WO2025074320A1

WO2025074320A1 - Modified-release granulate of active ingredients and/or nutritional ingredients and methods of making

Info

Publication number: WO2025074320A1
Application number: PCT/IB2024/059732
Authority: WO
Inventors: Andrea Domizio Costa; Elena Madaro
Original assignee: SIIT Servizio Internazionale Imballaggi Termosaldanti SRL
Current assignee: SIIT Servizio Internazionale Imballaggi Termosaldanti SRL
Priority date: 2023-10-04
Filing date: 2024-10-04
Publication date: 2025-04-10
Anticipated expiration: 2026-04-04
Also published as: IT202300020562A1; WO2025074320A4

Abstract

A modified-release granulate comprising or, alternatively, consisting of: (i) at least one active ingredient/nutritional ingredient selected from the group comprising or, alternatively, consisting of: - at least one vitamin; - at least one mineral, particularly iron and/or magnesium and/or salts or complexes thereof and/or mixtures thereof; - at least one amino acid; - at least one dry extract titrated in polyphenols, such as a green tea extract and a grape vine extract, and/or mixtures thereof; - at least one fermented red rice and/or its extract titrated in monacolin K and/or other sources of monacolin K and/or mixtures thereof; and/or mixtures thereof; (ii) sodium alginate; and (iii) calcium lactate.

Description

MODIFIED-RELEASE GRANULATE OF ACTIVE INGREDIENTS AND/OR NUTRITIONAL INGREDIENTS AND METHODS OF MAKING

The present invention has as its object a modified-release granulate of active ingredients and/or nutritional ingredients and pharmaceutical compositions and/or dietary supplements comprising said granulate. The invention also relates to a combination comprising or consisting of said active ingredients and/or nutritional ingredients, sodium alginate and calcium lactate.

BACKGROUND OF THE INVENTION

The granulation technique is a process widely used in the pharmaceutical and dietary supplement industries to convert active ingredients/nutritional ingredients in powder form into uniformly sized granules or agglomerates. In the pharmaceutical industry as well as in the dietary supplement industry, this technique is of utmost importance for several reasons:

- improved bioavailability: granulation can improve bioavailability of active ingredients/nutritional ingredients in drug/food supplements. This is particularly important for drug/food supplements that would otherwise have low bioavailability in addition to being difficult to absorb in the body;

- dosage control: granules allow more precise dosing of active ingredients/nutritional ingredients in drugs/food supplements than powders. This is crucial to ensure that each dose contains the exact amount of active ingredient/nutritional ingredient needed for treatment;

- dust reduction: dust can be inhaled and can be harmful to pharmaceutical industry workers. Granulation reduces the production of fine dust, improving workplace safety;

- improved stability: granulation can improve the stability of drugs/food supplements by protecting the active ingredients/nutritional ingredients from degradation caused by moisture or oxidation.

- ease of mixing: granules are easier to mix with other formulation ingredients, such as excipients, dyes or additives, to create complex formulations.

Granulation techniques used in the pharmaceutical and dietary supplement industries include wet granulation, dry granulation and spray granulation.

Wet granulation is a process where the drug/dietary supplement components are mixed with a liquid to form a wet mass which is then granulated. This method is widely used because it offers precise control over the size and distribution of the granules.

Dry granulation is a process that involves compressing dry powders to form granules. This method is suitable for materials that are sensitive to moisture or heat.

In spray granulation, a liquid solution containing the active ingredient/nutritional ingredient is sprayed onto a mixture of powders, creating granules as the liquid evaporates. This method is effective for obtaining uniform and stable granules.

Therefore, granulation techniques are crucial in the pharmaceutical and dietary supplement industries because they enable improved quality, stability, and efficacy of drugs/food supplements, as well as facilitate their production and precise dosing.

According to the definition of the Official Pharmacopoeia, 12th Ed., granulate is a solid preparation consisting of solid, dry aggregates of powder particles, sufficiently resistant to vigorous manipulation and intended for oral administration. The granulate contains one or more active ingredients with or without excipients and, if necessary, authorized dyes or flavoring substances. They may be swallowed as such, chewed or dissolved or dispersed in water or other suitable liquid before administration.

A particular type of granulate that can be produced is a modified release granulate, useful for administering active ingredients and/or nutritional ingredients, in a controlled manner, into the human body.

Modified release granulates are granulates, which can be coated or uncoated, which contain special granulation ingredients and/or which are prepared with special processes such as to modify the speed with which and/or the site in which and/or the time at which and/or the time during which, the active ingredient and/or nutritional ingredient is released. Modified release granulates include prolonged release granulates and delayed release granulates. Prolonged-release granulates allow a controlled and prolonged release over time, of a useful, acceptable and effective amount for the treated subject of active ingredients and/or nutritional ingredients. They simplify the administration schedule to the patient by reducing the amount of recommended daily intakes, improve patient compliance and reduce adverse events, for example those related to high plasma peaks, thereby ensuring a more regular plasma concentration over a few hours or the day.

Prolonged -release granulates are known in the art. Typical materials usually used to obtain a prolonged-release are, for example, ethylcellulose, methylcellulose, hydroxypropylcellulose, cellulose acetate, polyvinyl acetate, poly acrylates, polymethacrylate copolymers and ammonium methacrylates.

Delayed-release granulates allow the release of the active ingredient and/or nutritional ingredient to be delayed with respect to the time of intake of the drug/food supplement. Enteric-coated granulates, useful when the active ingredient and/or nutritional ingredient damages the lining of the gastric wall or decomposes in an acidic environment, are a typical example of delayed-release granulates and are prepared so that they resist gastric fluid and release (in a more or less rapid way) the active ingredient and/or nutritional ingredient into the intestinal fluid. These properties are typically achieved by coating the granulates with a gastro-resistant substance (enteric-coated granulates).

The materials used for enteric coatings include wax, plastics or vegetable fibres, such as starch. Other materials used are certain types of shellac and fatty acids. Most materials used for enteric coatings are artificial or natural polymers and do not decompose below pH levels of 5.5. Conventional materials used are film-forming resin solutions. However, since the solvents for these solutions are organic solvents, there is concern about the potential toxicity of trace amounts of residual solvents in the coating. In filming processes that do not require organic solvents (water-based filming), the presence of a plasticizer (in amounts usually 10-20%) is required.

Prolonged -release granulates, including enteric-coated ones (prolonged and delayed release granulates), are known. They often require complex manufacturing processes involving complex combinations of formulation ingredients, which typically include, in addition to release-modifying agents, binders and fillers so as to achieve structurally stable granulates that at the same time have prolonged release with the desired profile. Such manufacturing processes often require the use of organic solvents and/or the use of inert cores, and enteric coating typically requires either the use of organic solvents or the use of a plasticizer. Often the materials used to make the enteric coating, for example when based on acrylic resins, are exogenous substances that, while soluble at gut pH, are not biologically degradable.

The technical problem that the present invention addresses and solves is that of providing a prolonged - and delayed-release granulate that is advantageous compared to the granulates of the prior art. The Applicant, as a result of intensive research, has developed a prolonged and delayed release granulate that is structurally stable, resistant to degradation due to humidity, heat, oxidation, easily manipulated, suitable for a wide heterogeneity of active principles/nutritional ingredients and which requires, for its production, the use of only two granulation ingredients, sodium alginate and calcium lactate, properly combined in the appropriate percentages and ratios, and applied in a specific sequence in a simple, highly reproducible process that does not require the use of organic solvents.

Advantageously, the prolonged and delayed release granulate of the invention, in addition to allowing the slow and gradual release of a wide heterogeneity of active ingredients/nutritional ingredients at the level of the intestinal fluid, can be used not only in common pharmaceutical/nutritional supplement forms (such as chewable or swallowable tablets capsules, sachets containing powder/granule mixtures that are orosoluble or to be dissolved in water or other liquid), but also in gummy candies that involve cooking steps at high temperatures (> 60°C) and are therefore more susceptible to degradation.

In addition, the prolonged and delayed release granulate of the invention also possesses, should the active ingredient or nutrient have an unpleasant taste to the palate, taste masking activity that can improve the compliance of the granulate itself when delivered in chewable or orosoluble pharmaceutical/food forms.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a modified release granulate, particularly a prolonged and delayed- release granulate, based on a wide heterogeneity of active principles /nutritional ingredients.

Preferably, said granulate comprises or, alternatively, consists of: at least one active ingredient/nutritional ingredient selected from the group comprising or, alternatively, consisting of:

- at least one vitamin, in particular: one vitamin A and/or at least one vitamin D, including vitamins D2, D3 and/or mixtures thereof; and/or one vitamin C and/or one or more natural extracts comprising vitamin C; and/or at least one vitamin of the B group, including vitamins B1, B2, B3, B6, B12, pantothenic acid (e.g., vitamin B5), folic acid (e.g., vitamin B9, biotin (e.g., vitamin B8), and/or mixtures thereof; and/or one vitamin E; and/or a mixture of said vitamins;

- at least one mineral, especially iron and/or magnesium and/or salts or complexes and/or mixtures thereof;

- at least one amino acid, particularly Leucine, Valine, Isoleucine, Methionine, Histidine, Lysine, Phenylalanine, Threonine, Tryptophan, and/or mixtures thereof;

- at least one dry extract titrated in polyphenols, such as a green tea extract and a red vine extract, and/or mixtures thereof;

- at least one fermented red rice and/or its extract titrated in monacolin K and/or other source of monacolin K and/or mixtures thereof; and/or mixtures thereof; and ii) sodium alginate; and ill) calcium lactate.

Preferably, said at least one mineral, particularly iron and/or magnesium and/or salts or complexes and/or mixtures thereof, may for example be selected preferably from iron bis-glycinate and/or magnesium bis-glycinate, iron sulfate, magnesium oxide or magnesium citrate, or mixtures thereof.

Preferably, said at least one dry extract titrated in polyphenols, such as a green tea extract and/or a red vine extract, and/or mixtures thereof, may for example preferably be selected from a green tea leaf extract PE 95% POLY.UV/60% CATEC, HPLC/30% EGCG HPLC; e.g., Tea plant (Camellia sinensis (L.) Kuntze, syn Thea sinensis L, Thea viridis /..); leaves; preferably, spray drying extraction process; extraction solvent 100% water; purification solvent ethyl acetate; yield: 1 kg of product is obtained from about 9 kg of green tea leaves); preferably, said green tea extract has a bulk density of 0.30 to 0.70 g/ml; preferably, Loss on drying less than or equal to 8%; particles less than 70 Mesh (200 microns) greater than or equal to 95%; caffeine less than or equal to 8%; total polyphenols greater than or equal to 95%; Epigallocatechin gallate (EGCG) greater than or equal to 30%; Catechins greater than or equal to 60%.

Preferably, said at least one dry extract titrated in polyphenols, such as a green tea extract and/or a red vine extract, and/or mixtures thereof, may for example preferably be selected from a 95% grape seed extract, Vitis Vinifera L, ethanol/water solvent; proanthocyanidins (UV) greater than or equal to 95%; polyphenols (UV F-C) greater than or equal 80%; preferably Loss on drying less than or equal to 5%; particle size greater than or equal to 95% through 80 Mesh.

Preferably, said at least one fermented red rice and/or its extract titrated to monacolin K and/or other source of monacolin K and/or mixtures thereof, may, for example, preferably be selected from a fermented red rice extract (Rice (Oryza sativa L.) fermented by Monascus purpureus Went.) having a total monacolin K (HPLC) of about NLT 3% and a total monacoline (HPLC) of about NMT 4.5%, preferably Loss on drying of about NMT 5% and a bulk density of 420 to 520 g/l, and preferably a maltodextrin as carrier.

In a second aspect, the present invention provides a process for the preparation of a granulate of the invention, wherein said process comprises the following steps: a. a wet granulation of a mixture comprising or, alternatively, consisting of i) at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, II) sodium alginate, and ill) calcium lactate, to form granules intended to be coated; b. a coating of the granules obtained from step (a) through two sequential steps: b'. a granulation of the granules obtained from step (a) with calcium lactate; and b". a granulation of the granules obtained from step (b¹) with sodium alginate.

Preferably, the present invention provides a process for preparing a granulate of the invention, wherein said process comprises the following steps: a. a first wet granulation, preferably in a High Shear Mixer type granulator (e.g., Diosna), of a mixture comprising or alternatively consisting of I) at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, ii) sodium alginate, and ill) calcium lactate, to form granules intended to be coated; b. a second granulation, preferably wet in Fluid Bed (e.g. Glatt), of the granules obtained from step (a) through two sequential granulation steps or stages: b'. a granulation of granules obtained from step (a) with calcium lactate and sodium alginate; and b”. a granulation of the granules obtained from step (b¹) with sodium alginate.

The granulation process is carried out wet, preferably with the addition of water in a variable amount by weight, and not dry without the addition of water. Preferably, the coating process (b) involves, among other things, two sequential granulation phases or steps (b¹ and b").

Preferably, for an active ingredient such as, e.g., melatonin, or for a mixture of active ingredients such as, e.g., vitamins and/or amino acids, present in an amount less than 10% by weight, e.g., 0.1 % to less than 10%, preferably 4% or 8% by weight, relative to the total weight of the active ingredient or mixture of active ingredients, as well as sodium alginate and calcium lactate, it is preferred to prepare the granulates by a process involving (a) an initial wet granulation in High Shear Mixer granulator and (b) a second wet granulation, in Fluid Bed, of the granules, obtained in step (a), by two granulation steps or phases (b¹ and b"). For example, see Example 1 where step (a) involves the use of melatonin (99% titer) in an amount by weight of 2%, and sodium alginate 49% and calcium lactate 49% by weight, relative to the total weight.

Preferably, said process, in step (a), involves loading sodium alginate, e.g., about 49% by weight, melatonin, e.g., about 2% by weight, and calcium lactate (e.g., calcium lactate pentahydrate), e.g., about 49% by weight, into the High Shear Mixer granulator in that order. Then, preferably under agitation (impeller, fan or rotor), e.g., at 100-500 rpm, preferably 200-400 rpm, purified water is poured in flush just enough to obtain a homogeneous slurry. Once the water has been added, the chopper (cutting blades) is set to, for example, 1000 rpm and the impeller to, for example, 200 rpm for a time ranging from 1 to 15 minutes, for example 5 to 10 minutes. Once the kneading step is complete, the wet granulate is preferably passed through a mesh of, for example, 3 mm. Preferably, a drying phase follows where the granulate is placed, for example, in an oven at a temperature of between 40°C and 80°C, for example, at 60°C, for a time ranging from 2 to 12 hours, for example 8 hours. Preferably, a calibration step may follow through a 1.2 mm mesh.

Next, step (b) preferably involves granules obtained from step (a), described above, being wet granulated in Fluid Bed by a 2-step process (b¹ and b").

Specifically, the granules obtained in step (a) are loaded into the Fluid Bed, and to these are added an amount by weight of sodium alginate ranging from 0.1 % to 1 .5% by weight, preferably ranging from 0.4% to 1 % by weight, and an amount by weight of calcium lactate ranging from 0.5% to 3% by weight, preferably ranging from 1% to 2% by weight, relative to the total granule weight of step (a), sodium alginate and calcium lactate. Preferably, step b' involves granulation in a Fluid Bed (e.g., Glatt mod. Uniglatt). Preferably, the coating solution is obtained by solubilizing calcium lactate in water. Preferably, the coating step involves loading the granule obtained from step (a) into the Fluid Bed basket and spraying the coating solution by setting, by way of non-limiting example, the following parameters: Inlet air Temp. = 40°C - 45°C; Product Temp. = 27°C - 30°C; Spray pressure = 1.5 bar; Liquid flow rate = 15 - 20 g/ min; Airflow = Flap position 15. Preferably, the drying step can be set, for example, by adopting the following parameters: Inlet air Temp.= 60°C - 65°C; Product Temp.= 50°C - 55°C; Air flow = Flap position 15; LOD control = 6.5 - 7.5 %.

Subsequently step b" follows, which involves granulation in a Fluid Bed (e.g., Glatt mod. Uniglatt). Preferably, the coating solution is obtained by solubilizing sodium alginate in water. Preferably, the coating step involves loading the granulate obtained in step (b¹) into the Fluid Bed basket and spraying the coating solution by setting, by way of non-limiting example, the following parameters: Inlet air Temp. = 40°C - 45°C; Product Temp. = 27°C - 30°C; Spray pressure = 1.5 bar; Liquid flow rate = 15 - 20 g/ min; Air flow = Flap position 15. Preferably, the drying step can be set, for example, by adopting the following parameters: Inlet air Temp. = 60°C - 65°C; Product Temp. = 50°C - 55°C; Air flow = Flap position 15; LOD control = 6.5 - 7.5 %. Preferably, a granule calibration step follows through, for example, a 1.2 mm mesh. Preferably, a granule of the present invention is obtained having, for example, at least one of the following technological parameters:

Particle size distribution

Not more than 5 % > 1000 pm; and/or

Not more than 10 % > 710 pm; and/or

Not more than 80 % between >125 pm - < 710 pm; and/or

Not more than 25 % < 125 pm; and/or

LOD (70°C): 6.0 % - 15.0 %; and/or

Density: 0.4 - 0.8 g/ml; and/or

Flowability (100 grams): < 25 seconds.

Alternatively, the process for preparing the granulate of the invention may be carried out by a single Fluid Bed granulation of a mixture of i) at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, ii) sodium alginate, and iii) calcium lactate, followed by a single coating step, comprising the following phases: a. a wet granulation of a mixture comprising or, alternatively, consisting of said (i) at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, (ii) sodium alginate, and (iii) calcium lactate, to form granules intended to be coated through; b. a coating of granules obtained by passing (a) through a single coating step with a mixture of ii) sodium alginate and iii) calcium lactate, to form coated granules.

Preferably, the process of preparing the granules of the invention can be accomplished by a single granulation step in Fluid Bed of a mixture of i) at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, ii) sodium alginate and iii) calcium lactate, so as to achieve granule coating through a single granulation step with a mixture of ii) sodium alginate and iii) calcium lactate, to form coated granules.

The granulation process is carried out wet in Fluid Bed, preferably with the addition of water in a variable amount by weight, and not dry without the addition of water. Preferably, the coating process (b) involves, among other things, only one coating step or stage. Preferably, for an active ingredient such as, e.g., melatonin, or for a mixture of active ingredients such as, e.g., vitamins and/or amino acids, present in an amount greater than or equal to 10% by weight, e.g., 10% to 30%, preferably 15% to 20% by weight, relative to the total weight of the active ingredient or mixture of active ingredients, and sodium alginate and calcium lactate, it is preferred to prepare the granules by a process involving (a) wet granulation and (b) granule coating. For example, see Example 2 where step (a) involves the use of melatonin (99% titer) in an amount by weight of 10%, and sodium alginate 45% and calcium lactate 45% by weight, relative to the total weight.

Preferably, said process involves a single granulation step in a Glatt-type Fluid Bed with all ingredients and 40% purified water.

Preferably, said process involves a coating step or phase in which melatonin, e.g., about 10% by weight, sodium alginate, e.g., 45% by weight, and calcium lactate, e.g., 45% by weight, are loaded into the Fluid Bed basket and water, e.g., purified water, is sprayed by setting, by way of non-limiting example, the following parameters: Inlet air Temp. = 40°C - 45°C; Product Temp. = 27°C - 30°C; Spray pressure = 1.5 bar; Liquid flow rate = 15 - 20 g/ min; Air flow = Flap position 15.

Preferably, once the water wetting step is completed, drying can be carried out by setting, by way of non-limiting example, the following parameters: Inlet air temp. = 60°C - 65°C; Product temp. = 50°C - 55°C; Air flow = Flap position 15; LOD control = 6.5 - 7.5%.

Preferably, a granule calibration step follows through a 1.2 mm mesh.

Preferably, the granulate may have for example the following granulometry specifications: Not more than 10%: > 710 pm; 80% between 125 pm and 710 pm; Not more than 10 %: < 125 pm; LOD (70°C): 6.0 % - 8.0 %; Density: 0.4 - 0.6 g/ml; Flowability (100 grams): < 25 sec.

In a third aspect, the present invention relates to a combination consisting of: i) at least one active ingredient /nutritional ingredient selected from the group comprising or, alternatively, consisting of:

- at least one vitamin, in particular: a vitamin A and/or at least one vitamin D, including vitamins D2, D3 and/or mixtures thereof; and/or a vitamin C and/or one or more natural extracts including vitamin C; and/or at least one vitamin of the B group, including vitamins B1 , B2, B3, B6, B12, pantothenic acid, folic acid, biotin, and/or mixtures thereof; and/or a vitamin E; and/or a mixture of said vitamins;

- at least one mineral, in particular iron and/or magnesium and/or their salts or complexes and/or mixtures thereof;

- at least one amino acid, in particular Leucine, Valine, Isoleucine, Methionine, Histidine, Lysine, Phenylalanine, Threonine, Tryptophan and/or their mixtures;

- at least one fermented red rice and/or its extract titrated in monacolin K and/or another source of monacolin K and/or mixtures thereof; and/or mixtures thereof; and ii) sodium alginate; and ill) calcium lactate.

In a fourth aspect, the present invention provides a pharmaceutical and/or food composition comprising the modified release granulate of the invention, together with one or more conventional excipients and/or vehicles. Said composition is preferably for oral use. Preferably, said composition is in the form of a gummy candy.

The Applicant has found that the granulate of the invention, obtained by wet granulation, as defined above:

- is structurally stable;

- is resistant to degradation due to humidity, heat, oxidation, acid environment;

- is easily manipulated in a safe manner for operators;

- is suitable for a wide heterogeneity of active ingredients/nutritional ingredients;

- it allows to obtain a prolonged and delayed release of a wide heterogeneity of active ingredients /nutritional ingredients, or the slow and gradual release of a wide heterogeneity of active ingredients /nutritional ingredients at the level of the intestinal fluid, thus avoiding both damage to the lining of the gastric wall and/or problems of gastric reflux and/or decomposition in an acid environment as well as side effects/adverse events related to high plasma peaks, ensuring a more regular plasma concentration over a few hours or a day with high tolerability;

- it allows to simplify the administration scheme to the subject/patient by reducing the quantity of recommended daily intakes, improving the compliance of the subject/patient;

- it requires, for its production, the use of only two granulation ingredients, sodium alginate and calcium lactate, properly combined, in the appropriate percentages and ratios, and applied in a specific sequence, in a simple and economical process, being highly reproducible and which does not require the use of organic solvents;

- it can be used not only in common pharmaceutical/food forms (such as chewable or swallowable tablets, capsules, sachets containing mixtures of orosoluble powders/granules or to be dissolved in water or other liquid), but also in forms, such as gummy candies, which require cooking phases at high temperatures (> 60°C) and are therefore more sensitive to thermal degradation;

- it also has, if the active ingredient or nutrient has an unpleasant taste to the palate, a taste masking activity capable of improving the compliance of the granulate itself when it is conveyed in chewable or orosoluble pharmaceutical/food forms.

The granulate and/or compositions of the invention, therefore, are envisaged as particularly advantageous for ingredients that increase their activity if released in the intestine (delayed release) and that are advantageously administered slowly and gradually over time (prolonged release).

These and other objects, which will be apparent from the detailed description that follows, are achieved by the modified-release granulate of the invention and/or compositions containing it, due to the technical features claimed in the appended claims.

DESCRIPTION OF THE FIGURES

Figure 1 refers to the release of vitamin C as a function of the intensity of the vitamin C peak expressed in pi V over time. DETAILED DESCRIPTION OF THE INVENTION

The Applicant, after a long and intense research and development activity, has developed a modified-release granulate, in particular a prolonged and delayed-release, based on a wide heterogeneity of active ingredients /nutritional ingredients, resistant to degradation due to humidity, heat, oxidation, acid environment, with taste masking activity, easy to produce, easy to formulate and/or administer, free from side effects and/or with high tolerability.

The granulate of the invention is particularly advantageous for the ingredients/nutrients that increase their activity if released in the intestine (delayed release) and which, advantageously, are administered slowly and gradually over time (prolonged release).

In a first aspect, the present invention provides a modified release granulate, in particular prolonged and delayed release, based on a wide heterogeneity of active ingredients/nutritional ingredients, wherein said granulate comprises or, alternatively, consists of:

I) at least one active ingredient /nutritional ingredient selected from the group comprising or, alternatively, consists of:

- at least one vitamin, in particular: a vitamin A and/or at least one vitamin D, including vitamins D2, D3 and/or mixtures thereof; and/or a vitamin C and/or one or more natural extracts comprising vitamin C; and/or at least one vitamin of the B group, including vitamins B1 , B2, B3, B6, B12, pantothenic acid, folic acid, biotin, and/or mixtures thereof; and/or a vitamin E; and/or a mixture of said vitamins;

- at least one amino acid, in particular Leucine, Valine, Isoleucine, Methionine, Histidine, Lysine, Phenylalanine, Threonine, Tryptophan and/or mixtures thereof;

- at least one dry extract titrated in polyphenols, such as a green tea extract and a red vine extract, and/or mixtures thereof; and

- at least one fermented red rice and/or its extract titrated in monacolin K and/or another source of monacolin K and/or mixtures thereof; and/or mixtures thereof; ii) sodium alginate; and ill) calcium lactate.

The granulate of the present invention comprises I) at least one active ingredient /nutritional ingredient and/or mixtures of active ingredients /nutritional ingredients.

The granulate of the present invention may comprise a vitamin A, a fat-soluble vitamin that can advantageously be administered with prolonged and delayed release at the level of the intestinal fluid.

The granulate of the present invention may comprise at least one vitamin D, including vitamins D2, D3 and/or mixtures thereof. Vitamin D (group of fat-soluble prohormones) can advantageously be administered with prolonged and delayed release at the level of the intestinal fluid.

The granulate of the present invention may comprise a vitamin C and/or a natural extract comprising vitamin C and/or mixtures thereof.

Preferably, vitamin C is included in the form of a natural extract comprising vitamin C, for example a dry extract of Rosa Canina with a vitamin C content of 50% or 25% and/or a dry extract of Acerola with a vitamin C content of 25%.

Vitamin C (or L-ascorbic acid) is an organic compound with antioxidant properties present in nature; while in the metabolism of most mammals this principle is synthesized autonomously, humans need to take it through food. Vitamin C is an ingredient particularly unstable to oxidation, has a very acidic pH and a high intake of vitamin C can cause side effects: gastrointestinal disorders (hyperacidity, diarrhea, abdominal cramps), formation of kidney stones.

The modified release granulate of the invention, thanks to the gelatinous coating formed by calcium lactate and sodium alginate, which give rise to a gelatinous coating comprising calcium alginate, described in more detail below, helps to overcome these drawbacks for the following reasons:

- it forms a protective shell that prevents the oxidation and degradation of vitamin C;

- it prevents the interaction between vitamin C and gastric mucosa and the side effects related to its strong acidity;

- it reduces the renal load determined by high immediate intakes of vitamin C: vitamin C is particularly water-soluble and therefore rapidly absorbed.

The immediate absorption of high quantities of vitamin involves an excessive workload for the kidneys which are responsible for excreting excess vitamin C. A gradual release of vitamin C therefore determines a better distributed absorption of the same over time and fewer side effects at renal level.

The granulate of the present invention may comprise at least one vitamin of the B group, including vitamins B1 , B2, B3, B6, B12, pantothenic acid, folic acid, biotin, and/or mixtures thereof.

B vitamins are a water-soluble group of vitamins and advantageously can be administered with prolonged and delayed release at the level of the intestinal fluid.

The granulate of the present invention may comprise a vitamin E being a powerful fat-soluble antioxidant and can advantageously be administered with prolonged and delayed release at the level of the intestinal fluid.

The granulate of the present invention may comprise at least one mineral, in particular iron and/or magnesium and/or their salts or complexes and/or mixtures thereof.

Preferably, said at least one mineral, in particular iron and/or magnesium and/or their salts or complexes and/or mixtures thereof, can for example be preferably selected from iron bis-glycinate and/or magnesium bis-glycinate, iron sulphate, magnesium oxide or magnesium citrate, or mixtures thereof.

The granulate of the present invention can comprise at least one amino acid, in particular Leucine, Valine, Isoleucine, Methionine, Histidine, Lysine, Phenylalanine, Threonine, Tryptophan and/or mixtures thereof.

Amino acids and iron and magnesium salts are known in the galenic art for their particularly unpleasant taste; therefore, they are usually not used in chewable or orosoluble compositions.

The modified-release granulate of the invention, by exercising a taste-masking action, allows said unpleasant- tasting ingredients to be used even in chewable or orosoluble compositions.

Furthermore, the delayed release of said ingredients means that they are not immediately released into the stomach, but into the intestine, which is the site where they are optimally absorbed.

The granulate of the present invention may comprise at least one dry extract titrated in polyphenols, such as a green tea extract and a red vine extract, and/or mixtures thereof. For example, the dry extract titrated in polyphenols is a green tea extract with a polyphenol content of 50% or 98% and/or a red vine extract with a polyphenol content of 95%.

Preferably, said at least one dry extract titrated in polyphenols, such as a green tea extract and/or a red vine extract, and/or mixtures thereof, may for example be selected preferably from a green tea leaf extract PE 95% POLY.UV/60% CATEC, HPLC/30% EGCG HPLC; for example, Tea plant (Camellia sinensis (L.) Kuntze, syn Thea sinensis L, Thea viridis L); leaves; preferably spray drying extraction process; extraction solvent 100% water; purification solvent ethyl acetate; yield: 1 kg of product is obtained from approximately 9 kg of green tea leaves); preferably, said green tea extract has a bulk density of between 0.30 and 0.70 g/ml; preferably Loss on drying less than or equal to 8%; particles less than 70 Mesh (200 microns) greater than or equal to 95%; caffeine less than or equal to 8%; total polyphenols greater than or equal to 95%; Epigallocatechin gallate (EGCG) greater than or equal to 30%; Catechins greater than or equal to 60%.

Preferably, said at least one dry extract titrated in polyphenols, such as a green tea extract and/or a red vine extract, and/or mixtures thereof, may for example be selected from a 95% grape seed extract, Vitis Vinifera L, solvent ethanol/water; proanthocyanidins (UV) greater than or equal to 95%; polyphenols (UV F-C) greater than or equal to 80%; preferably Loss on drying less than or equal to 5%; particle size greater than or equal to 95% through 80 Mesh.

Extracts rich in polyphenols are natural antioxidants and may advantageously be administered with prolonged and delayed release at the level of the intestinal fluid.

The granulate of the present invention may comprise at least one fermented red rice and/or its extract titrated in monacolin K and/or another source of monacolin K and/or mixtures thereof.

Preferably, said at least one fermented red rice and/or its extract titrated in monacolin K and/or another source of monacolin K and/or mixtures thereof, may for example be selected preferably from a fermented red rice extract (Rice (Oryza sativa L.) fermented by Monascus purpureus Went.) having a total of monacolin K (HPLC) of about NLT 3% and a total of monacolins (HPLC) of about NMT 4.5%, preferably Loss on drying of about NMT 5% and an apparent density of 420 to 520 g/l, and preferably a maltodextrin as carrier.

Monacolin is a natural molecule present in red rice yeast extract and is mainly known for its hypocholesterolemic properties, i.e. the ability to lower blood cholesterol levels. The best-known and most studied monacolin is monacolin K.

Red rice is known in the galenic technique for its particularly unpleasant/bitter taste; therefore, they are usually not used in chewable or orosoluble compositions.

The modified-release granulate of the invention, by exerting a taste-masking action, allows said unpleasant-tasting ingredients to be used even in chewable or orosoluble compositions.

Monacolin K is also a chemical molecule sensitive to high temperatures, light and humidity.

At very high temperatures, such as those required during the production process of a gummy candy, monacolin degrades very quickly.

As will be further detailed in the experimental section that follows, it is possible to formulate the modified release granulate of the present invention also in forms, such as gummy candies, which involve cooking steps at high temperatures (> 60°C) without degrading the heat-sensitive active ingredients/nutritional ingredients present, such as monacolin K.

The granulate of the present invention also comprises ii) sodium alginate and iii) calcium lactate as the only granulation ingredients (in addition to water, used as the only solvent). Alginates are linear copolymers of natural origin extracted from the cell wall of brown algae Laminaria and Ascophillum. Alginates from algae must undergo a series of treatments before they can be effectively used for applications where their high purification is required. Since the alginate salts found in algae are insoluble, their transformation into, for example, sodium alginate, or other soluble salts of alginic acid is necessary.

Alginates encounter considerable application interest primarily because of their ability to form polymeric gels in the presence of bivalent cations (e.g., Ca2+). The application interest in alginates stems mainly from their ability to form gels, wherein the study of the gelation process assumes paramount importance.

A gel is a solid consisting of a three-dimensional network of molecules held together by junction zones (of a physical or chemical nature), to form a solid phase in which the dispersed liquid medium remains incorporated. The network gives the gel the characteristic properties of a solid, while the liquid phase controls its density. These polymers, placed in solution in the presence of divalent cations, induce the establishment of ionic bonds between the different polymer chains, promoting a sol-gel transition.

Divalent cations bind, first, to G groups until the available binding sites are saturated. Next, bonds with M-groups, consisting of monomeric units of mannuronic acid, proceed (at least at the macroscopic level and, especially, when neighboring units consist of G-residues) until the association of the chains is limited by the network. The explanation for this observation lies in the different ability of the M and G blocks to form junction zones with divalent cations. The latter are both polyanionic and will form intermolecular anionic bonds with divalent cations. However, G blocks are also able to chelate divalent cations due to their spatial organization, forming a binding site between two adjacent G blocks and thus giving rise to a stronger interaction. This forms dimeric junctions rather than aggregates. Hence the "egg-box” model that takes its name from the characteristic shape of the molecular structure that is created.

Furthermore, a relative scale of affinity with alginate was established for several divalent cations of interest: Pb2+>Cu2+>Cd2+>Ba2+>Sr2+>Ca2+>Co2+=Ni2+=Zn2+>Mn2+>Mg2+.

The Applicant selected sodium alginate among all soluble alginate salts and, after many attempts, found it useful to combine sodium alginate with a soluble salt of a Ca2+.

Among all possible bivalent cations, the Applicant selected Ca2+, both according to affinity and taking into account safety. Among all soluble Ca2+ salts, the choice was made in favor of calcium lactate.

When using alginate gels, one of the main problems is the low chemical stability. Substances with a high affinity for the latter (such as phosphates or citrates) can sequester calcium ions and destabilize the initial gel. The gel may also be destabilized by the presence of other non-gelling cations. For these reasons, the choice of calcium lactate does not appear obvious but is rather the result of careful selection reasoning that takes into account the chemical-physical properties of calcium lactate itself and of the other components present in the composition of the granulate (sodium alginate and at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients) being object of the present invention. Among all possible calcium salts, calcium lactate was selected because of a number of characteristics that make calcium lactate the salt of choice for the preparation of granulate of at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, which are the object of the present invention: I) good solubility in water; II) pH of the 5% solution of calcium lactate in water in the range of 6 to 8; ill) Ca2+ titer in the range of 12% to 18%, preferably in the range of 13.4% to 14.5%.

The other possible calcium salts were excluded either because they are insoluble in water (e.g., calcium carbonate) or because they are poorly soluble (e.g., calcium citrate) or because, although soluble, once dissolved in water they result in a pH value that is incompatible with the other two ingredients in the granulate composition (at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients and sodium alginate).

The choice could also have fallen on a salt formed by the binding of lactic acid with a bivalent cation that is just as "safe” as Ca2+, namely Mg2+. The salt formed when lactic acid binds the bivalent cation Mg2+ is magnesium lactate. Magnesium lactate turns out to be very similar to calcium lactate in terms of its chemical and physical characteristics:

- good solubility in water;

- pH of 5% calcium lactate solution in water: 6.5-8.5;

- Mg titer: 10.0% - 10.5%.

However, magnesium lactate, while having similar chemical and physical characteristics to calcium lactate, is not believed to be a viable candidate, equivalent to calcium lactate in terms of functionality within the modified-release granulate of the invention, because the Mg2+ ion does not have gelling properties equal to those of the Ca2+ ion in an acidic environment. This has been confirmed experimentally by preparing a granulate based on melatonin, sodium alginate and calcium lactate and comparing the gelling properties in an acidic environment with those of a granulate based on melatonin, sodium alginate and magnesium lactate.

All the components of the granulate of the invention are known to the art and available on the market. Preferably, the granulate of the invention comprises from 1 % to 80% by weight, with respect to the total weight of the granulate, of said at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients.

Preferably, the granulate of the invention comprises from 5% to 60% by weight, with respect to the total weight of the granulate, of sodium alginate preferably from 20% to 50%.

Preferably, the granulate of the invention comprises from 5% to 60% by weight, with respect to the total weight of the granulate, of calcium lactate preferably from 20% to 50%.

Preferably, the granulate of the invention comprises:

- from 1 % to 80% by weight, with respect to the total weight of the granulate, of said at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients; and

- from 5% to 60% by weight, with respect to the total weight of the granulate, of sodium alginate preferably from 20% to 50%; and

- from 5% to 60% by weight, with respect to the total weight of the granulate, of calcium lactate preferably from 20% to 50%.

Preferably, in the granulate of the invention the weight ratio between sodium alginate and calcium lactate varies in the range from 0.5:2 to 2:0.5 (1 :4 to 4: 1), preferably included from 1 :2 to 2; 1, being preferably equal to about 1 : 1. According to another of its aspects, the invention has as its object a process for the preparation of the granulate of the invention which comprises or, alternatively, consists of the following steps: a. a wet granulation of a mixture comprising or, alternatively, consisting of said at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, sodium alginate and calcium lactate, to form granules intended to be coated; b. a coating of the granules obtained from step (a) through two sequential steps: b'. a granulation of the granules obtained from step (a) with calcium lactate; and b”. a granulation of the granules obtained from step (b’) with sodium alginate.

Preferably, in said step a., from 1 % to 80% by weight, with respect to the total weight of the granulate, of said at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients; from 5% to 60% by weight, with respect to the total weight of the granulate, of sodium alginate, preferably from 20% to 50%; and from 5% to 60% by weight, with respect to the total weight of the granulate, of calcium lactate, preferably from 20% to 50% are used.

Preferably, in said step b'., from 0.1 % to 2% by weight, with respect to the total weight of the granulate, of calcium lactate is used, preferably from 0.2% to 1 %.

Preferably, in said step b”., 0.1 % to 2% by weight, with respect to the total weight of the granulate, of sodium alginate is used, preferably 0.2% to 1 %.

In step (a), a wet granulation is carried out by mixing, preferably, 1 % to 80% by weight, with respect to the total weight of the granulate, of said at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, with 5% to 60% by weight, with respect to the total weight of the granulate, of sodium alginate, and with 5 to 60% by weight, with respect to the total weight of the granulate, of calcium lactate and water, according to known techniques.

The granules obtained in step (a) are dried, for example in an oven, preferably at a temperature of 40°C to 80°C, more preferably from 50°C to 70°C, for example at 60°C and for a time preferably between 2 hours and 12 hours, more preferably from 4 hours to 10 hours, for example 8 hours. Preferably, the dried granules are subjected to a calibration phase using for example a net or sieve with mesh sizes of 0.5 mm to 2.5 mm, preferably from 1 mm to 2 mm, for example 1 .2 mm, or 1 .4 mm, or 1 .6 mm.

These dried granules, coming from step (a), are then covered by step (b) through two subsequent granulations (b’) and (b”); first the granules are treated with calcium lactate, preferably from 0.1 % to 2% by weight, with respect to the total weight of the granulate, in step (b’) to obtain granules coated with calcium lactate, then the latter are further coated with sodium alginate, preferably from 0.1 % to 2% by weight, with respect to the total weight of the granulate, of sodium alginate, in step (b”). The granules obtained after granulation in each of steps (a), (b’) and (b”) are dried according to known techniques.

According to a preferred embodiment, the granulations of steps (b) are fluid bed or slurry granulations.

Alternatively, the process of preparing the granulate of the invention may be carried out by a single granulation of a mixture of at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, sodium alginate and calcium lactate, followed by a single coating step, comprising the following steps: a. a wet granulation of a mixture comprising or, alternatively, consisting of said at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, sodium alginate and calcium lactate, to form granules intended to be coated; b. a coating of the granules obtained by phase (a) through a single coating step with a mixture of sodium alginate and calcium lactate, to form coated granules.

Preferably, in said step a., 1 % to 80% by weight, relative to the total weight of the granules, of said at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients; 5% to 60% by weight, relative to the total weight of the granules, of sodium alginate, preferably 20% to 50%; and 5% to 60% by weight, relative to the total weight of the granules, of calcium lactate, preferably 20% to 50%; and in said step b., an aqueous mixture comprising from 0.1 % to 2% by weight, relative to the total weight of the granules, of sodium alginate, preferably from 0.2% to 1 %; and from 0.1 % to 2% by weight, relative to the total weight of the granules, of calcium lactate, preferably from 0.2% to 1 %, is used.

According to a preferred embodiment, the granules have a size ranging from 0.8 mm to 1 .5 mm, preferably ranging from 1 mm to 1.4 mm.

Some details of the method of the present invention are provided in the Experimental Section that follows, for purely illustrative purposes.

The granulate of the invention allows obtaining a prolonged and delayed release of a wide heterogeneity of active ingredients/nutritional ingredients, or the slow and gradual release of a wide heterogeneity of active ingredients/nutritional ingredients at the level of the intestinal fluid.

Said granulate can be used as such, for example it can be included in gelatin capsules.

Preferably, the granulate of the invention can be used for the preparation of pharmaceutical compositions and food supplements with modified release of at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients.

According to a further aspect, the invention also has as its object a pharmaceutical and/or food composition that comprises the modified-release granulate of the invention, together with one or more conventional excipients and/or vehicles. Said composition is preferably for oral use. Preferably, said composition is in the form of chewable or swallowable tablets, capsules, sachets containing mixtures of powders/granules that are orosoluble or dissolve in water or other liquid, chewing gum or gummy sweets. Even more preferably, said composition is in the form of gummy candies.

The modified-release granulate of the present invention, in addition to being stable to degradation due to humidity, oxidation, acidic environment, is stable to heat. Therefore, it is possible to formulate the modified-release granulate of the present invention also in forms, such as gummy sweets, which involve cooking phases at high temperatures (> 60°C) without degrading any thermosensitive active ingredients/nutritional ingredients present.

Gummy candies are traditionally accepted by the public. Their chewiness allows for the use of even high doses of active ingredients, without having to be swallowed whole.

Consider that a swallowable tablet can weigh up to 1.8 grams, while a "gummy” form of administration can weigh up to 8 grams. The chewable composition is particularly suitable for patients with dysphagia and swallowing problems, both young and old.

The components for preparing a gummy candy are well known to the expert in the sector. For example, a gummy candy can be made using the following excipients of the gummy matrix: glucose syrup, sugar, water, edible gelatine, acidifier: citric acid, flavourings, colourings: E120, E131 , E161b.

Furthermore, the formulation of the gummy base or matrix affects the release rate: by varying the formulation of the gummy matrix of a gummy candy, a further prolonged release characteristic can be conferred which is added to that of the modified release granulate of the invention. For example, the Applicant has verified that the addition of starch to the matrix formulation, ceteris paribus, further slows down the release kinetics of the active ingredients /nutritional ingredients present in the granulate of the invention. The maximum amount of starch to be added can reach up to 8%, preferably up to 5%; the minimum amount is the one effective for delaying the release kinetics. For the preparation of the preferred compositions of the invention, the granulate of the invention can be mixed with excipients known to the ones skilled in the art for the production of gummy candies, chewable tablets, capsules or chewing gum. For example, for the preparation of gummy candies, sugars, including glucose syrup, modified starches, gelatins, pectins, water, vegetable oils can be used and conventional flavourings, colourings and coating agents can also be added.

Alternatively, the compositions of the invention may be in the form of tablets, hard capsules, soft capsules, granules, fine granules, powders, tablets, syrups, emulsions, suspensions and solutions suitable for oral administration. Other suitable pharmaceutical/food forms may also be used.

Such compositions may be taken alone, for example, when in the form of gummy sweets, chewable tablets or chewing gum, or with water when in the form of capsules or, especially when in the form of powders or granules, they may be mixed with other foods, for example with yoghurt, creams, gels and the like.

Alternatively, the compositions of the invention may be in a ready-to-use drinkable form, such as for example in the form of drinking sachets, of the "stick pack” type, in this case preferably in the form of cream or gel.

In addition to those already mentioned, the types of pharmaceutical and food additives used for the preparation of the compositions of the invention, the ratios of contents of the additives to the active ingredients and the methods for preparing the pharmaceutical composition or the food supplement, can be appropriately selected by the person skilled in the art.

For conventional vehicles and excipients, organic or inorganic substances, or solid or liquid substances can be used as excipients and vehicles, provided that they are edible, physiologically acceptable, and compatible with all the other components of the composition. As mentioned, the person skilled in the art is perfectly able to select the most suitable vehicles and excipients for the preparation of the composition.

By way of example, organic or inorganic substances, or solid or liquid substances may be used as excipients and vehicles, provided that they are edible and pharmaceutically acceptable. Examples of excipients used for the preparation of solid pharmaceutical/food compositions include for example lactose, sucrose, starch, talc, cellulose, dextrins, kaolin, calcium carbonate, stearic acid or magnesium stearate, lactose, polyethylene glycol, mannitol, sorbitol, chelating agents, anti-caking agents, sweetening agents, preservatives and flavouring agents. For the preparation of liquid compositions for oral administration, a conventional inert diluent such as water or an oil, for example a vegetable oil, may be used. The liquid composition may contain in addition to the inert diluent, auxiliaries such as wetting agents, suspending agents, sweeteners, flavourings, colourings and preservatives. The liquid composition may be included in capsules of an absorbable material, such as gelatin.

Sweeteners may be one or more natural sugars, optionally reduced, such as sucrose, dextrose, xylitol, mannitol or sorbitol, or a synthetic product such as sodium saccharin, aspartame, acesulfame K or sucralose. Acidifying agents may also be added.

Flavouring agents are aromas and flavours, acceptable from a pharmaceutical point of view, of synthetic oils or natural oils, the latter being extracted from plants, flowers, fruits and combinations thereof, such as cinnamon, mint, anise, and citrus leaves, bitter almonds, citrus fruits, in particular orange and/or lemon oils, lime, vanilla, chocolate and grapefruit. Advantageously, chocolate, vanilla or eucalyptus flavours and fruit essences, in particular apple, pear, peach, strawberry, apricot, orange, lemon and grape, may also be used.

Examples of compositions of the invention are provided in the Experimental Section below, for illustrative purposes only.

The granulate and/or compositions of the invention are non-toxic and are intended for administration to mammals, preferably humans, in any age group: from adolescents to the elderly.

The wet granulation step and the one or more granule coating steps are capable of creating a gelatinous coating layer that, when the granule is then dried, remains firmly attached to the at least one active substance/nutritional ingredient and/or mixtures of active substances/nutritional ingredients. When the modified-release granule, conveyed in the oral pharmaceutical composition and/or a food supplement comprising it, reaches the stomach due to the low pH of the stomach, the delayed release active ingredient granule swells to form an insoluble hydrogel coating.

Then, the granule reaches the small intestine where, due to the higher pH (6-7), the coating becomes soluble, slowly dissolves and the active ingredient is gradually released from the granule.

According to another of its aspects, the invention also has as its object an association consisting of:

I) at least one active ingredient /nutritional ingredient selected from the group that comprises or, alternatively, consists of: - at least one vitamin, in particular: a vitamin A and/or at least one vitamin D, including vitamins D2, D3 and/or mixtures thereof; and/or a vitamin C and/or one or more natural extracts comprising vitamin C; and/or at least one vitamin of the B group, including vitamins B1 , B2, B3, B6, B12, pantothenic acid, folic acid, biotin, and/or mixtures thereof; and/or a vitamin E; and/or a mixture of said vitamins;

- at least one fermented red rice and/or its extract titrated in monacolin K and/or another source of monacolin K and/or mixtures thereof; and/or mixtures thereof; and ii) sodium alginate; and iii) calcium lactate.

The invention will now be described in more detail in the Experimental Section that follows, for illustrative and in no way limiting purposes.

Experimental Section

Example 1

AMINO ACID, MAGNESIUM AND IRON GRANULATE FOR OROSOLUBLE POWDER

A mixture of amino acids, a magnesium salt, an iron salt, sodium alginate and calcium lactate was prepared in the quantities reported in the following Table 1. The mixture was wet granulated and the resulting granules were dried. The dried granules were subjected to a first granulation step with an aqueous solution of calcium lactate (quantities reported in Table 1 below) to form granules coated with calcium lactate. The latter were dried and subjected to a second granulation step with an aqueous solution of sodium alginate (quantities reported in Table 1 below) to form modified-release granules of the invention.

Table 1 [PD=Dispersible Dust]

Step (a):

Load in order sodium alginate, amino acids, magnesium salt, iron salt, and calcium lactate pentahydrate. Set impeller to 200 rpm and pour in as much purified water as required. After addition is finished, set chopper to 1000 rpm and impeller to 200 rpm for 5 minutes. Pass the wet granulate through 3 mm mesh.

Drying phase

Dry the granulate in an oven at 60°C for 8 hours. LOD control = 6.3%

Calibration phase

Calibrate through a 1.2 mm mesh

Step (b’): Granulation in Fluid Bed Glatt mod. Uniglatt

Preparation of coating solution

Solubilize the calcium lactate in purified water as required.

Coating Phase

Load the granule obtained in step 1 into the fluid bed basket. Spray the coating solution by setting the following parameters:

Inlet Air Temp = 40°C - 45°C

Product temp. = 27°C - 30°C

Spray pressure = 1 .5 bar

Liquid flow rate = 15 - 20 g/ min

Air flow = Flap pos. 15

Once the coating solution is finished, dry by setting the following parameters:

Inlet air temp. = 60°C - 65°C

Product temp. = 50°C - 55°C Air flow = Flap pos. 15

LOD control = 6.5 - 7.5 %

Step (b”)

Granulation in Fluid Bed Glatt mod. Uniglatt

Preparation of coating solution

Solubilize Sodium Alginate in water

Coating phase

Load the granulate obtained in step (b’) into the fluid bed basket. Spray the coating solution by setting the following parameters:

Inlet air temp. = 40°C - 45°C

Product temp. = 27°C - 30°C

Spray pressure = 1 .5 bar

Liquid flow rate = 15 - 20 g/min

Air flow = Flap position 15

Once the coating solution is finished, dry by setting the following parameters:

Inlet air temp. = 60°C - 65°C

Product temp. = 50°C - 55°C

Air flow = Flap pos. 15 Control

LOD = 6.5 - 7.5 %

Calibration phase

Calibrate the granulate through a 1.2 mm mesh.

Amino acids and iron and magnesium salts are known in the galenical technique for their particularly unpleasant taste; therefore, they are usually not used in chewable or orosoluble compositions.

Furthermore, a modified release of these ingredients means that they are not immediately released in the stomach but rather in the intestine which is the site where they are optimally absorbed.

The granulation of these ingredients according to the invention therefore allows the following advantages:

- controlled release in the correct intestinal tract for better absorption

- taste masking

Example 2

VITAMIN C GRANULATE FOR OROSOLUBLE POWDER OR TO BE DISSOLVED IN WATER OR TO BE USED IN A GUMMY CANDY

Using the same process as in Example 1 , a vitamin C-based granulate was prepared using the total quantities reported in the following Table 2:

Table 2

To have an even longer release, a new formula variant was developed by employing the total amounts shown in

Table 2a below:

Table 2a The release of vitamin C over time was then determined for both formulations, comparing it with that of standard, non-granulated vitamin C, using the following apparatus.

Three beakers were prepared, one for each vitamin C sample to be tested (ungranulated raw material, granulate containing 60% vitamin C and granulate containing 30% vitamin C), containing 500mL of HCI 0.1 N+DTT (Dithiothreitol; antioxidant agent). Each beaker was stirred at 150rpm, each sample was placed inside the basket, and, as per the mirror below, each weighing was calculated to have 500 mg of Vitamin C per beaker or a solution of 1 mg/mL.

The 3 baskets containing the vitamin C, in the 3 variants, were then immersed in the acid solution and the following draws were made (1min_2min_5min_10min_15min_25min_60min), so that the release of vitamin C could be evaluated as a function of the intensity of the vitamin C peak expressed in piV over time, obtaining:

Utigraiiuhited vrt £ Granulate

Granulate vit. £ 30%

Table 3

The trial containing the 30% Vitamin C granulate has the most prolonged release as it releases Vitamin C in 1 hour.

The 30% Vitamin C granulate was then used to develop a single-layer gummy candy with a prolonged Vitamin C release. The dissolution test in 0.1 N HCI was then performed on this gummy candy, as shown in Table 4 below:

Table 4

In addition, vitamin C is a particularly unstable ingredient, it has a very acidic pH, and a high intake of vitamin C may lead to side effects such as gastrointestinal disorders (hyperacidity, diarrhea, abdominal cramps), and kidney stone formation.

The invention's prolonged and delayed-release granulate, due to the gelatinous coating formed by calcium and alginate, helps to overcome these drawbacks for the following reasons: it forms a protective shell that prevents oxidation and degradation of vitamin C; it prevents interaction between vitamin C and the gastric mucosa, as well as side effects related to its strong acidity; it reduces renal burden brought about by high immediate intakes of vitamin C: vitamin C is particularly water-soluble and therefore rapidly absorbed.

Immediate absorption of vitamin high amounts places an excessive workload on the kidneys, which are responsible for excreting excess vitamin C. Therefore, a gradual release of vitamin C results in a better distributed absorption of vitamin C over time and fewer kidney side effects.

Example 3

FERMENTED RED RICE EXTRACT GRANULATE TIT. 2.98% IN MONACOLIN FOR OROSOLUBLE POWDER OR TO BE DISSOLVED IN WATER, GUMMY CANDY OR CHEWABLE TABLET

Using the same precess as in Example 1 , a fermented red rice extract granulate with a monacolin K titer of 2.98% was prepared, employing the total amounts shown in Table 5 below:

Table 5

However, it is possible to formulate the modified release granulate of the present invention also in forms, such as gummy candies, which involve cooking phases at high temperatures (> 60°C) without degrading the thermosensitive active ingredients/nutritional ingredients present, such as monacolin K.

Using the granulate of Table 5, a red rice-based gummy single layer candy was produced, with a delayed and prolonged release, being able to remain stable during storage and with excellent palatability.

Example 4

FERMENTED RED RICE GUMMY CANDY TIT. 2.98% IN MONACOLINE STAMP-FORM "menthol boluses”

SINGLE CARAMEL WEIGHT Single candy: about 2 g

Ingredients:

Granulate obtained in Example 3, glucose syrup, sugar, modified starches, water, vegetable oil (coconut, canola), flavoring, coloring agent: E133, coating agent: carnauba wax.

Stability studies were conducted comparing a gummy candy prepared with granulated red rice according to the invention (Example 4), with a gummy candy prepared with non-granulated red rice. The data are shown in Table 6 below:

Table 6

It can be seen from the data that already at TO there is no presence of monacolin K in the gummy candy without granulate, indicating that it is completely degraded during the gummy candy production process.

In contrast, the monacolin K titer in the gummy candy with granules is very close to the target value (2.98 mg).

Example 5

FOLIC ACID GRANULATE FOR OROSOLUBLE POWDER OR TO BE DISSOLVED IN WATER, GUMMY CANDY OR CHEWABLE TABLET

Using the same method as in Example 1 , a folic acid granulate with a titer of 1 .6 percent was prepared, employing the total amounts shown in Table 7 below:

Table 7

The obtained granulate has the following technological parameters:

Particle size distribution

Not more than 5 % > 1000 m Not more than 10 % > 710 pm

Minimum 80 % between >125 pm - < 710 pm

Not more than 25 % < 125 pm

LOD (70°C; 15 minutes): 5.0 % - 15.0 %;

Density: 0.4 - 0.7 g/ml; Flowability (100 grams): < 25 sec.

The granulate obtained in Example 5 was then used to formulate a gummy candy that had stability problems because the standard folic acid, being heat sensitive, was degraded in the process of cooking the gummy candy.

In this regard, the stability data of the gummy candy formulated with uncoated folic acid, compared with those of the granulate, is as follows:

Table 8

As can be seen from the results shown in Table 8, the gummy candy containing the non-granulated folic acid at TO is already out of specification, indicating that this nutrient is largely degraded during the gummy candy manufacturing process.

Claims

1 . A modified-release granulate comprising or, alternatively, consisting of: i) at least one active ingredient/nutritional ingredient selected from the group comprising or, alternatively, consisting of:

- at least one vitamin, particularly: a vitamin A; and/or at least a vitamin D, including vitamins D2, D3 and/or mixtures thereof; and/or a vitamin C and/or one or more natural extracts comprising vitamin C; and/or at least a vitamin of the B group, including vitamins B1 , B2, B3, B6, B12, pantothenic acid, folic acid, biotin, and/or mixtures thereof; and/or a vitamin E; and/or a mixture of said vitamins;

- at least one mineral, particularly iron and/or magnesium and/or salts or complexes thereof and/or mixtures thereof;

- at least one amino acid, particularly Leucine, Valine, Isoleucine, Methionine, Histidine, Lysine, Phenylalanine, Threonine, Tryptophan and/or mixtures thereof;

- at least one dry extract titrated in polyphenols, such as a green tea extract and a grape vine extract, and/or mixtures thereof;

- at least one fermented red rice and/or its extract titrated in monacolin K and/or other sources of monacolin K and/or mixtures thereof; and/or mixtures thereof; ii) sodium alginate; and iii) calcium lactate, wherein said granulate is prolonged-release and delayed-release.

2. The granulate according to any one of claims 1 , characterized by the fact that said granulate comprises from 1 % to 80% by weight, with respect to the total weight of the granulate, of said at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients; from 5% to 60% by weight, with respect to the total weight of the granulate, of sodium alginate, preferably from 20% to 50%; and from 5% to 60% by weight, with respect to the total weight of the granulate, of calcium lactate, preferably from 20% to 50%.

3. The granulate according to any one of claims 1 -2, characterized by the fact that in said granulate the weight ratio of sodium alginate to calcium lactate varies in the range from 0.5:2 to 2:0.5, being preferably about 1 : 1.

4. A process for the preparation of a granulate according to any one of claims 1 -3, wherein said process comprises the following steps: a. a wet granulation of a mixture comprising or, alternatively, consisting of said at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, sodium alginate and calcium lactate, to form granules intended to be coated; b. a coating of the granules obtained from step (a) through two sequential steps: b'. a granulation of the granules obtained from step (a) with calcium lactate; and b". a granulation of the granules obtained from step (b¹) with sodium alginate.

5. The process according to claim 4, wherein said process comprises the following steps: a. a first wet granulation of a mixture comprising or, alternatively, consisting of I) at least one active I ngredient/nutri tional ingredient and/or mixtures of active ingredients/nutritional ingredients, ii) sodium alginate and ill) calcium lactate, to form granules intended to be coated; b. a second coating of the granules obtained from step (a) through through two sequential steps:b'. a granulation of the granules obtained from step (a) with calcium lactate and sodium alginate; and b". a granulation of the granules obtained from step (b¹) with sodium alginate.

6. A process for the preparation of a granulate according to any one of claims 1-3, wherein said process comprises the following steps: a. a wet granulation of a mixture comprising or, alternatively, consisting of said at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, sodium alginate and calcium lactate, to form granules intended to be coated; b. a coating of the granules obtained from step (a) through a single coating step with a mixture of sodium alginate and calcium lactate, to form coated granules.

7. The process according to claim 6, wherein said process comprises a granulation in Fluid Bed of a mixture comprising I) at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients, ii) sodium alginate and ill) calcium lactate, so as to achieve granule coating through a single granulation step with a mixture of (ii) sodium alginate and (ill) calcium lactate, to form coated granules.

8. A process for the preparation of a granulate according to any one of claims 1-3, wherein:

- preferably, in said step a., it is used: from 1 % to 80% by weight, with respect to the total weight of the granulate, of said at least one active ingredient/nutritional ingredient and/or mixtures of active ingredients/nutritional ingredients; from 5% to 60% by weight, with respect to the total weight of the granulate, of sodium alginate, preferably from 20% to 50%; and from 5% to 60% by weight, with respect to the total weight of the granulate, of calcium lactate, preferably from 20% to 50%; and/or

- preferably, in said step b'., it is used from 0.1 % to 2% by weight, with respect to the total weight of the granulate, of calcium lactate, preferably from 0.2% to 1 %; and/or

- preferably, in said step b"., it is used from 0.1 % to 2% by weight, with respect to the total weight of the granulate, of sodium alginate, preferably from 0.2% to 1 %; or

- preferably, in said step b., it is used an aqueous mixture comprising from 0.1 % to 2% by weight, with respect to the total weight of the granulate, of sodium alginate, preferably from 0.2% to %1 ; and from 0.1 % to 2% by weight, with respect to the total weight of the granulate, of calcium lactate, preferably from 0.2% to 1 %.

9. A process for the preparation of a granulate according to any one of claims 1-3 characterized by the fact that no organic solvents are used, water being the only solvent used in all steps of the process.

10. An association consisting of:

I) at least one active ingredient/nutritional ingredient selected from the group comprising or, alternatively, consisting of:

- at least one vitamin, particularly: a vitamin A and/or at least a vitamin D, including vitamins D2, D3 and/or mixtures thereof; and/or a vitamin C and/or one or more natural extracts comprising vitamin C; and/or at least a vitamin of the B group, including vitamins B1 , B2, B3, B6, B12, pantothenic acid, folic acid, biotin, and/or mixtures thereof; and/or a vitamin E; and/or a mixture of said vitamins;

- at least one fermented red rice and/or its extract titrated in monacolin K and/or other sources of monacolin K and/or mixtures thereof; and/or mixtures thereof; and ii) sodium alginate; and ill) calcium lactate.

11. A pharmaceutical and/or food composition comprising the granulate according to any one of claims 1 -3, or the association of claim 10, together with one or more conventional excipients and/or vehicles.

12. The composition according to claim 11 , characterized by the fact that it is in the form of a composition for oral use.

13. The composition according to claim 11, characterized by the fact that it is in the form of chewable or swallowable tablets, capsules, sachets containing mixtures of powders/granules that are orosoluble or to be dissolved in water or other liquid, chewing gum or gummy candy.

14. The composition according to any one of claims 11 -13, characterized by the fact that it is in the form of a gummy candy.