IT202100016784A1 - Composition for the release of Magnesium ions - Google Patents

Description

DESCRIPTION

Of the Patent Application for Industrial Invention entitled:

?Composition for the release of Magnesium ions?

State of art

Magnesium? present in the human body where it plays multiple roles. At the molecular level, magnesium ? a cofactor of over 300 enzymes responsible for some of the most? important activities? biology in mammals, including humans. In living cells, magnesium is involved in the homeostasis of other minerals, such as sodium, potassium, and calcium, and in the formation, transfer, storage, and utilization of adenosine triphosphate (ATP), a major source of energy in living cells. In the human body, magnesium is involved in maintaining normal muscle and nerve function, heart rhythm, bone strength, and immune system health. Magnesium? also involved in regulating blood sugar levels and promoting normal blood pressure.

? state otherwise? reported a role of magnesium in the regulation of plasticity? synaptic.

Despite the crucial physiological role of magnesium, the population may not take sufficient quantities through the diet.

Studies have shown that the dietary intake of magnesium ? been historically inadequate in the US population (Ford et al., 2003 J. Nutr. 133, 2879-2882) or relatively low for some segments of the population.

Magnesium deficiencies are associated with loss of appetite, nausea, vomiting, fatigue, attention deficit disorder and hyperactivity. in children (ADHD), seizures, abnormal heart rhythms, up to diabetes and/or cardiovascular disease.

The recommended daily intake of magnesium for an adult? generally between about 15 mmol and 20 mmol (30 mEq to 40 mEq), and normal serum magnesium levels range from 0.7 mmol/L to 1.0 mmol/L. Foods rich in magnesium include legumes, whole grains, green leafy vegetables, nuts, coffee, chocolate and milk. The reference nutritional values for Magnesium according to EU Reg. 1169 are equal to 375 mg/day for an adult.

Although these foods are readily available, some individuals do not consume large amounts of them. adequate to meet the daily nutritional requirement. Additionally, increased consumption of processed foods, which tend to contain less magnesium, can explain the significant decline in dietary magnesium in the United States during the last century. Therefore, the continued use of an oral absorbable and bioavailable magnesium supplement? strongly recommended, since? Magnesium intervenes in the process of cell division, contributes to the maintenance of normal teeth and bones. Magnesium also contributes to normal protein synthesis and muscle function. Furthermore, Magnesium contributes to the normal functioning of the nervous system and to normal psychological function. Finally, Magnesium contributes to normal energy-yielding metabolism and electrolyte balance, reducing tiredness and fatigue.

Commercially available magnesium supplements include magnesium oxide tablets or capsules, various inorganic compounds of magnesium, such as magnesium hydroxide and magnesium sulfate, compounds of magnesium salts of organic acids, such as magnesium salts of gluconic acid, citric and lactic acid, and various chelated Magnesium compounds.

The subject of the present invention is a controlled release granule formulation which comprises a positively charged ion, preferably Magnesium.

Description

The granulate according to the present invention ? characterized by being constituted by a two-layer coating core, where the core comprises salts of a positively charged ion, said first coating layer ? hydroxypropylmethylcellulose, said second coating layer comprises at least one gelling agent, at least one vegetable fiber and microcrystalline cellulose.

Description of the figures

Figure 1: flowability of powders, flowability times relating to the samples analysed. For each sample, 3 values are reported (white columns), with relative margins of error equal to 10%, and the average value (grey columns).

Figure 2: compressibility index values? (Ic) relating to the samples analysed.

Figure 3: values of the angle of repose relating to the samples analysed.

Figure 4: Density? upon pouring (grey columns) and shaking (white columns) of the four analysis samples.

Figure 5: Particle distributions of the four samples under analysis, compared to the base granulate. Nine ranges of particle distribution are reported for each sample.

Figure 6: quantity? of Magnesium (?g/ml and percentage ratio with respect to the initial ion) released by the granule after 15 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 16 hours and 24 hours in an alkaline environment pH= 8.

Detailed description

The granulate according to the present invention consists of a core coated with two layers.

The core of the granulate according to the present invention comprises at least one salt of at least one positively charged ion. In one embodiment, said ion ? Magnesium and/or Calcium. Preferably ? Magnesium. In a preferred embodiment, said core consists of a mixture of magnesium oxide and magnesium hydroxide.

Magnesium oxide ? an ingredient authorized in food supplementation by Reg. CE 1170/2009 - List of vitamins and minerals and their forms that can be added to foods, including food supplements. Each gram of magnesium oxide contains 600 mg of magnesium. Magnesium oxide ? strongly hygroscopic, in the presence of water it transforms into the hydrated form, known as magnesium hydroxide which has better bioavailability compared to the forerunner.

Magnesium hydroxide ? authorized in food supplementation by the aforementioned regulation. ? characterized by a low solubility? and a high title in Magnesium. ? capable of recalling water by osmotic gradient.

Said first layer comprises hydroxypropyl methylcellulose, preferably consists of hydroxypropyl methylcellulose. L? Hydroxy-propyl-methylcellulose ? authorized in food supplementation by EC Reg. 1333/2008 relating to food additives. Does it have properties? viscosifiers and ? advantageously used in wet granulation processes, where it creates a coating around a pre-existing core. This coating, subsequently placed in contact with water, swells, creating a viscous lattice which slows down the solubilization and migration of the constituents of the inner core.

Said second coating layer comprises:

i) cellulose, authorized in food integration with the aforementioned EC Reg. 1333/2008. Due to its strong tendency to retain water, it lends itself to wet granulation of highly hygroscopic ingredients which, if wetted directly with water, tend to agglomerate, leading to the formation of an unstable and inhomogeneous compound. The presence of cellulose allows to slowly and gradually wet these substances, leading to the formation of a stable and homogeneous compound;

ii) at least one gelling agent, selected from the group comprising xanthan gum, acacia gum, guar, agar, pectin, carrageenan, gellan, or mixtures thereof. In a preferred form, called gelling agent ? acacia gum, authorized in food integration with the aforementioned Reg. CE 1333/2008. The acacia gum ? a high molecular weight polysaccharide which has excellent solubility? and stability in the water and one of the tires pi? commonly used in the food industry. The properties? viscosifiers of acacia gum, combined with the high solubility, make it ideal for the transformation processes of powder mixtures into compressible granules. ? able to form, during the granulation phase, liquid bridges between the particles, which subsequently solidify in the drying phase. The semi-finished product obtained with this rubber has greater smoothness, density? and homogeneity, characteristics favoring compression.

iii) at least one vegetable fibre, preferably selected from the group comprising beet fibre, carrot fibre, apple fibre, orange fibre, or mixtures thereof. In one embodiment, ? beetroot fiber, authorized in food supplementation with DM 10.08.2018. ? a fiber characterized by a particular ratio between the soluble fraction, which represents about 18% by weight, and the insoluble fraction, formed by cellulose and corresponding to about 57%. The presence of this relationship allows high properties? viscosifiers in contact with water.

In a preferred embodiment, said second layer consists of a mixture of cellulose, acacia gum and beet fibre. In one embodiment, said components are in a ratio of 1.5-1.7 cellulose : 0.9-1.1 acacia gum : 2 -2.2 beet fiber, or 1.5 cellulose : 1 gum d ?acacia : 2 beet fiber.

In a preferred form, said granulate comprises (% w/w):

Magnesium oxide: 18% - 24%

Magnesium hydroxide: 15% - 21%

hydroxypropylmethylcellulose (HPMC): 10% - 16%

microcrystalline cellulose: 13% - 19%

acacia gum: 7% - 13%

beetroot fiber : 17% - 25%

In a preferred form, said granulate comprises (% w/w):

Magnesium oxide: 20% - 22%

Magnesium hydroxide: 17% - 19%

hydroxypropylmethylcellulose (HPMC): 12% - 14%

microcrystalline cellulose: 15% - 17%

acacia gum: 9% - 11%

beetroot fiber : 20% - 22%

In a preferred form, said granulate comprises (% w/w):

Magnesium oxide: 21% - 22%

Magnesium hydroxide: 18% - 19%

hydroxypropylmethylcellulose (HPMC): 13%-14%

microcrystalline cellulose: 15% -16%

acacia gum: 10% - 11%

beet fiber : 21% - 22%

In a preferred form, said granulate comprises (% w/w):

Magnesium oxide: 21.15%

Magnesium hydroxide: 18.35%

hydroxypropylmethylcellulose (HPMC): 13.23%

microcrystalline cellulose: 15.72%

acacia gum: 10.37%

beet fiber : 21.18%

A further object of the present invention is a method for obtaining said granulate, wherein said method comprises:

1) Make available a powdered mixture of Calcium and/or Magnesium ion salts and hydroxy-propyl-methylcellulose (HPMC);

2) Transformation of said wet mixture into basic granulate;

3) Drying and calibration of the basic granulate;

4) Make available microcrystalline cellulose, at least one gelling agent, at least one vegetable fibre;

5) Wetting said microcrystalline cellulose;

6) Addition to said wet microcrystalline cellulose of the base granulate, the gelling agent and the vegetable fiber and granulation.

Preferably, said granulation steps are carried out in a four-way kneader.

Preferably, said drying step is carried out in a fluid bed granulator, at a T between 55? C and 65?C.

Preferably, said calibration step ? obtained with a calibrator mounting a mesh of 1250 ?M.

Surprisingly, the authors of the present invention have demonstrated that beetroot fibre, compared to other vegetable fibres, allows to obtain a granulate with advantageous characteristics.

In particular, the granulate obtained with the process according to the present invention allows to maintain almost at the end of the process the quantities of ions supplied by the salts remain unchanged.

The release studios also have demonstrated that the Magnesium released corresponds almost? to the total of the Magnesium loaded, where said release measure includes the initial free Magnesium, the Magnesium released in an acid environment and the Magnesium released in an alkaline environment.

Of the amount? of ion loaded in the formula, moreover, about the half? is released in the gastric environment and therefore is already? accessible 1 hour after administration. About 40% of the total is then released gradually and in a controlled manner over the next 24 hours in an alkaline environment.

Examples

Example 1: double layer granulation process, vegetable fiber selection

4 different granulated powders based on different vegetable fibers were created and selected, selected from beetroot fibre, carrot fibre, orange fiber and apple fibre. Table 1 below shows the quantitative composition of the 4 granules tested.

Table 1

Each sample underwent a double wet granulation process using a ?Viani? type four-way mixer. and ?Viani? type fluid bed granulator, in order to create, for each of them, a granulate having a structure consisting of a nucleus represented by magnesium oxides, a first coating of hydroxy-propyl-methylcellulose and a second coating of acacia gum, vegetable fiber and microcrystalline cellulose.

Granulation process N? 1

This first granulation process, common to the four samples in table 1, involves the granulation of magnesium oxide, magnesium hydroxide and hydroxy-propyl-methylcellulose.

This type of process includes two stages:

1. Wetting of the powder mixture and transformation of the same into basic granulate;

2. Drying and calibration of the basic granulate.

The first phase of the process consists in the transformation of the powders using a four-way mixer of the ?Viani? type. During this stage, the powders are mixed together via two mixing belts mounted on a common counter-rotating shaft and simultaneously wetted with water via vertical nebulization (top spray).

The second stage of the process consists in the mobilization of the granulate obtained by means of a ?Viani? type fluid bed granulator, through a continuous flow of air at a constant temperature between 55?C and 65?C. During this phase, the granular particles obtained, flowing by gravity on the internal surfaces of the granulator, they acquire a semi-spherical and homogeneous shape.

The granulate obtained is then calibrated using a ?Viani? type calibrator, mounting a mesh with 1250 ?m meshes. The forced passage of the granules through the mesh makes the semi-finished product homogeneous in size.

To the resulting semi-finished product ? given the name of ?basic granulate? and represents the common component of all four samples under analysis. Of the ?basic granulate? the following parameters were analyzed and defined:

1. Smoothness;

2. Compressibility index;

3. Angle of rest;

4. Density?;

5. Particle size distribution;

All the above analyzes were carried out according to the guidelines reported in the European Pharmacopoeia X edition.

1. Smoothness

The flowability analysis of a powder? been performed by measuring the time taken by 100 g of the same to flow from a funnel which includes a hopper with a diameter of 12.5 cm with an inclination of 30?, a drawn hole 1.2 cm wide and 12.5 cm long with a? terminal inclination, at the outlet point of the powder to be tested, of 45?.

For each sample studied, the analysis? been performed three times. The times were measured using a HANHART chronograph, model DELTA E 200. By definition, a powder is defined as flowing if each of the 3 measured values does not deviate from the average value for more than one hour. by 10%.

2. Compressibility index?

The index of compressibility? of a powder is measured starting from the values of volume upon pouring and volume upon shaking of the same.

The analytical method involves pouring 100 g of product to be tested into a 250 ml graduated cylinder, using a funnel.

The volume value on payment? represented by the height initially reached by the powder inside the cylinder, this height ? defined V0.

To measure the shaking volume (Vf), the powder inside the cylinder is subjected to a capping process, which consists of a series of consecutive shaking and vibrations divided into three different steps: the first corresponds to 10 shakings, the second to 500 and the third to 1250.

The analysis consists in the evaluation of the height reached by the powder in the cylinder and therefore of the corresponding volume, at each of the three passages. The values are referred to as V10, V500 and V1250.

If the difference between the V500 and the V1250 is less than 2 ml, the V1250 is defined as the volume when the powder is shaken, if instead the difference between the two is ? greater than 2 ml, the analysis requires performing the third step again with a further 1250 shakings. What is the final volume? got correspond? to the volume on shaking.

The index of compressibility? (Ic) corresponds to the percentage value obtained by dividing the difference between V0 and Vf, by the value of V0.

Ic = [(V0-Vf)/V0] x 100

Greater ? the value of Ic minor ? the flowability of the powder.

3. Angle of rest

The calculation of the angle of repose of a powder ? obtained starting from the height and diameter values of the symmetrical cone that it generates by flowing through a funnel having the following characteristics:

- a hopper with a diameter of 12.5 cm with an inclination of 30?;

- a drawn hole 1.2 cm wide and 12.5 cm long with a terminal inclination, at the point where the powder to be tested comes out, of 45?.

The angle of rest? defined as the value obtained by dividing the height of the symmetrical cone by half? of the diameter value.

? = h / (0.5 x d)

Greater ? the minor angle of rest ? the flowability of the powder.

4. Density?

The density? of a powder? defined by the density? to the payment and from the density? to shaking. Both measurements are obtained by dividing 100 g of the powder to be analyzed by the corresponding measured volume value.

5. Particle size distribution

The analysis of particle size distribution? based on the selective sieving of a powder sample and on the percentage calculation of its distribution in the size classes corresponding to the sieve meshes.

Particle size analysis by sieving makes use of 8 sieves arranged in series, each of which retains the fraction of solid whose grains are larger than the holes in the sieve.

The mesh sizes of the sieves used are, in descending order: 710 ?m, 500 ?m, 355 ?m, 250 ?m, 180 ?m, 125 ?m, 90 ?m and 63 ?m.

The column of sieves rests on a mechanical shaker, called a vibrating sieve. During the analysis, the vibrating sieve shakes the column for 15 minutes, after which the solid fractions retained by each plate are weighed.

The weight of each solid fraction is then compared to the weight of the total solid, to obtain the percentage (by mass) of solid retained in each dish.

Tables 2 and 3 below show the results obtained. The numbers in the first row refer to the parameters measured as specified above.

Table 2

Table 3

As can be seen from table 3, about 80% of the powder analyzed has a particle size distribution of between 125 and 710 microns.

Granulation process N? 2

The second granulation process starts from the basic granulate, obtained from the N? 1, which is reworked in the presence of vegetable fibre, acacia gum and microcrystalline cellulose, components specified in Table 1.

This second process consists of the same two previous macro-phases, with a substantial difference in the processing of the powders during the wetting phase of the mixture.

In fact, instead of spray water directly on the powders and then have a direct wetting of the same, you exploit the capacity? of the microcrystalline cellulose to capture water and release it slowly if subjected to thrust and shear forces, allowing indirect wetting, which avoids uncontrolled agglomeration of the compound being processed.

The wetting phase of the powders in this second wet granulation process is divided into two sub-phases.

to. In a first sub-phase, using a four-way mixer of the ?Viani? type, the quantity? of water calculated for the realization of the mixture is sprayed exclusively on the microcrystalline cellulose.

b. In the second, the basic granulate, acacia gum and vegetable fiber are added to the microcrystalline cellulose enriched in water. The thrust and shear forces of the four-way kneader induce the cellulose to gradually release water onto the remaining powders, favoring more effective wetting. homogeneous and inducing the formation of new viscous liquid bridges between them by the acacia rubber and the vegetable fibre, which will create a second coating around the preformed granulate.

Were they like this? made the 4 samples and have been analyzed and compared their properties? in terms of the following 4 parameters:

1. Smoothness;

2. Compressibility index;

3. Angle of rest;

4. Density?;

The four values are predictive of the behavior of the granulate in the event of further processing, such as compression.

Pi? are the parameters of density high? and smoothness of a powder and more? low are the values of? angle of repose and of? index of compressibility?, pi? a powder lends itself to being transformed into a tablet. The results obtained are reported in Table 4.

Table 4

The BF5C, CF 1525 C and PECTIN samples can be defined as free-flowing powders, as the analysis times detected do not deviate from the relative average values by a value greater than the margin of error, as shown in the graph in figure 1.

According to the scale of smoothness relating to the indices of compressibilit? reported in European Pharmacopoeia X, the BF5C and PECTIN samples present a flowability defined as ?good?, while the CF 1525 C and KF15C samples present an ?acceptable? flowability, as shown by the graph in figure 2.

When the smoothness ? given by the angle of repose, according to the flowability scale relating to the angle of repose reported in the European Pharmacopoeia X, the BF5C and CF 1525 C samples have a defined ?acceptable? flowability, the PECTIN sample has a ?low? flowability, while the KF15C sample has a "very low" smoothness, as shown in figure 3.

Based on the density values? detected and shown in figure 4, the powders which lend themselves most to being transformed into tablets are the samples CF 1525 C, BF5C and PECTINS.

The data obtained show that:

? the semi-finished products that have a pi? high degree of flowability are, in descending order, the samples BF5C and CF 1525 C;

? the semi-finished products that have a pi? low index of compressibility? they are, in descending order, the BF5C and PECTIN samples;

? the semi-finished products that have a pi? low value relative to the angle of repose are, in decreasing order, the samples BF5C and CF 1525 C;

? the semi-finished products that have a pi? high degree of density? they are, in descending order, the CF 1525 C and BF5C samples as well as the PECTINE sample;

In parallel to the aforementioned analyses, ? the particle distribution of each sample was also evaluated. In fact, by analyzing the granulometric distribution values of each individual sample and comparing it with that of the base granulate, ? It is possible to verify whether the final semi-finished products obtained actually correspond to a single granulate, characterized by a double coating.

A particle size distribution oriented to a high percentage of larger particles, ? index of a high degree of success of the second granulation process and of the effective formation of a double coating around the nucleus of magnesium salts, while a particle size distribution oriented towards a high percentage of particles of smaller size, similar or comparable to that of the basic granulate, ? index of a parallel granulation and not of a double coating of the starting granulate. The results, shown in table 5 below, indicate that, as for the basic granulate, the KF15C and PECTIN samples present approximately 80% of the powder distributed between 125 and 710 microns. The BF5C and CF 1525 C samples instead present respectively about 88% and 86% of the powder distributed between 125 and 710 microns. In particular, the BF5C sample presents 67% of dust between 250 and 710 microns, while the CF 1525 C sample, approximately 59%.

Table 5

The observation? evident from figure 5, where the graph allows the peaks of the different samples to be compared with those of the basic granulate. Greater ? the height of the peaks between 125?m and 710?m, and less? that of the peaks between 125?m and 0?m, pi? high ? the degree of success of the second granulation process.

The sample that presents the particle size distribution tending to have the pi? high percentage of larger particles ? the BF5C sample.

The analysis of the parameters considered made it possible to select the beet fiber as the preferred one for the purpose.

Example 2: load study

The BF5C sample obtained as per example 1? underwent a load study. The purpose of the analysis? that of verifying that the double wet granulation process did not compromise the quantity? of Magnesium present in the core of the granule.

The title of Magnesium ? was determined by analytical process EPA 3051A 2007 and EPA 6010D 2018.

Briefly, an aliquot of 0.5 g of the granulate BF5C ? was digested in a solution of 8 ml of 65% concentrated nitric acid (HNO3) and 2 ml of 36% concentrated hydrochloric acid (HCl), at a temperature of 175 ?C for 5 minutes.

After digestion, the sample ? been filtered through a filter characterized by a porosity? of 0.45 µm and made up to the volume of 100 ml with deionized water.

The solution obtained? was then analyzed using optical emission spectrometric instrumentation (ICP-OES), capable of detecting the element. The expanded uncertainty reported in the test report ? calculated with a coverage factor k = 2, corresponding to a confidence level of approximately 95%. The measured Magnesium titre corresponds to 20.9%, consistent with the theoretical hypothesized one of 20.4%.

Example 3: release study

After confirming that the title of Magnesium present in the BF5C sample corresponds to that assumed on the basis of the quantity? of ingredients inserted and the relative title, the sample ? been subjected to evaluations to verify its performance of controlled and prolonged release of Magnesium ions over time. The study includes two phases:

1. evaluate the quantity? of Magnesium in free form, this cio? on the surface of the granule and not inside it;

2. evaluate the quantity? of Magnesium which is released over time, both in acid and alkaline environments.

To confirm the quantity? of Magnesium actually encapsulated inside the double coating, solutions of sample BF5C in water were tested, at a concentration of 1 mg/ml and 0.1 mg/ml.

The analysis technique involved the use of a colorimetric assay ?Magnesium Assay Kit? .

This procedure is based on the Magnesium-dependent phosphorylation reaction, catalyzed by the enzyme glycerol kinase, whose reactants are glycerol and ATP (adenosine triphosphate) and whose products are glycerol-3-phosphate and ADP (adenosine diphosphate).

By incubating the reaction products with a calmagite-based dye solution, the formation of a complex between the dye and glycerol-3-phosphate is induced, the intensity of which is of color? directly proportional to the free magnesium concentration of the sample.

The absorbance of the sample is read at a wavelength of 450 nm using a colorimetric reader and the relative quantity? of free ion, ? calculated using a calibration line constructed with known and increasing concentrations of Magnesium.

During the entire analysis process, only the initially free Magnesium is detected, as the fraction enclosed in the granule is not available for the enzymatic phosphorylation reaction.

For the study of the release of Magnesium, ? instead, a solution containing 100 mg of sample BF5C, diluted in 20 ml of water, was tested.

The release study envisaged two experimental conditions:

- solution mimicking the gastric environment at pH=2;

- solution mimicking the alkaline environment at pH=8;

For the release study in an acid environment, 18 ml of concentrated HCl were added to the solution of 100 mg of BF5C sample and 20 ml of water. The analysis sample? been incubated at 37?C on an orbital shaker at a speed? of 300rpm.

The final concentration of magnesium ion in solution? equal to 0.536 mg/ml. For the release study in an alkaline environment, 12 ml of pancreatin, 6 ml of bile acids and 1N sodium hydroxide (NaOH) were added to the solution of 100 mg of BF5C sample and 20 ml of water, until reaching the pH desired. Also in this case, the sample of analysis ? was incubated at 37 ?C on an orbital shaker at a speed? of 300rpm.

Also for this study, the final concentration of Magnesium ion in solution ? equal to 0.536 mg/ml.

Assuming a limited permanence time of the product in the stomach, the acid solution? been tested at t0 and t1ora, while the alkaline ? been tested at: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 16 hours and 24 hours.

For the surveys of the quantities? of ion released at various time intervals, ? the same colorimetric assay ?Magnesium Assay Kit? was used. Results

quantity of Magnesium in the maximum load study (free Magnesium).

? It is possible that during the granulation process not all the Magnesium is placed inside the two layers of the granulate, but that a part migrates on the surface making the ion immediately available in solution. In both tests conducted, both solutions show a quantity? of free Magnesium less than 10% (table 6).

Table 6

For the release in the gastric environment, the quantity? of free Magnesium ion reported at different time intervals ? subtracted from the free ion value detected in the previous phase of the study. For each experimental condition analyzed ? the percentage of Magnesium released with respect to the initial ion load is indicated. The release of 46% of the Magnesium contained in the granule is observed (table 7).

Table 7

For the release in an alkaline environment, the release of Magnesium from the granulate is tested after 15 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 16 hours and 24 hours in an alkaline environment pH=8.

The quantity? of free Magnesium ion reported at different time intervals ? subtracted from the free ion value detected in the previous phase of the study. For each experimental condition analyzed ? Table 8 shows the percentage of Magnesium released with respect to the initial ion load. Data show that after 24 hours about 39% of ? passed from the granule to the alkaline solution.

Table 8

Figure 6 shows the quantities? of Magnesium released from the granule after 15 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 16 hours and 24 hours in an alkaline environment pH=8. The values of released Magnesium are expressed in ?g/ml and as a percentage ratio with respect to the initial ion. The values found indicate a constant and gradual release over time, reaching, after 24 hours, a release value of more than 39% with respect to the quantity? of charged ion.

Claims (8)

1. A granulate suitable for use as a dietary supplement, comprising granules consisting of a core and a double layer coating, wherein said core comprises at least one salt of a positively charged ion, said first layer coating comprises hydroxypropyl -methylcellulose (HPMC) and said second layer comprises cellulose, at least one gelling agent, at least one vegetable fibre. 2. The granulate according to claim 1, wherein said ions are Calcium and/or Magnesium, preferably Magnesium. 3. The granulate according to claim 1 or 2, wherein said core comprises Magnesium oxide and Magnesium hydroxide. 4. The granulate according to one of the claims from 1 to 3, where said at least one gelling agent? selected from the group which includes xanthan gum, acacia gum, guar, agar, pectin, carrageenan, gellan, or mixtures thereof. 5. The granulate according to one of claims 1 to 4, wherein does it say at least one vegetable fiber? selected from the group which includes beet fiber, carrot fiber, apple fiber, orange fiber, or mixtures thereof. 6. The granulate according to one of claims 1 to 5, wherein said core comprises Magnesium oxide and Magnesium hydroxide, said first layer consists of HPMC, said second layer consists of acacia gum, cellulose, beet fibre. 7. A method for obtaining a granulate according to one of claims 1 to 6, wherein said method comprises: - Make available a powder mixture of calcium ion salts and/or magnesium and hydroxy-propyl-methylcellulose (HPMC); - Transformation of said wet mixture into basic granulate; - Drying and calibration of the basic granulate; - Make available microcrystalline cellulose, at least one gelling agent, at least one vegetable fibre; - Wetting said microcrystalline cellulose; - Addition to said wet microcrystalline cellulose of the base granulate, the gelling agent and the vegetable fiber and granulation. 8. The method according to claim 7, wherein said drying step is carried out in a fluid bed granulator, at a T between 55? C and 65?C.