Modified release granules of active and / or nutritional ingredients and methods of making the same

Abstract

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

Description

[0001] The object of this invention is to provide modified-release granules of active ingredients and / or nutrients, and pharmaceutical compositions and / or dietary supplements comprising said granules. This invention also relates to a composition comprising said active ingredients and / or nutrients, sodium alginate and calcium lactate, or a combination thereof. Background Technology

[0002] Granulation technology is a widely used method in the pharmaceutical and dietary supplement industries for converting powdered active ingredients / nutrients into uniformly sized particles or aggregates. This technology is extremely important in the pharmaceutical and dietary supplement industries for several reasons: - Improved bioavailability: Granulation can improve the bioavailability of active ingredients / nutrients in pharmaceuticals / food supplements. This is particularly important for pharmaceuticals / food supplements, as these supplements are not only difficult for the body to absorb, but also have low bioavailability; - Dosage control: Compared to powders, granules allow for more precise delivery of active ingredients / nutrients in medications / food supplements. This is crucial for ensuring that each dose contains the exact amount of active ingredients / nutrients required for treatment; - Reduced dust: Dust can be inhaled and can be harmful to workers in the pharmaceutical industry. Granulation reduces the generation of fine dust, thereby improving workplace safety; - Improved stability: Granulation can improve the stability of pharmaceutical / food supplements by protecting active ingredients / nutrients from degradation caused by moisture or oxidation.

[0003] - Easy to mix: The granules are easier to mix with other formulation ingredients (such as excipients, dyes or additives) to create complex formulations.

[0004] Granulation technologies used in the pharmaceutical and dietary supplement industry include wet granulation, dry granulation, and spray granulation.

[0005] Wet granulation is a method of mixing pharmaceutical / dietary supplement components with a liquid to form a wet substance, which is then granulated. This method is widely used because it provides precise control over particle size and particle distribution.

[0006] Dry granulation is a method that involves compressing dry powder to form granules. This method is suitable for materials that are sensitive to moisture or heat.

[0007] In spray granulation, a liquid solution containing active ingredients / nutrients is sprayed onto a powder mixture, and granules are formed as the liquid evaporates. This method can efficiently obtain uniform and stable granules.

[0008] Therefore, granulation technology is crucial in the pharmaceutical and dietary supplement industries because it can improve the quality, stability, and efficacy of pharmaceutical / food supplements, as well as facilitate their production and precise dosing.

[0009] According to the definition in the 12th edition of the official pharmacopoeia, granules are solid dosage forms consisting of solid dry aggregates of powdered particles, which are sufficiently resistant to vigorous handling and intended for oral administration. Granules contain one or more active ingredients, with or without excipients, and, if desired, permitted dyes or flavoring substances. They can be swallowed directly, chewed, or dissolved or dispersed in water or other suitable liquids prior to administration.

[0010] The specific type of granules that can be produced are controlled-release granules, which can deliver active ingredients and / or nutrients to the human body in a controlled manner.

[0011] Modified-release particles are particles that may be coated or uncoated, containing special particle components and / or prepared using special methods, such as altering the release rate and / or site and / or time and / or duration of active ingredients and / or nutrients. Modified-release particles include extended-release particles and delayed-release particles.

[0012] Extended-release particles allow for controlled and prolonged release of the active ingredient and / or nutrients over time in amounts that are useful, acceptable, and effective for the treatment subjects. They simplify the administration schedule for patients by reducing the recommended daily intake, improving patient compliance, and reducing adverse events, such as those associated with high plasma peaks, thereby ensuring more consistent plasma concentrations over hours or throughout the day.

[0013] Extended-release particles are known in the art. Typical materials commonly used to obtain extended release are, for example, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, cellulose acetate, polyvinyl acetate, polyacrylate, polymethacrylate copolymers, and ammonium methacrylate.

[0014] Delayed-release particles allow for a delayed release of the active ingredient and / or nutrients relative to the time of ingestion of the medication / food supplement. Enteric-coated particles are a typical example of delayed-release particles, suitable for situations where the active ingredient and / or nutrients damage the stomach lining or decompose in an acidic environment. Their preparation method is resistant to gastric juices, releasing the active ingredient and / or nutrients (at a rate that may be fast or slow) into the intestinal fluid. These properties are typically achieved by coating the particles with a gastric-resistant substance (enteric-coated particles).

[0015] Materials used for enteric coatings include waxes, plastics, or plant fibers such as starch. Other available materials are certain types of shellac and fatty acids. Most materials used for enteric coatings are synthetic or natural polymers that do not decompose below pH 5.5. The conventional material used is a film-forming resin solution. However, because these solutions use organic solvents, there are concerns that trace amounts of solvent remaining in the coating may be toxic. In film-forming methods that do not require organic solvents (water-based film-forming), the presence of a plasticizer (typically 10% to 20%) is necessary.

[0016] Extended-release particles, including enteric-coated particles (extended-release particles and delayed-release particles), are known. They typically require complex manufacturing processes involving intricate combinations of formulation components, often including binders and fillers in addition to release modifiers, to obtain structurally stable particles with the desired extended-release properties. Such manufacturing processes often require the use of organic solvents and / or inert cores, and enteric coating typically requires the use of organic solvents or plasticizers. Often, the materials used to manufacture enteric coatings (e.g., when based on acrylic resins) are exogenous substances that, while soluble at intestinal pH, are not biodegradable.

[0017] The technical problem this invention aims to solve is to provide particles with delayed and extended release that are more advantageous than those of existing technologies. Through in-depth research, the applicant has developed a delayed and extended release particle. This particle has a stable structure, is resistant to degradation due to humidity, heat, and oxidation, is easy to handle, and is suitable for a wide range of heterogeneous nutrients and / or active ingredients. The production of this particle requires only two particle components, sodium alginate and calcium lactate, compounded in appropriate percentages and proportions, and applied in a specific order using a simple, highly reproducible method that eliminates the need for organic solvents.

[0018] Advantageously, the extended and delayed release particles of the present invention not only allow for the slow, gradual release of active ingredients / nutrients with broad heterogeneity at the intestinal fluid level, but can also be used in the form of conventional pharmaceutical / nutritional supplements (e.g., chewable or swallowable tablets, capsules, sachets containing powder / particle mixtures that are orally soluble or soluble in water or other liquids), or in the form of gummy candies involving high-temperature (>60°C) processing steps and therefore more readily degradable.

[0019] Furthermore, the extended and delayed release particles of the present invention also have a taste-masking effect, which can improve compliance when the active ingredient or nutrient is delivered in a chewable or palatable pharmaceutical / food form if the taste is unpleasant. Summary of the Invention

[0020] In a first aspect, the present invention provides release-modifying particles of active ingredients / nutrients based on broad heterogeneity, particularly extended-release particles and delayed-release particles.

[0021] Preferably, the particles comprise or consist of the following: i) At least one active ingredient / nutrient selected from the group consisting of: - At least one vitamin, particularly: vitamin A; and / or at least one vitamin D, including vitamin D2, D3 and / or mixtures thereof; and / or vitamin C and / or one or more natural extracts containing vitamin C; and / or at least one B vitamin, including vitamin 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 vitamin E; and / or mixtures of said vitamins; - At least one mineral, especially iron and / or magnesium and / or its 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 with polyphenols, such as green tea extract and red vine extract, and / or mixtures thereof; - At least one fermented red yeast rice titrated with monacolin K and / or an extract thereof; and / or other sources of monacolin K, and / or mixtures thereof; and / or mixtures thereof; and ii) Sodium alginate; and iii) Calcium lactate.

[0022] Preferably, the at least one mineral, particularly iron and / or magnesium and / or its salts or complexes and / or mixtures thereof, may be selected, for example, from iron diglycinate and / or magnesium diglycinate, ferric sulfate, magnesium oxide or magnesium citrate or mixtures thereof.

[0023] Preferably, the at least one polyphenol-titrated dry extract (e.g., green tea extract and / or grapevine extract, and / or mixtures thereof) may be preferably selected, for example, from: green tea leaf extract, PE 95% POLY.UV / 60% CATEC, HPLC / 30% EGCG HPLC; for example, tea tree ( Camellia sinensis (L.) Kuntze, syn Thea sinensis L, Thea viridis L.(); leaves, preferably extracted by spray drying; extraction solvent is 100% water; purification solvent is ethyl acetate; yield: approximately 9 kg of plant yields 1 kg of product); preferably, the bulk density of the green tea extract is 0.30 g / ml to 0.70 g / ml; preferably, drying loss is less than or equal to 8%; particles smaller than 70 mesh (200 micrometers) are greater than or equal to 95%; caffeine is less than or equal to 8%; total polyphenols are greater than or equal to 95%; epigallocatechin gallate (EGCG) is greater than or equal to 30%; catechins are greater than or equal to 60%.

[0024] Preferably, the at least one polyphenol-titrated dry extract (e.g., green tea extract and / or grapevine extract, and / or mixtures thereof) can be, for example, preferably selected from 95% grape seed extract, wine grape ( Vitis Vinifera L .), ethanol / water solvent; proanthocyanidins (UV) ≥ 95%; polyphenols (UV FC) ≥ 80%; preferably drying loss ≤ 5%; ≥ 95% of particle size passes through an 80-mesh sieve.

[0025] Preferably, the at least one fermented red yeast rice and / or its extract, titrated with monacolin K, and / or other sources of monacolin K and / or mixtures thereof, for example, preferably fermented red rice extract (Oryza sativa L.) fermented from Monascus purpureus Went., has a monacolin K (HPLC) content of about NLT 3%, a total monacolin (HPLC) content of about NMT 4.5%, a drying loss of about NMT 5%, a bulk density of 420 g / L to 520 g / L, and preferably uses maltodextrin as a carrier.

[0026] In a second aspect, the present invention provides a method for preparing the particles of the present invention, wherein the method comprises the following steps: a. Wet granulation of a mixture comprising or consisting of: i) at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; ii) sodium alginate; and iii) calcium lactate, to form granules to be coated; b. Coating the particles obtained from step (a) in two consecutive steps: b'. Granulation of the particles obtained from step (a) with calcium lactate; and b''. Granulate the particles obtained from step (b') using sodium alginate.

[0027] Preferably, the present invention provides a method for preparing the particles of the present invention, wherein the method includes the following steps: a. A first wet granulation is performed on a mixture comprising or consisting of: i) at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; ii) sodium alginate; and iii) calcium lactate, to form granules to be coated; b. The particles obtained from step (a) are subjected to a second granulation through two consecutive granulation steps or stages, preferably wet granulation in a fluidized bed (e.g., Glatt): b'. Granulate the particles obtained from step (a) using calcium lactate and sodium alginate; and b''. Granulate the particles obtained from step (b') using sodium alginate.

[0028] The granulation method employs a wet process, preferably with the addition of varying weights of water, rather than a dry process without the addition of water. Preferably, the coating method (b) involves two consecutive granulation stages or steps (b' and b'').

[0029] Preferably, for the active ingredient (e.g., melatonin), or for a mixture of active ingredients (e.g., vitamins and / or amino acids), its content relative to the total weight of the active ingredient or mixture of active ingredients and sodium alginate and calcium lactate is less than 10% by weight, for example, from 0.1% by weight to less than 10% by weight, preferably from 4% by weight to 8% by weight, and preferably prepared by a method involving: (a) initial wet granulation in a high-shear mixer granulator; and (b) a second wet granulation of the granules obtained in step (a) in a fluidized bed via two granulation steps or stages (b' and b''). For example, see Example 1, where step (a) involves using 2% by weight of melatonin (99% titer) and 49% by weight of sodium alginate and 49% by weight of calcium lactate relative to the total weight.

[0030] Preferably, in step (a), the method involves adding sodium alginate (e.g., about 49 wt%), melatonin (e.g., about 2 wt%), and calcium lactate (e.g., calcium lactate pentahydrate) (e.g., about 49 wt%) in this order to a high-shear mixer granulator. Then, preferably under stirring (impeller, fan, or rotor), for example at 100 rpm to 500 rpm, preferably 200 rpm to 400 rpm, purified water is added in a single pour, just enough to obtain a homogeneous slurry. After the water addition is complete, the shredder (cutting blade) is set to, for example, 1000 rpm, and the impeller is set to, for example, 200 rpm, for 1 minute to 15 minutes, for example, 5 minutes to 10 minutes. After the kneading step is complete, the wet granules are preferably passed through, for example, a 3 mm sieve. Preferably, a drying stage is then performed, wherein the granules are placed in an oven at a temperature of 40°C to 80°C (e.g., 60°C) for 2 to 12 hours, for example, 8 hours. Preferably, a calibration step can then be performed using a 1.2 mm sieve.

[0031] Next, step (b) preferably involves wet granulation of the particles obtained in step (a) in a fluidized bed through a two-step process (b' and b'').

[0032] Specifically, the particles obtained in step (a) are loaded into a fluidized bed, and 0.1% to 1.5% by weight, preferably 0.4% to 1% by weight, of sodium alginate and 0.5% to 3% by weight, preferably 1% to 2% by weight of calcium lactate are added relative to the total weight of the particles, sodium alginate, and calcium lactate from step (a). Preferably, step b' involves loading the fluidized bed (e.g., Glatt mod. Uniglatt Granulation is performed in the fluidized bed basket. Preferably, the coating solution is obtained by dissolving calcium lactate in water. Preferably, the coating step involves loading the granules obtained in step (a) into a fluidized bed basket and spraying the coating solution by setting the following parameters (only non-limiting examples): inlet air temperature = 40°C to 45°C; product temperature = 27°C to 30°C; spray pressure = 1.5 bar; liquid flow rate = 15 g / min to 20 g / min; air flow rate = baffle position 15. Preferably, the drying step can be set, for example, with the following parameters: inlet air temperature = 60°C to 65°C; product temperature = 50°C to 55°C; air flow rate = baffle position 15; LOD control = 6.5% to 7.5%.

[0033] The subsequent step b'' involves fluidized beds (e.g., Glatt mod. UniglattGranulation is performed in step (a). Preferably, the coating solution is obtained by dissolving sodium alginate in water. Preferably, the coating step involves loading the particles obtained in step (a) into a fluidized bed basket and spraying the coating solution by setting the following parameters (only non-limiting examples): inlet air temperature = 40°C to 45°C; product temperature = 27°C to 30°C; spray pressure = 1.5 bar; liquid flow rate = 15 g / min to 20 g / min; air flow rate = baffle position 15. Preferably, the drying step can be set, for example, with the following parameters: inlet air temperature = 60°C to 65°C; product temperature = 50°C to 55°C; air flow rate = baffle position 15; LOD control = 6.5% to 7.5%. Preferably, a particle correction step is then performed by passing the particles through, for example, a 1.2 mm sieve. Preferably, the particles of the present invention thus obtained have at least one of the following technical parameters: Particle size distribution Not exceeding 5% ≥ 1000 µm; and / or Not exceeding 10% ≥ 710 µm; and / or Not more than 80% are between ≥125 µm and <710 µm; and / or Not exceeding 25% < 125 µm; and / or LOD (70℃): 6.0% to 15.0%; and / or Density: 0.4 g / ml to 0.8 g / ml; and / or Flowability (100g): ≤ 25 seconds Alternatively, the method for preparing granules according to the present invention can be carried out by single-step fluidized bed granulation of i) at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients, ii) a mixture of sodium alginate and iii) calcium lactate, followed by a single-step coating step, which includes the following stages: a. Wet granulation of a mixture comprising or consisting of: i) at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; ii) sodium alginate; and iii) calcium lactate, to form granules to be coated; b. Coated particles are formed by coating the particles with a single-step coating step via a mixture of (a) sodium alginate and (iii) calcium lactate.

[0034] Preferably, the method for preparing the particles of the present invention can be accomplished by a single-step granulation step in a fluidized bed of i) at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients, ii) a mixture of sodium alginate and iii) calcium lactate, thereby achieving particle coating by the single-step granulation step of the mixture of ii) sodium alginate and iii) calcium lactate, thereby forming coated particles.

[0035] The granulation process is carried out wet in a fluidized bed, preferably with the addition of a variable weight of water, rather than a dry process without the addition of water. Preferably, the coating method (b) involves only one coating step or stage.

[0036] Preferably, for the active ingredient (e.g., melatonin), or for a mixture of active ingredients (e.g., vitamins and / or amino acids), its content relative to the total weight of the active ingredient or mixture of active ingredients and sodium alginate and calcium lactate is greater than or equal to 10% by weight, for example, 10% to 30% by weight, preferably 15% to 20% by weight, and preferably prepared by a method involving (a) wet granulation and (b) particle coating. For example, see Example 2, where step (a) involves using 10% by weight of melatonin (99% titer) and 45% by weight of sodium alginate and 45% by weight of calcium lactate relative to the total weight.

[0037] Preferably, the method involves a single-step granulation step in a Glatt-type fluidized bed for all components and 40% purified water.

[0038] Preferably, the method involves a coating step or stage in which, for example, about 10% by weight of melatonin, for example, 45% by weight of sodium alginate and for example, 45% by weight of calcium lactate are loaded into a fluidized bed basket, and water (e.g., purified water) is sprayed by setting (as a non-limiting example) the following parameters: inlet air temperature = 40°C to 45°C; product temperature = 27°C to 30°C; spray pressure = 1.5 bar; liquid flow rate = 15 g / min to 20 g / min; air flow rate = baffle position 15.

[0039] Preferably, once the wetting step is complete, drying can be performed by setting the following parameters as a non-limiting example: inlet air temperature = 60°C to 65°C; product temperature = 50°C to 55°C; airflow = baffle position 15; LOD control = 6.5% to 7.5%.

[0040] Preferably, a particle correction step is then performed using a 1.2 mm sieve.

[0041] Preferably, the particles may have the following particle size specifications, for example: not more than 10%: ≥ 710 µm; 80% 125 µm to 710 µm; not more than 10% < 125 µm; LOD (70°C): 6.0% to 8.0%; density: 0.4 g / ml to 0.6 g / ml; flowability (100 g): ≤ 25 seconds.

[0042] In a third aspect, the present invention relates to a combination of the following: i) At least one active ingredient / nutrient selected from the group consisting of or comprising: - At least one vitamin, particularly: vitamin A; and / or at least one vitamin D, including vitamin D2, D3 and / or mixtures thereof; and / or vitamin C and / or one or more natural extracts containing vitamin C; and / or at least one B vitamin, including vitamin B1, B2, B3, B6, B12, pantothenic acid, folic acid, biotin and / or mixtures thereof; and / or vitamin E; and / or mixtures of said vitamins; - At least one mineral, particularly iron and / or magnesium and / or its 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 with polyphenols, such as green tea extract and grapevine extract, and / or a mixture thereof; - At least one fermented red yeast rice titrated with monacolin K and / or an extract thereof; and / or other sources of monacolin K, and / or mixtures thereof; and / or mixtures thereof; and ii) Sodium alginate; and iii) Calcium lactate.

[0043] In a fourth aspect, the present invention provides a pharmaceutical and / or food composition comprising the release-modifying granules of the present invention and one or more conventional excipients and / or carriers. The composition is preferably intended for oral administration. Preferably, the composition is in the form of a gummy candy.

[0044] The applicant has discovered that the particles of the present invention obtained by the above-described constant-wet granulation method are: -Structural stability; - Resistant to degradation caused by humidity, heat, oxidation, and acidic environments; - To facilitate safe operation by personnel; - Suitable for active ingredients / nutrients with a wide range of heterogeneity; - It allows for the prolonged and delayed release of highly heterogeneous active ingredients / nutrients, or the slow, gradual release of highly heterogeneous active ingredients / nutrients at the intestinal fluid level. This avoids damage to the gastric lining and / or problems with gastric reflux and / or decomposition in acidic environments, as well as side effects / adverse events associated with excessively high plasma concentrations, ensuring more consistent and tolerable plasma concentrations over hours to a day; - It allows for a simplified usage protocol for subjects / patients by reducing the recommended number of daily intakes, thereby improving subject / patient compliance; - For its production, only two granular components are required, sodium alginate and calcium lactate. They only need to be properly combined in the appropriate percentage and ratio and applied in a specific order. The method is simple, economical, highly repeatable, and does not require the use of organic solvents. It can be used not only in the form of conventional pharmaceuticals / foods (e.g., chewable or swallowable tablets, capsules, sachets containing powder / granule mixtures that are soluble in water or other liquids), but also in forms that require processing at high temperatures (>60°C) and are therefore more susceptible to thermal degradation (e.g., gummies).

[0045] - In addition, it can mask the taste of active ingredients or nutrients if they are not palatable, thus improving patient compliance when the granules are delivered in chewable or palatable drug / food form.

[0046] Therefore, it is envisioned that the particles and / or compositions of the present invention are particularly advantageous for ingredients that, when released in the intestine, increase their activity (delayed release) and are advantageously administered slowly and gradually over time (prolonged release).

[0047] The release particles and / or compositions containing them of the present invention achieve these objectives through the technical features claimed in the appended claims, as well as other objectives that will become apparent in the following detailed description. Attached Figure Description

[0048] Figure 1 This represents the release of vitamin C, where the peak intensity of vitamin C (in μV) changes over time. Detailed Implementation

[0049] After long-term and in-depth research and development, the applicant has developed a release-modifying granule based on a wide range of heterogeneous active ingredients / nutrients, particularly extended and delayed release granules. These granules are resistant to degradation caused by humidity, heat, oxidation, and acidic environments, are easy to manufacture, easy to formulate and / or apply, and have no side effects and / or high tolerability.

[0050] The granules of the present invention are particularly advantageous for ingredients / nutrients whose activity is enhanced upon release in the intestine (delayed release) and which are advantageously administered slowly and gradually over time (prolonged release).

[0051] In a first aspect, the present invention provides release-modifying particles of active ingredients / nutrients based on broad heterogeneity, particularly extended-release particles and delayed-release particles, wherein the particles comprise or consist of: i) At least one active ingredient / nutrient selected from the group consisting of or comprising: - At least one vitamin, particularly: vitamin A; and / or at least one vitamin D, including vitamin D2, D3 and / or mixtures thereof; and / or vitamin C and / or one or more natural extracts containing vitamin C; and / or at least one B vitamin, including vitamin B1, B2, B3, B6, B12, pantothenic acid, folic acid, biotin and / or mixtures thereof; and / or vitamin E; and / or mixtures of said vitamins; - At least one mineral, particularly iron and / or magnesium and / or its 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 with polyphenols, such as green tea extract and grapevine extract, and / or mixtures thereof; and - At least one fermented red yeast rice titrated with monacolin K and / or an extract thereof; and / or other sources of monacolin K, and / or mixtures thereof; and / or mixtures thereof; ii) Sodium alginate; and iii) Calcium lactate.

[0052] The particles of the present invention comprise i) at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients.

[0053] The granules of the present invention may contain vitamin A, a fat-soluble vitamin, which can advantageously prolong release and delay release administration at the intestinal fluid level.

[0054] The granules of the present invention may contain at least one vitamin D, including vitamin D2, D3 and / or mixtures thereof. Vitamin D (fat-soluble prohormones) can advantageously be administered with prolonged and delayed release at the intestinal fluid level.

[0055] The granules of the present invention may contain vitamin C and / or natural extracts containing vitamin C and / or mixtures thereof.

[0056] Preferably, the vitamin C is present in the form of a natural extract containing vitamin C, such as dog rose (with a vitamin C content of 50% or 25%). Rosa Canina Acerola cherry with a dry extract and / or vitamin C content of 25% Acerola Dry extract.

[0057] Vitamin C (or L-ascorbic acid) is a naturally occurring organic compound with antioxidant properties; most mammals synthesize this substance autonomously during metabolism, while humans need to obtain it through food. Vitamin C is particularly unstable against oxidation, has a relatively acidic pH, and excessive intake can cause side effects such as gastrointestinal discomfort (excessive stomach acid, diarrhea, abdominal cramps) and kidney stone formation.

[0058] The release-regulating particles of the present invention have a gel coating formed from calcium lactate and sodium alginate, which forms a gel coating containing calcium alginate (described in detail below), which helps to overcome these disadvantages for the following reasons: - It forms a protective shell that prevents vitamin C from oxidizing and degrading; - It avoids the interaction between vitamin C and the gastric mucosa, as well as the side effects associated with its strong acidity; - It reduces the burden on the kidneys caused by the rapid intake of large amounts of vitamin C: vitamin C is particularly water-soluble, so it is absorbed very quickly.

[0059] The rapid absorption of large amounts of vitamin C overburdens the kidneys, which are responsible for excreting excess vitamin C. Therefore, the gradual release of vitamin C allows for better distribution and absorption over time, resulting in fewer side effects at the renal level.

[0060] The granules of the present invention may contain at least one B vitamin, including vitamins B1, B2, B3, B6, B12, pantothenic acid, folic acid, biotin, and / or mixtures thereof.

[0061] B vitamins are a group of water-soluble vitamins that can be advantageously administered at intestinal fluid levels with prolonged and delayed release.

[0062] The granules of the present invention may contain vitamin E, a potent fat-soluble antioxidant that can advantageously prolong and delay release administration at the intestinal fluid level.

[0063] The particles of the present invention may contain at least one mineral, particularly iron and / or magnesium and / or its salts or complexes and / or mixtures thereof.

[0064] Preferably, the at least one mineral, particularly iron and / or magnesium and / or its salts or complexes and / or mixtures thereof, may be selected, for example, from iron diglycinate and / or magnesium diglycinate, ferric sulfate, magnesium oxide or magnesium citrate or mixtures thereof.

[0065] The particles of the present invention may contain at least one amino acid, particularly leucine, valine, isoleucine, methionine, histidine, lysine, phenylalanine, threonine, tryptophan and / or mixtures thereof.

[0066] In the pharmaceutical industry, amino acids, as well as iron and magnesium salts, are known for their unpleasant taste, and therefore are not typically used in chewable or palatable compositions.

[0067] The adjusting granules of the present invention can be used to mask unpleasant-tasting ingredients even in chewable or palatable compositions by performing a taste-masking effect.

[0068] Furthermore, the delayed release of these components means that they are not released immediately in the stomach, but rather in the intestines where absorption is most efficient.

[0069] The particles of the present invention may contain at least one dry extract titrated with polyphenols, such as green tea extract and grapevine extract, and / or a mixture thereof. For example, the dry extract titrated with polyphenols is a green tea extract with a polyphenol content of 50% or 98% and / or a grapevine extract with a polyphenol content of 95%.

[0070] Preferably, the at least one polyphenol-titrated dry extract (e.g., green tea extract and / or grapevine extract, and / or mixtures thereof) may be preferably selected, for example, from: green tea leaf extract, PE 95% POLY.UV / 60% CATEC, HPLC / 30% EGCG HPLC; for example, tea tree ( Camellia sinensis (L.) Kuntze, syn Thea sinensis L, Thea viridis L. (); leaves, preferably extracted by spray drying; extraction solvent is 100% water; purification solvent is ethyl acetate; yield: approximately 9 kg of plant yields 1 kg of product); preferably, the bulk density of the green tea extract is 0.30 g / ml to 0.70 g / ml; preferably, the loss on drying is less than or equal to 8%; particles smaller than 70 mesh (200 micrometers) are greater than or equal to 95%; caffeine is less than or equal to 8%; total polyphenols are greater than or equal to 95%; epigallocatechin gallate (EGCG) is greater than or equal to 30%; catechins are greater than or equal to 60%.

[0071] Preferably, the at least one dry extract titrated with polyphenols (e.g., green tea extract and / or grapevine extract, and / or mixtures thereof) can be selected, for example, from 95% grape seed extract. Vitis Vinifera L Solvent: ethanol / water; Proanthocyanidins (UV) ≥ 95%; Polyphenols (UV FC) ≥ 80%; Preferably, drying loss ≤ 5%; ≥ 95% of particle size passes through an 80-mesh sieve.

[0072] The extract, rich in polyphenols, is a natural antioxidant and can be advantageously administered at the intestinal fluid level with prolonged and delayed release.

[0073] The particles of the present invention may contain at least one fermented red yeast rice titrated with monacolin K and / or an extract thereof; and / or other sources of monacolin K, and / or mixtures thereof.

[0074] Preferably, the at least one fermented red yeast rice and / or its extract, titrated with monacolin K, and / or other sources of monacolin K and / or mixtures thereof, for example, preferably fermented red rice extract (Oryza sativa L.) fermented from Monascus purpureus Went., has a monacolin K (HPLC) content of about NLT 3%, a total monacolin (HPLC) content of about NMT 4.5%, a drying loss of about NMT 5%, an apparent density of 420 g / L to 520 g / L, and preferably uses maltodextrin as a carrier.

[0075] Monacoline is a natural molecule found in red yeast extract, primarily known for its cholesterol-lowering properties, specifically its ability to reduce blood cholesterol levels. The most well-known and studied monacoline is Monacoline K.

[0076] In pharmaceutical technology, red yeast rice is known for its particularly unpleasant / bitter taste, and therefore it is not typically used in chewable or palatable compositions.

[0077] The adjusting particles of the present invention can be used to mask unpleasant-tasting ingredients even in chewable or palatable compositions by performing a taste-masking effect.

[0078] Monacoline K is also a chemical molecule that is sensitive to high temperature, light and humidity.

[0079] Monacoline degrades very rapidly at very high temperatures, such as those required in gummy candy production methods.

[0080] As will be further detailed in the experimental section below, the release granules of the present invention can also be formulated into, for example, gummy candies, in a form that does not degrade the heat-sensitive active ingredients / nutrients (e.g., Monacoline K) present therein, even if the processing involves steps at high temperatures (> 60°C).

[0081] The particles of this invention also contain ii) sodium alginate and iii) calcium lactate as the sole particle components (water is used as the sole solvent, in addition to water). Alginate is derived from brown algae of the genus Laminaria (…). Laminaria ) and the genus *Pachyphyta* ( AscophillumLinear copolymers of natural origin extracted from the cell walls of algae. Alginate from algae must undergo a series of processing steps before they can be effectively used in applications requiring high purification. Because alginate present in algae is insoluble, it needs to be converted into other soluble salts such as sodium alginate or alginic acid.

[0082] Alginate has attracted widespread attention for its applications, primarily because it can form polymeric gels in the presence of divalent cations (such as Ca2+). The interest in alginate applications stems mainly from its gel-forming ability, making the study of the gelation process crucial.

[0083] A gel is a solid composed of a three-dimensional molecular network, where molecules are linked by connective regions (physical or chemical properties) to form a solid phase within which a dispersed liquid medium is embedded. The network imparts the properties of the gel solid, while the liquid phase controls its density. In solutions containing divalent cations, these polymers induce ionic bonds between different polymer chains, promoting the sol-gel transition.

[0084] The divalent cation first binds to the G group until the available binding sites are saturated. Next, it continues to bind to the M groups, which are composed of monomeric units of mannuronic acid (at least at the macroscopic level, especially when adjacent units consist of G residues), until chain binding is constrained by the network. The explanation for this observation lies in the different abilities of the M and G blocks to form linker regions with the divalent cation. The latter are both polyanionic and will form intermolecular anionic bonds with the divalent cation. However, due to the spatial organization of the G block, the G block can also chelate the divalent cation, thus forming binding sites between two adjacent G blocks, resulting in a stronger interaction. This forms dimer links rather than aggregates. Therefore, the "egg-box" model emerged, named after the characteristic shape of the molecular structure created.

[0085] In addition, relative alginate affinity rankings were established for several divalent cations of interest: Pb2+>Cu2+>Cd2+>Ba2+>Sr2+>Ca2+>Co2+=Ni2+=Zn2+>Mn2+>Mg2+.

[0086] The applicant selected sodium alginate from all soluble alginates and, after several attempts, found that combining sodium alginate with a soluble salt of Ca2+ was useful.

[0087] Of all possible divalent cations, Ca2+ was chosen considering both affinity and safety. Among all soluble Ca2+ salts, calcium lactate was the preferred choice.

[0088] One of the main problems when using alginate gels is their low chemical stability. Substances with a high affinity for calcium ions (such as phosphates or citrates) can chelate calcium ions, making the initial gel unstable. The gel may also be unstable due to the presence of other non-gelling cations.

[0089] For these reasons, the selection of calcium lactate was not obvious, but rather the result of careful selection, taking into account the physicochemical properties of calcium lactate itself and other components present in the particulate composition to which this invention is aimed (sodium alginate and at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients). Calcium lactate was chosen from all possible calcium salts because it possesses numerous properties that make it the preferred salt for preparing particles of at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients, for the purposes of this invention, namely: i) good water solubility; ii) a pH range of 6 to 8 for a 5% aqueous solution of calcium lactate; and iii) a Ca2+ titer of 12% to 18%, preferably 13.4% to 14.5%.

[0090] Other possible calcium salts were ruled out because they are insoluble in water (e.g., calcium carbonate) or have poor solubility (e.g., calcium citrate), or although soluble, their pH value is incompatible with the other two components in the granular composition (at least one active ingredient / nutrient and / or active ingredient / nutrient and sodium alginate) once dissolved in water.

[0091] Alternatively, a salt can be formed from lactic acid and a divalent cation (Mg2+) that is comparable to Ca2+. The salt formed by the combination of lactic acid and the divalent cation Mg2+ is magnesium lactate. Magnesium lactate is very similar to calcium lactate in chemical and physical properties. - Good water solubility; -5% calcium lactate aqueous solution pH: 6.5 to 8.5; -Mg titer: 10.0% to 10.5%.

[0092] However, although magnesium lactate is similar to calcium lactate in chemical and physical properties, it is not considered a viable candidate for the release particles of this invention that is functionally equivalent to calcium lactate, because Mg2+ ions do not exhibit the same gelling properties as Ca2+ ions in acidic environments. This has been experimentally verified: particles based on melatonin, sodium alginate, and calcium lactate were prepared, and their gelling properties in acidic environments were compared with those of particles based on melatonin, sodium alginate, and magnesium lactate.

[0093] All components of the granules of the present invention are known in the art and are commercially available. Preferably, the granules of the present invention contain 1% to 80% by weight of the at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients, relative to the total weight of the granules.

[0094] Preferably, the particles of the present invention contain 5% to 60% by weight, more preferably 20% to 50% by weight, sodium alginate relative to the total weight of the particles.

[0095] Preferably, the particles of the present invention contain 5% to 60% by weight, more preferably 20% to 50% by weight, of calcium lactate relative to the total weight of the particles.

[0096] Preferably, the particles of the present invention comprise: -1% by weight to 80% by weight of the at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; and - Sodium alginate, 5% to 60% by weight, preferably 20% to 50% by weight, relative to the total weight of the particles; and Calcium lactate comprises 5% to 60% by weight, preferably 20% to 50% by weight, relative to the total weight of the particles.

[0097] Preferably, in the particles of the present invention, the weight ratio between sodium alginate and calcium lactate varies in the range of 0.5:2 to 2:0.5 (1:4 to 4:1), preferably including 1:2 to 2:1, and more preferably equal to about 1:1.

[0098] According to another aspect of the present invention, an object of the present invention is to provide a method for preparing the particles of the present invention, which includes or consists of the following steps: a. Wet granulation of a mixture comprising or consisting of: at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; sodium alginate; and calcium lactate, to form granules to be coated; b. Coating the particles obtained from step (a) in two consecutive steps: b'. Granulation of the particles obtained from step (a) with calcium lactate; and b''. Granulate the particles obtained in step (b') using sodium alginate.

[0099] Preferably, in step a, the following are used: 1% to 80% by weight of the at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients, relative to the total weight of the particles; 5% to 60% by weight, preferably 20% to 50% by weight, of sodium alginate relative to the total weight of the particles; and 5% to 60% by weight, preferably 20% to 50% by weight, of calcium lactate relative to the total weight of the particles.

[0100] Preferably, in step b', the amount of calcium lactate used is 0.1% to 2% by weight, more preferably 0.2% to 1% by weight, relative to the total weight of the particles.

[0101] Preferably, in step b'', the amount of sodium alginate used is 0.1% to 2% by weight, more preferably 0.2% to 1% by weight, relative to the total weight of the particles.

[0102] In step (a), wet granulation is performed according to known techniques by mixing the following components: preferably 1% to 80% by weight of the at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients relative to the total weight of the granules, with 5% to 60% by weight of sodium alginate relative to the total weight of the granules, and 5% to 60% by weight of calcium lactate relative to the total weight of the granules, and water.

[0103] The particles obtained in step (a) are dried, for example, in an oven, preferably at a temperature of 40°C to 80°C, more preferably at 50°C to 70°C, such as 60°C, for a duration preferably of 2 hours to 12 hours, more preferably 4 hours to 10 hours, such as 8 hours. Preferably, the dried particles are subjected to a calibration stage, for example using a sieve or screen with a mesh size of 0.5 mm to 2.5 mm, preferably 1 mm to 2 mm, such as 1.2 mm, 1.4 mm or 1.6 mm.

[0104] In step (b), the dried granules from step (a) are coated via two consecutive granulation steps (b') and (b''). First, in step (b'), the granules are treated with calcium lactate, preferably 0.1% to 2% by weight relative to the total weight of the granules, to obtain calcium lactate-coated granules. Then, in step (b''), the granules are further coated with sodium alginate, preferably 0.1% to 2% by weight relative to the total weight of the granules. The granules obtained after each step (a), (b'), and (b'') are dried according to known techniques.

[0105] According to a preferred embodiment, the granulation in step (b) is fluidized bed or slurry granulation.

[0106] Alternatively, the method for preparing granules according to the present invention can be performed by single-step granulation of at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients, a mixture of sodium alginate and calcium lactate, followed by a single-step coating step, which includes the following steps: a. Wet granulation of a mixture comprising or consisting of: at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; sodium alginate; and calcium lactate, to form granules to be coated; b. Coated particles are formed by coating the particles obtained in stage (a) with a mixture of sodium alginate and calcium lactate in a single-step coating process.

[0107] Preferably, in step a, the following are used: 1% to 80% by weight of the at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients, relative to the total weight of the particles; 5% to 60% by weight, preferably 20% to 50% by weight, of sodium alginate relative to the total weight of the particles; and 5% to 60% by weight, preferably 20% to 50% by weight, of calcium lactate relative to the total weight of the particles; in step b, an aqueous mixture is used comprising 0.1% to 2% by weight, preferably 0.2% to 1% by weight, of sodium alginate relative to the total weight of the particles; and 0.1% to 2% by weight, preferably 0.2% to 1% by weight, of calcium lactate relative to the total weight of the particles.

[0108] According to a preferred embodiment, the particle size is 0.8 mm to 1.5 mm, preferably 1 mm to 1.4 mm.

[0109] The following experimental section provides some details of the method of the present invention, which are for illustrative purposes only.

[0110] The particles of the present invention allow for the prolonged and delayed release of active ingredients / nutrients with broad heterogeneity at the intestinal fluid level, or for the slow, gradual release of active ingredients / nutrients with broad heterogeneity.

[0111] The particles can be used directly, for example, they can be contained in gelatin capsules.

[0112] Preferably, the granules of the present invention can be used to prepare controlled-release pharmaceutical compositions and food supplements having at least one active ingredient / nutrient and / or a mixture of active ingredients / nutrients.

[0113] According to another aspect, the present invention also aims to provide a pharmaceutical and / or food composition comprising the release-modifying granules of the present invention and one or more conventional excipients and / or carriers. The composition is preferably for oral administration. Preferably, the composition is in the form of chewable or swallowable tablets, capsules, sachets containing a powder / granule mixture that is orally soluble or soluble in water or other liquids, chewing gum, or gummies. Even more preferably, the composition is in the form of gummies.

[0114] In addition to being stable against degradation caused by humidity, oxidation, and acidic environments, the release-regulating particles of the present invention are also thermally stable. Therefore, the release-regulating particles of the present invention can also be formulated into, for example, gummy candies, in a form that will not cause degradation of any heat-sensitive active ingredients / nutrients present, even when processing at high temperatures (>60°C).

[0115] Gummies are traditionally widely accepted. Their chewable nature means that even when using even high doses of active ingredients, they do not need to be swallowed whole.

[0116] Considering that the weight of a swallowable tablet can be up to 1.8 grams, while the weight of an application in "gummy" form can be up to 8 grams, chewable compositions are particularly suitable for patients with dysphagia and swallowing problems, regardless of age.

[0117] The components used to prepare gummies are well known to those skilled in the art. For example, gummies can be made using the following gummy matrix excipients: glucose syrup, sugar, water, edible gelatin, acidifier: citric acid, flavoring agent, and coloring agent: E120, E131, E161b.

[0118] Furthermore, the formulation of the gummy base or matrix affects the release rate: by altering the formulation of the gummy matrix, it is possible to impart further prolonged release characteristics, which can be superimposed on the release characteristics of the regulated-release particles of this invention. For example, the applicant has demonstrated that, all other things being equal, adding starch to the matrix formulation further slows the release kinetics of the active ingredients / nutrients present in the particles of this invention. The maximum amount of starch added can be up to 8%, preferably up to 5%; the minimum amount is the amount that effectively delays release kinetics.

[0119] To prepare the preferred composition of the present invention, the particles of the present invention can be mixed with excipients known to those skilled in the art for use in the manufacture of gummies, chewable tablets, capsules, or chewing gum. For example, in the preparation of gummies, sugar (including glucose syrup), modified starch, gelatin, pectin, water, and vegetable oil can be used, and conventional flavoring agents, coloring agents, and coating agents can also be added.

[0120] Alternatively, the compositions of the present 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.

[0121] These compositions can be taken alone, for example, when in the form of gummies, chewable tablets or gum; or when in the form of capsules and taken with water; or, especially when in the form of powder or granules, can be mixed with other foods, such as yogurt, cream, gels, etc.

[0122] Alternatively, the compositions of the present invention may be in the form of ready-to-use beverages, such as drinking sachets, "strip packaging," in which case cream or gel is preferred.

[0123] In addition to what has already been mentioned, those skilled in the art can appropriately select the types of pharmaceutical and food additives used to prepare the compositions of the present invention, the content ratio of additives to active ingredients, and the methods for preparing pharmaceutical compositions or food supplements.

[0124] For conventional carriers and excipients, organic or inorganic substances, or solid or liquid substances, can be used as carriers and excipients, provided that they are edible, physiologically acceptable, and compatible with all other components of the composition.

[0125] As mentioned above, those skilled in the art are fully capable of selecting the most suitable carriers and excipients to prepare the composition.

[0126] For example, organic or inorganic substances, or solid or liquid substances, can be used as excipients and carriers, provided they are edible and pharmaceutically acceptable. Examples of excipients used in the preparation of solid pharmaceutical / food compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, stearic acid or magnesium stearate, lactose, polyethylene glycol, mannitol, sorbitol, chelating agents, anti-caking agents, sweeteners, preservatives, and flavoring agents. For the preparation of liquid compositions for oral administration, conventional inert diluents, such as water or oils, such as vegetable oils, can be used. In addition to inert diluents, liquid compositions may contain adjuvants such as wetting agents, suspending agents, sweeteners, flavoring agents, coloring agents, and preservatives. Liquid compositions may be contained in capsules made of absorbable materials, such as gelatin.

[0127] Sweeteners can be one or more natural sugars, optionally reducing sugars such as sucrose, glucose, xylitol, mannitol, or sorbitol, or synthetic products such as sodium saccharin, aspartame, acesulfame K, or sucralose. Acidulants may also be added.

[0128] Flavoring agents are pharmaceutically acceptable aroma and flavoring agents that can be derived from synthetic or natural oils, the latter being extracted from plants, flowers, fruits, or combinations thereof, such as cinnamon, peppermint, fennel, and citrus leaves, bitter almonds, citrus fruits (especially oranges and / or lemons), lime, vanilla, chocolate, and grapefruit oils. Advantageously, chocolate, vanilla, or eucalyptus flavoring agents and fruit flavorings, particularly apple, pear, peach, strawberry, apricot, orange, lemon, and grape, may also be used.

[0129] The experimental section below provides examples of the compositions of the present invention for illustrative purposes only.

[0130] The particles and / or compositions of the present invention are non-toxic and intended for use on mammals, preferably humans, and are suitable for any age group: from adolescents to the elderly.

[0131] The wet granulation step and one or more particle coating steps can produce a gel-like coating layer that remains firmly attached to at least one active ingredient / nutrient and / or a mixture of active ingredients / nutrients when the particles are subsequently dried. When the oral pharmaceutical composition and / or food supplement containing modulated-release particles reaches the stomach, the delayed-release active ingredient particles swell due to the low pH in the stomach, thereby forming an insoluble hydrogel coating.

[0132] Then, the particles reach the small intestine, where the coating becomes soluble due to the higher pH (6-7), dissolving slowly and releasing the active ingredients gradually from the particles.

[0133] Therefore, the particles and / or compositions of the present invention are considered particularly advantageous for ingredients that, when released in the intestine, increase their activity (delayed release) and are advantageously administered slowly and gradually over time (prolonged release).

[0134] According to another aspect, the object of the present invention also lies in the following association: i) At least one active ingredient / nutrient selected from the group consisting of or comprising: - At least one vitamin, particularly: vitamin A; and / or at least one vitamin D, including vitamin D2, D3 and / or mixtures thereof; and / or vitamin C and / or one or more natural extracts containing vitamin C; and / or at least one B vitamin, including vitamin B1, B2, B3, B6, B12, pantothenic acid, folic acid, biotin and / or mixtures thereof; and / or vitamin E; and / or mixtures of said vitamins; - At least one mineral, particularly iron and / or magnesium and / or its 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 with polyphenols, such as green tea extract and grapevine extract, and / or a mixture thereof; - At least one fermented red yeast rice titrated with monacolin K and / or an extract thereof; and / or other sources of monacolin K, and / or mixtures thereof; and / or mixtures thereof; and ii) Sodium alginate; and iii) Calcium lactate.

[0135] The invention will now be described in more detail in the experimental section below, for illustrative purposes only and in no way limiting the invention.

[0136] Experimental Section

[0137] Example 1

[0138] Amino acids, magnesium, and iron particles used in colloidal powders

[0139] Prepare a mixture of amino acids, magnesium salts, iron salts, sodium alginate, and calcium lactate in the amounts shown in Table 1 below. Perform wet granulation on the mixture and dry the resulting granules.

[0140] The dried granules were subjected to a first granulation step using an aqueous solution of calcium lactate (in the amounts shown in Table 1 below) to form calcium lactate-coated granules. The latter were then dried and subjected to a second granulation step using an aqueous solution of sodium alginate (in the amounts shown in Table 1 below) to form the controlled-release granules of the present invention.

[0141]

[0142] Table 1 [PD = Dispersible Dust]

[0143] Step (a): Add sodium alginate, amino acids, magnesium salt, iron salt, and calcium lactate pentahydrate in that order. Set the impeller to 200 rpm and pour in the required amount of purified water. After adding the ingredients, set the shredder to 1000 rpm and the impeller to 200 rpm for 5 minutes. Pass the wet particles through a 3 mm sieve.

[0144] Drying stage

[0145] The granules were dried in an oven at 60°C for 8 hours. LOD control = 6.3%.

[0146] Correction phase

[0147] Correction is performed using a 1.2 mm sieve.

[0148] Step (b'): Granulation is carried out in a fluidized bed Glatt mod. Uniglatt.

[0149] Preparation of coating solution

[0150] Dissolve calcium lactate in the required amount of purified water.

[0151] Coating stage

[0152] The particles obtained in step 1 are loaded into a fluidized bed basket. The coating solution is then sprayed using the following parameters: Inlet air temperature = 40℃ to 45℃ Product temperature = 27℃ to 30℃ Spraying pressure = 1.5 bar Liquid flow rate = 15 g / min to 20 g / min Airflow = baffle position 15

[0153] After spraying the coating solution, dry the product by setting the following parameters: Inlet air temperature = 60℃ to 65℃ Product temperature = 50℃ to 55℃ Airflow = baffle position 15 LOD control = 6.5% to 7.5%

[0154] Step (b'')

[0155] Granulation was carried out in a fluidized bed Glatt mod. Uniglatt.

[0156] Preparation of coating solution

[0157] Dissolve sodium alginate in water

[0158] Coating stage

[0159] The particles obtained in step (b') are loaded into a fluidized bed basket. The coating solution is then sprayed using the following parameters: Inlet air temperature = 40℃ to 45℃ Product temperature = 27℃ to 30℃ Spraying pressure = 1.5 bar Liquid flow rate = 15 g / min to 20 g / min Airflow = baffle position 15

[0160] After spraying the coating solution, dry the product by setting the following parameters: Inlet air temperature = 60℃ to 65℃ Product temperature = 50℃ to 55℃ Airflow = Baffle position 15 control LOD = 6.5% to 7.5%

[0161] Correction phase

[0162] Particles are corrected using a 1.2 mm sieve.

[0163] In pharmaceutical technology, amino acids, iron salts, and magnesium salts are known for their unpleasant taste; therefore, they are not typically used in chewable or palatable compositions.

[0164] Furthermore, the modulation of these components means that they are not released immediately in the stomach, but rather in the intestines where their absorption is most efficient.

[0165] Therefore, granulation of these components according to the present invention has the following advantages: - Controlled release in the correct gut for better absorption -masking

[0166] Example 2

[0167] Vitamin C granules for use in oral dissolving powders, water-soluble forms, or in gummies.

[0168] Vitamin C-based granules were prepared using the same method as in Example 1, with the total amounts shown in Table 2 below:

[0169] Table 2

[0170] To achieve even longer release effects, new formulation variants were developed using the total amounts shown in Table 2a below:

[0171] Table 2a

[0172] The release of vitamin C from both formulations over time was then measured using the following equipment and compared with standard ungranulated vitamin C.

[0173] Prepare three beakers, each containing 500 mL of HCl 0.1N+DTT (dithiothreitol; antioxidant), and use them for one sample of vitamin C to be tested (ungranulated raw material, granules containing 60% vitamin C, and granules containing 30% vitamin C).

[0174] Stir each beaker at 150 rpm, place each sample in a basket, and calculate the weight of each sample as shown in the table below, so that each beaker contains 500 mg of vitamin C, or a solution of 1 mg / mL.

[0175] Then, three baskets containing three variants of vitamin C were immersed in an acidic solution, and samples were taken according to the following schedule (1 min, 2 min, 5 min, 10 min, 15 min, 25 min, 60 min). This allowed for the assessment of vitamin C release based on the change in peak vitamin C intensity over time (expressed in μV).

[0176] Table 3

[0177] The test containing 30% vitamin C granules had the longest release time, releasing vitamin C within 1 hour.

[0178] Then, 30% vitamin C granules were used to develop a monolayer gummy with extended vitamin C release. The gummy was then tested for solubility in 0.1 N HCl, as shown in Table 4 below:

[0179] Table 4

[0180] In addition, vitamin C is a particularly unstable component with a high pH level. Excessive intake of vitamin C can cause side effects such as gastrointestinal discomfort (excessive stomach acid, diarrhea, abdominal cramps) and the formation of kidney stones.

[0181] The extended and delayed release particles of the present invention, due to the gel-like coating formed by calcium and alginate, help overcome these disadvantages for the following reasons: - It forms a protective shell to prevent vitamin C from oxidizing and degrading; it also prevents the interaction between vitamin C and the gastric mucosa, as well as the side effects associated with its strong acidity; - It reduces the burden on the kidneys caused by rapid and large intake of vitamin C: Vitamin C is particularly water-soluble and is absorbed very quickly.

[0182] Rapid absorption of large amounts of vitamin C can overburden the kidneys, which are responsible for excreting excess vitamin C. Therefore, the gradual release of vitamin C allows for better distribution and absorption over time, resulting in fewer kidney side effects.

[0183] Example 3

[0184] Monacoline titration value of 2.98% for red yeast rice extract granules used in oral soluble powders, water-soluble forms, or for use in gummies or chewable tablets.

[0185] Using the same method as in Example 1, fermented red yeast rice extract granules with a Monacoline K titer of 2.98% were prepared using the total amounts shown in Table 5 below:

[0186] Table 5

[0187] Monacoline is a natural molecule found in red yeast extract, primarily known for its cholesterol-lowering properties, specifically its ability to reduce blood cholesterol levels. The most well-known and studied monacoline is Monacoline K.

[0188] In pharmaceutical technology, red yeast rice is known for its particularly unpleasant / bitter taste, and therefore it is not typically used in chewable or palatable compositions.

[0189] The adjusting particles of the present invention can be used to mask unpleasant-tasting ingredients even in chewable or palatable compositions by performing a taste-masking effect.

[0190] Monacoline K is also a chemical molecule that is sensitive to high temperature, light and humidity.

[0191] Monacoline degrades very rapidly at very high temperatures, such as those required in gummy candy production methods.

[0192] However, the release granules of the present invention can also be formulated into, for example, gummy candies, in a form that will not degrade the heat-sensitive active ingredients / nutrients (e.g., Monacoline K) present therein, even if the processing involves a stage at high temperature (> 60°C).

[0193] Using the granules in Table 5, a red yeast rice-based monolayer gummy was manufactured, which has delayed and extended release properties, remains stable during storage, and has excellent palatability.

[0194] Example 4

[0195] Monacoline-titration-valued fermented red yeast rice soft candy embossed with the label "menthol boluses" at 2.98%.

[0196] Weight of a single candy: Approximately 2 g

[0197] Element: The granules obtained from Example 3, glucose syrup, sugar, modified starch, water, vegetable oil (coconut oil, rapeseed oil), flavoring agent, coloring agent: E133, coating agent: carnauba wax.

[0198] Stability studies were conducted by comparing gummies prepared using the granulated red yeast rice of the present invention (Example 4) with gummies prepared using ungranulated red yeast rice. The data are shown in Table 6 below:

[0199] Table 6

[0200] The data shows that monacolin K is no longer present at T0 in the ungranulated gummies, indicating that it has been completely degraded during the gummies' production process.

[0201] Conversely, the monacolin K titer in the granulated gummies was very close to the target value (2.98 mg).

[0202] Example 5

[0203] Folic acid granules are used in oral soluble powders, dissolved in water, or in gummies or chewable tablets.

[0204] Using the same method as in Example 1, folic acid granules with a titer of 1.6% were prepared using the total amounts shown in Table 7 below:

[0205] Table 7

[0206] The obtained particles have the following technical parameters: Particle size distribution Not exceeding 5% ≥ 1000 µm Not exceeding 10% ≥ 710 µm At least 80% are between ≥125 µm and <710 µm Not exceeding 25% < 125 µm LOD (70℃; 15 minutes): 5.0% to 15.0%; Density: 0.4 g / ml to 0.7 g / ml; Flowability (100g): ≤25 seconds The granules obtained in Example 5 were then used to formulate gummies. Since conventional folic acid is heat-sensitive, it will degrade during the gummy processing, thus causing stability issues for the gummies.

[0207] Regarding this point, the stability data of gummies formulated with uncoated folic acid were compared with the stability data of gummies formulated with these granules. The results are as follows:

[0208] Table 8

[0209] As can be seen from the results shown in Table 8, gummies containing ungranulated folic acid at T0 no longer meet the specifications, indicating that this nutrient is degraded in large quantities during the gummy manufacturing process. Claims (as amended under Article 19 of the Treaty) 1. A modulating particle, comprising or consisting of: i) At least one active ingredient / nutrient selected from the group consisting of or comprising: - At least one vitamin, particularly: vitamin A; and / or at least one vitamin D, including vitamin D2, D3 and / or mixtures thereof; and / or vitamin C and / or one or more natural extracts containing vitamin C; and / or at least one B vitamin, including vitamin B1, B82, B3, B6, B12, pantothenic acid, folic acid, biotin and / or mixtures thereof; and / or vitamin E; and / or mixtures of said vitamins; - At least one mineral, particularly iron and / or magnesium and / or its 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 with polyphenols, such as green tea extract and grapevine extract, and / or a mixture thereof; - At least one fermented red yeast rice titrated with monacolin K and / or an extract thereof; and / or other sources of monacolin K, and / or mixtures thereof; and / or mixtures thereof; ii) Sodium alginate; and iii) Calcium lactate, wherein the particles are of prolonged release and delayed release. The granules are characterized in that they contain at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients, at 1% to 80% by weight relative to the total weight of the granules; sodium alginate at 5% to 60% by weight relative to the total weight of the granules; and calcium lactate at 5% to 60% by weight relative to the total weight of the granules. 2. The particles according to claim 1, wherein the particles preferably contain 20% to 50% by weight of sodium alginate relative to the total weight of the particles; and preferably 20% to 50% by weight of calcium lactate relative to the total weight of the particles. 3. The particles according to any one of claims 1 to 2, characterized in that, in the particles, the weight ratio of sodium alginate to calcium lactate varies in the range of 0.5:2 to 2:0.5, preferably about 1:1. 4. A method for preparing particles according to any one of claims 1 to 3, wherein the method comprises the following steps: a. Wet granulation of a mixture comprising or consisting of: at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; sodium alginate; and calcium lactate, to form granules to be coated; b. Coating the particles obtained from step (a) in two consecutive steps: b'. Granulating the particles obtained from step (a) with calcium lactate; and b''. Granulate the particles obtained from step (b') using sodium alginate. 5. The method according to claim 4, wherein the method comprises the following steps: a. To perform a first wet granulation on a mixture comprising or consisting of: i) at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; ii) sodium alginate; and iii) calcium lactate, to form granules to be coated; b. A second coating is applied to the particles obtained in step (a) through two consecutive steps: b'. Granulation of the particles obtained in step (a) with calcium lactate and sodium alginate; and b''. Granulate the particles obtained from step (b') using sodium alginate. 6. A method for preparing particles according to any one of claims 1 to 3, wherein the method comprises the following steps: a. Wet granulation of a mixture comprising or consisting of: at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; sodium alginate; and calcium lactate, to form granules to be coated; b. Coated particles are formed by coating the particles obtained in step (a) with a mixture of sodium alginate and calcium lactate in a single-step coating process. 7. The method of claim 6, wherein the method comprises fluidized bed granulation of a mixture comprising: i) at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; ii) sodium alginate; and iii) a mixture of calcium lactate, wherein granules are coated by a granulation step using the mixture of ii) sodium alginate and iii) calcium lactate to form coated granules. 8. A method for preparing particles according to any one of claims 1 to 3, wherein: - Preferably, in step a., the dosage is: 1% to 80% by weight of the at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients, relative to the total weight of the particles; 5% to 60% by weight, preferably 20% to 50% by weight, of sodium alginate relative to the total weight of the particles; and 5% to 60% by weight, preferably 20% to 50% by weight, of calcium lactate relative to the total weight of the particles; and / or - Preferably, in step b', the amount of calcium lactate used is 0.1% to 2% by weight, more preferably 0.2% to 1% by weight, relative to the total weight of the particles; and / or - Preferably, in step b'', the amount of sodium alginate used is 0.1% to 2% by weight, more preferably 0.2% to 1% by weight, relative to the total weight of the particles; or - Preferably, in step b., an aqueous mixture is used, comprising, relative to the total weight of the particles, 0.1% to 2% by weight, preferably 0.2% to 1% by weight of sodium alginate; and relative to the total weight of the particles, 0.1% to 2% by weight, preferably 0.2% to 1% by weight of calcium lactate. 9. A method for preparing particles according to any one of claims 1 to 3, characterized in that no organic solvent is used, and water is used as the sole solvent in all steps of the method. 10. An assembly comprising the following: i) At least one active ingredient / nutrient selected from the group consisting of or comprising: - At least one vitamin, particularly: vitamin A; and / or at least one vitamin D, including vitamin D2, D3 and / or mixtures thereof; and / or vitamin C and / or one or more natural extracts containing vitamin C; and / or at least one B vitamin, including vitamin B1, B2, B3, B6, B12, pantothenic acid, folic acid, biotin and / or mixtures thereof; and / or vitamin E; and / or mixtures of said vitamins; - At least one mineral, particularly iron and / or magnesium and / or its 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 with polyphenols, such as green tea extract and grapevine extract, and / or a mixture thereof; - At least one fermented red yeast rice titrated with monacolin K and / or an extract thereof; and / or other sources of monacolin K, and / or mixtures thereof; and / or mixtures thereof; and ii) Sodium alginate; and iii) Calcium lactate. 11. A pharmaceutical and / or food composition comprising particles according to any one of claims 1 to 3, or the combination according to claim 10, and one or more conventional excipients and / or carriers. 12. The composition according to claim 11, wherein the composition is in the form of a composition for oral administration. 13. The composition according to claim 11, wherein the composition is in the form of a chewable or swallowable tablet, capsule, sachet containing a powder / granule mixture that is orally soluble or soluble in water or other liquids, chewing gum or gummies. 14. The composition according to any one of claims 11 to 13, characterized in that the composition is in the form of a gummy candy.

Claims

1. A modulating particle, comprising or consisting of: i) At least one active ingredient / nutrient selected from the group consisting of or comprising: - At least one vitamin, particularly: vitamin A; and / or at least one vitamin D, including vitamin D2, D3 and / or mixtures thereof; and / or vitamin C and / or one or more natural extracts containing vitamin C; and / or at least one B vitamin, including vitamin B1, B2, B3, B6, B12, pantothenic acid, folic acid, biotin and / or mixtures thereof; and / or vitamin E; and / or mixtures of said vitamins; - At least one mineral, particularly iron and / or magnesium and / or its 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 with polyphenols, such as green tea extract and grapevine extract, and / or a mixture thereof; - At least one fermented red yeast rice titrated with monacolin K and / or an extract thereof; and / or other sources of monacolin K, and / or mixtures thereof; and / or mixtures thereof; ii) Sodium alginate; and iii) Calcium lactate, wherein the particles are extended-release and delayed-release.

2. The particles according to claim 1, characterized in that, The granules comprise, relative to the total weight of the granules, 1% to 80% of the at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; 5% to 60% of sodium alginate, preferably 20% to 50% of sodium alginate, relative to the total weight of the granules; and 5% to 60% of calcium lactate, preferably 20% to 50% of calcium lactate, relative to the total weight of the granules.

3. The particles according to any one of claims 1 to 2, characterized in that, In the particles, the weight ratio of sodium alginate to calcium lactate varies in the range of 0.5:2 to 2:0.5, preferably about 1:

1.

4. A method for preparing particles according to any one of claims 1 to 3, wherein, The method includes the following steps: a. Wet granulation of a mixture comprising or consisting of: at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; sodium alginate; and calcium lactate, to form granules to be coated; b. Coating the particles obtained from step (a) in two consecutive steps: b'. Granulating the particles obtained from step (a) with calcium lactate; and b''. Granulate the particles obtained from step (b') using sodium alginate.

5. The method according to claim 4, wherein, The method includes the following steps: a. To perform a first wet granulation on a mixture comprising or consisting of: i) at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; ii) sodium alginate; and iii) calcium lactate, to form granules to be coated; b. A second coating is applied to the particles obtained in step (a) through two consecutive steps: b'. Granulation of the particles obtained in step (a) with calcium lactate and sodium alginate; and b''. Granulate the particles obtained from step (b') using sodium alginate.

6. A method for preparing particles according to any one of claims 1 to 3, wherein, The method includes the following steps: a. Wet granulation of a mixture comprising or consisting of: at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; sodium alginate; and calcium lactate, to form granules to be coated; b. Coated particles are formed by coating the particles obtained in step (a) with a mixture of sodium alginate and calcium lactate in a single-step coating process.

7. The method of claim 6, wherein the method comprises fluidized bed granulation of a mixture comprising: i) at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients; ii) sodium alginate; and iii) a mixture of calcium lactate, wherein granules are coated by a granulation step using the mixture of ii) sodium alginate and iii) calcium lactate to form coated granules.

8. A method for preparing particles according to any one of claims 1 to 3, wherein: - Preferably, in step a., the dosage is: 1% to 80% by weight of the at least one active ingredient / nutrient, and / or a mixture of active ingredients / nutrients, relative to the total weight of the particles; 5% to 60% by weight, preferably 20% to 50% by weight, of sodium alginate relative to the total weight of the particles; and 5% to 60% by weight, preferably 20% to 50% by weight, of calcium lactate relative to the total weight of the particles; and / or - Preferably, in step b', the amount of calcium lactate used is 0.1% to 2% by weight, more preferably 0.2% to 1% by weight, relative to the total weight of the particles; and / or - Preferably, in step b'', the amount of sodium alginate used is 0.1% to 2% by weight, more preferably 0.2% to 1% by weight, relative to the total weight of the particles; or - Preferably, in step b., an aqueous mixture is used, comprising, relative to the total weight of the particles, 0.1% to 2% by weight, preferably 0.2% to 1% by weight of sodium alginate; and relative to the total weight of the particles, 0.1% to 2% by weight, preferably 0.2% to 1% by weight of calcium lactate.

9. A method for preparing particles according to any one of claims 1 to 3, characterized in that, No organic solvents are used; water is the only solvent in all steps of the method.

10. An assembly comprising the following: i) At least one active ingredient / nutrient selected from the group consisting of or comprising: - At least one vitamin, particularly: vitamin A; and / or at least one vitamin D, including vitamin D2, D3 and / or mixtures thereof; and / or vitamin C and / or one or more natural extracts containing vitamin C; and / or at least one B vitamin, including vitamin B1, B2, B3, B6, B12, pantothenic acid, folic acid, biotin and / or mixtures thereof; and / or vitamin E; and / or mixtures of said vitamins; - At least one mineral, particularly iron and / or magnesium and / or its 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 with polyphenols, such as green tea extract and grapevine extract, and / or a mixture thereof; - At least one fermented red yeast rice titrated with monacolin K and / or an extract thereof; and / or other sources of monacolin K, and / or mixtures thereof; and / or mixtures thereof; and ii) Sodium alginate; and iii) Calcium lactate.

11. A pharmaceutical and / or food composition comprising particles according to any one of claims 1 to 3, or the combination according to claim 10, and one or more conventional excipients and / or carriers.

12. The composition according to claim 11, characterized in that, The composition is in the form of a composition for oral administration.

13. The composition according to claim 11, characterized in that, The composition is in the form of chewable or swallowable tablets, capsules, sachets containing a mixture of powders / granules that are soluble or water- or other liquids, chewing gum, or gummies.

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

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