deficiency.

[0574] In addition, improved effects on vitamin stability have been observed, thanks to the presence of phosphate salt selected from tricalcium phosphate salts.

[0575] EXPERIMENTAL PART 2

[0576] 1. Study

[0577] To evaluate the efficacy of vitamin B12 administration for the uses according to the invention compared to the administration of vitamin B12 as such in patients undergoing treatment with a drug (e.g., metformin) which, even in the absence of intrinsic factor IF alteration, impairs ileal absorption of the vitamin B12-IF complex, a study was conducted in an in vitro model using UltraBI 2 (Sucrosomial Vitamin B12 according to the invention) in comparison with free cyanocobalamin B12 in the absence or presence of IF (intrinsic factor) and / or MET (metformin).

[0578] 2. Materials and methods

[0579] The following materials were used:

[0580] - Caco-2 cell line (conventional in vitro model for studying intestinal absorption and the epithelial barrier of the human intestine);

[0581] - Epilntestinal tissue-based in vitro model;

[0582] Epilntestinal is a human 3D in vitro model of the small intestine, developed by MatTek Corporation.

[0583] It consists of primary human intestinal epithelial cells, grown on a porous membrane that allows growth in apical and basolateral polarity, forming a structure similar to human intestinal tissue with: microvilli (brush border), tight junctions, mucus secretion, metabolic activity, and functional transporters. - UltraBI 2 (Sucrosomial vVitamin B12 according to the invention comprising cyanocobalamin, sunflower lecithin, sucrester, and pregelatinized rice starch);

[0584] - free cyanocobalamin B12 (Vitamin B12 as such);

[0585] - metformin;

[0586] - intrinsic factor IF.

[0587] Study design

[0588] An initial screening phase was carried out on Caco-2 cells using an MTT assay to determine the optimal dosage of vitamin B12, UltraB12, metformin (MET), and intrinsic factor (IF).

[0589] Subsequently, the 3D Epilntestinal tissues were treated with B12 and UltraBI 2, both individually and in combination with IF and MET. Tissue viability was assessed at 24 and 48 hours using MTT, and apparent permeability (Papp) was also determined at the same timepoints.

[0590] 3. Assays and results

[0591] Determination of the optimal dosage of vitamin B12, UltraB12, metformin (MET), and intrinsic factor (IF)

[0592] Cell viability was assessed using an MTT assay on Caco-2 cells after treatment with different concentrations of vitamin B12, UltraBI 2, metformin (MET), and intrinsic factor (IF) to determine the correct dosage to use.

[0593] The viability test allowed the following optimal dosages (corresponding to viability greater than 80%) to be determined, which were used for the subsequent phases of the study:

[0594] UltraBI 2 (UB12) and free vitamin B12 (B12): 5 ppm

[0595] Metformin (MET): 0.5 mM

[0596] Intrinsic factor (IF): 1.6 .g / ml

[0597] A second MTT viability assay on Caco-2 cells was performed using 5 ppm of B12 or UB12 in combination with the selected concentrations of intrinsic factor (IF) or intrinsic factor (IF) + metformin (MET).

[0598] The assay confirmed cell viability greater than 80% even after combining vitamin B12 (5 ppm) and UltraB12 (5 ppm) with intrinsic factor (IF: 1.6 pig / ml) and metformin (0.5 mM).

[0599] Determination of the viability of Epilntestinal tissues treated for 24 hours (a) or 48 hours (b) with UB12 / B12 and in the absence or presence of IF and / or MET.

[0600] An MMT viability assay was performed on Epilntestinal 3D tissues by treating the tissues separately for 24 hours or 48 hours with:

[0601] - UltraB12 (UB12);

[0602] - Free B12 (B12) 5 ppm;

[0603] - Metformin (MET) 0.5 mM;

[0604] - Intrinsic factor (IF): 1.6 ig / ml;

[0605] - Free B12 (B12) 5 ppm + Intrinsic factor (IF): 1.6 ig / ml;

[0606] - Free B12 (B12) 5 ppm + Metformin (MET) 0.5 mM;

[0607] - Free B12 (B12) 5 ppm + Intrinsic factor (IF): 1.6 ig / ml + Metformin (MET) 0.5 mM; - UltraB12 (UB12) 5 ppm + Intrinsic factor (IF): 1.6 gg / ml;

[0608] - UltraBI 2 (UB12) 5 ppm + Metformin (MET) 0.5 mM;

[0609] - UltraB12 (UB12) 5 ppm + Intrinsic factor (IF): 1.6 ig / ml + Metformin (MET) 0.5 mM.

[0610] The results of the MTT viability assay performed 24 hours (Figure 1A left) and 48 hours (Figure 1A right) posttreatment for all experimental conditions are excellent in terms of cell viability on Epilntestinal 3D tissues.

[0611] Quantification of permeation at 24 hours following treatment of Epilntestinal tissues.

[0612] After treating the 3D Epilntestinal tissues separately for 24 hours with:

[0613] - UltraB12 (UB12);

[0614] - Free B12 (B12) 5 ppm;

[0615] - Metformin (MET) 0.5 mM;

[0616] - Intrinsic factor (IF): 1.6 ig / ml;

[0617] - Free B12 (B12) 5 ppm + Intrinsic factor (IF): 1.6 ig / ml;

[0618] - Free B12 (B12) 5 ppm + Metformin (MET) 0.5 mM;

[0619] - Free B12 (B12) 5 ppm + Intrinsic factor (IF): 1.6 ig / ml + Metformin (MET) 0.5 mM;

[0620] - UltraB12 (UB12) 5 ppm + Intrinsic factor (IF): 1.6 ig / ml;

[0621] - UltraBI 2 (UB12) 5 ppm + Metformin (MET) 0.5 mM;

[0622] - UltraB12 (UB12) 5 ppm + Intrinsic factor (IF): 1.6 ig / ml + Metformin (MET) 0.5 mM. permeation was evaluated by determining apparent permeability (Papp).

[0623] Figure 1 B shows the results obtained:

[0624] - in the presence of intrinsic factor (IF), the permeation of cyanocobalamin from UltraBI 2 (UB12) is significantly greater than that of cyanocobalamin as such (B12);

[0625] - in the absence of intrinsic factor (IF), the concentration of cyanocobalamin after treatment with UltraBI 2 (UB12) increases significantly compared to that of cyanocobalamin as such (B12);

[0626] - in the presence of metformin, UltraBI 2 permeation is higher after 24 hours of treatment than that of cyanocobalamin as such (B12).

[0627] Quantification of permeation at 48 hours following treatment of Epilntestinal tissues.

[0628] After treating 3D Epilntestinal tissues separately for 48 hours with:

[0629] - UltraB12 (UB12);

[0630] - Free B12 (B12) 5 ppm;

[0631] - Metformin (MET) 0.5 mM;

[0632] - Intrinsic factor (IF): 1.6 ig / ml;

[0633] - Free B12 (B12) 5 ppm + Intrinsic factor (IF): 1.6 ig / ml;

[0634] - Free B12 (B12) 5 ppm + Metformin (MET) 0.5 mM;

[0635] - Free B12 (B12) 5 ppm + Intrinsic factor (IF): 1.6 ig / ml + Metformin (MET) 0.5 mM;

[0636] - UltraB12 (UB12) 5 ppm + Intrinsic factor (IF): 1.6 ig / ml; - UltraBI 2 (UB12) 5 ppm + Metformin (MET) 0.5 mM;

[0637] - UltraB12 (UB12) 5 ppm + Intrinsic factor (IF): 1.6 ig / ml + Metformin (MET) 0.5 mM. permeation was evaluated by determining apparent permeability (Papp).

[0638] Figure 1C shows the results obtained:

[0639] - in the presence of intrinsic factor (IF), after 48 hours of treatment, no significant differences are observed between the permeation of cyanocobalamin from UltraBI 2 (UB12) and that of cyanocobalamin as such (B12);

[0640] - in the absence of intrinsic factor (IF), after 48 hours of treatment, the concentration of cyanocobalamin from UltraBI 2 (UB12) increases significantly compared to that of cyanocobalamin as such (B12);

[0641] - in the presence of metformin, the permeation of UltraBI 2 is higher after 48 hours of treatment than that of cyanocobalamin as such (B12).

[0642] 4. Conclusions

[0643] Vitamin B12 deficiency is a common concern in patients undergoing treatment with a drug (e.g., metformin) which, even in the absence of intrinsic factor IF alteration, impairs ileal absorption of the vitamin B12-IF complex.

[0644] For example, vitamin B12 deficiency is a common concern in patients with diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS), and certain forms of metabolic syndrome undergoing prolonged treatment with metformin, and this deficiency can, over time, also have serious consequences such as megaloblastic anemia and peripheral neuropathy. This deficiency can also occur in the presence of a normal intrinsic factor, because the problem lies in the ileal absorption of the B12-IF complex.

[0645] Data from the in vitro study performed show that the optimized support system for oral supplementation of vitamin B12 (preferably cyanocobalamin) of the invention may allow, for this particularly at-risk patient population, more effective oral administration than vitamin B12 as such.

Claims

CLAIMS1 . A formulation in solid form consisting of:- (a) a nutrient, wherein said nutrient is a vitamin, wherein said vitamin is selected from the group comprising or, alternatively, consisting of: vitamin B12, vitamin C, vitamin D3, vitamin E;- (b) a phospholipid;- (c) a first agent selected from (c-i) a carrageenan or (c-ii) an acacia gum, and / or- (d) at least one sucrester or a carbohydrate ester of fatty acids;- (z) at least one phosphate salt, as a stabilizing agent for said at least one vitamin, said (z) being selected from tricalcium phosphate salts, and, optionally,- (e) a starch of plant origin.

2. The formulation according to claim 1, wherein said (z) at least one phosphate salt, selected from tricalcium phosphate salts, is present in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%; preferably, it is comprised from 0.1 % to 2%; more preferably, it is comprised from 0.3% to 1.5%; even more preferably, it is comprised from 0.5% to 1%, for example, from 0.35% to 0.85%.

3. The formulation according to claim 1 or 2, wherein said (z) at least one phosphate salt, selected from tricalcium phosphate salts, is present in a weight ratio, relative to the weight of said (b) at least one phospholipid, comprised from 1 :5 to 5:1 ; preferably, comprised from 1 :4 to 4:1 ; more preferably, comprised from 1 :3 to 3:1; even more preferably, comprised from 1 :2 to 2:1.

4. The formulation according to any one of the preceding claims, wherein said (d) at least one sucrester or carbohydrate ester of fatty acids is preferably a sucrester comprising from 70% to 90% by weight, relative to the total weight of the sucrester, of monoesters obtained by esterification of sucrose with one or more fatty acids of plant origin; even more preferably, said fatty acids are selected from stearic acid and / or palmitic acid.

5. The formulation according to any one of the preceding claims, wherein said (c) first agent consists of said (c-i) carrageenan; preferably, said carrageenan can be a carrageenan of the E407 type.

6. The formulation according to any one of the preceding claims, wherein said (c) first agent consists of said (c-ii) acacia gum; preferably, said acacia gum can be an acacia gum of the E414 type; more preferably, said acacia gum can be an acacia gum of the E414 type having an average molecular weight preferably in the range from 250,000 to 400,000.

7. The formulation according to any one of the preceding claims, wherein said (e) at least one starch of plant origin can be a gelatinized or pregelatinized starch; preferably, wherein said (e) at least one starch is selected from rice starch or corn starch; more preferably, wherein said starch is a pregelatinized rice starch.

8. The formulation according to any one of the preceding claims, wherein said (b) at least one phospholipid is a phosphatidylcholine or a lecithin; preferably, wherein said (b) phospholipid is a lecithin selected from the group comprising or, alternatively, consisting of: sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof.

9. The formulation according to any one of the preceding claims, wherein a weight ratio between said first agent (c) and said phospholipid (b) [(c): (b)], or, alternatively, a weight ratio between the weight of the sum of said first agent (c) and / or said sucrester (d), and the weight of said phospholipid [[(c) and / or (d)]:(b)] is comprised from 50:1 to 10: 1 , preferably from 40:1 to 10: 1 , more preferably from 30: 1 to 15:1; preferably wherein said (b) phospholipid is a lecithin.

10. The formulation according to any one of the preceding claims, wherein with respect to 100 parts by weight of a sum of said first agent (c) and / or said sucrester (d); preferably, said (c) first agent is comprised in a percentage by weight from zero% to 100% and said (d) sucrester is comprised from 100% to zero%; more preferably, said (c) first agent is comprised from 1 % to 100% and said (d) sucrester is comprised from 0% (absent) to 99%; even more preferably, said first agent (c) is comprised from 50% to 95% and said sucrester (d) is comprised from 5% to 50%; more preferably, said first agent (c) is comprised from 70% to 80% and said sucrester (d) is comprised from 20% to 30%.

11. The formulation according to any one of the preceding claims 1-10, for use as a medicament12. The formulation for use according to the preceding claim, wherein said formulation is for use in a method of preventive and / or curative treatment of a deficiency of said vitamin, or for use in a method of treatment of pathologies, symptoms or disorders associated with or resulting from said deficiency, in a subject in need.

13. The formulation for use according to the preceding claim, wherein said pathologies, symptoms, or disorders associated with or resulting from said deficiency are selected from the group comprising or, alternatively, consisting of:- alterations in carbohydrate metabolism and associated pathologies and disorders, diabetes, type II diabetes mellitus, hyperglycemia, insulin resistance, elevated carbohydrate absorption, blood glucose dysregulation, metabolic syndrome;- alterations in muscle energy metabolism and / or associated disorders, reduction in muscle mass, reduction in muscle strength, reduction in physical resistance to muscular effort, poor absorption of amino acids;- dyslipidemia or alterations in lipid metabolism and associated pathologies and disorders, cholesterolemia, high triglyceride levels, and obesity or overweight;- cognitive disorders or alterations in the cognitive-emotional sphere;- cardiometabolic disorders:- alterations in the immune system;- states of stress associated with anxiety and depression, fatigue, chronic fatigue, asthenia, impaired reflexes and coordination;- rachitis or delayed bone growth in children, osteomalacia in adults, osteoporosis, and hyperparathyroidism.- gingivitis; brittle nails, hair, and / or skin as a result of inflammation or medical treatments.

14. Non-therapeutic use of the formulation according to any one of the preceding claims 1-10, for the supplementation of said (a) at least one vitamin in a healthy subject.

15. Non-therapeutic use according to claim 14, wherein said use is selected from the group comprising: increasing muscle mass, increasing muscle strength, increasing physical endurance to muscular effort, reducing recovery time after physical effort, increasing mental performance, strengthening nails and hair.

16. A composition comprising:- at least one formulation in solid form according to any one of claims 1-10; and, optionally,- at least one acceptable pharmaceutical or food grade additive and / or excipient.

17. The composition according to the preceding claim for use as a medicament.

18. The composition for use according to the preceding claim, wherein said composition is for use in a method of preventive and / or curative treatment of a deficiency of said vitamin, or for use in a method of treatment of pathologies, symptoms, or disorders associated with or resulting from said deficiency, in a subject in need19. The composition for use according to the preceding claim, wherein said pathologies, symptoms, or disorders associated with or resulting from said deficiency are selected from the group comprising or, alternatively, consisting of:- alterations in carbohydrate metabolism and associated pathologies and disorders, diabetes, type II diabetes mellitus, hyperglycemia, insulin resistance, elevated carbohydrate absorption, blood glucose dysregulation, metabolic syndrome;- alterations in muscle energy metabolism and / or associated disorders, reduction in muscle mass, reduction in muscle strength, reduction in physical resistance to muscle effort, poor absorption of amino acids;- dyslipidemia or alterations in lipid metabolism and associated pathologies and disorders, cholesterolemia, hightriglyceride levels, and obesity or overweight;- cognitive disorders or alterations in the cognitive-emotional sphere;- cardiometabolic disorders:- alterations in the immune system;- states of stress associated with anxiety and depression, fatigue, chronic fatigue, asthenia, impaired reflexes and coordination;- rachitis or delayed bone growth in children, osteomalacia in adults, osteoporosis, and hyperparathyroidism.- gingivitis; brittle nails, hair, and / or skin as a result of inflammation or medical treatment.

20. Non-therapeutic use of the composition according to claim 16, for the supplementation of said (a) at least one vitamin in a healthy subject.

21. Non-therapeutic use of the composition according to claim 20, wherein said use is selected from: increasing muscle mass, increasing muscle strength, increasing physical endurance to muscular effort, reducing recovery time after physical effort, increasing mental performance, strengthening nails and hair.

22. A formulation in solid form of a vitamin B 12 comprising or, alternatively, consisting of:- (a) a nutrient, wherein said nutrient is at least one vitamin B12;- (b) a phospholipid, preferably a phosphoglyceride, more preferably a phosphatidylcholine or a lecithin; and an agent selected from:(c) at least one polysaccharide selected from (c-i) at least one carrageenan and / or (c-ii) at least one acacia gum;(d) at least one sucrester or carbohydrate ester of fatty acids; or mixtures of (c) and (d); and which, optionally, also comprises one or more of:(e) at least one starch of plant origin and (z) at least one phosphate salt selected from tricalcium phosphate salts; for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient undergoing treatment with a drug which, optionally in the absence of intrinsic factor IF alteration, impairs ileal absorption of the vitamin B12-IF complex.

23. The formulation for use according to claim 22, wherein the vitamin B12 is cyanocobalamin.

24. The formulation for use according to any one of claims 22-23, wherein said drug is metformin.

25. The formulation for use according to any one of claims 22-24, wherein said patient suffers from one or more pathologies selected from the group comprising or, alternatively, consisting of: diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS), and metabolic syndrome.

26. The formulation for use according to any one of claims 22-25, wherein said drug is metformin and said patient suffers from one or more pathologies selected from the group comprising or, alternatively, consisting of: diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS), and metabolic syndrome.

27. The formulation for use according to claim 26, wherein said drug is metformin and said patient suffers from type 2 diabetes.

28. The formulation for use according to any one of claims 22-27, wherein said vitamin B12 deficiency occurs in the presence of normal intrinsic factor.

29. The formulation for use according to any one of claims 22-28, wherein said vitamin B12 deficiency occurs in the presence of altered intrinsic factor.

30. The formulation for use according to any one of claims 22-29, wherein said (d) at least one sucrester or carbohydrate ester of fatty acids is preferably a sucrester comprising from 70% to 90% by weight, relative to the total weight of the sucrester, of monoesters obtained by esterification of sucrose with one or more fatty acids of plant origin; even more preferably, said fatty acids are selected from stearic acid and / or palmitic acid.

31. The formulation for use according to any one of claims 22-30, wherein said (c) consists of said (c-i) carrageenan; preferably, said carrageenan can be a carrageenan of the E407 type.

32. The formulation for use according to any one of claims 22-31 , wherein said (c) consists of said (c-ii) acacia gum; preferably, said acacia gum can be an acacia gum of the E414 type; more preferably, said acacia gum can be an acacia gum of the E414 type having an average molecular weight preferably in the range from 250,000 to 400,000.

33. The formulation for use according to any one of claims 22-32, wherein, if present, said (e) at least one starch of plant origin is a gelatinized or pregelatinized starch; preferably, wherein said (e) at least one starch is selected from rice starch or corn starch; more preferably, wherein said starch is a pregelatinized rice starch.

34. The formulation for use according to any one of claims 22-33, wherein said (z) at least one phosphate salt, selected from tricalcium phosphate salts, if present, is in an amount by weight, relative to the total weight of the formulation, comprised from 0.05% to 3%; preferably, it is comprised from 0.1 % to 2%; more preferably, it is comprised from 0.3% to 1.5%; even more preferably, it is comprised from 0 5% to 1 %, for example, from 0.35% to 0.85%.

35. The formulation for use according to any one of claims 22-34, wherein said (z) at least one phosphate salt, selected from tricalcium phosphate salts, if present, is in a weight ratio, relative to the weight of said (b) at least one phospholipid, comprised from 1 :5 to 5:1; preferably, comprised from 1 :4 to 4: 1; more preferably, comprised from 1 :3 to 3: 1; even more preferably, comprised from 1 :2 to 2:

136. The formulation for use according to any one of claims 22-35, wherein said (b) at least one phospholipid is a phosphatidylcholine or a lecithin; preferably, wherein said (b) phospholipid is a lecithin selected from the group comprising or, alternatively, consisting of: sunflower lecithin, corn lecithin, soy lecithin, and mixtures thereof.

37. The formulation for use according to any one of claims 22-36, wherein a weight ratio between said agent (c) and said phospholipid (b) [(c):(b)], or, alternatively, a weight ratio between the weight of the sum of said agent (c) and / or said sucrester (d), and the weight of said phospholipid [[(c) and / or (d)]:(b)] is comprised from 50: 1 to 10:1, preferably from 40:1 to 10:1 , more preferably from 30:1 to 15:1; preferably wherein said (b) phospholipid is a lecithin.

38. The formulation for use according to any one of claims 22-37, wherein with respect to 100 parts by weight of a sum of said agent (c) and said sucrester (d); preferably, said agent (c) is comprised in a percentage by weight from zero% to 100% and said (d) sucrester is comprised from 100% to zero%.

39. A composition comprising:- at least one formulation in solid form of vitamin B12 for the uses according to any one of the preceding claims; and, optionally,- at least one acceptable pharmaceutical or food grade additive and / or excipient.

40. The composition according to claim 39, for use in preventing, reducing, or treating a vitamin B12 deficiency in a patient undergoing treatment with a drug which, optionally in the absence of intrinsic factor IF alteration, impairs ileal absorption of the vitamin B12-IF complex.

41. The composition for use according to claim 40, wherein said drug is metformin and said patient suffers from one or more pathologies selected from the group comprising or, alternatively, consisting of: diabetes (preferably type 2 diabetes), polycystic ovary syndrome (PCOS), and metabolic syndrome; more preferably, said drug is metformin and said patient suffers from type 2 diabetes.