WO2019239372A1 - Composition comprising sucrosomial minerals containing mineral salts for use in conditions of deficiency of such minerals - Google Patents

Composition comprising sucrosomial minerals containing mineral salts for use in conditions of deficiency of such minerals Download PDF

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Publication number
WO2019239372A1
WO2019239372A1 PCT/IB2019/054962 IB2019054962W WO2019239372A1 WO 2019239372 A1 WO2019239372 A1 WO 2019239372A1 IB 2019054962 W IB2019054962 W IB 2019054962W WO 2019239372 A1 WO2019239372 A1 WO 2019239372A1
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Prior art keywords
mineral
composition
preparation
lecithin
sucrosomial
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PCT/IB2019/054962
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French (fr)
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WO2019239372A4 (en
Inventor
Andrea Lacorte
Germano Tarantino
Original Assignee
Pharmanutra S.P.A.
Alesco S.R.L.
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Application filed by Pharmanutra S.P.A., Alesco S.R.L. filed Critical Pharmanutra S.P.A.
Publication of WO2019239372A1 publication Critical patent/WO2019239372A1/en
Publication of WO2019239372A4 publication Critical patent/WO2019239372A4/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/015—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/035—Organic compounds containing oxygen as heteroatom
    • A23L29/04—Fatty acids or derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
    • A23L29/212—Starch; Modified starch; Starch derivatives, e.g. esters or ethers
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/16—Fluorine compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
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    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
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    • A61K9/20—Pills, tablets, discs, rods
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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    • A61K9/4866—Organic macromolecular compounds
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals

Definitions

  • composition comprising sucrosomial minerals containing mineral salts for use in conditions of deficiency of such minerals.
  • the present invention refers to a composition comprising a preparation comprising one mineral or several minerals, said preparation also alternatively called "sucrosomial® mineral” (sucrosomial®; registered trademark owned by Pharmanutra S.p.A e Alesco S.r.l), for use in the treatment of symptoms or disorders relating to a deficiency of said mineral/s, such as magnesium, calcium, iron, zinc, iodine and/or selenium.
  • Said preparation comprises or, alternatively, consists of said mineral (or mixture of minerals), lecithin, a first agent such as Atster (fatty acid carbohydrates) and at least one further first agent selected from among a cyclodextrin, a C6-C18 fatty acid isomer, a chitosan derivative and the mixtures thereof.
  • a first agent such as Atster (fatty acid carbohydrates)
  • at least one further first agent selected from among a cyclodextrin, a C6-C18 fatty acid isomer, a chitosan derivative and the mixtures thereof.
  • the present invention refers to a composition in solid form.
  • the present invention refers to a method for preparing said sucrosomial® mineral.
  • the composition of the present invention is recommended for use in subjects in paediatric age, adolescents, sportsmen/sportswomen, men, women, pregnant women and the elderly for supplementing a deficiency of said minerals.
  • Mixtures comprising minerals, such as for example magnesium, calcium, zinc or iron, which are used for preparing compositions, for example in solid form, for human use, are available in the market.
  • compositions in solid form comprising minerals recommended for oral use ( per os) reveal limits and/or contraindications that considerably limit the use thereof.
  • a first limit lies in the fact that the compositions, in particular the compositions in solid form, containing a mineral for oral use currently available in the market have the mineral, for example iron or magnesium or calcium or zinc, in a chemical form, such as cation, which is scarcely, or poorly, absorbable by the organism and, thus, poorly if not even non-bioavailable for the organism.
  • the known compositions comprising minerals must be administered away from meals. In this case, there are chances that oral administration long after meals could create grounds for further drawbacks.
  • iron salts can be scarcely absorbed by the organism when administered orally, for example in form of ferrous sulphate or gluconate.
  • the known compositions comprising iron salts must be administered away from meals.
  • taking iron in the chemical form of trivalent cation (Fe(lll)) per os can cause constipation and epigastralgia which entail the need for administering compositions comprising iron on a full stomach with an ensuing and inevitable drastic reduction of the absorption thereof in the organism.
  • a second limit lies in the fact that, due to the scarce absorption of minerals obtained through oral administration of the compositions comprising minerals currently available in the market, said compositions need to be administered for extended periods of time before the deposits of said minerals in the organism are usefully reconstituted and used.
  • the basic therapy of said iron salts is generally extended for a period of time comprised between 3 and 6 before the iron deposits of the organism are usefully reconstituted
  • a third limit lies in the fact that oral administration of compositions comprising minerals, in many cases, is not well tolerated due to frequent adverse effects.
  • the oral administration of compositions containing iron salts, and in particular ferrous sulphate is characterised by frequent gastrointestinal (Gl) adverse effects which limit the use thereof, such as for example peptic ulcers, gastritis, ulcerative colitis.
  • a fourth drawback lies in the fact that the compositions in solid form are difficult to process from an industrial point of view given that they are affected by the external conditions, and they at times tend to compact and not flow hence creating problems relating to poor reproducibility of the titre of the mineral in the composition and they can create grain size variations such to jeopardise the preparation of the compositions as finished products.
  • compositions comprising minerals for oral use often reveal unpleasant palatability and they are not stable over time from the chemical/physical and organoleptic point of view, i.e. they change colour, odour, flavour and taste.
  • compositions comprising minerals depend on how said compositions (in liquid or solid form) are prepared, in particular on the mineral used, on the type of mineral salt used and on the additional components, additives and/or excipients used, on the addition sequence of the single components, additives and/or excipients used in the preparation method and on the preparation operating conditions adopted.
  • a preparation method that is optimal enough to create around the mineral, considered as the cation present in the mineral salt used, a chemical/physical environment capable of producing a composition comprising minerals having advantageous and improving characteristics is yet to be created.
  • compositions in solid or liquid form or in form of suspension comprising minerals, such as for example magnesium, calcium, iron, zinc, iodine, selenium or the mixtures thereof, for use in the treatment of patients suffering from lack/deficiency of one or more of said minerals.
  • the mineral present as a mineral salt (or as a cation of the mineral salt), both in a form such to make it bioavailable and effectively absorbable and - at the same time - that said compositions do not reveal the limits and the contraindications still found in known compositions comprising minerals (or mineral salts) available in the market.
  • compositions in solid form comprising minerals that, besides making the mineral highly bioavailable and absorbable by the organism, are free of adverse effects and tolerated well enough to be administered, even on an empty stomach, to all categories of subjects including pregnant women, that have good palatability and that are stable over time from a chemical/physical point of view (without formation of agglomerates, change of colour) and organoleptic point of view (without change of odour, flavour and taste).
  • An object of the present invention is to provide an appropriate response to the limits still observable in compositions existing in the prior art and to the technical problem described above.
  • compositions comprising preparations comprising a mineral salt or several mineral salts, called sucrosomial® minerals.
  • Said preparations comprise minerals such as, for example, magnesium, calcium, iron, zinc, iodine, selenium or mixtures thereof.
  • the minerals are made effectively absorbable and bioavailable and, thus, said compositions are well tolerated by the organism so that they can be administered orally, once formulated for example in solid form as such or in mouth-soluble e solid form, even on an empty stomach, to subjects in paediatric age, adolescents, sportsmen/sportswomen, men, women, pregnant women and the elderly.
  • said compositions have a good palatability, they are well tolerated and they are stable over time both from a chemical/physical and organoleptic point of view.
  • Forming an object of the present invention is a composition, preferably in solid form, comprising a preparation (sucrosomial® mineral) comprising, or alternatively, consisting of a mineral such as, for example, magnesium, calcium, iron, zinc, iodine, selenium (or mixture of minerals, lecithin and at least one first agent selected from among a withster (fatty acid carbohydrates), a cyclodextrin, a C6-C18 fatty acid isomer and a chitosan derivative and mixture thereof.
  • a preparation such as, for example, magnesium, calcium, iron, zinc, iodine, selenium (or mixture of minerals, lecithin and at least one first agent selected from among ahester (fatty acid carbohydrates), a cyclodextrin, a C6-C18 fatty acid isomer and a chitosan derivative and mixture thereof.
  • Forming an object of the present invention is a composition, preferably in solid form, comprising said preparation (sucrosomial® mineral) comprising at least one mineral, for use in a method for treating symptoms or disorders relating to or deriving from an absolute or relative deficiency of said at least mineral such as, for example, magnesium, calcium, iron, zinc, iodine, selenium or mixtures thereof, having the characteristics as outlined in the attached claims.
  • Forming an object of the present invention are the methods for preparing said preparation (sucrosomial® mineral) comprising said at least one mineral having the characteristics as outlined in the description and in the attached claims.
  • Forming an object of the present invention is said composition in solid form, in particular in solid form as such or in mouth-soluble solid form, or in liquid form having the characteristics as outlined in the attached claims.
  • Forming a further object of the present invention is the use, not for therapeutic purposes, of said composition comprising said preparation (sucrosomial® mineral) comprising said at least one mineral, for modulating and/or improving disorders or illnesses relating to or deriving from an absolute or relative deficiency of said at least mineral such as, for example, magnesium, calcium, iron, zinc, iodine, selenium or mixtures thereof, having the characteristics as outlined in the attached claims.
  • composition of the present invention comprising said preparation (sucrosomial® mineral) comprising said at least one mineral, is recommended for subjects in paediatric age, adolescents, sportsmen/sportswomen, men, the elderly, women and pregnant women; preferably in women both during pregnancy and in the period after pregnancy; preferably also in women before, during and after the menstrual cycle.
  • mineral is preferably used to indicate a mineral consisting of only one chemical element, for example, magnesium, calcium, iron, zinc, iodine, selenium.
  • the expression “mineral salt” is used to indicate a salt of a mineral wherein said mineral is, preferably, a mineral consisting of only one chemical element, for example, magnesium, calcium, iron, zinc, iodine or selenium, in form of cation.
  • the expression “cation of the mineral” (or mineral cation) is used to indicate the chemical form of a mono or multivalent cation of a mineral wherein said mineral is, preferably, a mineral consisting of only one chemical element, for example, magnesium, calcium, iron, zinc, iodine or selenium, in form of cation.
  • mineral and “cation of the mineral” (or mineral cation) can be used interchangeably.
  • the expression "sucrosomial® mineral” is used to indicate a formulation of a mineral ((a) + (b) + (c)) in which said mineral, for example a mineral from among those mentioned above (Fe, Mg, Zn, Ca, I, Se), is processed and formulated by means of the preparation methods described hereinafter in the present invention (first method and second method).
  • said formulation of the mineral is referred to using the expression “sucrosomial® mineral” or "preparation” or “preparation of the invention”.
  • said sucrosomial® mineral is for example alternatively called "sucrosomial® iron”.
  • sucrosomial® mineral where iron is in form of sucrosomial® iron.
  • the content of a component in a composition refers to the percentage by weight of that component with respect to the total weight of the composition.
  • compositions consisting of one or more components means that other components - besides the one, or the ones, indicated specifically - can be present and the indication that a composition "consists” of determined components means that the presence of other components is excluded.
  • Figure 1 concentration of Fe(lll) in the blood of rats as a function of the time (hours) following the administration of the compositions in question containing iron (Fe(lll)).
  • FIG 2 similar to Figure 1 except for the fact that the data of the Control (non-treated animals) is also illustrated;
  • FIG. 3 Plasmatic concentration of FITC-labelled SRM over time following administration of FITC- labelled SRM containing the dose of 5 mg/Kg of iron;
  • Figure 4 amount of Mg (II) which traverses the intestinal epithelium over time;
  • Figure 5 amount of Mg (II) which traverses the intestinal epithelium over time (initial amount 1/10 with respect to Figure 4;
  • Figure 6 amount of Zn (II) which traverses the intestinal epithelium over time.
  • FIG. 7 Confocal laser scanning microscopy. Images representing the sections of the rat intestine after 30 minutes, 1 hour and 2 hours of incubation in the Ussing chamber.
  • TM tunica mucosa (mucous membrane);
  • TS tunica serosa (serous membrane).
  • Single fluorescent channels light grey (SRM) and dark grey (nuclei).
  • SRM light grey
  • N dark grey
  • A two-dimensional image of the maximum intensity projection.
  • B enlargement of the three-dimensional images box with the respective orthogonal projections.
  • FIG. 8 Confocal laser scanning microscopy: images representing the sections of the rat intestine after 1 hour and 2 hours of incubation in the Ussing chamber. The asterisks indicate enterocytes while the arrows indicate the connective cells. TM: tunica mucosa (mucous membrane). Single fluorescent channels: light grey (SRM) and dark grey (nuclei). Scale 10 pm.
  • FIG. 9 Confocal laser scanning microscopy: images representing the sections of the rat intestine after 30 minutes and 1 hour of incubation in the Ussing chamber. The negative control obtained by omitting the primary antibodies is shown in the double-line box. Single fluorescent channels: light grey (SRM), dark grey (positive cells at CD68) and very dark grey (nuclei). Scale 25 pm.
  • FIG. 10 Confocal laser scanning microscopy: images representing the sections of the rat intestine after 30 minutes and 1 hour of incubation in the Ussing chamber. The negative control obtained by omitting the primary antibodies is shown in the double-line box. Single fluorescent channels: light grey (SRM), dark grey (positive cells at GP2) and very dark grey (nuclei). Scale 25 pm.
  • composition of the invention preferably in solid form, comprises a preparation (hereinafter “preparation of the invention” or “sucrosomial® mineral”), as defined below, and, optionally, at least one technological additive and/or at least one pharmaceutical or food grade excipient.
  • composition of the invention preferably in solid form, comprising a preparation (preparation of the invention), as defined below, also called sucrosomial® mineral, for use in a method for the preventive and/or symptomatic treatment of symptoms or disorders relating to or deriving from an absolute or relative deficiency of at least one mineral selected from among the group comprising or, alternatively, consisting of magnesium, calcium, iron, zinc, iodine, selenium or mixtures thereof
  • present invention regards a method for the preventive and/or symptomatic treatment of symptoms or disorders relating to or deriving from absolute or relative deficiency of at least one mineral selected from among the group comprising or, alternatively, consisting of magnesium, calcium, iron, zinc, iodine, selenium or mixtures thereof, in needy subjects by administering to said subjects said composition of the invention, preferably in solid form, comprising said preparation of the invention, as defined below, also called sucrosomial® mineral.
  • the present invention regards the use of said composition, preferably in solid form, for modulating and/or improving disorders relating to or deriving from an absolute or relative deficiency of at least one mineral selected from among the group comprising or, alternatively, consisting of magnesium, calcium, iron, zinc, iodine, selenium or mixtures thereof in a subject, wherein said use is not for medical or therapeutic purposes.
  • the treatments of a disorder relating to an absolute, partial or relative deficiency of at least one mineral are effective both if conducted on healthy subjects and if conducted on subjects who have been diagnosed with a symptom or disorder relating to or deriving from said deficiency.
  • the preparation comprises at least one mineral (selected from among the ones indicated) which, following a specific processing method and preparation (subject of the present invention
  • the preparation (or sucrosomial® mineral or preparation of the invention) comprises or, alternatively, consists of:
  • - (a) at least one mineral in form of a mineral salt wherein said mineral (or cation of the mineral) is selected from among the group comprising or, alternatively, consisting of: magnesium, preferably (a-i) magnesium (II), calcium, preferably (a-ii) calcium (II), iron, preferably (a-iii) iron (II) or iron (III), zinc, preferably (a-iv) zinc (II), iodine, preferably (a-v) iodine (V), selenium, preferably (a-vi) selenium (IV) and/or the mixtures thereof,
  • magnesium preferably (a-i) magnesium (II), calcium, preferably (a-ii) calcium (II), iron, preferably (a-iii) iron (II) or iron (III), zinc, preferably (a-iv) zinc (II), iodine, preferably (a-v) iodine (V), selenium, preferably (a-vi
  • lecithin preferably E322 lecithin, preferably non-hydrolysed lecithin (non-hydrolysed E322 lecithin),
  • composition of the invention preferably in solid form, comprises a preparation, called sucrosomial® mineral, comprising or, alternatively, consisting of:
  • a at least one mineral in form of a mineral salt thereof, wherein said mineral is selected from among the group comprising or, alternatively, consisting of: (a-i) magnesium (II), (a-ii) calcium (II), (a-iii) iron (III), (a- iv) zinc (II), (a-v) iodine (V), (a-vi) selenium (IV) and mixtures thereof;
  • a first agent (c-i) consisting of a carbohydrate fatty acid ester or acutester
  • At least one further first agent selected from among the group comprising or, alternatively, consisting of: (c-ii) a cyclodextrin (c-iii) a C6-C18 fatty acid isomer, (c-iv) a chitosan derivative, and mixtures thereof; and, optionally, said composition comprises at least one technological additive and/or at least one pharmaceutical or food grade excipient.
  • composition of the invention preferably in solid form, comprises a preparation, called sucrosomial® mineral, comprising or, alternatively, consisting of:
  • a at least one mineral in form of a mineral salt thereof, wherein said mineral is selected from among the group comprising or, alternatively, consisting of: (a-i) magnesium (II), (a-ii) calcium (II), (a-iii) iron (III), (a- iv) zinc (II), (a-v) iodine (V), (a-vi) selenium (IV) and mixtures thereof;
  • At least one first agent selected from among the group comprising or, alternatively, consisting of: (c-ii) a cyclodextrin, (c-iii) a C6-C18 fatty acid isomer, (c-iv) a chitosan derivative, and mixtures thereof, wherein (c-i) a carbohydrate fatty acid ester or atimester is not present in said preparation;
  • composition comprises at least one technological additive and/or at least one pharmaceutical or food grade excipient.
  • composition of the invention preferably in solid form, as such or for use in a treating method or for non-therapeutic use, are comprised in the present invention:
  • the preparation comprises or, alternatively, consists of (a), (b), (c-i) and (c-ii);
  • the preparation comprises or, alternatively, consists of (a), (b), (c-i) and (c-iii);
  • the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-i) and (c-iv);
  • - FRd wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-i), (c-ii) and (c-iii);
  • the preparation comprises or, alternatively, consists of (a), (b), (c-i), (c-ii) and (c-iv);
  • the preparation comprises or, alternatively, consists of (a), (b), (c-i), (c-iii) and (c-iv);
  • sucrosomial® mineral comprises or, alternatively, consists of (a), (b) e (c-i);
  • sucrosomial® mineral comprises or, alternatively, consists of (a), (b) and (c-ii);
  • sucrosomial® mineral comprises or, alternatively, consists of (a), (b) and (c-iii);
  • sucrosomial® mineral comprises or, alternatively, consists of (a), (b) and (c-iv);
  • the preparation comprises or, alternatively, consists of (a), (b), (c-ii) and (c-iii);
  • the preparation comprises or, alternatively, consists of (a), (b), (c-ii) and (c-iv);
  • the preparation comprises or, alternatively, consists of (a), (b), (c-iii) and (c-iv);
  • the preparation comprises or, alternatively, consists of (a), (b), (c-ii), (c-iii) and (c-iv);
  • the components called (a), (b), (c-i), (c-ii), (c-iii) and (c-iv) are as defined in the present invention, preferably (a) is iron or magnesium or zinc or called or iodine or selenium or mixture of two or three or four or five of them; more preferably (a) is iron or magnesium or zinc; and wherein in embodiments FRh to FRp (c-i) it is not present.
  • composition of the invention preferably in solid form, as such or for use in a treatment method or for non-therapeutic use, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-i), preferably (a) is selenium.
  • the mineral in form of cation (mineral cation) (a-i) magnesium (II) is present in said preparation (or sucrosomial® mineral) as magnesium oxide mineral salt or, alternatively, as magnesium hydroxide mineral salt;
  • the mineral in form of cation (mineral cation) (a-ii) calcium (II) is present in said mixture as tricalcium phosphate mineral salt, preferably E341 tricalcium phosphate;
  • the mineral in form of cation (mineral cation) (a-iii) iron(lll) is present in said mixture as ferric pyrophosphate mineral salt;
  • the mineral in form of cation (mineral cation) (a-iv) zinc (II) is present in said mixture as zinc oxide mineral salt;
  • the mineral in form of cation (mineral cation) (a-v) iodine (V) is present in said mixture as sodium iodate mineral salt;
  • said preparation may contain two or more of said minerals (two or three or four or five minerals), preferably each in form of mineral salt.
  • said (a) mineral salt is a magnesium salt, preferably magnesium oxide (II), or a zinc salt, preferably zinc oxide (II)
  • said (a) mineral salt is present in the preparation at an amount by weight comprised between 20 and 90%, preferably between 30 and 80%, even more preferably between 40 and 70%, with respect to the total weight of the preparation.
  • said (a) mineral salt is an iron salt, preferably iron (III) pyrophosphate
  • said (a) mineral salt is present in the preparation at an amount by weight comprised between 10 and 80%, preferably between 20 and 70%, even more preferably between 30 and 60%, with respect to the total weight of the preparation.
  • the iron (III) pyrophosphate used ⁇ [Fe ⁇ Oz ⁇ xP O], CAS 10058-44-3, anhydrous molecular weight 745,22 ⁇ is preferably in form of powder or in any form and type of grinding or micro grinding.
  • said (a) mineral salt is an iodine salt, preferably sodium iodate, or a selenium salt, preferably sodium selenite
  • said (a) mineral salt is present in the preparation at an amount by weight between 0.01 and 30%, preferably between 0.05 and 20%, even more preferably between 0.1 and 10%, with respect to the total weight of the preparation.
  • said (a) mineral salt is a calcium salt, preferably tricalcium phosphate
  • said (a) mineral salt is present in the preparation at an amount by weight between 50 and 100%, preferably between 65 and 100%, even more preferably between 75 and 100%, with respect to the total weight of the preparation.
  • the preparation or sucrosomial® mineral of the present invention has a mineral content, expressed in mineral mg (or cation of the mineral) over one gram of preparation, in the following intervals: - (a-i) magnesium (II), if present as magnesium oxide salt, comprised between 50 and 800 mg/g, preferably between 100 and 600 mg/g, or
  • magnesium hydroxide salt if present as magnesium hydroxide salt, comprised between 50 and 600 mg/g, preferably between 100 and 450 mg/g, or
  • - (a-ii) calcium (II), if present as tricalcium phosphate salt comprised between 50 and 800 mg/g, preferably between 100 and 600 mg/g, or
  • ferric pyrophosphate salt if present as ferric pyrophosphate salt, comprised between 1 mg/g and 400 mg/g, preferably between 10 mg/g and 300 mg/g, or
  • - (a-iv) zinc (II), if present as zinc oxide salt comprised between 100 and 800 mg/g, preferably between 200 and 700 mg/g, or
  • V - (a-v) iodine (V), if present as sodium iodate salt, comprised between 0.1 and 40 mg/g, preferably between 0.5 and 30 mg/g, or
  • said (b) lecithin preferably non-hydrolysed lecithin, is present in the preparation (or sucrosomial® mineral) at an amount by weight comprised in the range between 0.05 and 20% with respect to the weight of the composition, preferably between 0.1 and 10%, more preferably ⁇ 1 %.
  • the lecithin is a mixture of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides and phospholipids.
  • Phospholipids represent main components thereof; the latter derive from the structure of the triglycerides, where a fatty acid is substituted by a phosphate group which confers a negative charge and thus polarity to the molecule; this molecule is generally referred to as phosphatide.
  • lecithin is often represented by phosphatidylcholine.
  • Phospholipids are characterised by a water-soluble polar head, which dissolves well in water, while the two saturated fatty acids represent the two non-polar tails, that are not water-soluble but lipophilic. Molecules of this type are called amphipathic and in presence of water and fat they are arranged between the fat molecule and the water molecule emulsifying them.
  • Lecithin is a natural emulsifier.
  • the preparation (or sucrosomial® mineral) of the present invention comprises an E322 lecithin.
  • E322 lecithin if a food additive (Directive 95/2/CE dated 20.2.95 published in the Official Gazette L61 dated 18.3.95). Due to its chemical/physical properties, lecithin mainly carries out an emulsifying function. Being rich in natural antioxidant substances, it also has a secondary antioxidant function.
  • the preparation (or sucrosomial® mineral) of the present invention does neither contains a hydrolysed lecithin nor an enzymatically hydrolysed lecithin.
  • the (b) lecithin present in the preparation is a non-hydrolysed lecithin selected from among sunflower, corn or soy lecithin; more preferably it is E322 sunflower lecithin (non-hydrolysed), more preferably allergen free sunflower lecithin ( allergen free means that it does not have allergen residues) (non-hydrolysed).
  • said lecithin is a powder lecithin with water content comprised between 1,5 a 4,5% with respect to the weight of lecithin, preferably between 2% and 4%, even more preferably between 2.5% and 3.5%.
  • the lecithin of the present invention is E322 powder sunflower lecithin.
  • the E322 sunflower lecithin contains an amount of glucose by weight comprised between 20% and 60% with respect to the weight of lecithin, preferably between 30% and 50%, for example about 45%.
  • An E322 sunflower lecithin that can be used in the context of the present invention may have the following composition by weight (chemical/physical analysis): sunflower lecithin between 40% and 50%, carbohydrates between 40% and 50% (for example about 42%), proteins between 6% and 10%, ashes between 3% and 8%, moisture between 2% and 5% and another flowing agent between 0.5% and 1.5%.
  • Said (c) at least one first agent, or mixture of two or more of said first agents comprised between (c-i) and (c-iv), in the present preparation (or sucrosomial® mineral)has the function of increasing absorption capacity of said (a) mineral (cation of the mineral) contained in the solid composition of the invention at intestinal level.
  • said (c) first agent is (c-i) a carbohydrate ester with one or more fatty acids, commonly called Atster or saccharose ester with C6-C12 medium chain fatty acids, linear or branched, saturated or unsaturated, or with C13-C21 long chain, preferably C14-C18, linear or branched, saturated or unsaturated, preferably (c-i) isethylenester E473.
  • the alsters are obtained from the esterification of the fatty acids or from the trans-esterification of the methyl esters of the fatty acids with carbohydrates (also called saccharides). Saccharose (monosaccharide) and polysaccharides are generally the carbohydrates used. This is why atsters are also referred to as saccharose esters of fatty acids. The chemical/physical properties of these compounds depend on the number and the type of esterified fatty acids.
  • the initials E473 indicates that the excessively purified water.
  • the intensive care unit is essentially emulsifiers and they are added so as to determine a greater stabilisation of an aqueous phase with a fatty phase.
  • E473esters are present in the preparation of the composition of the present invention with an HLB (hydrophilic-lipophilic balance) value of about 14-18, advantageously with an HLB value of about 15 or 16.
  • HLB hydrophilic-lipophilic balance
  • the (c-i) E473ester contains at least 70% of monoesters, for example 80% or 95%, obtained through the esterification of saccharose with fatty acids of plant origin (stearic and palmitic acid) of the saccharose mono-stearate type.
  • Aerster that can be used in the context of the present invention may have the following composition by weight: total ester content at least at 90%; free fatty acids (such as oleic acid) content not exceeding 3%; free saccharose content not exceeding 2%; moisture not exceeding 4%; acidity value not exceeding 5.
  • free fatty acids such as oleic acid
  • free saccharose content not exceeding 2%
  • moisture not exceeding 4%
  • acidity value not exceeding 5.
  • SP70 saccharose esters manufactured by Chimab S.p. A -Italia manufactured by Chimab S.p. A -Italia.
  • the preparation (or sucrosomial® mineral) is in solid form such as for example in form of powder, granulate, chips or agglomerates.
  • the preparation and the composition of the present invention a diglycerol fatty acid ester.
  • said (c) first agent is (c-ii) a cyclodextrin or mixtures of cyclodextrins, preferably it is an alpha-cyclodextrin.
  • the cyclodextrins (CyD or CD) are natural cyclic oligosaccharides consisting of 6, 7 or 8 monomers of D-(+)glucopyranose linked together by an a, 1-4 glycosidic and closed-loop bond.
  • Alpha- cyclodextrin is an oligosaccharide with 6 monomers of D-(+)glucopyranose.
  • said (c-ii) cyclodextrin is Cavamax® W6 Food (CAS 10016-20-3) cyclodextrin sold by Wecker Chemie AG.
  • said (c) first agent is (c-iii) a medium chain fatty acid with a number of C6-C18 carbon atoms, linear or branched, saturated or unsaturated, or mixtures of said C6-C18 fatty acids (abbreviated as, "C6-C18 fatty acid”), preferably it is lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0) and/or stearic acid -C18H36O2 (C18:0).
  • C6-C18 fatty acid a medium chain fatty acid with a number of C6-C18 carbon atoms, linear or branched, saturated or unsaturated, or mixtures of said C6-C18 fatty acids
  • Said (c) first agent (c-iii) may also be any isomer of a C6-C18 medium chain fatty acid, for example any cis isomer or trans isomer of any fatty acid having between 6 and 18 carbon atoms.
  • said (c) first agent is (c-iv) a chitosan derivative, or mixtures of chitosan derivatives, preferably it is carboxymethyl chitosan.
  • the chitosan is a linear polysaccharide consisting of D-glucosamine and N-acetyl-D-glucosamine, linked by b(1 -4) bonds.
  • chitosan derivative is used to indicate, by way of non-limiting example in the context of the present invention, any compound that can be obtained using chitosan or a derivative thereof or a precursor thereof as the initial material and subjecting said initial material to chemical transformations known to the man skilled in the art, so that said chitosan derivative has characteristics such to confer to said (a) mineral (cation of the mineral) comprised in the preparation (or sucrosomial® mineral) a higher bioavailability and absorption capacity in the organism.
  • said (c) first agent is a mixture of two or three or four from among (c-i), (c-ii), (c-iii) and (c- iv), as indicated in the embodiments of the invention from FRa to FRp.
  • said (c) first agent (c-i), (c-ii), (c-iii), (c-iv) or, alternatively, mixture of two or three or four of said first agent (c-i)-(c-iv), as indicated in the embodiments of the invention from FRa to FRp, is present in the preparation at an amount by weight between 1% and 75% with respect to the weight of the preparation, preferably between 1% and 60%, even more preferably between 5% and 40%.
  • the composition in solid form of the present invention comprises a preparation (or sucrosomial® mineral) comprising, or alternatively, consisting of: (a) at least one mineral (or cation of the mineral) present as mineral salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above.
  • the composition in solid form of the present invention comprises a preparation comprising or, alternatively, consisting of: (a-i) a magnesium salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above.
  • the magnesium salt (II) is magnesium oxide or, alternatively, magnesium hydroxide
  • the lecithin is E322 sunflower and/or corn lecithin
  • the especiallyster is E473145
  • the cyclodextrin is alpha- cyclodextrin
  • the fatty acid is stearic acid
  • the chitosan derivative is carboxymethyl chitosan.
  • the composition in solid form of the present invention comprises a preparation comprising or, alternatively, consisting of: (a-ii) a calcium salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above.
  • a preparation comprising or, alternatively, consisting of: (a-ii) a calcium salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/
  • the calcium salt (II) is E341 tricalcium phosphate
  • the lecithin is E322 sunflower and/or corn lecithin
  • the especiallyster is E473145
  • the cyclodextrin is alpha-cyclodextrin
  • the fatty acid is stearic acid
  • the chitosan derivative is carboxymethyl chitosan.
  • the composition in solid form of the present invention comprises a preparation comprising or, alternatively, consisting of (a-iii) an iron salt (lll)or iron (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above.
  • the iron salt (III) is ferric pyrophosphate
  • the lecithin is E322 sunflower and/or corn lecithin
  • the especiallyster is E473145
  • the cyclodextrin is alpha-cyclodextrin
  • the fatty acid is stearic acid
  • the chitosan derivative is carboxymethyl chitosan.
  • the composition in solid form of the present invention comprises a preparation comprising or, alternatively, consisting of: (a-iv) a zinc salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above.
  • the zinc salt (II) is zinc oxide
  • the lecithin is E322 sunflower and/or corn lecithin
  • the especiallyster is E473145
  • the cyclodextrin is alpha-cyclodextrin
  • the fatty acid is stearic acid
  • the chitosan derivative is carboxymethyl chitosan.
  • the composition in solid form of the present invention comprises a preparation comprising or, alternatively, consisting of: (a-v) an iodine salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above.
  • a preparation comprising or, alternatively, consisting of: (a-v) an iodine salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (
  • the iodine salt (V) is sodium iodate
  • the lecithin is E322 sunflower and/or corn lecithin
  • the excessivester is E473145
  • the cyclodextrin is alpha-cyclodextrin
  • the fatty acid is stearic acid
  • the chitosan derivative is carboxymethyl chitosan.
  • the composition in solid form of the present invention comprises a preparation comprising or, alternatively, consisting of: (a-vi) a selenium salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above.
  • a preparation comprising or, alternatively, consisting of: (a-vi) a selenium salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-
  • the selenium salt (IV) is sodium selenite
  • the lecithin is E322 sunflower and/or corn lecithin
  • the excessivester is E473145
  • the cyclodextrin is alpha-cyclodextrin
  • the fatty acid is stearic acid
  • the chitosan derivative is carboxymethyl chitosan.
  • a gelatinised or pre-gelatinised starch of plant origin preferably, wherein said (d) starch is selected from among the group comprising or, alternatively, consisting of rice and/or corn starch; preferably, wherein said (d) starch is pre-gelatinised; more preferably pre-gelatinised rice starch.
  • the starch of plant origin is selected from among rice starches (Oryza sativa) or corn starches.
  • the starch is a rice starch.
  • the rice starch is a gelatinised or pre- gelatinised native rice starch.
  • a pre-gelatinised rice starch that can be used in the context of the present invention may have the following chemical/physical characteristics: moisture not exceeding 7%; protein content not exceeding 1%; ashes content not exceeding 1%; pH (solution 10%) comprised between 5.5 and 7.5, density 0.40-0.48 g/cm 3 ; minimum starch content at 97% and fats not exceeding 0.1%.
  • a pre-gelatinised rice starch AX-FG-P manufactured by Reire Sri -Italia The gelatinised or pre- gelatinised starch of plant origin is present in the preparation at an amount by weight comprised between 10% and 95% with respect to the total weight of the preparation, preferably between 20% and 90%.
  • said composition (besides said preparation comprising, or alternatively, consisting of (a) at least one mineral (or cation of the mineral) present as mineral salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to Frp, and, optionally, (d) a starch of plant origin) may also comprise:
  • B group vitamins preferably vitamin B6 and/or B9 and/or B12,
  • said (e) vitamin is (e-i) vitamin C (L-ascorbic acid and/or L-sodium ascorbate).
  • each single vitamin being present in the composition at an amount equivalent to 100% RDA (recommended dietary allowance).
  • the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of: (a) at least one mineral (or cation of the mineral) present as mineral salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above.
  • the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of: (a-i) a magnesium salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above.
  • a magnesium salt II
  • lecithin either hydrolysed nor enzymatically hydrolysed
  • c-i a carbohydrate ester of one or more fatty acids (sucrester) and/or
  • the magnesium salt (II) is magnesium oxide or, alternatively, magnesium hydroxide
  • the lecithin is E322 sunflower and/or corn lecithin
  • the especiallyster is E473145
  • the cyclodextrin is alpha-cyclodextrin
  • the fatty acid is stearic acid
  • the chitosan derivative is carboxymethyl chitosan
  • the starch is a pre-gelatinised rice starch (Oryza sativa)
  • the vitamin, if present, is vitamin C.
  • the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of a (a-ii) calcium salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above.
  • a-ii) calcium salt (II) a lecithin (neither hydrolysed nor enzymatically hydrolysed)
  • the calcium salt (II) is E341 tricalcium phosphate
  • the lecithin is E322 sunflower and/or corn lecithin
  • the especiallyster is E473145
  • the cyclodextrin is alpha-cyclodextrin
  • the fatty acid is stearic acid
  • the chitosan derivative is carboxymethyl chitosan
  • the starch is a pre-gelatinised rice starch (Oryza sativa)
  • the vitamin, if present, is vitamin C.
  • the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of: (a-iii) an iron salt(lll) or iron (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above.
  • the iron salt (III) is ferric pyrophosphate
  • the lecithin is E322 sunflower and/or corn lecithin
  • the especiallyster is E473145
  • the cyclodextrin is alpha-cyclodextrin
  • the fatty acid is stearic acid
  • the chitosan derivative is carboxymethyl chitosan
  • the starch is a pre-gelatinised rice starch (Oryza sativa)
  • the vitamin, if present, is vitamin C.
  • the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of: (a-iv) a zinc salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C16 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above.
  • the zinc salt (II) is zinc oxide
  • the lecithin is E322 sunflower and/or corn lecithin
  • the especiallyster is E473145
  • the cyclodextrin is alpha-cyclodextrin
  • the fatty acid is stearic acid
  • the chitosan derivative is carboxymethyl chitosan
  • the starch is a pre-gelatinised rice starch (Oryza sativa)
  • the vitamin, if present, is vitamin C.
  • the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of (a-v) an iodine salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above.
  • the iodine salt (V) is sodium iodate
  • the lecithin is E322 sunflower and/or corn lecithin
  • the especiallyster is E473145
  • the cyclodextrin is alpha-cyclodextrin
  • the fatty acid is stearic acid
  • the chitosan derivative is carboxymethyl chitosan
  • the starch is a pre-gelatinised rice starch (Oryza sativa)
  • the vitamin, if present, is vitamin C.
  • the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of (a-vi) a selenium salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above.
  • the selenium salt (IV) is sodium selenite
  • the lecithin is E322 sunflower and/or corn lecithin
  • the especiallyster is E473145
  • the cyclodextrin is alpha-cyclodextrin
  • the fatty acid is stearic acid
  • the chitosan derivative is carboxymethyl chitosan
  • the starch is a pre-gelatinised rice starch (Oryza sativa)
  • the vitamin, if present, is vitamin C.
  • said composition (besides said preparation comprising, or alternatively, consisting of (a) at least one mineral (or cation of the mineral) present as mineral salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and, optionally, (d) a starch of plant origin), may optionally comprise, (e) a vitamin, and as well as.
  • said (f) group of organic and/or inorganic salts consists of: (f-i) magnesium glycinate, (f-ii) selenium methionine, and (f-iii) zinc gluconate; preferably each single salt being present in the composition at an amount equivalent to 100% RDA (recommended dietary allowance).
  • said (g) group of antioxidant substances comprises or, alternatively, consists of: (g-i) N- acetyl cysteine (NAC), (g-ii) Coenzyme Q10 (CoQ10) and/or (g-iii) Acetyl-L-carnitine ALC; preferably each single antioxidant substance being present in the composition at an amount equivalent to 100 mg/day.
  • said (h) at least one probiotic bacterial strain, or a mixture of probiotic bacterial strains belongs to the Lactobacilli or Bifidobatteri genus; preferably, it belongs to the species selected from among the group comprising or, alternatively, consisting of: Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus rhamnosus, Bifidobacterium lungum, Bifidobacterium lactis, Bifidobacterium infantis, Bifidobacterium bifidum.
  • the preparation (or sucrosomial® mineral) of the present invention is a mixture at solid state.
  • the expression solid state is used to indicate that the preparation of the present invention can be in form of granules or powder or chips or agglomerates whose dimensions and grain size varies as a function of the final formulation of the composition.
  • the preparation (or sucrosomial® mineral) according to the embodiments described above, is formulated with at least one technological additive and/or a pharmaceutical or food grade excipient to obtain the composition of the present invention, preferably in solid form of powder, granules or chips, appropriate for oral use.
  • the technological additive or pharmaceutical or food grade excipient can be selected from among all substances known to the man skilled in the pharmaceutical art or skilled in preparing food products, such as, by way of non-limiting examples, preservatives, emulsifiers and/or thickeners such as for example hydroxyethylcellulose, sweeteners, dyes such as for example E171 dye, natural and artificial flavours, antioxidants, stabilisers, fillers, anticaking agents such as for example vegetable magnesium stearate, fatty acids magnesium salts and silicon dioxide, charging agents such as for example microcrystalline cellulose and the mixtures thereof.
  • preservatives such as for example hydroxyethylcellulose
  • sweeteners dyes such as for example E171 dye, natural and artificial flavours, antioxidants, stabilisers
  • anticaking agents such as for example vegetable magnesium stearate, fatty acids magnesium salts and silicon dioxide
  • charging agents such as for example microcrystalline cellulose and the mixtures thereof.
  • composition of the present invention is for oral use and it can be in solid, or semi-solid or liquid form, preferably in solid or semi-solid form.
  • the composition in solid form, can be in form of powder, granules, chips, aggregates, or for mouth-soluble or mouth-dissolving formulations.
  • the composition in liquid form, can be in form of solution, dispersion or suspension of a solid in a liquid.
  • composition in solid or semi-solid form of the present invention can be in any form suitable for oral administration to a subject and known to a man skilled in the art such as, for example, a sachet, a tablet, a bar, a pill or a capsule or a softgel.
  • the obtained tablets may have various shapes including those known in the pharmaceutical industry, such as for example cylindrical-shaped or spherical-shaped.
  • the tablets may have a weight comprised between 200 and 2000 mg.
  • a hard tablet may have a weight comprised between 800 and 1000 mg
  • a chewable tablet may have a weight comprised between 1000 and 2000 mg.
  • the tablets may be coated or filmed with one or more layers or films of coating capable of going past the gastric barrier.
  • the coating is prepared using bee wax solution or a sugar-based solution.
  • the capsules can be made of rigid gelatine or soft gelatine or soft gel.
  • a gelatine capsule may have a weight of 500 mg.
  • the composition of the present invention is a pharmaceutical composition, a medical device composition according to the European regulation on medical devices [UE 2017/745 -(MDR), Directive 93/42/CEE -(MDD)] or a food supplement composition.
  • the present invention regards a method (first and second method) for preparing the preparation (or sucrosomial® mineral) of the present invention in one of the embodiments as defined above, for example in the embodiments from FRa to FRp.
  • said method (first method) for preparing the preparation(or sucrosomial® mineral) comprises or, alternatively, consists of several processing steps through which said (a) mineral in form of mineral is coated or wrapped or encapsulated, fully or partly, with said (b) lecithin, with said (c) first agent, which can be selected from among between (c-i) and (c-iv) or, alternatively, a mixture between two or more of said (c-i)-(c-iv), and/or preferably between said (d) plant starch, wherein (a), (b), (c) and (d) have the characteristics indicated above.
  • the components (a), (b), (c) and (d) are all in solid form, in particular in form of powders.
  • said (a) mineral salt in solid state is placed at close physical contact firstly with said (b) lecithin. Then, only subsequently, once fully or partly coated or wrapped or encapsulated with said (b) lecithin, said mineral is placed at contact with at least one of said (c) first agent, selected from among (c-i) a carbohydrate ester of one or more fatty acids (sucrester), (c-ii) cyclodextrin, (c-iii) C6-C18 fatty acid, (c-iv) chitosan derivative or, alternatively, with two or more of said first agent selected from among (c-i)-(c-iv) as indicated in the embodiments of the invention from FRa to FRp, and/or preferably with said (d) plant starch.
  • said (c) first agent selected from among (c-i) a carbohydrate ester of one or more fatty acids (sucrester), (c-ii) cyclodextrin,
  • the processing time during which the (a) mineral salt and the (b) lecithin are placed at contact is comprised between 1 and 60 minutes, preferably between 10 and 50 minutes, even more preferably between 20 and 40 minutes.
  • the (b) lecithin, placed at contact with said (a) mineral salt is distributed in the most uniform manner possible on said mineral salt, fully or partly, and, thus, also on the mineral present in the mineral salt in form of magnesium (II) or calcium (II) or iron (III) or iron (II) or zinc (II) or iodine (V) or selenium (IV) mineral cation.
  • the (a) mineral salt in solid state of powder or granules or chips or agglomerates has a water content comprised between 0.05% and lesser than 20% by weight, preferably between 0.1% and lesser than 10%, even more preferably between 1% and 3%.
  • the (a) mineral salt containing the magnesium (II) or calcium (II) or iron (III) or iron (II) or zinc (II) or iodine (V) or selenium (IV) mineral (or mineral cation) is used at an amount by weight with respect to the total weight of the preparation (or sucrosomial® mineral) variable depending on the salt used, as specified in the previous part describing the preferred embodiments of the preparation of the composition of the invention.
  • the (b) lecithin used in said first method is an E322 sunflower lecithin, in powder. Neither a hydrolysed lecithin nor an enzymatically hydrolysed lecithin is used in said first method.
  • the lecithin is present at an amount by weight comprised between 0.05 and 20% with respect to the total weight of the preparation, preferably between 0.1 and 10%.
  • the (c) first agent (c-i), (c-ii), (c-iii), (c-iv) or, alternatively, mixture of two or three or four of said first agent (c-i)-(c-iv), is present in the preparation at an amount by weight between 1% and 75% with respect to the weight of the preparation, preferably between 1% and 60%, even more preferably between 5% and 40%.
  • said at least one (c) first agent is only (c-i) or, alternatively, said at least one (c) first agent is (c- i) and at least one or more from among (c-ii), (c-iii) and (c-iv) or, alternatively, said at least one (c) first agent does not comprise (c-i) and it is at least one from among (c-ii), (c-iii) and (c-iv).
  • the (d) starch is a gelatinised or pre-gelatinised native rice starch, when present.
  • the starch is present in the preparation of the present invention at an amount by weight comprised between 10% and 95% with respect to the total weight of the preparation, preferably between 20% a 90%, even more preferably between 25% and 85%.
  • the starch in form of gelatinised or pre-gelatinised starch has the advantage of being more fluid and flowing and it allows to be dosed accurately without creating weight errors or variations; furthermore, it is distributed in a more uniform and homogeneous manner.
  • the gelatinised or pre-gelatinised starch improves the bioavailability of the mineral salt and, thus, of the mineral (mineral cation content in said mineral salt) given that the compound that is obtained dissolves better at temperatures comprised between 15°C and 30°C (pressure 1 atmosphere and ambient temperature of 20°C), preferably between 20°C and 25°C, even more preferably between 18°C and 23°C.
  • the preparation Obtained at the end of said first preparation method is the preparation (or sucrosomial® mineral) contained in the composition of the present invention in solid form (powder or granules or chips or agglomerates); said preparation has a water content comprised between 0.05% and lesser than 5% by weight with respect to the total weight of the preparation, preferably between 0.1% and lesser than 3%, even more preferably between 0.5% and 2% by weight.
  • the preparation (or sucrosomial® mineral) in solid form obtained according to said first method described above comprises or, alternatively, consists of: (a) at least one mineral in form of mineral salt (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), at least one (c) first agent, selected from among (c-i) a carbohydrate ester of one or more fatty acids (sucrester), (c-ii) cyclodextrin, (c-iii) C6-C18 fatty acid, (c-iv) chitosan derivative, or mixtures of two or more of said first agent (c-i)-(c-iv) according to one of the embodiments from FRa to FRp; and, preferably, (d) a gelatinised or pre-gelatinised starch of plant origin, at the amounts by weight indicated in the present description.
  • said at least one (c) first agent is only (c-i) or, alternatively, said at least (c) first agent is (c-i) and at least one or more from among (c-ii), (c- iii) and (c-iv) or, alternatively, said at least one (c) first agent does not comprise (c-i) and it is at least one from among (c-ii), (c-iii) and (c-iv).
  • the preparation (or sucrosomial® mineral) in solid form obtained according to said first method described above comprises or, alternatively, consists of a mineral (or cation of the mineral), selected from among magnesium (II), calcium (II), iron (III), iron (II), zinc (II), iodine (V), selenium (IV) or the mixtures thereof, an E322 sunflower lecithin (neither hydrolysed nor enzymatically hydrolysed), preferably allergen free sunflower lecithin, an E473145 and/or alpha-cyclodextrin and/or stearic acid and/or carboxymethyl chitosan, according to one of the embodiments from FRa to FRp, and, optionally, a pre-gelatinised rice starch, at the amounts by weight indicated in the present description; preferably, in this embodiment, said at least one (c) first agent is only E473entrester or, alternatively, said at least one (c) one first agent is E473145
  • the preparation of the invention obtained using said first or second method, comprises the (b) lecithin at a by weight % comprised in the range between 0.1 and 10%, preferably between 0.5 and 5%, more preferably between 0,1 and 1% or between 0,5 and 1%, with respect to the total weight of the preparation.
  • the Applicant found that in order to have high bioavailability in the organism of the mineral (or cation of the mineral) it is important to use - in the method for preparing the preparation (or sucrosomial® mineral), combined with a low amount by weight of (b) lecithin - a determined amount by weight of (c) first agent, preferablyesthesia.
  • the ratio between the (c) first agent, preferablyhester, or mixture thereof, and the (b) lecithin is comprised between 25:1 and 1 :1, preferably between 20:1 and 5:1, even more preferably between 15:1 and 10:1. In an embodiment, said ratio is comprised between 20:1 and 10:1.
  • said method (second method) for preparing the preparation comprises or, alternatively, consists of a technology designed to create - around the mineral salt - a coating or wrapping or encapsulation such to improve the stability and the bioavailability of the mineral (or cation of the mineral) contained in the mineral salt.
  • the difference between the first and the second method lies in the order with which (b) a lecithin and (c) at least one first agent are added to (a) at least one.
  • a lecithin is added (a) to at least one mineral and, then, only subsequently, there follows the addition of (c) at least one first agent.
  • at least (c) one first agent is added to (a) at least one mineral and, then, only subsequently, there follows the addition of (b) a lecithin.
  • at least one first agent is added to (a) at least one mineral and, then, only subsequently, there follows the addition of (b) a lecithin.
  • at least one first agent and (b) a lecithin can be added - together and simultaneously - to (a) at least one mineral.
  • the preparation (or sucrosomial® mineral) in solid form (powder, granules, chips or agglomerates) obtained according to said second method comprises or, alternatively, consists of: (a) at least one mineral in form of mineral salt, a (b) lecithin, at least one (c) first agent, selected from among (c-i)utester, (c-ii) cyclodextrin, (c-iii) C6-C18 fatty acid, (c-iv) chitosan derivative, or mixtures of two or more of said first agent (c-i)-(c-iv) according to one of the embodiments of the invention from FRa to FRp; and, preferably, a (d) gelatinised or pre-gelatinised starch, at the amounts by weight indicated in the present description.
  • said at least one (c) first agent is only (c-i) or, alternatively, said at least (c) first agent is (c-i) and at least one or more from among (c-ii), (c-iii) and (c-iv) or, alternatively, said at least one (c) first agent does not comprise (c-i) and it is at least one from among (c-ii), (c-iii) and (c-iv).
  • the preparation (or sucrosomial® mineral) obtained according to said second method comprises or, alternatively, consists of: a mineral (or metallic cation), such as magnesium (II), calcium (II), iron (III), zinc (II), iodine (V), selenium (IV) or the mixtures thereof, an E322 sunflower lecithin (neither hydrolysed nor enzymatically hydrolysed), an E473145 and/or alpha-cyclodextrin and/or stearic acid and/or carboxymethyl chitosan, according to one of the embodiments of the invention from FRa to FRp, and, optionally, a pre-gelatinised rice starch, at the amounts by weight indicated in the present description; preferably, in this embodiment, said at least one (c) first agent is only E473entrester or, alternatively, said at least one (c) one first agent is E473145 and at least one or more from among alpha-cyclodextrin
  • lecithin and said (c) first agent have the function of increasing the bioavailability and absorption of the mineral (or cation of the mineral) contained in said mineral salt.
  • agglomerates for example "chimeric” agglomerates which are capable of fully or partly protecting and shielding the mineral (or cation of the mineral) present in said mineral salt, against gastric acid.
  • the mineral salt containing the mineral (or cation of the mineral) is used at the amounts by weight indicated in the present description.
  • the processing time during which the (a) mineral salt and the (b) lecithin are placed at contact is comprised between 1 and 60 minutes, preferably between 10 and 50 minutes, even more preferably between 20 and 40 minutes.
  • the (b) lecithin used is a sunflower powder lecithin, preferably allergen free sunflower lecithin
  • (b) is present at an amount by weight comprised between 0.05 and 20% with respect to the total weight of the preparation, preferably between 0.1 and lesser than 1%, more preferably between 0.1 and 1%.
  • lecithin is fully or partly distributed on the outer surface of the granules or of the powders of the mineral salts if directly added on said mineral salts (first method) before adding said (c) first agent; or it is distributed on the outer surface of the granules or of the powders comprising the (a) mineral salt and the
  • first agent preferablyholster, if added subsequently to the (c) first agent (second method).
  • a gelatinised or pre-gelatinised starch of plant origin is preferably used subsequently.
  • the starch is a gelatinised or pre-gelatinised native rice starch.
  • the starch, if present, is present in the preparation (or sucrosomial® mineral) of the present invention at an amount by weight comprised between 10 and 95% with respect to the total weight of the preparation, preferably between 20 and 90%.
  • the gelatinised or pre-gelatinised starch is prepared according to the equipment and techniques known to the man skilled in the art.
  • the rice flour gelatinisation process has the purpose of modifying the technological properties thereof inducing a molecular restructuring of the starch component: such modifications allow to confer greater plasticity and viscosity to the mixtures and improving various characteristics in the products in which they are used.
  • the properties acquired through the gelatinisation and upon the ensuing change of the structure of the native starches contained in the rice, allow the process to confer greater hydration rapidity and greater viscosity to the flours.
  • the gelatinised starch strongly links the water to the starch matrix making it less available. This entails longer preservation period and lesser impact of the chemical and enzymatic degradation phenomena.
  • Pre-gelatinisation is a physical technique (which thus does not provide for adding other component) which changes the properties of starch and it is based on the cooking and the subsequent drying of an aqueous suspension of native starch (i.e. "raw” flour).
  • Pre-gelatinised starches reveal important functional properties of absorbing a high amount of water, thus they are used as thickeners in many food grade formulations, especially when (and this specifically applies to rice or corn flours) the protein fraction of gluten is not present.
  • the cooking-extrusion i.e. the short treatment at high temperatures and pressure
  • the drying obtained on the cylinders are the most common method used to obtain pre-gelatinisation.
  • pre-gelatinised starch-based products reveal good preservation characteristics.
  • the (b) lecithin is used at an amount by weight comprised between 0.1 and 10%, preferably between 0.5 and 5%, more preferably between 0.1 and 1% or between 0.5 and 1%, while the (c) first agent, preferably is used at an amount by weight comprised between 1 and 60%, preferably between 10 and 30% or between 1 and 20%, with respect to the weight of the preparation of the present invention.
  • the preparation (or sucrosomial® mineral) of the present invention is the raw material at solid state (powder or granules or chips or agglomerates) which is subsequently mixed with other components, such as for example (e) vitamins, preferably (e-i) vitamin C, and/or (f) organic and/or inorganic salts, and/or (g) antioxidant substances, and/or (h) probiotic bacterial strains, and/or (i) folic acid, and with a technological additive and/or at least one pharmaceutical or food grade excipient to obtain the composition, preferably in solid form, of the present invention in formulations appropriate for oral use.
  • other components such as for example (e) vitamins, preferably (e-i) vitamin C, and/or (f) organic and/or inorganic salts, and/or (g) antioxidant substances, and/or (h) probiotic bacterial strains, and/or (i) folic acid, and with a technological additive and/or at least one pharmaceutical or food grade excipient to obtain the
  • composition of the present invention for oral use according to one of the embodiments described above (for example one of the embodiments from FRa to FRp), preferably in solid form, comprising in the preparation (or sucrosomial® mineral) the iron such as iron salt (III), can be validly used in the treatment of disorders or symptoms relating to or deriving from an iron deficiency in subjects in paediatric age, adolescents, sportsmen/sportswomen, men, the elderly, women and pregnant women.
  • composition of the present invention according to one of the embodiments described above, comprising the preparation (or sucrosomial® mineral), is recommended for an administration lasting for a period comprised between 1 and 5 months, preferably between 2 and 4 months.
  • composition of the present invention comprising the preparation, according to one of the embodiments from FRa to FRp, comprising an iron salt (III), preferably iron (III) pyrophosphate, can be validly used in the prevention, reduction or treatment or anaemia and it useful for increasing the haemoglobin and ferritin values in needy subjects.
  • the preparation is called "sucrosomial mineral” or, more precisely, “sucrosomial® iron”.
  • said composition comprising iron (III) can be validly used in the reduction, prevention or treatment of anaemia when it is administered on the aforementioned subjects at a dose comprised between 10 and 40 mg of iron (lll)/day, preferably between 15 and 35 mg of iron (lll)/day, even more preferably 30 mg of iron (lll)/day.
  • composition comprising iron (III) is recommended for pregnant women in that it increases the weight of the baby at birth, it prevents maternal anaemia and it acts effectively to maintain or increase the haemoglobin and ferritin values.
  • said composition comprising iron (III) (sucrosomial® iron) is administered for a period lasting the entire pregnancy period, in particular starting from the 12th week, up to 6 weeks after delivery ⁇ postpartum ); the recommended dose is comprised between 10 and 40 mg of iron (lll)/day, preferably between 15 and 35 mg of iron (lll)/day, advantageously 30 mg of iron (lll)/day.
  • composition of the present invention comprising the preparation, according to one of the embodiments from FRa to FRp, wherein (a) is magnesium salt (II), preferably magnesium oxide or magnesium hydroxide, can be validly used in the prevention, reduction or treatment of musculoskeletal, cardiometabolic, emotional sphere (e.g. stress) and immune system (e.g. physical and mental fatigue) disorders.
  • the preparation is called "sucrosomial mineral” or, more precisely, "sucrosomial® magnesium”.
  • composition of the present invention comprising the preparation, according to one of the embodiments from FRa to FRp, wherein (a) is zinc salt (II), preferably zinc oxide, can be validly used in the prevention, reduction or treatment of growth and development, metabolism (intermediary metabolism, DNA metabolism), immune system, sight and cognitive behaviour disorders.
  • the preparation is called "sucrosomial mineral” or, more precisely, “sucrosomial® zinc”.
  • the amount of zinc required daily is relatively small, about 2-3 mg, so as to compensate the low loss of this element through urine, faeces and sweat.
  • the recommended dietary allowance must consider numerous factors, such as sex, age and metabolic conditions such as pregnancy and breastfeeding Flowever, the recommended dietary allowance does not consider the zinc absorption inhibitor effects and thus the required dose may vary contingently and from case to case.
  • composition of the present invention comprising the preparation, according to one of the embodiments from FRa to FRp, wherein (a) is selenium salt (IV), preferably sodium selenite, can be validly used in the prevention, reduction or treatment of pregnancy (i.e. foetal development), metabolic and immune system disorders.
  • the preparation is called "sucrosomial mineral” or, more precisely, “sucrosomial® selenium”.
  • selenium deficiency can weaken the immunity defences of the mother, making the organism more susceptible to infections, as well as facilitating foetal growth retardations and metal retardations.
  • composition of the present invention comprising the preparation, according to one of the embodiments from FRa to FRp, wherein (a) is calcium salt (II), preferably tricalcium phosphate, can be validly used in the prevention, reduction or treatment of pregnancy (i.e. foetal development), state of mind, bone muscle and pressure disorders.
  • the preparation is called "sucrosomial mineral” or, more precisely, “sucrosomial® calcium”.
  • composition of the present invention comprising the preparation, according to one of the embodiments from FRa to FRp, wherein (a) is iodine salt (V), preferably sodium iodate, can be validly used in the prevention, reduction or treatment of pregnancy (i.e. foetal development), state of mind, metabolism, cardiovascular and energy deficiency disorders.
  • V iodine salt
  • the preparation is called "sucrosomial mineral” or, more precisely, "sucrosomial® iodine”.
  • composition of the present invention comprising the preparation comprising the mineral or several minerals (sucrosomial mineral/s), reveals considerable changes in subjects after taking it (effectiveness).
  • continuously taking the composition of the invention according to the doses described above considerably improves the levels of mineral/s present in the composition of the invention in the individuals subject of treatment (symptomatic or healthy persons), both in the blood and in the organs, such as for example the liver which is the organ where surplus iron is stored, in form of Fe(lll), and it transports part of the iron (transporter iron) through the blood to the tissues in need thereof.
  • composition of the invention does not reveal any adverse effects and it is suitable to be taken by all types of subjects, including pregnant women, whether on a full or empty stomach.
  • the composition of the present invention is easy to take, in particular if in solid form, and it does not reveal any problems relating to unpleasant palatability.
  • the composition of the present invention reveals chemical/physical and organoleptic stability over time.
  • the preparation (or sucrosomial® mineral) comprised in the composition of the present invention is easy to process to obtain the composition of the present invention as finished product, preferably in solid form, suitable for oral use.
  • Embodiments (FRnr) of the present invention are indicated below:
  • composition in solid form comprising a preparation, called sucrosomial® mineral, comprising or, alternatively, consisting of;
  • a at least one mineral in form of a mineral salt thereof, wherein said mineral is selected from among the group comprising or, alternatively, consisting of: (a-i) magnesium (II), (a-ii) calcium (II), (a-iii) iron (III), (a- iv) zinc (II), (a-v) iodine (V), (a-vi) selenium (IV) or mixtures thereof;
  • lecithin preferably E322 lecithin
  • compositions comprises at least one technological additive and/or at least one pharmaceutical or food grade excipient,
  • composition being for use in the preventive and/or curative treatment of symptoms or diseases relating to or deriving from a deficiency of said mineral or mixtures thereof.
  • composition for use according to FR1 wherein said preparation, called sucrosomial® mineral, further comprises:
  • (d) a gelatinised or pre-gelatinised starch of plant origin; preferably, wherein said (d) starch is selected from among the group comprising or, alternatively, consisting of rice and corn starch; preferably, wherein said (d) starch is pre-gelatinised rice.
  • said (e) vitamin is (e-i) vitamin C; and/or
  • said (a-i) magnesium (II) mineral salt is selected from among magnesium oxide and magnesium hydroxide
  • said (a-ii) calcium (II) mineral salt is E341 tricalcium phosphate
  • said (a-iii) iron (III) mineral salt is ferric pyrophosphate
  • said (a- iv) zinc (II) mineral salt is zinc oxide
  • FR 5 The composition for use according to any one from FR1 to FR4, wherein said (b) lecithin is present in the preparation, called sucrosomial® mineral, at an amount by weight comprised between 0.05 and 20% of the total weight of the preparation, preferably between 0.1 and 10%; preferably, wherein said (b) lecithin is an E322 lecithin and it is selected from among the group comprising or, alternatively, consisting of: corn lecithin, sunflower lecithin and soy lecithin; more preferably it is E322 sunflower lecithin. FR6.
  • sucrosomial® mineral sucrosomial® mineral
  • magnesium (II) between 50 and 800 mg/g if the mineral salt is magnesium oxide, preferably between 100 and 600 mg/g,
  • magnesium (II) between 50 and 600 mg/g if the mineral salt is magnesium hydroxide, preferably between 100 and 450 mg/g,
  • iron (III) between 1 and 400 mg/g if the mineral salt is ferric pyrophosphate, preferably between 10 and 300 mg/g,
  • sucrosomial® mineral comprising or, alternatively, consisting of: - (a) at least one mineral in form of a mineral salt thereof, wherein the mineral is selected from among the group comprising or, alternatively, consisting of: (a-i) magnesium (II), (a-ii) calcium (II), (a-iii) iron (III), (a- iv) zinc (II), (a-v) iodine (V), (a-vi) selenium (IV) or mixtures thereof;
  • lecithin preferably E322 lecithin
  • said composition comprises at least one technological additive and/or at least one pharmaceutical or food grade excipient, for modulating and/or improving disorders relating to or deriving from a deficiency of said mineral or mixtures thereof in a subject, wherein said use is not for therapeutic purposes.
  • sucrosomial® mineral further comprises:
  • (d) a gelatinised or pre-gelatinised starch of plant origin; preferably, wherein said (d) starch is selected from among the group comprising or, alternatively, consisting of rice and corn starch; preferably, wherein said (d) starch is pre-gelatinised rice.
  • composition according to FR9 or FR10 wherein said composition further comprises:
  • said (e) vitamin is (e-i) vitamin C; and/or
  • composition according to any one from FR9 to FR11, wherein said (a-i) magnesium (II) mineral salt is selected from among magnesium oxide and magnesium hydroxide, said (a-ii) calcium (II) mineral salt is E341 tricalcium phosphate, said (a-iii) iron (III) mineral salt is ferric pyrophosphate, said (a- iv) zinc (II) mineral salt is zinc oxide, said (a-v) iodine (V) mineral salt is sodium iodate, said (a-vi) selenium (IV) mineral salt is sodium selenite; more preferably said (a) mineral salt is ferric pyrophosphate.
  • said (a) magnesium (II) mineral salt is selected from among magnesium oxide and magnesium hydroxide
  • said (a-ii) calcium (II) mineral salt is E341 tricalcium phosphate
  • said (a-iii) iron (III) mineral salt is ferric pyrophosphate
  • composition according to any one from FR9 to FR12, wherein said (b) lecithin is present in the preparation, called sucrosomial® mineral, at an amount by weight comprised between 0.05 and 20% of the total weight of the preparation, preferably between 0.1 and 10%; preferably, wherein said (b) lecithin is an E322 lecithin and it is selected from among the group comprising or, alternatively, consisting of: corn lecithin, sunflower lecithin and soy lecithin; more preferably it is E322 sunflower lecithin.
  • composition according to any one from FR9 to FR13, wherein said (c) first agent, or mixture thereof, is present in the preparation, called sucrosomial® mineral, at an amount by weight comprised between 1 and 75% of the total weight of the preparation, preferably between 1 and 60%; preferably, wherein, if present, (c-i) is an E473utester, preferably saccharose and stearic acid and palmitic acid E473utester, (c-ii) is alpha-cyclodextrin, (c-iii) is stearic acid, (c-iv) is carboxymethyl chitosan; more preferably, wherein (c) first agent is a mixture of two or more of said first agents comprised between (c-i) and (c-iv).
  • composition in solid form comprising
  • sucrosomial® mineral comprising or, alternatively, consisting of:
  • a at least one mineral in form of a mineral salt thereof, wherein said mineral is selected from among the group comprising or, alternatively, consisting of: (a-i) magnesium (II), (a-ii) calcium (II), (a-iii) iron (III), (a- iv) zinc (II), (a-v) iodine (V), (a-vi) selenium (IV) and mixtures thereof;
  • said preparation does not comprise (c-i) a carbohydrate fatty acid ester or ahester, and, optionally, said composition comprises at least one technological additive and/or at least one pharmaceutical or food grade excipient.
  • composition according to FR16 or FR17, wherein said preparation, called sucrosomial® mineral, further comprises:
  • said (a) is (a-i) is magnesium in form of magnesium (II) mineral salt, preferably magnesium oxide or magnesium hydroxide, or it is (a-iii) iron in form of iron (III) mineral salt, preferably ferric pyrophosphate, or it is (a-iv) zinc, in form of zinc (II) mineral salt, preferably zinc oxide.
  • sucrosomial® mineral at a (c):(b) by weight ratio comprised in the range between 25:1 and 1 :1; preferably between 20:1 and 10:1.
  • composition according to any one from FR16 to FR23, wherein said composition is for use in a method for the preventive and/or symptomatic treatment of symptoms or disorders relating to or deriving from a deficiency of said (a) mineral or of mixtures thereof.
  • composition in solid form for modulating and/or improving disorders relating to or deriving from a deficiency of said mineral or mixtures thereof in a subject, wherein said use is not for therapeutic purposes.
  • the transport of iron through the intestinal epithelium may occur through two different ways: the transport of Fe(ll) is mainly mediated by thye DMT-1 transporter , while Fe(lll) in the formulation according to the composition of the invention (sucrosomial® iron) is partly encapsulated in a vesicular system which can permeate through the intestinal tissue by means of transcytosis which is another transport pathway ( Fabiano A, et al; EurJ Pharm Sci. 2018; 111 :425-431).
  • the objective of the present experimental part is to prove whether the vesicles that are simultaneously formed once the sucrosomial® iron comes into contact with the physiologic fluids are internalised by the cells of the intestinal epithelium by means of transcytosis and whether they are able to pass through the intestinal tissue (Experimental part (II)) and, lastly, if this further iron transport pathway can improve the in vivo bioavailability of iron (Experimental part (I) thus reducing the adverse effects caused by the iron not absorbed in the intestine.
  • an excessive amount non-absorbed iron can stimulate the virulence of the pathogenic bacteria present in the intestine and contribute towards creating an oxidative pro-inflammatory environment.
  • the free iron in the colon can generate toxic free radicals and reactive oxygen species, which can affect the wholeness of the cells of the intestinal epithelium by enhancing redox stress.
  • compositions of the present invention containing iron (sucrosomial® iron) in rats in terms of improving the bioavailability of iron with respect to administering known compositions containing iron which is not a sucrosomial® iron.
  • the method for UV determination of concentration of Fe(lll)in aqueous solutions is based on the formation of a coloured complex between Fe(lll) and toluidine mediated by the formation of the nucleophile which is formed between the Fe(lll) and the oxidised catechol as described in Shyla et al. “Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy”, 2012.
  • the standards were prepared with known concentration of Fe(lll) by dissolving NFUFeiSO ⁇ FhO in water in the presence of HCI so as to obtain an Fe(lll) concentration of 20 pg/ml. Furthermore, an aqueous solution of catechol (0,005 M), one of o-toluidine (100 pg/ml) and one of 1.10-phenanthroline (0.25%) were prepared.
  • Composition 1 Ferric pyrophosphate (abbreviated as FP)
  • Composition 2 Composition according to the invention: sucrosomial® iron A (Sideral ® r.m., abbreviated as SRM, manufactured by Pharmanutra-Alesco, registered trademarks) (ferric pyrophosphate, saccharide esters of fatty acids, sunflower lecithin supported on glucose syrup, pre-gelatinised rice starch, tricalcium phosphate), L-ascorbic acid (vitamin C), vitamin B12 (cyanocobalamin, maltodextrin), charging agent: microcrystalline cellulose, food grade gelatin, hydroxypropyl cellulose, anticaking agent: fatty acids magnesium salts and silicon dioxide, dye: titanium dioxide.
  • Composition 3 (comparison composition): chelated iron, L-ascorbic acid (vitamin C), folic acid.
  • Composition 4 Composition according to the invention
  • sucrosomial® iron B (Sideral® forte, manufactured by Pharmanutra-Alesco, registered trademarks) (ferric pyrophosphate, saccharide esters of fatty acids, sunflower lecithin (E322), pre-gelatinised rice starch), L-ascorbic acid (vitamin C), charging agent: microcrystalline cellulose, food grade gelatin, hydroxypropyl cellulose, anticaking agent: vegetable magnesium stearate and silicon dioxide, E171 dye.
  • Each of the four compositions was administered in rats at the dose of 5 mg/Kg, i.e. 5 mg of iron element per Kg of weight.
  • liver, spleen and bone marrow were collected, isolated and homogenised using PBS acidified to pH 3 at 8000 rpm for 10 minutes using an Ultra-Turrax ( Tozaki H, et al. J. Control. Release 2002; 82:51-61).
  • the homogenised sample was centrifuged at 10000 rpm for 5 minutes and the collected supernatant was analysed for Fe(lll) content using the method for UV spectrophotometric determination of Fe(lll) as described in paragraph 1.1.
  • Figure 1 in absence of control
  • Figure 2 in presence of control
  • Figure 1 shows the serum iron values (Fe(lll)) concentration in the blood drawn from the rats at time 0 and in the subsequent 5 hours following administration of the formulations containing Fe(lll) in question: composition 1 , composition 2, composition 3 and composition 4 (see paragraph 2.1).
  • compositions according to the present invention A maximum peak was observed on all compositions after 3 hours from the administration of the composition in question, followed by a deterioration of the iron concentration in the blood. This increase was more marked in case of administration of Composition 2 and Composition 4 (compositions according to the present invention) with respect to Composition 1 (ferric pyrophosphate) and Composition 3 (comparison composition, composition known in literature).
  • Composition 3 comparativ composition, composition known in literature
  • the trend of iron concentration in the blood is not significantly different from that of ferric pyrophosphate, whereas its performance is lower than that of Composition 2 (composition according to the present invention, Sideral® r.m.).
  • Composition 4 composition according to the present invention, Sideral® forte
  • the trend of iron concentration in the blood is significantly different from that of Composition 1 (ferric pyrophosphate) while it is not significantly different from that of Composition 2 (composition according to the present invention, Sideral® r.m.), as observable from the AUC ( area under curve) data indicated in Table 1.
  • Composition 2 (Sideral® r.m.) and Composition 4 (Sideral® forte) are capable of significantly increasing both the AUC and the Cmax, thus increasing the bioavailability of iron (AUCrel) by 1.8 and 1.6 times with respect to the control ( Figure 2).
  • Table 2 shows: i) the Fe(lll) content found in liver, spleen and bone marrow and ii) the increase factor (FI) of the Fe(lll) content respectively determined in the liver and in the bone marrow and calculated as the ratio between the Fe(lll) content determined in the liver or in the marrow in rats treated with the formulations in question comprising Fe(lll) (point 1.2) and the Fe(lll) content determined in the liver or in the marrow in rats which were not administered with a formulation comprising Fe(lll) (control) .
  • FI increase factor
  • Composition 1 Fe(lll) content both with respect to the control and with respect to the rats which were administered with Composition 1 (ferric pyrophosphate) and Composition 3 (comparison composition, composition known in literature) was determined in the liver and in the bone marrow of the rats which were administered with Composition 1 (composition according to the present invention, Sideral® r.m.) or Composition 4 (composition according to the present invention, Sideral® forte). Furthermore, as regards Composition 1 and 4 the value of FI in the liver is respectively 1.6 and 1.8.
  • polyester membrane filters (pore size 0.4 pm, area 1.12 cm 2 ): Celbio, Milano, Italy;
  • - Composition 1 Ferric pyrophosphate (abbreviated as FP), used as reference.
  • composition 2 composition according to the invention: sucrosomial® iron (Sideral ® r.m., abbreviated as SRM), as defined in point 1.2. Experimental part (I).
  • the procedure was conducted in a manner similar to the one indicated in Fabiano A, et al. J Drug Del Technol. 2016; 32:291-297.
  • the intestinal mucosa used for these studies was obtained from non-fasting male Wistar rats weighing 250-300 g. After sacrificing the rats, the first 20 cm of jejunum was immediately removed. The isolated intestine was cut into 1.5 cm strips, rinsed of the lumen content and mounted in Ussing-type chambers (0.78 cm 2 exposed surface area) without eliminating the underlying muscular layer.
  • One and 3 ml of PB pH 7.4, 0.13 M (isosmotic) were respectively added to the mucosal compartment (donor) and serosal compartment (receiver) of the permeation cell.
  • intestinal tissue strips were fixed in a solution at 4% of paraformaldehyde in phosphate buffer at 4 ° C. The samples were then dried using ethanol, eliminated using xylene and embedded in paraffin according to standard histological techniques. 8 pm-thick sections were cut along the long axis of the gut lumen to obtain sections of whole thickness of the intestinal wall, from the mucosal to serosal side. Mounted on glass slides, the sections were deparaffined, rehydrated and incubated for 15 min using nuclear dye TO-Pro.
  • the slides were examined by means of a confocal laser scanning microscope (TC SSP8 Leica Microsystems, Mannheim, Germany) using x20, x40, x63 oil immersion lenses and 488 nm and a 642 nm excitation wavelength laser.
  • TC SSP8 Leica Microsystems TC SSP8 Leica Microsystems, Mannheim, Germany
  • the analysis of the sample was performed in at least three non-consecutive sections for each sample.
  • Negative controls for secondary antibodies were performed without omitting the primary antibodies and incubating the specimens using nonimmune serum.
  • the sections were observed under confocal laser scanning microscopy using x20, x40, x63 oil immersion lenses and 488 nm, 561 nm and a 642 nm excitation wavelength laser.
  • the fluorescence (light grey area) consists of considerably small vesicular structures.
  • Such vesicular structures were observed in the enterocytes and in the cells of the connective tissue up to 1 hr of incubation with SRM, while after 2 hrs of incubation the fluorescent particles (light grey area) are exclusively found in the connective cells (Figure 8).
  • Figure 8 When said Figure 8 is represented coloured, the fluorescence is represented by the green areas and the nuclei are represented by the blue areas.
  • the obtained results show that these cells do not seem implicated in the englobing of the vesicular systems, at least as concerns the incubation times that were tested.
  • the light grey (green) and dark grey (red) fluorescent signals do not coincide and in the merged images, the cells containing the vesicular systems remain light grey (green).
  • Composition 2 (Sideral® r.m.) revealed an increase of the permeability of Fe(lll) through the isolated rat intestine, and that the increase revealed to be due to the formation of vesicles capable of permeating through the intestinal tissue without disintegrating, we can affirm that the addition of this particular penetration pathway to the traditional one based on the DMT1 transporter contributes towards increasing the in vivo bioavailability of the iron of the composition according to the invention (Composition 2 (Sideral® r.m.) as proven in the "Experimental part (I)” (see point 2.1 and 3.1).
  • composition according to the invention revealed the capacity to considerably increase serum iron with respect to ferric pyrophosphate (FP) by enhancing absorption.
  • the object of this experimental study is to evaluate the capacity of the composition of the invention to increase the absorption and thus the bioavailability of magnesium.
  • composition 5 comprising Mg sucrosomial® (Ultramag® manufactured by Pharmanutra-Alesco);
  • the method for fluorometric determination of Mg(ll) is based on the capacity of the fura-2 indicator to bind Mg(ll) in presence of EGTA chelating agent (ethylene glycol-bis (b-aminoethyl ether)-N, N, N’, N’-tetraacetic acid).
  • EGTA chelating agent ethylene glycol-bis (b-aminoethyl ether)-N, N, N’, N’-tetraacetic acid.
  • the equipment used for determining the release kinetics of Mg (I I) from the matrices consisted on an external circulation thermostat adjusted to a temperature of 37 °C, and a beaker (inner diameter, 95 mm; height, 100 mm) provided with a thermostating jacket, placed on an elevator, a 120 rpm synchronous motor, which actuated a blade stirrer (length 49 mm, height 15 mm), into which the 500 mg of the formulation to be tested were introduced.
  • the stirrer was submerged into the receiving phase (100 ml), contained in the beaker, and pre-thermostated to 37 °C.
  • the described equipment allowed to control the hydrodynamics around the matrix.
  • a measured volume (1 ml) of the receiving phase which was fluorometrically analysed for the concentration of Mg(ll) after centrifugation at 14000 rpm for 10 minutes was collected at 30-minute time intervals.
  • the elution means were simulated gastrointestinal fluids, consisting of the following solutions:
  • Simulated gastric fluid consisting of HCI 0.04 M, pH 1.2, made isotonic using NaCI (40 g of HCI 1 N and 1 g of NaCI for 500 ml).
  • FDS Simulated jejunum fluid
  • TF phosphate buffer
  • 0.13M phosphate buffer
  • the intestinal mucosa of male Wistar rats was isolated and treated as described in point 4.4 of the Experimental part (I).
  • the Ussing chambers were placed in a water bath at 37°C. After 20 min of balancing, the means in each donor compartment was substituted using 1 ml of the suspension of the formulation to be tested which was previously treated to simulate the transit thereof in the stomach.
  • 0.2 g of pepsin were solubilised in 5m I of an aqueous solution of HCI 0.1 M so as to simulate gastric digestion.
  • 2.5 g of Chelex-100 resin were added thereto and they were stirred 30 minutes. The suspension was then transferred in column and another 5 ml of HCI 0.1 M were added in column after collecting the eluate.
  • the final volume of the eluate was 8 ml.
  • a predetermined amount of sample was placed in a container with a screw cap, then 10 ml of an aqueous solution containing NaCI (140 mM) and KCI (5mM) were added, the suspension was brought to pH 2 using HCI 5 M and 0.5 ml of the pepsin solution were added thereto.
  • the suspension was then degassed using carboxicarb so as to create the anaerobic conditions found in the gastrointestinal tract, then the container - tightly closed - was placed in a stirrer bath at 37°C for 60 min.
  • experiments similar to the one described were conducted maintaining PBS pH 6.8 in the donor compartment.
  • Figure 5 and the relative Table 4 show the data obtained using Composition 5 (Ultramag®) at the concentration of Mg(ll) in the donor phase 10 times lesser than the one tested in Figure 4, observable in which is the capacity of Composition 5 (Ultramag®) to enhance absorption of Mg(ll), even though such capacity is in a 1.2 enhancement ratio with respect to the control (MgO), this denoting that the speed of absorption of magnesium is mainly affected by the dissolution speed of magnesium due to the poor solubility thereof to the neutral pH of the intestine rather than the permeation capacity thereof through the paracellular pathway.
  • the Composition 5 (sucrosomial® magnesium, Ultramag®) according to the invention revealed to be capable of enhancing the absorption of Mg(ll) in the intestine.
  • the study on the capacity to enhance absorption revealed that by administering the lower concentrations of Mg(ll) (Ultramag®) allows to obtain a much higher percentage of Mg(ll) percentage (94.6%) and that such percentage lowers considerably for higher concentrations of Mg(ll) applied (19%).
  • the absorption of Mg(ll) is a process that can be saturated and that the increase of the absorption thereof when administered as sucrosomial® magnesium is potentially due to the use of a further absorption pathway, like the one of transcytosis of vesicles loaded with Mg(ll).
  • the object of this experimental study is to evaluate the capacity of the composition of the invention to increase the absorption and thus the bioavailability of magnesium.
  • composition Zn sucrosomial® (Ultrazin®“Allergen Free” manufactured by Pharmanutra- Alesco);
  • the method for the UV determination of concentration of Zn(ll) is based on the formation of a complex between the Zn(ll) and the dithizone.
  • the standards with known concentration of Zn(ll) were prepared by dissolving - in water acidulated with HCI, ZnO - so as to obtain a concentration of Zn(ll) of 0.1 mg/mL.
  • a dithizone stock solution (HDz) 0.01% (w/v) in 100 mL of an acetone/propanol mixture (1/1 , v/v) had to be prepared. 2 mL of each standard with known concentration of Zn(ll) and 4 mL of the HDz solution were placed in 10 mL volumetric flasks and then brought to volume using an acetone/propanol mixture (1/1, v/v). After waiting 10 min, the standards thus prepared were read under UV at the 520 nm wavelength against an appropriate white reagent.
  • Zinc reaches the enterocyte, passes through the baseline membrane and reaches the circulation.
  • the mechanism involves the Zn-T1 transporter present at villi level. This experiment allows to monitor the permeability of the Zn(ll) ion.
  • Composition 5 Ultrazin®
  • ZnO zinc oxide

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Abstract

The present invention refers to a composition in solid form comprising a preparation comprising one mineral or several minerals, said preparation also alternatively called "sucrosomial® mineral", for use in the treatment of symptoms or diseases relating to a deficiency of said mineral/s, such as magnesium, calcium, iron, zinc, iodine and/or selenium. Said preparation (or "sucrosomial® mineral") comprises or, alternatively, consists of said mineral (or mixture of minerals), lecithin, a first agent such as sucrester (fatty acid carbohydrates) and at least one further first agent selected from among a cyclodextrin, a C6-C18 fatty acid isomer, a chitosan derivative and the mixtures thereof. Furthermore, the present invention refers to a method for preparing said sucrosomial® mineral. The composition of the present invention is recommended for use in subjects in paediatric age, adolescents, sportsmen/sportswomen, men, women, pregnant women and the elderly for supplementing a deficiency of said minerals.

Description

DESCRIPTION of the invention having the title: “Composition comprising sucrosomial minerals containing mineral salts for use in conditions of deficiency of such minerals”.
The present invention refers to a composition comprising a preparation comprising one mineral or several minerals, said preparation also alternatively called "sucrosomial® mineral” (sucrosomial®; registered trademark owned by Pharmanutra S.p.A e Alesco S.r.l), for use in the treatment of symptoms or disorders relating to a deficiency of said mineral/s, such as magnesium, calcium, iron, zinc, iodine and/or selenium. Said preparation (or "sucrosomial® mineral”) comprises or, alternatively, consists of said mineral (or mixture of minerals), lecithin, a first agent such as sucrester (fatty acid carbohydrates) and at least one further first agent selected from among a cyclodextrin, a C6-C18 fatty acid isomer, a chitosan derivative and the mixtures thereof. In particular, the present invention refers to a composition in solid form.
Lastly, the present invention refers to a method for preparing said sucrosomial® mineral. The composition of the present invention is recommended for use in subjects in paediatric age, adolescents, sportsmen/sportswomen, men, women, pregnant women and the elderly for supplementing a deficiency of said minerals.
Mixtures comprising minerals, such as for example magnesium, calcium, zinc or iron, which are used for preparing compositions, for example in solid form, for human use, are available in the market.
However, the compositions in solid form comprising minerals recommended for oral use ( per os) reveal limits and/or contraindications that considerably limit the use thereof.
A first limit lies in the fact that the compositions, in particular the compositions in solid form, containing a mineral for oral use currently available in the market have the mineral, for example iron or magnesium or calcium or zinc, in a chemical form, such as cation, which is scarcely, or poorly, absorbable by the organism and, thus, poorly if not even non-bioavailable for the organism. In some cases, in order to prevent the absorption from dropping even further in the organism, the known compositions comprising minerals must be administered away from meals. In this case, there are chances that oral administration long after meals could create grounds for further drawbacks.
For example, iron salts can be scarcely absorbed by the organism when administered orally, for example in form of ferrous sulphate or gluconate. Thus, in order to prevent the absorption from dropping even further, the known compositions comprising iron salts must be administered away from meals. However, taking iron in the chemical form of trivalent cation (Fe(lll)) per os can cause constipation and epigastralgia which entail the need for administering compositions comprising iron on a full stomach with an ensuing and inevitable drastic reduction of the absorption thereof in the organism.
A second limit lies in the fact that, due to the scarce absorption of minerals obtained through oral administration of the compositions comprising minerals currently available in the market, said compositions need to be administered for extended periods of time before the deposits of said minerals in the organism are usefully reconstituted and used. For example, given that a low absorption of the iron mineral administered in form of iron salts (iron(ll) or iron (III)) is linked to the low bioavailability of ferrous or ferric iron in the organism, the basic therapy of said iron salts is generally extended for a period of time comprised between 3 and 6 before the iron deposits of the organism are usefully reconstituted
A third limit lies in the fact that oral administration of compositions comprising minerals, in many cases, is not well tolerated due to frequent adverse effects. For example, the oral administration of compositions containing iron salts, and in particular ferrous sulphate, is characterised by frequent gastrointestinal (Gl) adverse effects which limit the use thereof, such as for example peptic ulcers, gastritis, ulcerative colitis.
A fourth drawback lies in the fact that the compositions in solid form are difficult to process from an industrial point of view given that they are affected by the external conditions, and they at times tend to compact and not flow hence creating problems relating to poor reproducibility of the titre of the mineral in the composition and they can create grain size variations such to jeopardise the preparation of the compositions as finished products.
Lastly, a further drawback lies in the fact that the compositions comprising minerals for oral use often reveal unpleasant palatability and they are not stable over time from the chemical/physical and organoleptic point of view, i.e. they change colour, odour, flavour and taste.
The limits and drawbacks outlined above are just a few among the most common and recurrent observable in the compositions comprising minerals available in the market.
The limits outlined above, with reference to the known compositions comprising minerals, depend on how said compositions (in liquid or solid form) are prepared, in particular on the mineral used, on the type of mineral salt used and on the additional components, additives and/or excipients used, on the addition sequence of the single components, additives and/or excipients used in the preparation method and on the preparation operating conditions adopted. Basically, a preparation method that is optimal enough to create around the mineral, considered as the cation present in the mineral salt used, a chemical/physical environment capable of producing a composition comprising minerals having advantageous and improving characteristics is yet to be created.
Thus, the operators of the industry are still in high need for providing compositions in solid or liquid form or in form of suspension comprising minerals, such as for example magnesium, calcium, iron, zinc, iodine, selenium or the mixtures thereof, for use in the treatment of patients suffering from lack/deficiency of one or more of said minerals. It is desirable that in said compositions the mineral, present as a mineral salt (or as a cation of the mineral salt), both in a form such to make it bioavailable and effectively absorbable and - at the same time - that said compositions do not reveal the limits and the contraindications still found in known compositions comprising minerals (or mineral salts) available in the market.
In particular, there arises the need for being able to provide said compositions in solid form comprising minerals that, besides making the mineral highly bioavailable and absorbable by the organism, are free of adverse effects and tolerated well enough to be administered, even on an empty stomach, to all categories of subjects including pregnant women, that have good palatability and that are stable over time from a chemical/physical point of view (without formation of agglomerates, change of colour) and organoleptic point of view (without change of odour, flavour and taste).
Lastly, there arises the need for being able to provide a method for preparing said compositions comprising minerals having the aforementioned characteristics.
An object of the present invention is to provide an appropriate response to the limits still observable in compositions existing in the prior art and to the technical problem described above.
Summary of the invention
After an intense and extended research and development activity the Applicant created compositions comprising preparations comprising a mineral salt or several mineral salts, called sucrosomial® minerals. Said preparations (or sucrosomial® minerals), comprise minerals such as, for example, magnesium, calcium, iron, zinc, iodine, selenium or mixtures thereof. In said compositions, preferably in solid form, comprising minerals in form of mineral salts, the minerals are made effectively absorbable and bioavailable and, thus, said compositions are well tolerated by the organism so that they can be administered orally, once formulated for example in solid form as such or in mouth-soluble e solid form, even on an empty stomach, to subjects in paediatric age, adolescents, sportsmen/sportswomen, men, women, pregnant women and the elderly. Furthermore, said compositions have a good palatability, they are well tolerated and they are stable over time both from a chemical/physical and organoleptic point of view.
Forming an object of the present invention is a composition, preferably in solid form, comprising a preparation (sucrosomial® mineral) comprising, or alternatively, consisting of a mineral such as, for example, magnesium, calcium, iron, zinc, iodine, selenium (or mixture of minerals, lecithin and at least one first agent selected from among a sucrester (fatty acid carbohydrates), a cyclodextrin, a C6-C18 fatty acid isomer and a chitosan derivative and mixture thereof.
Forming an object of the present invention is a composition, preferably in solid form, comprising said preparation (sucrosomial® mineral) comprising at least one mineral, for use in a method for treating symptoms or disorders relating to or deriving from an absolute or relative deficiency of said at least mineral such as, for example, magnesium, calcium, iron, zinc, iodine, selenium or mixtures thereof, having the characteristics as outlined in the attached claims.
Forming an object of the present invention are the methods for preparing said preparation (sucrosomial® mineral) comprising said at least one mineral having the characteristics as outlined in the description and in the attached claims.
Forming an object of the present invention is said composition in solid form, in particular in solid form as such or in mouth-soluble solid form, or in liquid form having the characteristics as outlined in the attached claims.
Forming a further object of the present invention is the use, not for therapeutic purposes, of said composition comprising said preparation (sucrosomial® mineral) comprising said at least one mineral, for modulating and/or improving disorders or illnesses relating to or deriving from an absolute or relative deficiency of said at least mineral such as, for example, magnesium, calcium, iron, zinc, iodine, selenium or mixtures thereof, having the characteristics as outlined in the attached claims.
The composition of the present invention, comprising said preparation (sucrosomial® mineral) comprising said at least one mineral, is recommended for subjects in paediatric age, adolescents, sportsmen/sportswomen, men, the elderly, women and pregnant women; preferably in women both during pregnancy and in the period after pregnancy; preferably also in women before, during and after the menstrual cycle.
Preferred embodiments of the present invention are indicated in the attached dependent claims.
The preferred embodiments of the present invention described in the description that follows, are indicated herein solely by way of non-limiting example of the extensive field of application of the present invention, which will be instantly clear to the man skilled in the art.
In the context of the present invention, the expression "mineral” is preferably used to indicate a mineral consisting of only one chemical element, for example, magnesium, calcium, iron, zinc, iodine, selenium.
In the context of the present invention, the expression "mineral salt” is used to indicate a salt of a mineral wherein said mineral is, preferably, a mineral consisting of only one chemical element, for example, magnesium, calcium, iron, zinc, iodine or selenium, in form of cation. In the context of the present invention, the expression "cation of the mineral” (or mineral cation) is used to indicate the chemical form of a mono or multivalent cation of a mineral wherein said mineral is, preferably, a mineral consisting of only one chemical element, for example, magnesium, calcium, iron, zinc, iodine or selenium, in form of cation.
In the context of the present invention, the expression "mineral” and "cation of the mineral” (or mineral cation) can be used interchangeably.
In the context of the present invention, the expression "sucrosomial® mineral” is used to indicate a formulation of a mineral ((a) + (b) + (c)) in which said mineral, for example a mineral from among those mentioned above (Fe, Mg, Zn, Ca, I, Se), is processed and formulated by means of the preparation methods described hereinafter in the present invention (first method and second method). In the context of the present invention, said formulation of the mineral is referred to using the expression "sucrosomial® mineral” or "preparation” or "preparation of the invention”. Depending on the type of mineral of interest in the sucrosomial® mineral, for example iron mineral, said sucrosomial® mineral is for example alternatively called "sucrosomial® iron”. Basically, for example when iron (III) pyrophosphate, is processed and formulated together with other substances, by means of the preparation methods described hereinafter in the present invention (first method and second method), it gives forth a sucrosomial® mineral where iron is in form of sucrosomial® iron.
Unless specified otherwise, the content of a component in a composition refers to the percentage by weight of that component with respect to the total weight of the composition.
Unless specified otherwise, the indication that a composition "comprises” one or more components means that other components - besides the one, or the ones, indicated specifically - can be present and the indication that a composition "consists” of determined components means that the presence of other components is excluded.
Figures
Figure 1 : concentration of Fe(lll) in the blood of rats as a function of the time (hours) following the administration of the compositions in question containing iron (Fe(lll)).
Figure 2: similar to Figure 1 except for the fact that the data of the Control (non-treated animals) is also illustrated;
Figure 3: Plasmatic concentration of FITC-labelled SRM over time following administration of FITC- labelled SRM containing the dose of 5 mg/Kg of iron; Figure 4: amount of Mg (II) which traverses the intestinal epithelium over time;
Figure 5: amount of Mg (II) which traverses the intestinal epithelium over time (initial amount 1/10 with respect to Figure 4;
Figure 6: amount of Zn (II) which traverses the intestinal epithelium over time.
Figure 7. Confocal laser scanning microscopy. Images representing the sections of the rat intestine after 30 minutes, 1 hour and 2 hours of incubation in the Ussing chamber. TM: tunica mucosa (mucous membrane); TS: tunica serosa (serous membrane). Single fluorescent channels: light grey (SRM) and dark grey (nuclei). Scale 50 pm. A: two-dimensional image of the maximum intensity projection. B: enlargement of the three-dimensional images box with the respective orthogonal projections.
Figure 8. Confocal laser scanning microscopy: images representing the sections of the rat intestine after 1 hour and 2 hours of incubation in the Ussing chamber. The asterisks indicate enterocytes while the arrows indicate the connective cells. TM: tunica mucosa (mucous membrane). Single fluorescent channels: light grey (SRM) and dark grey (nuclei). Scale 10 pm.
Figure 9. Confocal laser scanning microscopy: images representing the sections of the rat intestine after 30 minutes and 1 hour of incubation in the Ussing chamber. The negative control obtained by omitting the primary antibodies is shown in the double-line box. Single fluorescent channels: light grey (SRM), dark grey (positive cells at CD68) and very dark grey (nuclei). Scale 25 pm.
Figure 10. Confocal laser scanning microscopy: images representing the sections of the rat intestine after 30 minutes and 1 hour of incubation in the Ussing chamber. The negative control obtained by omitting the primary antibodies is shown in the double-line box. Single fluorescent channels: light grey (SRM), dark grey (positive cells at GP2) and very dark grey (nuclei). Scale 25 pm.
Detailed description of the invention
The present invention regards a composition (hereinafter "composition of the invention”), preferably in solid form, comprises a preparation (hereinafter "preparation of the invention” or "sucrosomial® mineral”), as defined below, and, optionally, at least one technological additive and/or at least one pharmaceutical or food grade excipient.
The present invention regards a composition (composition of the invention), preferably in solid form, comprising a preparation (preparation of the invention), as defined below, also called sucrosomial® mineral, for use in a method for the preventive and/or symptomatic treatment of symptoms or disorders relating to or deriving from an absolute or relative deficiency of at least one mineral selected from among the group comprising or, alternatively, consisting of magnesium, calcium, iron, zinc, iodine, selenium or mixtures thereof The present invention regards a method for the preventive and/or symptomatic treatment of symptoms or disorders relating to or deriving from absolute or relative deficiency of at least one mineral selected from among the group comprising or, alternatively, consisting of magnesium, calcium, iron, zinc, iodine, selenium or mixtures thereof, in needy subjects by administering to said subjects said composition of the invention, preferably in solid form, comprising said preparation of the invention, as defined below, also called sucrosomial® mineral.
Furthermore, the present invention regards the use of said composition, preferably in solid form, for modulating and/or improving disorders relating to or deriving from an absolute or relative deficiency of at least one mineral selected from among the group comprising or, alternatively, consisting of magnesium, calcium, iron, zinc, iodine, selenium or mixtures thereof in a subject, wherein said use is not for medical or therapeutic purposes.
Advantageously, in the present invention the treatments of a disorder relating to an absolute, partial or relative deficiency of at least one mineral are effective both if conducted on healthy subjects and if conducted on subjects who have been diagnosed with a symptom or disorder relating to or deriving from said deficiency.
Besides (b) and (c), the preparation comprises at least one mineral (selected from among the ones indicated) which, following a specific processing method and preparation (subject of the present invention
- first and second method) to which it is subjected, is in a form called "sucrosomial® mineral”.
The preparation (or sucrosomial® mineral or preparation of the invention) comprises or, alternatively, consists of:
- (a) at least one mineral in form of a mineral salt, wherein said mineral (or cation of the mineral) is selected from among the group comprising or, alternatively, consisting of: magnesium, preferably (a-i) magnesium (II), calcium, preferably (a-ii) calcium (II), iron, preferably (a-iii) iron (II) or iron (III), zinc, preferably (a-iv) zinc (II), iodine, preferably (a-v) iodine (V), selenium, preferably (a-vi) selenium (IV) and/or the mixtures thereof,
- (b) a lecithin, preferably E322 lecithin, preferably non-hydrolysed lecithin (non-hydrolysed E322 lecithin),
- (c) at least one first agent selected from among the group comprising or, alternatively, consisting of:
(c-i) a carbohydrate fatty acid ester (commonly called sucrester), preferably E473 sucrester,
(c-ii) a cyclodextrin,
(c-iii) a C6-C18 fatty acid isomer (for example cis isomer or trans isomer),
(c-iv) a chitosan derivative, and/or mixtures thereof;
In a preferred embodiment, the composition of the invention, preferably in solid form, comprises a preparation, called sucrosomial® mineral, comprising or, alternatively, consisting of:
- (a) at least one mineral in form of a mineral salt thereof, wherein said mineral is selected from among the group comprising or, alternatively, consisting of: (a-i) magnesium (II), (a-ii) calcium (II), (a-iii) iron (III), (a- iv) zinc (II), (a-v) iodine (V), (a-vi) selenium (IV) and mixtures thereof;
- (b) a lecithin;
- (c) a first agent (c-i) consisting of a carbohydrate fatty acid ester or a sucrester, and
at least one further first agent selected from among the group comprising or, alternatively, consisting of: (c-ii) a cyclodextrin (c-iii) a C6-C18 fatty acid isomer, (c-iv) a chitosan derivative, and mixtures thereof; and, optionally, said composition comprises at least one technological additive and/or at least one pharmaceutical or food grade excipient.
In a further preferred embodiment, the composition of the invention, preferably in solid form, comprises a preparation, called sucrosomial® mineral, comprising or, alternatively, consisting of:
- (a) at least one mineral in form of a mineral salt thereof, wherein said mineral is selected from among the group comprising or, alternatively, consisting of: (a-i) magnesium (II), (a-ii) calcium (II), (a-iii) iron (III), (a- iv) zinc (II), (a-v) iodine (V), (a-vi) selenium (IV) and mixtures thereof;
- (b) a lecithin;
- (c) at least one first agent selected from among the group comprising or, alternatively, consisting of: (c-ii) a cyclodextrin, (c-iii) a C6-C18 fatty acid isomer, (c-iv) a chitosan derivative, and mixtures thereof, wherein (c-i) a carbohydrate fatty acid ester or a sucrester is not present in said preparation;
and, optionally, said composition comprises at least one technological additive and/or at least one pharmaceutical or food grade excipient.
The following embodiments (FR) of the composition of the invention, preferably in solid form, as such or for use in a treating method or for non-therapeutic use, are comprised in the present invention:
- FRa, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-i) and (c-ii);
- FRb, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-i) and (c-iii);
- FRc, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-i) and (c-iv); - FRd, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-i), (c-ii) and (c-iii);
- FRe, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-i), (c-ii) and (c-iv);
- FRf, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-i), (c-iii) and (c-iv);
- FRg, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b) e (c-i);
- FRh, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b) and (c-ii);
- FRi, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b) and (c-iii);
- FRI, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b) and (c-iv);
- FRm, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-ii) and (c-iii);
- FRn, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-ii) and (c-iv);
- FRo, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-iii) and (c-iv);
- FRp, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-ii), (c-iii) and (c-iv);
wherein in all said embodiments comprised between FRa and FRp, the components called (a), (b), (c-i), (c-ii), (c-iii) and (c-iv) are as defined in the present invention, preferably (a) is iron or magnesium or zinc or called or iodine or selenium or mixture of two or three or four or five of them; more preferably (a) is iron or magnesium or zinc; and wherein in embodiments FRh to FRp (c-i) it is not present.
In embodiment FRg of the composition of the invention, preferably in solid form, as such or for use in a treatment method or for non-therapeutic use, wherein the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of (a), (b), (c-i), preferably (a) is selenium.
Preferably, if present, the mineral in form of cation (mineral cation) (a-i) magnesium (II) is present in said preparation (or sucrosomial® mineral) as magnesium oxide mineral salt or, alternatively, as magnesium hydroxide mineral salt; the mineral in form of cation (mineral cation) (a-ii) calcium (II) is present in said mixture as tricalcium phosphate mineral salt, preferably E341 tricalcium phosphate; the mineral in form of cation (mineral cation) (a-iii) iron(lll) is present in said mixture as ferric pyrophosphate mineral salt; the mineral in form of cation (mineral cation) (a-iv) zinc (II) is present in said mixture as zinc oxide mineral salt; the mineral in form of cation (mineral cation) (a-v) iodine (V) is present in said mixture as sodium iodate mineral salt; the mineral in form of cation (mineral cation) (a-vi) selenium (IV) is present in said mixture as sodium selenite mineral salt.
Advantageously, said preparation (or sucrosomial® mineral) may contain two or more of said minerals (two or three or four or five minerals), preferably each in form of mineral salt.
In an embodiment, when said (a) mineral salt is a magnesium salt, preferably magnesium oxide (II), or a zinc salt, preferably zinc oxide (II), said (a) mineral salt is present in the preparation at an amount by weight comprised between 20 and 90%, preferably between 30 and 80%, even more preferably between 40 and 70%, with respect to the total weight of the preparation.
In an embodiment, when said (a) mineral salt is an iron salt, preferably iron (III) pyrophosphate, said (a) mineral salt is present in the preparation at an amount by weight comprised between 10 and 80%, preferably between 20 and 70%, even more preferably between 30 and 60%, with respect to the total weight of the preparation.
In an embodiment, the iron (III) pyrophosphate used {[Fe^Oz^xP O], CAS 10058-44-3, anhydrous molecular weight 745,22} is preferably in form of powder or in any form and type of grinding or micro grinding.
In an embodiment, when said (a) mineral salt is an iodine salt, preferably sodium iodate, or a selenium salt, preferably sodium selenite, said (a) mineral salt is present in the preparation at an amount by weight between 0.01 and 30%, preferably between 0.05 and 20%, even more preferably between 0.1 and 10%, with respect to the total weight of the preparation.
In an embodiment, when said (a) mineral salt is a calcium salt, preferably tricalcium phosphate, said (a) mineral salt is present in the preparation at an amount by weight between 50 and 100%, preferably between 65 and 100%, even more preferably between 75 and 100%, with respect to the total weight of the preparation.
Preferably, the preparation (or sucrosomial® mineral of the present invention has a mineral content, expressed in mineral mg (or cation of the mineral) over one gram of preparation, in the following intervals: - (a-i) magnesium (II), if present as magnesium oxide salt, comprised between 50 and 800 mg/g, preferably between 100 and 600 mg/g, or
- (a-i) magnesium (II), if present as magnesium hydroxide salt, comprised between 50 and 600 mg/g, preferably between 100 and 450 mg/g, or
- (a-ii) calcium (II), if present as tricalcium phosphate salt, comprised between 50 and 800 mg/g, preferably between 100 and 600 mg/g, or
- (a-iii) iron (III), if present as ferric pyrophosphate salt, comprised between 1 mg/g and 400 mg/g, preferably between 10 mg/g and 300 mg/g, or
- (a-iv) zinc (II), if present as zinc oxide salt, comprised between 100 and 800 mg/g, preferably between 200 and 700 mg/g, or
- (a-v) iodine (V), if present as sodium iodate salt, comprised between 0.1 and 40 mg/g, preferably between 0.5 and 30 mg/g, or
- (a-vi) selenium (IV), if present as sodium selenite salt, comprised between 0.1 and 40 mg/g, preferably between 0.5 and 30 mg/g.
In an embodiment, said (b) lecithin, preferably non-hydrolysed lecithin, is present in the preparation (or sucrosomial® mineral) at an amount by weight comprised in the range between 0.05 and 20% with respect to the weight of the composition, preferably between 0.1 and 10%, more preferably < 1 %.
From a chemical point of view, the lecithin is a mixture of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides and phospholipids. Phospholipids represent main components thereof; the latter derive from the structure of the triglycerides, where a fatty acid is substituted by a phosphate group which confers a negative charge and thus polarity to the molecule; this molecule is generally referred to as phosphatide. A more complex organic molecule - generally serine, choline, ethanolamine, inositol or a single hydrogen atom - is linked to the phosphate group obtaining a phospholipid called, respectively, phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol or phosphatidic acid. In its narrowest sense, lecithin is often represented by phosphatidylcholine. Phospholipids are characterised by a water-soluble polar head, which dissolves well in water, while the two saturated fatty acids represent the two non-polar tails, that are not water-soluble but lipophilic. Molecules of this type are called amphipathic and in presence of water and fat they are arranged between the fat molecule and the water molecule emulsifying them. Lecithin is a natural emulsifier.
Preferably, the preparation (or sucrosomial® mineral) of the present invention comprises an E322 lecithin. E322 lecithin if a food additive (Directive 95/2/CE dated 20.2.95 published in the Official Gazette L61 dated 18.3.95). Due to its chemical/physical properties, lecithin mainly carries out an emulsifying function. Being rich in natural antioxidant substances, it also has a secondary antioxidant function. Directive 2008/84/CE dated 27 August 2008 published in the European Community Official Gazette n.°L253) establishes the purity requirements to be met by a lecithin in order to be considered to be of food-grade quality (E322 lecithin): Insoluble in acetone (basically the active part of lecithin): 60% min.; Moisture: 2% max.; Acidity number: 35 max.; Peroxides number: 10 max.; Insoluble in toluene (the impurities basically): 0.3% max.
The preparation (or sucrosomial® mineral) of the present invention does neither contains a hydrolysed lecithin nor an enzymatically hydrolysed lecithin.
Preferably, the (b) lecithin present in the preparation is a non-hydrolysed lecithin selected from among sunflower, corn or soy lecithin; more preferably it is E322 sunflower lecithin (non-hydrolysed), more preferably allergen free sunflower lecithin ( allergen free means that it does not have allergen residues) (non-hydrolysed). Advantageously, said lecithin is a powder lecithin with water content comprised between 1,5 a 4,5% with respect to the weight of lecithin, preferably between 2% and 4%, even more preferably between 2.5% and 3.5%. Advantageously, the lecithin of the present invention is E322 powder sunflower lecithin. In an embodiment, the E322 sunflower lecithin contains an amount of glucose by weight comprised between 20% and 60% with respect to the weight of lecithin, preferably between 30% and 50%, for example about 45%. An E322 sunflower lecithin that can be used in the context of the present invention may have the following composition by weight (chemical/physical analysis): sunflower lecithin between 40% and 50%, carbohydrates between 40% and 50% (for example about 42%), proteins between 6% and 10%, ashes between 3% and 8%, moisture between 2% and 5% and another flowing agent between 0.5% and 1.5%.
Said (c) at least one first agent, or mixture of two or more of said first agents comprised between (c-i) and (c-iv), in the present preparation (or sucrosomial® mineral)has the function of increasing absorption capacity of said (a) mineral (cation of the mineral) contained in the solid composition of the invention at intestinal level.
In an embodiment, said (c) first agent is (c-i) a carbohydrate ester with one or more fatty acids, commonly called sucrester or saccharose ester with C6-C12 medium chain fatty acids, linear or branched, saturated or unsaturated, or with C13-C21 long chain, preferably C14-C18, linear or branched, saturated or unsaturated, preferably (c-i) is sucrester E473.
The sucresters are obtained from the esterification of the fatty acids or from the trans-esterification of the methyl esters of the fatty acids with carbohydrates (also called saccharides). Saccharose (monosaccharide) and polysaccharides are generally the carbohydrates used. This is why sucresters are also referred to as saccharose esters of fatty acids. The chemical/physical properties of these compounds depend on the number and the type of esterified fatty acids.
The initials E473 indicates that the sucresters are food grade additives allowed by the European law and regulated by the Ministerial Decree (D.M.1996). They are essentially emulsifiers and they are added so as to determine a greater stabilisation of an aqueous phase with a fatty phase.
Advantageously, E473 sucresters are present in the preparation of the composition of the present invention with an HLB (hydrophilic-lipophilic balance) value of about 14-18, advantageously with an HLB value of about 15 or 16.
In an embodiment, the (c-i) E473 sucrester contains at least 70% of monoesters, for example 80% or 95%, obtained through the esterification of saccharose with fatty acids of plant origin (stearic and palmitic acid) of the saccharose mono-stearate type.
A sucrester that can be used in the context of the present invention may have the following composition by weight: total ester content at least at 90%; free fatty acids (such as oleic acid) content not exceeding 3%; free saccharose content not exceeding 2%; moisture not exceeding 4%; acidity value not exceeding 5. For example, SP70 saccharose esters manufactured by Chimab S.p. A -Italia.
The preparation (or sucrosomial® mineral) is in solid form such as for example in form of powder, granulate, chips or agglomerates.
The preparation and the composition of the present invention a diglycerol fatty acid ester.
In an embodiment, said (c) first agent is (c-ii) a cyclodextrin or mixtures of cyclodextrins, preferably it is an alpha-cyclodextrin. The cyclodextrins (CyD or CD) are natural cyclic oligosaccharides consisting of 6, 7 or 8 monomers of D-(+)glucopyranose linked together by an a, 1-4 glycosidic and closed-loop bond. Alpha- cyclodextrin is an oligosaccharide with 6 monomers of D-(+)glucopyranose. Preferably, said (c-ii) cyclodextrin is Cavamax® W6 Food (CAS 10016-20-3) cyclodextrin sold by Wecker Chemie AG.
In an embodiment, said (c) first agent is (c-iii) a medium chain fatty acid with a number of C6-C18 carbon atoms, linear or branched, saturated or unsaturated, or mixtures of said C6-C18 fatty acids (abbreviated as, "C6-C18 fatty acid”), preferably it is lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0) and/or stearic acid -C18H36O2 (C18:0). Said (c) first agent (c-iii) may also be any isomer of a C6-C18 medium chain fatty acid, for example any cis isomer or trans isomer of any fatty acid having between 6 and 18 carbon atoms.
In an embodiment, said (c) first agent is (c-iv) a chitosan derivative, or mixtures of chitosan derivatives, preferably it is carboxymethyl chitosan. The chitosan is a linear polysaccharide consisting of D-glucosamine and N-acetyl-D-glucosamine, linked by b(1 -4) bonds. The expression chitosan derivative is used to indicate, by way of non-limiting example in the context of the present invention, any compound that can be obtained using chitosan or a derivative thereof or a precursor thereof as the initial material and subjecting said initial material to chemical transformations known to the man skilled in the art, so that said chitosan derivative has characteristics such to confer to said (a) mineral (cation of the mineral) comprised in the preparation (or sucrosomial® mineral) a higher bioavailability and absorption capacity in the organism.
Advantageously, said (c) first agent is a mixture of two or three or four from among (c-i), (c-ii), (c-iii) and (c- iv), as indicated in the embodiments of the invention from FRa to FRp.
In an embodiment, said (c) first agent (c-i), (c-ii), (c-iii), (c-iv) or, alternatively, mixture of two or three or four of said first agent (c-i)-(c-iv), as indicated in the embodiments of the invention from FRa to FRp, is present in the preparation at an amount by weight between 1% and 75% with respect to the weight of the preparation, preferably between 1% and 60%, even more preferably between 5% and 40%.
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation (or sucrosomial® mineral) comprising, or alternatively, consisting of: (a) at least one mineral (or cation of the mineral) present as mineral salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above.
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising or, alternatively, consisting of: (a-i) a magnesium salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above. Advantageously, the magnesium salt (II) is magnesium oxide or, alternatively, magnesium hydroxide, the lecithin is E322 sunflower and/or corn lecithin, the sucrester is E473 sucrester, the cyclodextrin is alpha- cyclodextrin, the fatty acid is stearic acid, the chitosan derivative is carboxymethyl chitosan.
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising or, alternatively, consisting of: (a-ii) a calcium salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above.
Advantageously, the calcium salt (II) is E341 tricalcium phosphate, the lecithin is E322 sunflower and/or corn lecithin, the sucrester is E473 sucrester, the cyclodextrin is alpha-cyclodextrin, the fatty acid is stearic acid, the chitosan derivative is carboxymethyl chitosan.
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising or, alternatively, consisting of (a-iii) an iron salt (lll)or iron (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above.
Advantageously, the iron salt (III) is ferric pyrophosphate, the lecithin is E322 sunflower and/or corn lecithin, the sucrester is E473 sucrester, the cyclodextrin is alpha-cyclodextrin, the fatty acid is stearic acid, the chitosan derivative is carboxymethyl chitosan.
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising or, alternatively, consisting of: (a-iv) a zinc salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above.
Advantageously, the zinc salt (II) is zinc oxide, the lecithin is E322 sunflower and/or corn lecithin, the sucrester is E473 sucrester, the cyclodextrin is alpha-cyclodextrin, the fatty acid is stearic acid, the chitosan derivative is carboxymethyl chitosan.
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising or, alternatively, consisting of: (a-v) an iodine salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above.
Advantageously, the iodine salt (V) is sodium iodate, the lecithin is E322 sunflower and/or corn lecithin, the sucrester is E473 sucrester, the cyclodextrin is alpha-cyclodextrin, the fatty acid is stearic acid, the chitosan derivative is carboxymethyl chitosan.
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising or, alternatively, consisting of: (a-vi) a selenium salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, at the amounts by weight indicated above. Advantageously, the selenium salt (IV) is sodium selenite, the lecithin is E322 sunflower and/or corn lecithin, the sucrester is E473 sucrester, the cyclodextrin is alpha-cyclodextrin, the fatty acid is stearic acid, the chitosan derivative is carboxymethyl chitosan.
In a further embodiment, said preparation (or sucrosomial® mineral) - besides (a) at least one mineral (or cation of the mineral) present as mineral salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to Frp - also comprises:
- (d) a gelatinised or pre-gelatinised starch of plant origin; preferably, wherein said (d) starch is selected from among the group comprising or, alternatively, consisting of rice and/or corn starch; preferably, wherein said (d) starch is pre-gelatinised; more preferably pre-gelatinised rice starch.
The starch of plant origin is selected from among rice starches (Oryza sativa) or corn starches. Advantageously, the starch is a rice starch. Advantageously, the rice starch is a gelatinised or pre- gelatinised native rice starch A pre-gelatinised rice starch that can be used in the context of the present invention may have the following chemical/physical characteristics: moisture not exceeding 7%; protein content not exceeding 1%; ashes content not exceeding 1%; pH (solution 10%) comprised between 5.5 and 7.5, density 0.40-0.48 g/cm3; minimum starch content at 97% and fats not exceeding 0.1%. For example, a pre-gelatinised rice starch AX-FG-P manufactured by Reire Sri -Italia. The gelatinised or pre- gelatinised starch of plant origin is present in the preparation at an amount by weight comprised between 10% and 95% with respect to the total weight of the preparation, preferably between 20% and 90%.
In a further embodiment, said composition (besides said preparation comprising, or alternatively, consisting of (a) at least one mineral (or cation of the mineral) present as mineral salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to Frp, and, optionally, (d) a starch of plant origin) may also comprise:
- (e) at least one vitamin selected from among the group of vitamins comprising or, alternatively, consisting of:
(e-i) C group vitamins, (e-ii) E group vitamins,
(e-iii) B group vitamins, preferably vitamin B6 and/or B9 and/or B12,
(e-iv) D group vitamins, preferably vitamin D3,
And/or mixtures thereof; preferably wherein said (e) vitamin is (e-i) vitamin C (L-ascorbic acid and/or L-sodium ascorbate).
Preferably, each single vitamin being present in the composition at an amount equivalent to 100% RDA (recommended dietary allowance).
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of: (a) at least one mineral (or cation of the mineral) present as mineral salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above.
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of: (a-i) a magnesium salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above. Advantageously, the magnesium salt (II) is magnesium oxide or, alternatively, magnesium hydroxide, the lecithin is E322 sunflower and/or corn lecithin, the sucrester is E473 sucrester, the cyclodextrin is alpha-cyclodextrin, the fatty acid is stearic acid, the chitosan derivative is carboxymethyl chitosan, the starch is a pre-gelatinised rice starch (Oryza sativa) and the vitamin, if present, is vitamin C.
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of a (a-ii) calcium salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above. Advantageously, the calcium salt (II) is E341 tricalcium phosphate, the lecithin is E322 sunflower and/or corn lecithin, the sucrester is E473 sucrester, the cyclodextrin is alpha-cyclodextrin, the fatty acid is stearic acid, the chitosan derivative is carboxymethyl chitosan, the starch is a pre-gelatinised rice starch (Oryza sativa) and the vitamin, if present, is vitamin C.
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of: (a-iii) an iron salt(lll) or iron (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above. Advantageously, the iron salt (III) is ferric pyrophosphate, the lecithin is E322 sunflower and/or corn lecithin, the sucrester is E473 sucrester, the cyclodextrin is alpha-cyclodextrin, the fatty acid is stearic acid, the chitosan derivative is carboxymethyl chitosan, the starch is a pre-gelatinised rice starch (Oryza sativa) and the vitamin, if present, is vitamin C.
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of: (a-iv) a zinc salt (II), (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C16 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above. Advantageously, the zinc salt (II) is zinc oxide, the lecithin is E322 sunflower and/or corn lecithin, the sucrester is E473 sucrester, the cyclodextrin is alpha-cyclodextrin, the fatty acid is stearic acid, the chitosan derivative is carboxymethyl chitosan, the starch is a pre-gelatinised rice starch (Oryza sativa) and the vitamin, if present, is vitamin C.
In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of (a-v) an iodine salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above. Advantageously, the iodine salt (V) is sodium iodate, the lecithin is E322 sunflower and/or corn lecithin, the sucrester is E473 sucrester, the cyclodextrin is alpha-cyclodextrin, the fatty acid is stearic acid, the chitosan derivative is carboxymethyl chitosan, the starch is a pre-gelatinised rice starch (Oryza sativa) and the vitamin, if present, is vitamin C. In a preferred embodiment, the composition in solid form of the present invention comprises a preparation comprising, or alternatively, consisting of (a-vi) a selenium salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and (d) a starch of plant origin and, optionally, said composition comprises (e) a vitamin at the amounts by weight indicated above. Advantageously, the selenium salt (IV) is sodium selenite, the lecithin is E322 sunflower and/or corn lecithin, the sucrester is E473 sucrester, the cyclodextrin is alpha-cyclodextrin, the fatty acid is stearic acid, the chitosan derivative is carboxymethyl chitosan, the starch is a pre-gelatinised rice starch (Oryza sativa) and the vitamin, if present, is vitamin C.
In a further embodiment, said composition (besides said preparation comprising, or alternatively, consisting of (a) at least one mineral (or cation of the mineral) present as mineral salt, (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), (c-i) a carbohydrate ester of one or more fatty acids (sucrester) and/or (c-ii) a cyclodextrin and/or (c-iii) a C6-C18 fatty acid and/or (c-iv) a chitosan derivative, as indicated in the embodiments of the invention from FRa to FRp, and, optionally, (d) a starch of plant origin), may optionally comprise, (e) a vitamin, and as well as.
- (f) at least one salt selected from among a group if organic and/or inorganic salts and/or
- (g) at least one substance selected from among a group of antioxidant substances; and/or
- (h) at least one probiotic bacterial strain, or mixtures of probiotic bacterial strains; and/or
- (i) folic acid.
Advantageously, said (f) group of organic and/or inorganic salts consists of: (f-i) magnesium glycinate, (f-ii) selenium methionine, and (f-iii) zinc gluconate; preferably each single salt being present in the composition at an amount equivalent to 100% RDA (recommended dietary allowance).
Advantageously, said (g) group of antioxidant substances comprises or, alternatively, consists of: (g-i) N- acetyl cysteine (NAC), (g-ii) Coenzyme Q10 (CoQ10) and/or (g-iii) Acetyl-L-carnitine ALC; preferably each single antioxidant substance being present in the composition at an amount equivalent to 100 mg/day.
Advantageously, said (h) at least one probiotic bacterial strain, or a mixture of probiotic bacterial strains, belongs to the Lactobacilli or Bifidobatteri genus; preferably, it belongs to the species selected from among the group comprising or, alternatively, consisting of: Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus rhamnosus, Bifidobacterium lungum, Bifidobacterium lactis, Bifidobacterium infantis, Bifidobacterium bifidum. The preparation (or sucrosomial® mineral) of the present invention is a mixture at solid state. The expression solid state is used to indicate that the preparation of the present invention can be in form of granules or powder or chips or agglomerates whose dimensions and grain size varies as a function of the final formulation of the composition.
The preparation (or sucrosomial® mineral) according to the embodiments described above, is formulated with at least one technological additive and/or a pharmaceutical or food grade excipient to obtain the composition of the present invention, preferably in solid form of powder, granules or chips, appropriate for oral use.
The technological additive or pharmaceutical or food grade excipient can be selected from among all substances known to the man skilled in the pharmaceutical art or skilled in preparing food products, such as, by way of non-limiting examples, preservatives, emulsifiers and/or thickeners such as for example hydroxyethylcellulose, sweeteners, dyes such as for example E171 dye, natural and artificial flavours, antioxidants, stabilisers, fillers, anticaking agents such as for example vegetable magnesium stearate, fatty acids magnesium salts and silicon dioxide, charging agents such as for example microcrystalline cellulose and the mixtures thereof.
The composition of the present invention is for oral use and it can be in solid, or semi-solid or liquid form, preferably in solid or semi-solid form.
In solid form, the composition can be in form of powder, granules, chips, aggregates, or for mouth-soluble or mouth-dissolving formulations. In liquid form, the composition can be in form of solution, dispersion or suspension of a solid in a liquid.
Advantageously, the composition in solid or semi-solid form of the present invention can be in any form suitable for oral administration to a subject and known to a man skilled in the art such as, for example, a sachet, a tablet, a bar, a pill or a capsule or a softgel.
The obtained tablets may have various shapes including those known in the pharmaceutical industry, such as for example cylindrical-shaped or spherical-shaped. The tablets may have a weight comprised between 200 and 2000 mg. For example, a hard tablet may have a weight comprised between 800 and 1000 mg, while a chewable tablet may have a weight comprised between 1000 and 2000 mg. The tablets may be coated or filmed with one or more layers or films of coating capable of going past the gastric barrier. The coating is prepared using bee wax solution or a sugar-based solution. The capsules can be made of rigid gelatine or soft gelatine or soft gel. For example, a gelatine capsule may have a weight of 500 mg.
Advantageously, the composition of the present invention is a pharmaceutical composition, a medical device composition according to the European regulation on medical devices [UE 2017/745 -(MDR), Directive 93/42/CEE -(MDD)] or a food supplement composition.
Furthermore, the present invention regards a method (first and second method) for preparing the preparation (or sucrosomial® mineral) of the present invention in one of the embodiments as defined above, for example in the embodiments from FRa to FRp.
In a first embodiment, said method (first method) for preparing the preparation(or sucrosomial® mineral) comprises or, alternatively, consists of several processing steps through which said (a) mineral in form of mineral is coated or wrapped or encapsulated, fully or partly, with said (b) lecithin, with said (c) first agent, which can be selected from among between (c-i) and (c-iv) or, alternatively, a mixture between two or more of said (c-i)-(c-iv), and/or preferably between said (d) plant starch, wherein (a), (b), (c) and (d) have the characteristics indicated above. Advantageously, the components (a), (b), (c) and (d) are all in solid form, in particular in form of powders.
Preferably, said (a) mineral salt in solid state is placed at close physical contact firstly with said (b) lecithin. Then, only subsequently, once fully or partly coated or wrapped or encapsulated with said (b) lecithin, said mineral is placed at contact with at least one of said (c) first agent, selected from among (c-i) a carbohydrate ester of one or more fatty acids (sucrester), (c-ii) cyclodextrin, (c-iii) C6-C18 fatty acid, (c-iv) chitosan derivative or, alternatively, with two or more of said first agent selected from among (c-i)-(c-iv) as indicated in the embodiments of the invention from FRa to FRp, and/or preferably with said (d) plant starch.
The processing time during which the (a) mineral salt and the (b) lecithin are placed at contact is comprised between 1 and 60 minutes, preferably between 10 and 50 minutes, even more preferably between 20 and 40 minutes.
The (b) lecithin, placed at contact with said (a) mineral salt is distributed in the most uniform manner possible on said mineral salt, fully or partly, and, thus, also on the mineral present in the mineral salt in form of magnesium (II) or calcium (II) or iron (III) or iron (II) or zinc (II) or iodine (V) or selenium (IV) mineral cation. The (a) mineral salt in solid state of powder or granules or chips or agglomerates has a water content comprised between 0.05% and lesser than 20% by weight, preferably between 0.1% and lesser than 10%, even more preferably between 1% and 3%.
The (a) mineral salt containing the magnesium (II) or calcium (II) or iron (III) or iron (II) or zinc (II) or iodine (V) or selenium (IV) mineral (or mineral cation) is used at an amount by weight with respect to the total weight of the preparation (or sucrosomial® mineral) variable depending on the salt used, as specified in the previous part describing the preferred embodiments of the preparation of the composition of the invention.
The (b) lecithin used in said first method is an E322 sunflower lecithin, in powder. Neither a hydrolysed lecithin nor an enzymatically hydrolysed lecithin is used in said first method. The lecithin is present at an amount by weight comprised between 0.05 and 20% with respect to the total weight of the preparation, preferably between 0.1 and 10%.
The (c) first agent (c-i), (c-ii), (c-iii), (c-iv) or, alternatively, mixture of two or three or four of said first agent (c-i)-(c-iv), is present in the preparation at an amount by weight between 1% and 75% with respect to the weight of the preparation, preferably between 1% and 60%, even more preferably between 5% and 40%. Preferably said at least one (c) first agent is only (c-i) or, alternatively, said at least one (c) first agent is (c- i) and at least one or more from among (c-ii), (c-iii) and (c-iv) or, alternatively, said at least one (c) first agent does not comprise (c-i) and it is at least one from among (c-ii), (c-iii) and (c-iv).
The (d) starch is a gelatinised or pre-gelatinised native rice starch, when present.
The starch is present in the preparation of the present invention at an amount by weight comprised between 10% and 95% with respect to the total weight of the preparation, preferably between 20% a 90%, even more preferably between 25% and 85%.
The starch in form of gelatinised or pre-gelatinised starch has the advantage of being more fluid and flowing and it allows to be dosed accurately without creating weight errors or variations; furthermore, it is distributed in a more uniform and homogeneous manner. Lastly, the gelatinised or pre-gelatinised starch improves the bioavailability of the mineral salt and, thus, of the mineral (mineral cation content in said mineral salt) given that the compound that is obtained dissolves better at temperatures comprised between 15°C and 30°C (pressure 1 atmosphere and ambient temperature of 20°C), preferably between 20°C and 25°C, even more preferably between 18°C and 23°C.
Obtained at the end of said first preparation method is the preparation (or sucrosomial® mineral) contained in the composition of the present invention in solid form (powder or granules or chips or agglomerates); said preparation has a water content comprised between 0.05% and lesser than 5% by weight with respect to the total weight of the preparation, preferably between 0.1% and lesser than 3%, even more preferably between 0.5% and 2% by weight.
The preparation (or sucrosomial® mineral) in solid form obtained according to said first method described above comprises or, alternatively, consists of: (a) at least one mineral in form of mineral salt (b) a lecithin (neither hydrolysed nor enzymatically hydrolysed), at least one (c) first agent, selected from among (c-i) a carbohydrate ester of one or more fatty acids (sucrester), (c-ii) cyclodextrin, (c-iii) C6-C18 fatty acid, (c-iv) chitosan derivative, or mixtures of two or more of said first agent (c-i)-(c-iv) according to one of the embodiments from FRa to FRp; and, preferably, (d) a gelatinised or pre-gelatinised starch of plant origin, at the amounts by weight indicated in the present description. Preferably said at least one (c) first agent is only (c-i) or, alternatively, said at least (c) first agent is (c-i) and at least one or more from among (c-ii), (c- iii) and (c-iv) or, alternatively, said at least one (c) first agent does not comprise (c-i) and it is at least one from among (c-ii), (c-iii) and (c-iv).
Advantageously, the preparation (or sucrosomial® mineral) in solid form obtained according to said first method described above comprises or, alternatively, consists of a mineral (or cation of the mineral), selected from among magnesium (II), calcium (II), iron (III), iron (II), zinc (II), iodine (V), selenium (IV) or the mixtures thereof, an E322 sunflower lecithin (neither hydrolysed nor enzymatically hydrolysed), preferably allergen free sunflower lecithin, an E473 sucrester and/or alpha-cyclodextrin and/or stearic acid and/or carboxymethyl chitosan, according to one of the embodiments from FRa to FRp, and, optionally, a pre-gelatinised rice starch, at the amounts by weight indicated in the present description; preferably, in this embodiment, said at least one (c) first agent is only E473 sucrester or, alternatively, said at least one (c) one first agent is E473 sucrester and at least one or more from among alpha-cyclodextrin, stearic acid and carboxymethyl chitosan or, alternatively, said at least one (c) first agent does not comprise E473 sucrester and it is at least one from among alpha-cyclodextrin, stearic acid and carboxymethyl chitosan or a mixture thereof.
The Applicant found that in order to have high bioavailability in the organism of the mineral (or cation of the mineral) following the administration of the composition of the invention to a subject, the amount by weight of (b) lecithin to be used in the method for preparing the preparation (or sucrosomial® mineral) must be reduced as much as possible in terms of quantity. Preferably, the preparation of the invention, obtained using said first or second method, comprises the (b) lecithin at a by weight % comprised in the range between 0.1 and 10%, preferably between 0.5 and 5%, more preferably between 0,1 and 1% or between 0,5 and 1%, with respect to the total weight of the preparation. Furthermore, the Applicant found that in order to have high bioavailability in the organism of the mineral (or cation of the mineral) it is important to use - in the method for preparing the preparation (or sucrosomial® mineral), combined with a low amount by weight of (b) lecithin - a determined amount by weight of (c) first agent, preferably sucrester.
Advantageously, the ratio between the (c) first agent, preferably sucrester, or mixture thereof, and the (b) lecithin is comprised between 25:1 and 1 :1, preferably between 20:1 and 5:1, even more preferably between 15:1 and 10:1. In an embodiment, said ratio is comprised between 20:1 and 10:1.
In a second embodiment, said method (second method) for preparing the preparation (or sucrosomial® mineral) comprises or, alternatively, consists of a technology designed to create - around the mineral salt - a coating or wrapping or encapsulation such to improve the stability and the bioavailability of the mineral (or cation of the mineral) contained in the mineral salt.
The difference between the first and the second method lies in the order with which (b) a lecithin and (c) at least one first agent are added to (a) at least one. In the first method (b) a lecithin is added (a) to at least one mineral and, then, only subsequently, there follows the addition of (c) at least one first agent. Whereas in the second method at least (c) one first agent is added to (a) at least one mineral and, then, only subsequently, there follows the addition of (b) a lecithin. Alternatively, in the second method (c) at least one first agent and (b) a lecithin can be added - together and simultaneously - to (a) at least one mineral. The preparation (or sucrosomial® mineral) in solid form (powder, granules, chips or agglomerates) obtained according to said second method comprises or, alternatively, consists of: (a) at least one mineral in form of mineral salt, a (b) lecithin, at least one (c) first agent, selected from among (c-i) sucrester, (c-ii) cyclodextrin, (c-iii) C6-C18 fatty acid, (c-iv) chitosan derivative, or mixtures of two or more of said first agent (c-i)-(c-iv) according to one of the embodiments of the invention from FRa to FRp; and, preferably, a (d) gelatinised or pre-gelatinised starch, at the amounts by weight indicated in the present description. Preferably said at least one (c) first agent is only (c-i) or, alternatively, said at least (c) first agent is (c-i) and at least one or more from among (c-ii), (c-iii) and (c-iv) or, alternatively, said at least one (c) first agent does not comprise (c-i) and it is at least one from among (c-ii), (c-iii) and (c-iv).
The components (a), (b), (c) and (d) have the characteristics indicated above in the description.
In a preferred embodiment, the preparation (or sucrosomial® mineral) obtained according to said second method comprises or, alternatively, consists of: a mineral (or metallic cation), such as magnesium (II), calcium (II), iron (III), zinc (II), iodine (V), selenium (IV) or the mixtures thereof, an E322 sunflower lecithin (neither hydrolysed nor enzymatically hydrolysed), an E473 sucrester and/or alpha-cyclodextrin and/or stearic acid and/or carboxymethyl chitosan, according to one of the embodiments of the invention from FRa to FRp, and, optionally, a pre-gelatinised rice starch, at the amounts by weight indicated in the present description; preferably, in this embodiment, said at least one (c) first agent is only E473 sucrester or, alternatively, said at least one (c) one first agent is E473 sucrester and at least one or more from among alpha-cyclodextrin, stearic acid and carboxymethyl chitosan or, alternatively, said at least one (c) first agent does not comprise E473 sucrester and it is at least one from among alpha-cyclodextrin, stearic acid and carboxymethyl chitosan or a mixture thereof.
The (b) lecithin and said (c) first agent, such as sucrester cyclodextrin, C6-C18 fatty acid or chitosan derivative or the mixtures thereof, have the function of increasing the bioavailability and absorption of the mineral (or cation of the mineral) contained in said mineral salt.
The presence of (b) lecithin and (d) starch facilitates the formation of agglomerates, for example "chimeric” agglomerates which are capable of fully or partly protecting and shielding the mineral (or cation of the mineral) present in said mineral salt, against gastric acid.
The mineral salt containing the mineral (or cation of the mineral) is used at the amounts by weight indicated in the present description.
The processing time during which the (a) mineral salt and the (b) lecithin are placed at contact is comprised between 1 and 60 minutes, preferably between 10 and 50 minutes, even more preferably between 20 and 40 minutes.
The (b) lecithin used is a sunflower powder lecithin, preferably allergen free sunflower lecithin The lecithin
(b) is present at an amount by weight comprised between 0.05 and 20% with respect to the total weight of the preparation, preferably between 0.1 and lesser than 1%, more preferably between 0.1 and 1%.
The at least (c) first agent, preferably sucrester, is present at an amount by weight comprised between 1% and 75%, preferably between 1% and 60%, even more preferably between 5 and 40% or between 1 and 20% with respect to the total weight of the preparation.
The (b) lecithin is fully or partly distributed on the outer surface of the granules or of the powders of the mineral salts if directly added on said mineral salts (first method) before adding said (c) first agent; or it is distributed on the outer surface of the granules or of the powders comprising the (a) mineral salt and the
(c) first agent, preferably sucrester, if added subsequently to the (c) first agent (second method). A (d) gelatinised or pre-gelatinised starch of plant origin is preferably used subsequently. Advantageously, the starch is a gelatinised or pre-gelatinised native rice starch. The starch, if present, is present in the preparation (or sucrosomial® mineral) of the present invention at an amount by weight comprised between 10 and 95% with respect to the total weight of the preparation, preferably between 20 and 90%.
The gelatinised or pre-gelatinised starch is prepared according to the equipment and techniques known to the man skilled in the art. The rice flour gelatinisation process has the purpose of modifying the technological properties thereof inducing a molecular restructuring of the starch component: such modifications allow to confer greater plasticity and viscosity to the mixtures and improving various characteristics in the products in which they are used. The properties acquired through the gelatinisation and upon the ensuing change of the structure of the native starches contained in the rice, allow the process to confer greater hydration rapidity and greater viscosity to the flours. Furthermore, the gelatinised starch strongly links the water to the starch matrix making it less available. This entails longer preservation period and lesser impact of the chemical and enzymatic degradation phenomena. Pre-gelatinisation is a physical technique (which thus does not provide for adding other component) which changes the properties of starch and it is based on the cooking and the subsequent drying of an aqueous suspension of native starch (i.e. "raw” flour). Pre-gelatinised starches reveal important functional properties of absorbing a high amount of water, thus they are used as thickeners in many food grade formulations, especially when (and this specifically applies to rice or corn flours) the protein fraction of gluten is not present. The cooking-extrusion (i.e. the short treatment at high temperatures and pressure) and the drying obtained on the cylinders are the most common method used to obtain pre-gelatinisation. Furthermore, pre-gelatinised starch-based products reveal good preservation characteristics. This is due to the fact that the water content is strongly structured and trapped in the pre-jellified starch matrix, thus becoming no longer available for the degradative reactions, while in the meanwhile the thermal treatment will have eliminated some enzymatic activities (lipase and lipoxygenase) which often, in "raw” flours and in the derivative products, facilitate the oxidative rancidification.
In a preferred embodiment, the (b) lecithin is used at an amount by weight comprised between 0.1 and 10%, preferably between 0.5 and 5%, more preferably between 0.1 and 1% or between 0.5 and 1%, while the (c) first agent, preferably sucrester, is used at an amount by weight comprised between 1 and 60%, preferably between 10 and 30% or between 1 and 20%, with respect to the weight of the preparation of the present invention. These combinations allow to increase the bioavailability of the mineral (or cation of the mineral) contained in the mineral salt of interest. The preparation (or sucrosomial® mineral) of the present invention, obtained from said first method or second method, is the raw material at solid state (powder or granules or chips or agglomerates) which is subsequently mixed with other components, such as for example (e) vitamins, preferably (e-i) vitamin C, and/or (f) organic and/or inorganic salts, and/or (g) antioxidant substances, and/or (h) probiotic bacterial strains, and/or (i) folic acid, and with a technological additive and/or at least one pharmaceutical or food grade excipient to obtain the composition, preferably in solid form, of the present invention in formulations appropriate for oral use.
Advantageously, the composition of the present invention for oral use according to one of the embodiments described above (for example one of the embodiments from FRa to FRp), preferably in solid form, comprising in the preparation (or sucrosomial® mineral) the iron such as iron salt (III), can be validly used in the treatment of disorders or symptoms relating to or deriving from an iron deficiency in subjects in paediatric age, adolescents, sportsmen/sportswomen, men, the elderly, women and pregnant women.
The composition of the present invention according to one of the embodiments described above, comprising the preparation (or sucrosomial® mineral), is recommended for an administration lasting for a period comprised between 1 and 5 months, preferably between 2 and 4 months.
Advantageously, the composition of the present invention comprising the preparation, according to one of the embodiments from FRa to FRp, comprising an iron salt (III), preferably iron (III) pyrophosphate, can be validly used in the prevention, reduction or treatment or anaemia and it useful for increasing the haemoglobin and ferritin values in needy subjects. In this case the preparation is called "sucrosomial mineral” or, more precisely, "sucrosomial® iron”. In particular, said composition comprising iron (III) (sucrosomial® iron) can be validly used in the reduction, prevention or treatment of anaemia when it is administered on the aforementioned subjects at a dose comprised between 10 and 40 mg of iron (lll)/day, preferably between 15 and 35 mg of iron (lll)/day, even more preferably 30 mg of iron (lll)/day.
The composition comprising iron (III) (sucrosomial® iron) is recommended for pregnant women in that it increases the weight of the baby at birth, it prevents maternal anaemia and it acts effectively to maintain or increase the haemoglobin and ferritin values. Preferably, said composition comprising iron (III) (sucrosomial® iron) is administered for a period lasting the entire pregnancy period, in particular starting from the 12th week, up to 6 weeks after delivery {postpartum ); the recommended dose is comprised between 10 and 40 mg of iron (lll)/day, preferably between 15 and 35 mg of iron (lll)/day, advantageously 30 mg of iron (lll)/day. Advantageously, the composition of the present invention comprising the preparation, according to one of the embodiments from FRa to FRp, wherein (a) is magnesium salt (II), preferably magnesium oxide or magnesium hydroxide, can be validly used in the prevention, reduction or treatment of musculoskeletal, cardiometabolic, emotional sphere (e.g. stress) and immune system (e.g. physical and mental fatigue) disorders. In this case the preparation is called "sucrosomial mineral” or, more precisely, "sucrosomial® magnesium”.
Advantageously, the composition of the present invention comprising the preparation, according to one of the embodiments from FRa to FRp, wherein (a) is zinc salt (II), preferably zinc oxide, can be validly used in the prevention, reduction or treatment of growth and development, metabolism (intermediary metabolism, DNA metabolism), immune system, sight and cognitive behaviour disorders. In this case the preparation is called "sucrosomial mineral” or, more precisely, "sucrosomial® zinc”.
The amount of zinc required daily is relatively small, about 2-3 mg, so as to compensate the low loss of this element through urine, faeces and sweat. The recommended dietary allowance must consider numerous factors, such as sex, age and metabolic conditions such as pregnancy and breastfeeding Flowever, the recommended dietary allowance does not consider the zinc absorption inhibitor effects and thus the required dose may vary contingently and from case to case.
Advantageously, the composition of the present invention comprising the preparation, according to one of the embodiments from FRa to FRp, wherein (a) is selenium salt (IV), preferably sodium selenite, can be validly used in the prevention, reduction or treatment of pregnancy (i.e. foetal development), metabolic and immune system disorders. In this case the preparation is called "sucrosomial mineral” or, more precisely, "sucrosomial® selenium”. During pregnancy, selenium deficiency can weaken the immunity defences of the mother, making the organism more susceptible to infections, as well as facilitating foetal growth retardations and metal retardations.
Advantageously, the composition of the present invention comprising the preparation, according to one of the embodiments from FRa to FRp, wherein (a) is calcium salt (II), preferably tricalcium phosphate, can be validly used in the prevention, reduction or treatment of pregnancy (i.e. foetal development), state of mind, bone muscle and pressure disorders. In this case the preparation is called "sucrosomial mineral” or, more precisely, "sucrosomial® calcium”.
Advantageously, the composition of the present invention comprising the preparation, according to one of the embodiments from FRa to FRp, wherein (a) is iodine salt (V), preferably sodium iodate, can be validly used in the prevention, reduction or treatment of pregnancy (i.e. foetal development), state of mind, metabolism, cardiovascular and energy deficiency disorders. In this case the preparation is called "sucrosomial mineral” or, more precisely, "sucrosomial® iodine”.
Taking the composition of the present invention, comprising the preparation comprising the mineral or several minerals (sucrosomial mineral/s), reveals considerable changes in subjects after taking it (effectiveness). In particular, continuously taking the composition of the invention according to the doses described above considerably improves the levels of mineral/s present in the composition of the invention in the individuals subject of treatment (symptomatic or healthy persons), both in the blood and in the organs, such as for example the liver which is the organ where surplus iron is stored, in form of Fe(lll), and it transports part of the iron (transporter iron) through the blood to the tissues in need thereof. Furthermore, continuously taking the composition of the invention according to the described doses does not reveal any adverse effects and it is suitable to be taken by all types of subjects, including pregnant women, whether on a full or empty stomach. Lastly, the composition of the present invention is easy to take, in particular if in solid form, and it does not reveal any problems relating to unpleasant palatability. In addition, the composition of the present invention reveals chemical/physical and organoleptic stability over time.
Furthermore, being in solid state, the preparation (or sucrosomial® mineral) comprised in the composition of the present invention is easy to process to obtain the composition of the present invention as finished product, preferably in solid form, suitable for oral use.
Embodiments (FRnr) of the present invention are indicated below:
FR1. A composition in solid form comprising a preparation, called sucrosomial® mineral, comprising or, alternatively, consisting of;
- (a) at least one mineral in form of a mineral salt thereof, wherein said mineral is selected from among the group comprising or, alternatively, consisting of: (a-i) magnesium (II), (a-ii) calcium (II), (a-iii) iron (III), (a- iv) zinc (II), (a-v) iodine (V), (a-vi) selenium (IV) or mixtures thereof;
- (b) a lecithin, preferably E322 lecithin;
- (c) at least one first agent selected from among the group comprising or, alternatively, consisting of:
(c-i) a carbohydrate fatty acid ester or sucrester,
(c-ii) a cyclodextrin,
(c-iii) a C6-C18 fatty acid isomer,
(c-iv) a chitosan derivative,
or mixtures thereof; and, optionally, said composition comprises at least one technological additive and/or at least one pharmaceutical or food grade excipient,
said composition being for use in the preventive and/or curative treatment of symptoms or diseases relating to or deriving from a deficiency of said mineral or mixtures thereof.
FR2. The composition for use according to FR1, wherein said preparation, called sucrosomial® mineral, further comprises:
- (d) a gelatinised or pre-gelatinised starch of plant origin; preferably, wherein said (d) starch is selected from among the group comprising or, alternatively, consisting of rice and corn starch; preferably, wherein said (d) starch is pre-gelatinised rice.
FR3. The composition for use according to FR1 or FR2, wherein said composition further comprises:
- (e) at least one vitamin selected from among the group of vitamins comprising or, alternatively, consisting of:
(e-i) C group vitamins,
(e-ii) E group vitamins,
(e-iii) B group vitamins,
(e-iv) D group vitamins,
or mixtures thereof; preferably wherein said (e) vitamin is (e-i) vitamin C; and/or
- (f) at least one salt selected from among a group if organic and/or inorganic salts and/or
- (g) at least one substance selected from among a group of antioxidant substances; and/or
- (h) at least one probiotic bacterial strain, or mixtures of probiotic bacterial strains; and/or
- (i) folic acid.
FR4. The composition for use according to any one from FR1 to FR3, wherein said (a-i) magnesium (II) mineral salt is selected from among magnesium oxide and magnesium hydroxide, said (a-ii) calcium (II) mineral salt is E341 tricalcium phosphate, said (a-iii) iron (III) mineral salt is ferric pyrophosphate, said (a- iv) zinc (II) mineral salt is zinc oxide, said (a-v) iodine (V) mineral salt is sodium iodate, said (a-vi) selenium (IV) mineral salt is sodium selenite.
FR 5. The composition for use according to any one from FR1 to FR4, wherein said (b) lecithin is present in the preparation, called sucrosomial® mineral, at an amount by weight comprised between 0.05 and 20% of the total weight of the preparation, preferably between 0.1 and 10%; preferably, wherein said (b) lecithin is an E322 lecithin and it is selected from among the group comprising or, alternatively, consisting of: corn lecithin, sunflower lecithin and soy lecithin; more preferably it is E322 sunflower lecithin. FR6. The composition for use according to any one from FR1 to FR5, wherein said (c) first agent, or mixture thereof, is present in the preparation, called sucrosomial® mineral, at an amount by weight comprised between 1 and 75% of the total weight of the preparation, preferably between 1 and 60%; preferably, wherein, if present, (c-i) is an E473 sucrester, preferably saccharose and stearic acid and palmitic acid E473 sucrester, (c-ii) is alpha-cyclodextrin, (c-iii) is stearic acid, (c-iv) is carboxymethyl chitosan; more preferably, wherein (c) first agent is a mixture of two or more of said first agents comprised between (c-i) and (c-iv).
FR7. The composition for use according to any one from FR1 to FR 6, wherein said (c) first agent, or mixture thereof, and said (b) lecithin are present in the preparation, called sucrosomial® mineral, at a ratio by weight comprised between 25:1 and 1 : 1 ; preferably at a ratio by weight comprised between 20: 1 and 10 1
FR8. The composition for use according to any one from FR1 to FR7, wherein said preparation, called sucrosomial® mineral, has a mineral content, expressed as mg of mineral over g of preparation, in the following range:
- (a-i) magnesium (II) between 50 and 800 mg/g if the mineral salt is magnesium oxide, preferably between 100 and 600 mg/g,
- (a-i) magnesium (II) between 50 and 600 mg/g if the mineral salt is magnesium hydroxide, preferably between 100 and 450 mg/g,
- (a-ii) calcium (II) between 50 and 800 mg/g if the mineral salt is tricalcium phosphate, preferably between 100 and 600 mg/g,
- (a-iii) iron (III) between 1 and 400 mg/g if the mineral salt is ferric pyrophosphate, preferably between 10 and 300 mg/g,
- (a-iv) zinc (II) between 100 and 800 mg/g if the mineral salt is zinc oxide, preferably between 200 and 700 mg/g,
- (a-v) iodine (V) between 0.1 and 40 mg/g if the mineral salt is sodium iodate, preferably between 0.5 and 30 mg/g, or,
- (a-vi) selenium (IV) between 0.1 and 40 mg/g if the mineral salt is sodium selenite, preferably between 0.5 and 30 mg/g.
FR9. Use of a composition in solid form called sucrosomial® mineral, comprising or, alternatively, consisting of: - (a) at least one mineral in form of a mineral salt thereof, wherein the mineral is selected from among the group comprising or, alternatively, consisting of: (a-i) magnesium (II), (a-ii) calcium (II), (a-iii) iron (III), (a- iv) zinc (II), (a-v) iodine (V), (a-vi) selenium (IV) or mixtures thereof;
- (b) a lecithin, preferably E322 lecithin;
- (c) at least one first agent selected from among the group comprising or, alternatively, consisting of:
(c-i) a carbohydrate fatty acid ester or sucrester,
(c-ii) a cyclodextrin,
(c-iii) a C6-C18 fatty acid isomer,
(c-iv) a chitosan derivative,
or mixtures thereof;
and, optionally, said composition comprises at least one technological additive and/or at least one pharmaceutical or food grade excipient, for modulating and/or improving disorders relating to or deriving from a deficiency of said mineral or mixtures thereof in a subject, wherein said use is not for therapeutic purposes.
FR10. Use of the composition according to FR9, wherein said preparation, called sucrosomial® mineral, further comprises:
- (d) a gelatinised or pre-gelatinised starch of plant origin; preferably, wherein said (d) starch is selected from among the group comprising or, alternatively, consisting of rice and corn starch; preferably, wherein said (d) starch is pre-gelatinised rice.
FR11. Use of the composition according to FR9 or FR10, wherein said composition further comprises:
- (e) at least one vitamin selected from among the group of vitamins comprising or, alternatively, consisting of:
(e-i) C group vitamins,
(e-ii) E group vitamins,
(e-iii) B group vitamins,
(e-iv) D group vitamins,
or mixtures thereof; preferably wherein said (e) vitamin is (e-i) vitamin C; and/or
- (f) at least one salt selected from among a group if organic and/or inorganic salts and/or
- (g) at least one substance selected from among a group of antioxidant substances; and/or
- (h) at least one probiotic bacterial strain, or mixtures of probiotic bacterial strains; and/or
- (i) folic acid. FR12. Use of the composition according to any one from FR9 to FR11, wherein said (a-i) magnesium (II) mineral salt is selected from among magnesium oxide and magnesium hydroxide, said (a-ii) calcium (II) mineral salt is E341 tricalcium phosphate, said (a-iii) iron (III) mineral salt is ferric pyrophosphate, said (a- iv) zinc (II) mineral salt is zinc oxide, said (a-v) iodine (V) mineral salt is sodium iodate, said (a-vi) selenium (IV) mineral salt is sodium selenite; more preferably said (a) mineral salt is ferric pyrophosphate.
FR13. Use of the composition according to any one from FR9 to FR12, wherein said (b) lecithin is present in the preparation, called sucrosomial® mineral, at an amount by weight comprised between 0.05 and 20% of the total weight of the preparation, preferably between 0.1 and 10%; preferably, wherein said (b) lecithin is an E322 lecithin and it is selected from among the group comprising or, alternatively, consisting of: corn lecithin, sunflower lecithin and soy lecithin; more preferably it is E322 sunflower lecithin.
FR14. Use of the composition according to any one from FR9 to FR13, wherein said (c) first agent, or mixture thereof, is present in the preparation, called sucrosomial® mineral, at an amount by weight comprised between 1 and 75% of the total weight of the preparation, preferably between 1 and 60%; preferably, wherein, if present, (c-i) is an E473 sucrester, preferably saccharose and stearic acid and palmitic acid E473 sucrester, (c-ii) is alpha-cyclodextrin, (c-iii) is stearic acid, (c-iv) is carboxymethyl chitosan; more preferably, wherein (c) first agent is a mixture of two or more of said first agents comprised between (c-i) and (c-iv).
FR15. Use of the composition according to any one from FR9 to FR 14, wherein said (c) first agent, or mixture thereof, and said (b) lecithin are present in the preparation, called sucrosomial® mineral, at a ratio by weight comprised between 25:1 and 1 :1; preferably at a ratio by weight comprised between 20:1 and 10 1
Further embodiments (FRnr) of the present invention are indicated below:
FR16. A composition in solid form comprising
a preparation, called sucrosomial® mineral comprising or, alternatively, consisting of:
- (a) at least one mineral in form of a mineral salt thereof, wherein said mineral is selected from among the group comprising or, alternatively, consisting of: (a-i) magnesium (II), (a-ii) calcium (II), (a-iii) iron (III), (a- iv) zinc (II), (a-v) iodine (V), (a-vi) selenium (IV) and mixtures thereof;
- (b) a lecithin;
- (c) at least one first agent selected from among the group comprising or, alternatively, consisting of:
(c-ii) a cyclodextrin,
(c-iii) a C6-C18 fatty acid isomer, (c-iv) a chitosan derivative,
and mixtures thereof;
wherein said preparation does not comprise (c-i) a carbohydrate fatty acid ester or a sucrester, and, optionally, said composition comprises at least one technological additive and/or at least one pharmaceutical or food grade excipient.
FR17. The composition according to FR16, wherein the (b) lecithin is a non-hydrolysed lecithin preferably non-hydrolysed E322 lecithin.
FR18. The composition according to FR16 or FR17, wherein said preparation, called sucrosomial® mineral, further comprises:
- (d) a gelatinised or pre-gelatinised starch of plant origin; preferably, wherein said (d) starch is pre gelatinised rice starch.
FR19. The composition according to any one from FR16 to FR18, wherein said (c) at least one first agent is (c-ii) a cyclodextrin, preferably alpha-cyclodextrin.
FR20. The composition according to any one from FR16 to FR18, wherein said (c) at least one first agent is (c-iii) a C6-C18 fatty acid isomer, preferably it is stearic acid.
FR21. The composition according to any one from FR16 to FR18, wherein said (c) at least one first agent is (c-iv) a chitosan derivative, preferably it is carboxymethyl chitosan.
FR22. The composition according to any one from FR16 to FR 21, wherein said (a) is (a-i) is magnesium in form of magnesium (II) mineral salt, preferably magnesium oxide or magnesium hydroxide, or it is (a-iii) iron in form of iron (III) mineral salt, preferably ferric pyrophosphate, or it is (a-iv) zinc, in form of zinc (II) mineral salt, preferably zinc oxide.
FR23. The composition according to any one from FR16 to FR22, wherein said (c) at least one first agent selected from among the group comprising or, alternatively, consisting of (c-ii), (c-iii), (c-iv) and the mixtures thereof, and said (b) lecithin are present in the preparation, called sucrosomial® mineral, at a (c):(b) by weight ratio comprised in the range between 25:1 and 1 :1; preferably between 20:1 and 10:1. FR24. The composition according to any one from FR16 to FR23, wherein said composition is for use in a method for the preventive and/or symptomatic treatment of symptoms or disorders relating to or deriving from a deficiency of said (a) mineral or of mixtures thereof.
FR25. Use of the composition in solid form according to any one from FR16 to FR23 for modulating and/or improving disorders relating to or deriving from a deficiency of said mineral or mixtures thereof in a subject, wherein said use is not for therapeutic purposes.
EXPERIMENTAL PART REGARDING IRON
Introduction
It was assumed that the transport of iron through the intestinal epithelium may occur through two different ways: the transport of Fe(ll) is mainly mediated by thye DMT-1 transporter , while Fe(lll) in the formulation according to the composition of the invention (sucrosomial® iron) is partly encapsulated in a vesicular system which can permeate through the intestinal tissue by means of transcytosis which is another transport pathway ( Fabiano A, et al; EurJ Pharm Sci. 2018; 111 :425-431).
In light of the above, the objective of the present experimental part is to prove whether the vesicles that are simultaneously formed once the sucrosomial® iron comes into contact with the physiologic fluids are internalised by the cells of the intestinal epithelium by means of transcytosis and whether they are able to pass through the intestinal tissue (Experimental part (II)) and, lastly, if this further iron transport pathway can improve the in vivo bioavailability of iron (Experimental part (I) thus reducing the adverse effects caused by the iron not absorbed in the intestine. As a matter of fact, an excessive amount non-absorbed iron can stimulate the virulence of the pathogenic bacteria present in the intestine and contribute towards creating an oxidative pro-inflammatory environment. Despite its crucial role in cell processes, the free iron in the colon can generate toxic free radicals and reactive oxygen species, which can affect the wholeness of the cells of the intestinal epithelium by enhancing redox stress.
Experimental part (I)
The Applicant conducted in vivo and ex-wVo studies aimed at evaluating the effects of administering compositions of the present invention containing iron (sucrosomial® iron) in rats in terms of improving the bioavailability of iron with respect to administering known compositions containing iron which is not a sucrosomial® iron. 1. Methods and materials
1.1 Method for UV spectrophotometric determination of Fed 11)
The method for UV determination of concentration of Fe(lll)in aqueous solutions is based on the formation of a coloured complex between Fe(lll) and toluidine mediated by the formation of the nucleophile which is formed between the Fe(lll) and the oxidised catechol as described in Shyla et al. “Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy”, 2012.
The standards were prepared with known concentration of Fe(lll) by dissolving NFUFeiSO^ FhO in water in the presence of HCI so as to obtain an Fe(lll) concentration of 20 pg/ml. Furthermore, an aqueous solution of catechol (0,005 M), one of o-toluidine (100 pg/ml) and one of 1.10-phenanthroline (0.25%) were prepared.
1.2 Tested compositions comprising Fe(lll)
0) Control: non-treated animals
1) Composition 1 : Ferric pyrophosphate (abbreviated as FP)
2) Composition 2 (composition according to the invention): sucrosomial® iron A (Sideral ® r.m., abbreviated as SRM, manufactured by Pharmanutra-Alesco, registered trademarks) (ferric pyrophosphate, saccharide esters of fatty acids, sunflower lecithin supported on glucose syrup, pre-gelatinised rice starch, tricalcium phosphate), L-ascorbic acid (vitamin C), vitamin B12 (cyanocobalamin, maltodextrin), charging agent: microcrystalline cellulose, food grade gelatin, hydroxypropyl cellulose, anticaking agent: fatty acids magnesium salts and silicon dioxide, dye: titanium dioxide.
3) Composition 3 (comparison composition): chelated iron, L-ascorbic acid (vitamin C), folic acid.
4) Composition 4 (composition according to the invention); sucrosomial® iron B (Sideral® forte, manufactured by Pharmanutra-Alesco, registered trademarks) (ferric pyrophosphate, saccharide esters of fatty acids, sunflower lecithin (E322), pre-gelatinised rice starch), L-ascorbic acid (vitamin C), charging agent: microcrystalline cellulose, food grade gelatin, hydroxypropyl cellulose, anticaking agent: vegetable magnesium stearate and silicon dioxide, E171 dye.
Each of the four compositions was administered in rats at the dose of 5 mg/Kg, i.e. 5 mg of iron element per Kg of weight.
2. In vivo and ex-wVo bioavailabilitv studies on compositions comprising Fe(lll)
In vivo bioavailability studies were conducted on male Wistar rats weighing 250-300 g. After anaesthetising the animal, electrodes were fixed to the feet so as to be able to monitor the respiratory and cardiac pattern and the trachea and carotid were canalised. Breathing ensured by means of an artificial fan.
2.1 In vivo study of the bioavailabilitv of iron
In the rats described above, after 15 minutes (required for stabilisation), a first 200 pL blood sample was drawn (baseline control) and -400 pL of iron (5mg/Kg) contained in the compositions to be tested (Composition 1 , 2, 3 and 4) were administered subsequently. Then, blood samples were drawn every hour for a total of 5 hrs. Each blood sample was centrifuged at 4°C and 2000 ref for 20 minutes and analysed for Fe(lll) content using the method for UV spectrophotometric determination of Fe(lll) as outlined in paragraph 1.1.
2.2 Study on the iron content in intestinal tissue
A method known in literature ( Tozaki , Hideyuki, et al. "Chitosan capsules for colon-specific drug delivery: enhanced localization of 5-aminosalicylic acid in the large intestine accelerates healing of TNBS-induced colitis in rats. " Journal of controlled release 82.1 (2002): 51-61) was used with the aim of evaluating the iron content present in the intestinal tissue.
2.3 Ex-vivo study on iron content in liver, spleen and bone marrow
At the end of the bioavailability study of Fe(lll) indicated in point 2.1 , liver, spleen and bone marrow were collected, isolated and homogenised using PBS acidified to pH 3 at 8000 rpm for 10 minutes using an Ultra-Turrax ( Tozaki H, et al. J. Control. Release 2002; 82:51-61). The homogenised sample was centrifuged at 10000 rpm for 5 minutes and the collected supernatant was analysed for Fe(lll) content using the method for UV spectrophotometric determination of Fe(lll) as described in paragraph 1.1.
This procedure was repeated on non-treated rats using formulations comprising iron (control).
3. Results
3.1 Determination of bioavailabilitv of iron
Figure 1 (in absence of control) and Figure 2 (in presence of control) shows the serum iron values (Fe(lll)) concentration in the blood drawn from the rats at time 0 and in the subsequent 5 hours following administration of the formulations containing Fe(lll) in question: composition 1 , composition 2, composition 3 and composition 4 (see paragraph 2.1).
A maximum peak was observed on all compositions after 3 hours from the administration of the composition in question, followed by a deterioration of the iron concentration in the blood. This increase was more marked in case of administration of Composition 2 and Composition 4 (compositions according to the present invention) with respect to Composition 1 (ferric pyrophosphate) and Composition 3 (comparison composition, composition known in literature). As concerns Composition 3 (comparison composition, composition known in literature), the trend of iron concentration in the blood is not significantly different from that of ferric pyrophosphate, whereas its performance is lower than that of Composition 2 (composition according to the present invention, Sideral® r.m.). In the case of Composition 4 (composition according to the present invention, Sideral® forte), the trend of iron concentration in the blood is significantly different from that of Composition 1 (ferric pyrophosphate) while it is not significantly different from that of Composition 2 (composition according to the present invention, Sideral® r.m.), as observable from the AUC ( area under curve) data indicated in Table 1. In particular, Composition 2 (Sideral® r.m.) and Composition 4 (Sideral® forte) are capable of significantly increasing both the AUC and the Cmax, thus increasing the bioavailability of iron (AUCrel) by 1.8 and 1.6 times with respect to the control (Figure 2).
Figure imgf000039_0001
Table 1 : *P<005.
3.2 Determination of iron content in liver, spleen and bone marrow
Table 2 shows: i) the Fe(lll) content found in liver, spleen and bone marrow and ii) the increase factor (FI) of the Fe(lll) content respectively determined in the liver and in the bone marrow and calculated as the ratio between the Fe(lll) content determined in the liver or in the marrow in rats treated with the formulations in question comprising Fe(lll) (point 1.2) and the Fe(lll) content determined in the liver or in the marrow in rats which were not administered with a formulation comprising Fe(lll) (control) . A significantly higher Fe(lll) content both with respect to the control and with respect to the rats which were administered with Composition 1 (ferric pyrophosphate) and Composition 3 (comparison composition, composition known in literature) was determined in the liver and in the bone marrow of the rats which were administered with Composition 1 (composition according to the present invention, Sideral® r.m.) or Composition 4 (composition according to the present invention, Sideral® forte). Furthermore, as regards Composition 1 and 4 the value of FI in the liver is respectively 1.6 and 1.8.
This data is based on the bioavailability results indicated in point 3.1 which revealed an increase of Fe(lll) concentration in the blood following the administration of Composition 1 (composition according to the present invention, Sideral® r.m.) and Composition 4 (composition according to the present invention, Sideral® forte) to the rats. The high increase of iron content in the bone marrow after administering Composition 1 or 4 to rats is partly due the capacity of the marrow per se to produce haemoglobin, erythropoiesis which is stimulated during the experiment due to drawing of blood.
Figure imgf000040_0001
Experimental part (II)
The Applicant conducted in vitro studies aimed at proving whether the vesicles that are formed simultaneously once the sucrosomial® iron of a composition of the present invention comes into contact with physiological fluids are internalised by the cells of the intestinal epithelium through transcytosis and whether they are able to pass through the intestinal tissue intact.
4. Materials and methods
4.1 Materials
Pepsin, pancreatin, Chelex-100 resin, fluorescein isothiocyanate (FITC): Sigma-Aldrich;
- the polyester membrane filters (pore size 0.4 pm, area 1.12 cm2): Celbio, Milano, Italy;
- the carbon dioxide/oxygen (95/5 v/v) mixture (Oxycarb): Sol, Pisa, Italy;
- mouse anti-CD68 monoclonal antibody (ab201340), used to identify macrophages, Abeam (Cambridge, UK);
- rabbit anti-GP2 polyclonal antibody (PA5-42593), used to identify M cells; ThermoFisher scientific (Waltham, MA, USA).
- Composition 1 : Ferric pyrophosphate (abbreviated as FP), used as reference.
- Composition 2 (composition according to the invention): sucrosomial® iron (Sideral ® r.m., abbreviated as SRM), as defined in point 1.2. Experimental part (I).
None of the powders tested contained any particles so small as to pass through a 106 m sieve. All chemicals and solvents used in this work were of reagent grade. 4.2 Fluorescent labelling of sucrester
The procedure conducted in a manner similar to the one indicated in Di Colo G, et a!.,. Drug Dev Ind Pharm. 2009; 35:941-949. A fluorescein isocyanate solution (code, FITC) in dimethyl sulfoxide (0.2 mL, 2 mg/mL) was added to an aqueous solution of sucrester (20 mL, 2 mg/mL), and the mixture was incubated for 8 h at 4 °C. The solution was then passed through a Sephadex G15 column to eliminate the non- reacted sucrester from the one labelled using FITC, and then lyophilized. In no case did the Sephadex column retain any fluorescence, indicating the absence of nonreacted FITC in all cases and the complete labelling of sucrester. Flence, the fluorophore bound to the sucrester could be calculated at 1 % of the total mass. This sucrester was used to prepare Composition 2 fluoresceinated using fluorescein isocyanate (abbreviated as, SRM fluoresceinated using FITC or FITC-labelled SRM).
4.3 Calibrating the sample based on fluoresceinated sucrester
In order to conduct in vivo-vitro bioavailability studies of the formulation containing fluoresceinated sucrester, there arose the need for a calibration curve of the aforementioned sample in rat serum. The standards with known concentration of sample based on a base sucrester fluoresceinated in serum were analysed under the fluorimeter at Aecc 490nm and Aem 520 nm, obtaining a curve whose r2was 0.9999.
4.4 Study of the internalisation of FITC-SRM through the intestines (Permeation study through the isolated rat intestine)
The procedure was conducted in a manner similar to the one indicated in Fabiano A, et al. J Drug Del Technol. 2016; 32:291-297. The intestinal mucosa used for these studies was obtained from non-fasting male Wistar rats weighing 250-300 g. After sacrificing the rats, the first 20 cm of jejunum was immediately removed. The isolated intestine was cut into 1.5 cm strips, rinsed of the lumen content and mounted in Ussing-type chambers (0.78 cm2 exposed surface area) without eliminating the underlying muscular layer. One and 3 ml of PB pH 7.4, 0.13 M (isosmotic) were respectively added to the mucosal compartment (donor) and serosal compartment (receiver) of the permeation cell. In order to guarantee oxygenation and stirring, a mixture of 95% O2 and 5% CO2 was gurgled through each compartment. The Ussing chamber was then placed a thermostatic water bath at 37 0 C. After 20 min of balancing, the means in the donor compartment was substituted with 1 ml of suspension of SRM fluoresceinated with FITC at the concentration of 64.2 mg/ml in PB pH 7.4, 0.13 M, containing 8.4 mg of iron in form of ferric pyrophosphate. This dispersion was prepared previously by stirring an appropriate amount of the sample in fluids simulating gastric digestion, so as to simulate the transit of the sample through the stomach, as described in. 1998; 128(9):554-1561. The same experiments were repeated at least three times.
The procedure below was implemented so as to observe the intestinal tissue incubated under fluorescence microscope. After 30 minutes or 1 , 2 hours of incubation in the Ussing chamber, intestinal tissue strips were fixed in a solution at 4% of paraformaldehyde in phosphate buffer at 4 ° C. The samples were then dried using ethanol, eliminated using xylene and embedded in paraffin according to standard histological techniques. 8 pm-thick sections were cut along the long axis of the gut lumen to obtain sections of whole thickness of the intestinal wall, from the mucosal to serosal side. Mounted on glass slides, the sections were deparaffined, rehydrated and incubated for 15 min using nuclear dye TO-Pro. After sealing with PBS/glycerol solution (1 :2), the slides were examined by means of a confocal laser scanning microscope (TC SSP8 Leica Microsystems, Mannheim, Germany) using x20, x40, x63 oil immersion lenses and 488 nm and a 642 nm excitation wavelength laser.
The analysis of the sample was performed in at least three non-consecutive sections for each sample.
In order to identify the cells that had internalised SRM, an immunohistochemical analysis was conducted on the samples for macrophages and M cells after 30 minutes or 1 hr of incubation in the Ussing chamber. In brief, the de-paraffined slides were incubated in blocking solution (0.1 % Tween, 0.25% BSA in PBS) for 1 hr., and then with antibodies diluted 1 : 200 (anti-CD68) or 1 : 120 (anti-GP2) overnight at 4 °C. After three washes, the slides were incubated 1.5 hr in the dark with relative fluorescent secondary antibodies diluted 1 : 250 in stock solution. Nuclear staining was performed using TO-Pro. Samples were mounted using PBS-glycerol solution.
Negative controls for secondary antibodies were performed without omitting the primary antibodies and incubating the specimens using nonimmune serum. The sections were observed under confocal laser scanning microscopy using x20, x40, x63 oil immersion lenses and 488 nm, 561 nm and a 642 nm excitation wavelength laser.
5. Results of the study on the internalisation of FITC-SRM through the intestinal barrier.
Sections of the intestinal wall were observed under a confocal microscopy after incubation with FITC- labelled SRM. The expression of the fluorescence was observed in the entire thickness of the intestinal wall, and then all incubation times were tested. This represents the fact that the vesicular structures present in the samples penetrate into the intestine from the mucosal side to the serosal side without disintegrating during their transit. It was observed that the fluorescence content in all samples incubated with SRM for times longer than (30 min<1 h<2hr) (Figure 7). In Figure 7 (black and white) the fluorescence is represented by the light grey areas and the nuclei are represented by the dark grey areas, while when said Figure 7 is represented coloured the fluorescence is represented by the green areas and the nuclei are represented by the blue areas.
In particular, upon observing the samples with greater magnification, it was observed that the fluorescence (light grey area) consists of considerably small vesicular structures. Such vesicular structures were observed in the enterocytes and in the cells of the connective tissue up to 1 hr of incubation with SRM, while after 2 hrs of incubation the fluorescent particles (light grey area) are exclusively found in the connective cells (Figure 8). When said Figure 8 is represented coloured, the fluorescence is represented by the green areas and the nuclei are represented by the blue areas.
Given that the morphological appearance of these connective cells alone is not enough to identify them clearly, an immunohistochemical analysis was conducted to evaluate the expression of specific antigens such as CD68 and Gp2 respectively specific for the macrophages and for M cells. As outlined in the representative examples of Figure 9, the results proved that the very small vesicular structures (light grey/green) are concentrated in CD68 positive cells (dark grey/red). As a matter of fact, in the merged images, obtained by superimposing the two channels (light grey/green-dark grey/red), the cells containing the light grey (green) vesicular systems appear as lighter grey (yellow) due to the superimposition of the light grey (green) fluorescent signal with the dark grey (red) one. In particular, as the incubation time increases, an increasingly higher number of CD68 positive macrophages seems involved in the internalisation of these vesicular systems.
As regards the GP2 positive cells, the obtained results show that these cells do not seem implicated in the englobing of the vesicular systems, at least as concerns the incubation times that were tested. As a matter of fact, as observable in Figure 10, the light grey (green) and dark grey (red) fluorescent signals do not coincide and in the merged images, the cells containing the vesicular systems remain light grey (green).
Given that Composition 2 (Sideral® r.m.) revealed an increase of the permeability of Fe(lll) through the isolated rat intestine, and that the increase revealed to be due to the formation of vesicles capable of permeating through the intestinal tissue without disintegrating, we can affirm that the addition of this particular penetration pathway to the traditional one based on the DMT1 transporter contributes towards increasing the in vivo bioavailability of the iron of the composition according to the invention (Composition 2 (Sideral® r.m.) as proven in the "Experimental part (I)” (see point 2.1 and 3.1).
Furthermore, it is known that most of the iron is transported to the bone marrow for the production of red cells, that smaller amounts go to other tissues for fundamental cell processes and that the surplus is transported to the liver for storage in form of Fe(lll). Besides this, if we are to consider that the further site of storage of iron in the organism are the macrophages, which - as we say - are involved in the internalisation of the vesicles loaded with Fe in the intestinal tissue, we can affirm that Composition 2 (Sideral® r.m. or SRM) and Composition 4 (Sideral® forte) not only have the capacity to increase the bioavailability of iron but also that of maintaining the correct concentration of iron in the blood over extended periods of time with respect to ferric pyrophosphate (FP). 6. In vivo bioavailability studies on iron after administration using FITC-labelled SRM
In vivo and ex vivo studies using the FITC-labelled SRM sample similar to those of the Experimental part (I) were also conducted so as to confirm the internalisation of the vesicles.
The data indicated in Figure 3, from which the values regarding the concentration of baseline Fe(lll) were removed for comparative purposes, shows that the concentration profile of FITC-labelled SRM in the blood can be exactly superimposed with the one regarding the concentration of Fe(lll). Given that in the FITC- labelled SRM sample the Fe(lll) and the fluoresceinated excipient have the same concentration, it is evincible that the surplus Fe(lll) found in the blood following the administration of Composition 2 (Sideral® r.m. or SRM) (point 2.1 and 3.1 of the experimental part (I)) is linked to the vesicles which are formed extemporaneously when the formulation comes into contact with physiological fluids.
7. Conclusions
The composition according to the invention (Composition 2 and 4) revealed the capacity to considerably increase serum iron with respect to ferric pyrophosphate (FP) by enhancing absorption.
Furthermore, this increase of bioavailability leads to an increase of the liver iron deposit. The iron deposited in the liver could be recalled to the blood whenever necessary, thus guaranteeing better management of serum iron in the anaemic patient and reduction of the adverse effects affecting the intestine. In this experimental study it was proven that the increase of bioavailability is also due to the extemporaneous formation - in the gastrointestinal tract - of vesicles loaded with iron that pass through the intestinal tissue intact.
EXPERIMENTAL PART REGARDING MAGNESIUM
The object of this experimental study is to evaluate the capacity of the composition of the invention to increase the absorption and thus the bioavailability of magnesium.
8. Methods and materials
8.1 Tested compositions
- Composition 5: comprising Mg sucrosomial® (Ultramag® manufactured by Pharmanutra-Alesco);
- MgO: Magnesium oxide
8.2. Method for fluorometric determination of Mq(ll) using the fura-2 indicator
The method for fluorometric determination of Mg(ll) is based on the capacity of the fura-2 indicator to bind Mg(ll) in presence of EGTA chelating agent (ethylene glycol-bis (b-aminoethyl ether)-N, N, N’, N’-tetraacetic acid). The standards with known concentration of Mg(ll) were prepared by adding different proportions of EGTA. 2 pL of fura-2 indicator (0.5 mg/mL concentration) were subsequently added to 5 mL of such solutions and the solutions were fluorometrically analysed at Aecc=340 nm and Aemis=510 nm. Upon indicating, in a chart, the fluorescence intensities as a function of the concentration of the of the various calibration solutions, the response of the indicator was linear.
8.3. Study on release of Mad I) from the formulations
The equipment used for determining the release kinetics of Mg (I I) from the matrices consisted on an external circulation thermostat adjusted to a temperature of 37 °C, and a beaker (inner diameter, 95 mm; height, 100 mm) provided with a thermostating jacket, placed on an elevator, a 120 rpm synchronous motor, which actuated a blade stirrer (length 49 mm, height 15 mm), into which the 500 mg of the formulation to be tested were introduced. At time t=0, the stirrer was submerged into the receiving phase (100 ml), contained in the beaker, and pre-thermostated to 37 °C. The described equipment allowed to control the hydrodynamics around the matrix. A measured volume (1 ml) of the receiving phase, which was fluorometrically analysed for the concentration of Mg(ll) after centrifugation at 14000 rpm for 10 minutes was collected at 30-minute time intervals. Unless indicated otherwise, the elution means were simulated gastrointestinal fluids, consisting of the following solutions:
• Simulated gastric fluid (FGS), consisting of HCI 0.04 M, pH 1.2, made isotonic using NaCI (40 g of HCI 1 N and 1 g of NaCI for 500 ml).
• Simulated jejunum fluid (FDS), consisting of phosphate buffer (TF) pH 6.8, 0.13M, made isotonic using NaCI (5.69 Na2HP04· 2H20, 4.56 g NaH2P04 .H20 and 0.5 g NaCI for 500 ml).
Such solutions were used in sequence for two hours each.
8.4. Study on permeation of Mad I) through the isolated rat intestine
As regards permeation studies, the intestinal mucosa of male Wistar rats was isolated and treated as described in point 4.4 of the Experimental part (I). The Ussing chambers were placed in a water bath at 37°C. After 20 min of balancing, the means in each donor compartment was substituted using 1 ml of the suspension of the formulation to be tested which was previously treated to simulate the transit thereof in the stomach. 0.2 g of pepsin were solubilised in 5m I of an aqueous solution of HCI 0.1 M so as to simulate gastric digestion. 2.5 g of Chelex-100 resin were added thereto and they were stirred 30 minutes. The suspension was then transferred in column and another 5 ml of HCI 0.1 M were added in column after collecting the eluate. The final volume of the eluate was 8 ml. A predetermined amount of sample was placed in a container with a screw cap, then 10 ml of an aqueous solution containing NaCI (140 mM) and KCI (5mM) were added, the suspension was brought to pH 2 using HCI 5 M and 0.5 ml of the pepsin solution were added thereto. The suspension was then degassed using carboxicarb so as to create the anaerobic conditions found in the gastrointestinal tract, then the container - tightly closed - was placed in a stirrer bath at 37°C for 60 min. As control, experiments similar to the one described were conducted maintaining PBS pH 6.8 in the donor compartment. 1 ml of sample was collected from the receiving compartment at 30-minute intervals for a total of 240 minutes and replaced with the same volume of fresh means. The permeated Mg (I I) content was determined according to the analytical method described in the previous paragraph. At least three duplicated different tests were conducted for each sample.
9. Results of the study on permeation of Mq(ll) through the isolated rat intestine
The studies on the isolated rat intestine allow to evaluate the permeability of the intestinal epithelium to
Mg(ll).
From Figure 4 and from Table 3, which show permeation enhancement factors, we see that the permeation of Mg(ll) is significantly promoted by Composition 5 (Ultramag®) with respect to the reference solely consisting of magnesium oxide (MgO). Composition 5 (Ultramag®), with a 2.4 enhancement ratio (ER) significantly increases the bioavailability of magnesium with respect to the to the reference magnesium oxide (MgO). Given that Mg(ll) at neutral pH of the intestine forms insoluble Mg(OH)2, the ions of this type found in the receiving phase past the membrane must have been transported as such encapsulated in vesicular systems capable of being internalised by the intestinal epithelium cells.
Figure imgf000046_0001
Table 3
Figure 5 and the relative Table 4 show the data obtained using Composition 5 (Ultramag®) at the concentration of Mg(ll) in the donor phase 10 times lesser than the one tested in Figure 4, observable in which is the capacity of Composition 5 (Ultramag®) to enhance absorption of Mg(ll), even though such capacity is in a 1.2 enhancement ratio with respect to the control (MgO), this denoting that the speed of absorption of magnesium is mainly affected by the dissolution speed of magnesium due to the poor solubility thereof to the neutral pH of the intestine rather than the permeation capacity thereof through the paracellular pathway.
Figure imgf000046_0002
Table 4 10. Conclusions
The Composition 5 (sucrosomial® magnesium, Ultramag®) according to the invention revealed to be capable of enhancing the absorption of Mg(ll) in the intestine. The study on the capacity to enhance absorption revealed that by administering the lower concentrations of Mg(ll) (Ultramag®) allows to obtain a much higher percentage of Mg(ll) percentage (94.6%) and that such percentage lowers considerably for higher concentrations of Mg(ll) applied (19%). Such result denotes that the absorption of Mg(ll) is a process that can be saturated and that the increase of the absorption thereof when administered as sucrosomial® magnesium is potentially due to the use of a further absorption pathway, like the one of transcytosis of vesicles loaded with Mg(ll).
EXPERIMENTAL PART REGARDING ZINC
The object of this experimental study is to evaluate the capacity of the composition of the invention to increase the absorption and thus the bioavailability of magnesium.
11. Methods and materials
11.1 Tested compositions
- Composition 6: composition Zn sucrosomial® (Ultrazin®“Allergen Free" manufactured by Pharmanutra- Alesco);
- Zinc oxide (ZnO): control.
11.2. Method for UV spectrophotometric determination of Zn(ll)
The method for the UV determination of concentration of Zn(ll) is based on the formation of a complex between the Zn(ll) and the dithizone. The standards with known concentration of Zn(ll) were prepared by dissolving - in water acidulated with HCI, ZnO - so as to obtain a concentration of Zn(ll) of 0.1 mg/mL.
A dithizone stock solution (HDz) 0.01% (w/v) in 100 mL of an acetone/propanol mixture (1/1 , v/v) had to be prepared. 2 mL of each standard with known concentration of Zn(ll) and 4 mL of the HDz solution were placed in 10 mL volumetric flasks and then brought to volume using an acetone/propanol mixture (1/1, v/v). After waiting 10 min, the standards thus prepared were read under UV at the 520 nm wavelength against an appropriate white reagent.
11.3. Study on release of ZndD from the formulations
Similarly to point 8.3 (Mg).
11.4. Study on permeation of Zn(ll) through the isolated rat intestine
Similarly to point 8.4 (Mg). 12. Results of the study on permeation of Zn(ll) through the isolated rat intestine
The studies on the isolated rat intestine allow to evaluate the permeability of the intestinal epithelium to
Zn(ll).
Zinc reaches the enterocyte, passes through the baseline membrane and reaches the circulation. The mechanism involves the Zn-T1 transporter present at villi level. This experiment allows to monitor the permeability of the Zn(ll) ion.
From Figure 6 and from Table 5, which show permeation enhancement factors, we see that the permeation of Zn(ll) is further enhanced by Composition 5 (Ultrazin®) with respect to the zinc oxide (ZnO) control. Thus, Composition 5 (Ultrazin®) reveals to be capable of enhancing absorption in the intestine in greater manner with respect to the zinc oxide (ZnO) control.
Figure imgf000048_0001
Table 5

Claims

1. A composition in solid form comprising
a preparation, called sucrosomial® mineral comprising or, alternatively, consisting of:
- (a) at least one mineral in form of a mineral salt thereof, wherein said mineral is selected from among the group comprising or, alternatively, consisting of: (a-i) magnesium (II), (a-ii) calcium (II), (a-iii) iron (III), (a- iv) zinc (II), (a-v) iodine (V), (a-vi) selenium (IV) and mixtures thereof;
- (b) a lecithin;
- (c) a first agent (c-i) consisting of a carbohydrate fatty acid ester or a sucrester, and
at least one further first agent selected from among the group comprising or, alternatively, consisting of:
(c-ii) a cyclodextrin,
(c-iii) a C6-C18 fatty acid isomer,
(c-iv) a chitosan derivative,
and mixtures thereof;
and, optionally, said composition comprises at least one technological additive and/or at least one pharmaceutical or food grade excipient.
2. The composition according to claim 1, wherein the (b) lecithin is a non-hydrolysed lecithin preferably non-hydrolysed E322 lecithin.
3. The composition according to claim 1 or 2, wherein said preparation, called sucrosomial® mineral, further comprises:
- (d) a gelatinised or pre-gelatinised starch of plant origin; preferably, wherein said (d) starch is pre gelatinised rice starch.
4. The composition according to anyone of claims 1 to 3, wherein said composition further comprises:
- (e) at least one vitamin selected from among the group of vitamins comprising or, alternatively, consisting of:
(e-i) C group vitamins,
(e-ii) E group vitamins,
(e-iii) B group vitamins,
(e-iv) D group vitamins,
and mixtures thereof; preferably wherein said (e) vitamin is (e-i) vitamin C; and/or
- (f) at least one salt selected from among a group if organic and/or inorganic salts and/or
- (g) at least one substance selected from among a group of antioxidant substances; and/or - (h) at least one probiotic bacterial strain, or mixtures of probiotic bacterial strains; and/or
- (i) folic acid.
5. The composition according to anyone of claims 1 to 4, wherein said (a) is (a-i) magnesium, in form of magnesium (II) mineral salt, preferably magnesium oxide or magnesium hydroxide.
6. The composition according to anyone of claims 1 to 4, wherein said (a) is (a-ii) calcium, in form of calcium (II) mineral salt, preferably E341 tricalcium phosphate.
7. The composition according to anyone of claims 1 to 4, wherein said (a) is (a-iii) iron, in form of iron (III) mineral salt, preferably ferric pyrophosphate.
8. The composition according to anyone of claims 1 to 4, wherein said (a) is (a-iv) zinc, in form of zinc (II) mineral salt, preferably zinc oxide.
9. The composition according to anyone of claims 1 to 4, wherein said (a) is (a-v) iodine, in form of iodine (V) mineral salt, preferably sodium iodate.
10. The composition according to anyone of claims 1 to 4, wherein said (a) is (a-vi) selenium, in form of selenium (IV) mineral salt, preferably sodium selenite.
11. The composition according to anyone of claims 1 to 10, wherein said (b) lecithin is present in the preparation, called sucrosomial® mineral, at an amount by weight comprised between 0.05% and 20% of the total weight of the preparation, preferably between 0.1% and 10%, more preferably between 0.1% and 1%; and wherein said (b) lecithin is a non-hydrolysed E322 lecithin; preferably it is non-hydrolysed E322 sunflower lecithin.
12. The composition according to anyone of claims 1 to 11, wherein said (c) first agent (c-i) or, alternatively, said (c-i) and at least one further first agent selected from among the group comprising or, alternatively, consisting of (c-ii), (c-iii), (c-iv) and the mixtures thereof, is present in the preparation, called sucrosomial® mineral, at an amount by weight comprised between 1% and 75% of the total weight of the preparation, preferably between 1% and 60%, more preferably between 1% and 20%; and wherein (c-i) is an E473 sucrester, preferably an E473 sucrester of saccharose and stearic acid and palmitic acid, and, if present, (c-ii) is alpha-cyclodextrin, (c-iii) is stearic acid, (c-iv) is carboxymethyl chitosan.
13. The composition according to anyone of claims 1 to 12, wherein said (c) first agent (c-i) or, alternatively, said (c-i) and at least one further first agent selected from among the group comprising or, alternatively, consisting of (c-ii), (c-iii), (c-iv) and the mixtures thereof, and said (b) lecithin are present in the preparation, called sucrosomial® mineral, at a (c):(b) by weight ratio comprised in the range between 25:1 and 1 :1; preferably between 20:1 and 10:1.
14. The composition according to anyone of claims 1 to 13, wherein said composition is for use in a method for the preventive and/or symptomatic treatment of symptoms or disorders relating to or deriving from a deficiency of said (a) mineral or of mixtures thereof.
15. Use of the composition in solid form according to anyone of claims 1 to 13 for modulating and/or improving disorders relating to or deriving from a deficiency of said mineral or mixtures thereof in a subject, wherein said use is not for therapeutic purposes.
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