“FORMULATION FOR ORAL ADMINISTRATION OF ACTIVE COMPOUNDS WITH LOW BIOAVAILABILITY AND CORRESPONDING

PRODUCTION METHOD”

FIELD OF THE INVENTION

Embodiments described here concern a formulation for oral administration with high bioavailability of active compounds with generally poor bioavailability, and the corresponding production method. The formulation, in particular, includes one or more active compounds both very polar, therefore lipophobic, and also apolar or moderately apolar and therefore hydrophobic which, thanks to the association with specific, suitably esterified lipid excipients, are made more bioavailable. The formulation according to the embodiments described here can for example be the pharmaceutical type or food supplement or nutraceutical type.

BACKGROUND OF THE INVENTION

It is known that many active compounds of pharmaceutical, food and/or nutraceutical interest are poorly absorbed by the gastrointestinal tract, thus representing a challenge in the development of a formulation for oral administration.

In fact, both the solubility and also the absorption of the active compounds are important parameters for obtaining preferred or recommended concentrations in the systemic circulation, in order to achieve a required pharmacological response. In particular, for formulations administered orally, the solubility of the active compounds is one of the parameters that most limits the absorption capacity, and therefore the bioavailability, to obtain a desired concentration in circulation for the purposes of the pharmacological response.

CN-A-107050023 discloses a formulation containing Berberine and various excipients and sweeteners with the aim of masking the bitter taste of Berberine. The formulation also contains glycerol behenate to aid in the formation of granules. Glycerol behenate is provided in the form of Compritol 888 ATO which is an unsuitable product for food consumption, it is not food grade or food supplement grade. This document also describes a method for making granules containing the formulation, which provides to add Berberine to glycerol behenate and to melt the mixture thus obtained at 80°C to encapsulate the Berberine in the glycerol behenate. Subsequently the powder obtained is crushed and mixed with the excipients and sweeteners. This document in no way teaches to improve the bioavailability of active compounds with generally poor bioavailability, such as

5 Berberine for example. Furthermore, with regard to the method of producing the formulation, CN-A- 107050023 does not provide any precise details on the conditions of preparation, in particular on possible stirring of the mixtures, on the cooling gradients and on the stirring times. This document indicates that granulation using fluidized bed granulators is to be avoided. ίq On the contrary, WO-A-2019/024949 describes a method to produce oral pharmaceutical forms containing Berberine in order to improve the workability of the powder making it suitable for dry granulation, homogenization, tableting and capsule filling. The preparation of pharmaceutical forms takes place cold and with the use of glidants and/or lubricants. The formulation used has a weight

15 ratio between Berberine and lubricants or glidants comprised between 200:1 to 5:1, that is, the Berberine is at a higher weight concentration than the lubricants or glidants. Even this document does not teach a formulation to improve the bioavailability of active ingredients with poor bioavailability, such as Berberine.

There is therefore a need to perfect a formulation or composition for oral 0 administration of active compounds with poor bioavailability and a corresponding production method, which can overcome at least one of the disadvantages of the state of the art.

In particular, one purpose of the present invention is to provide a formulation or composition, of a pharmaceutical or food supplement or nutraceutical type, for 5 oral administration which increases the absorption of one or more of said active compounds in the intestinal tract, in particular compounds or highly hydrophilic polar active substances, that is, not soluble in the lipids of cell membranes, or in non-polar solvents, or non-polar or moderately apolar lipophilic compounds and active substances that are not soluble or poorly soluble in body fluids. Among the 0 hydrophilic compounds or active substances, it is the ionized ones, that is, those with positive and/or negative charge, that have particularly poor bioavailability.

The Applicant has devised, tested and embodied the present invention to overcome the shortcomings of the state of the art and to obtain these and other purposes and advantages.

SUMMARY OF THE INVENTION

The present invention is set forth and characterized in the independent claims. The dependent claims describe other characteristics of the present invention or variants to the main inventive idea.

In accordance with the above purposes, some embodiments concern a formulation or composition for oral administration of active compounds with low bioavailability. The formulation comprises one or more active compounds, both very polar and therefore hydrophilic, and also apolar or moderately apolar and therefore lipophilic, and one or more pharmacologically acceptable lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters.

In some embodiments, the fatty acid esters comprise, or consist of, glyceryl dibehenate.

In some embodiments, the one or more active compounds, both highly hydrophilic and also highly lipophilic, are complexed by means of the lipid excipients. The lipid excipients therefore act as complexing agents. Therefore, an active compound-lipid excipient complex is formed.

In some embodiments, the one or more active compounds are compounds or active substances that are not soluble in the lipids of cell membranes, or in non polar, or apolar or moderately apolar solvents that are not soluble or poorly soluble in body fluids. Among the hydrophilic compounds or active substances, it is the ionized ones, that is, those with positive and/or negative charge, that have particularly low bioavailability. In some embodiments, the formulation can be in the form of a tablet, differentiated release tablet, multilayer tablet, differentiated release multilayer tablet, filmed or coated tablet, gastro-resistant tablet, time or pH-dependent controlled release tablet, capsule or powder for extemporaneous suspension or liquid dispersion.

In some embodiments, the active compounds as above are selected from a group comprising, or consisting of, Berberine, Curcumin, fat-soluble vitamins (D, E, and K), coenzyme Q10, Diosgenin, water-soluble vitamins (e.g. Bl, B2, B5, Folate, etc.), flavonoids, palmitoylethanolamide (PEA), Resveratrol, oleoresins, gingerols, shogaols, Melatonin.

In a specific implementation of the formulation described here, the active compound can be, or include, Berberine and the fatty acid esters can be, or include, glyceryl dibehenate.

Advantageously, the lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters, are effective in increasing the bioavailability of the one or more highly hydrophilic, because for example ionized, apolar or moderately apolar active compounds.

Favorably, the excipients have specific binding and lubricating properties, which make them particularly suitable, for example, for the preparation of pressed powder formulations, for example tablets.

Preferably, the lipid excipients are suitable for consumption, in particular they are of food grade or food supplement grade quality.

Other embodiments described here concern the use of pharmacologically acceptable lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters, to increase the bioavailability of highly hydrophilic, because for example ionized, apolar or moderately apolar active compounds.

Yet other embodiments concern a method to produce a formulation or composition for oral administration able to increase the bioavailability of the compounds contained therein. The method comprises a preparation step in which lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters, and one or more highly hydrophilic, for example because ionized, apolar or moderately apolar compounds are associated, after which this association can possibly be reduced to a fine powder.

In some embodiments, the preparation step as above is carried out by means of a technique selected from: extrusion, dry granulation, wet granulation, fluid bed granulation, kneading, spray-drying, dry co-grinding.

In some embodiments, the preparation step can be either carried out hot or cold.

In the embodiments in which the preparation step as above is carried out hot, it provides that the lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters, are heated and, subjected to stirring, at least the one or more compounds are then added, a subsequent step in which the mixture continues to be stirred and, finally, a slow cooling of the mixture itself is determined, in accordance with a desired cooling gradient. After which, once a desired temperature has been reached, the mixture is eventually reduced to a fine powder.

In some embodiments, the fine powder as above can be processed to obtain the desired form of the formulation, in particular tablet, differentiated release tablet, multilayer tablet, differentiated release multilayer tablet, filmed or coated tablet, gastro-resistant tablet, time or pH-dependent controlled release tablet, capsule or powder for extemporaneous suspension or liquid dispersion.

BRIEF DESCRIPTION OF THE DRAWINGS These and other aspects, characteristics and advantages of the present invention will become apparent from the following description of some embodiments, given as a non-restrictive example with reference to the attached drawings wherein:

- fig. 1 shows graphs of basolateral concentration profiles of Berberine after incubation of different Berberine-based formulations on Caco-2 cells (n=3);

- fig. 2 shows a graph showing the quantity of Berberine (mhioI/L) detected in the basolateral solution after 180 minutes of incubation on Caco-2 cells;

- fig. 3 shows a graph showing the relative percentage of Berberine present in the basolateral solution after 180 minutes of incubation on Caco-2 cells;

- fig. 4 shows a graph showing the percentage increase, compared to the control, of Berberine permeated through the Caco-2 monolayer after 180 minutes of incubation.

DETAILED DESCRIPTION OF SOME EMBODIMENTS We will now refer in detail to the possible embodiments of the invention, of which one or more examples are shown in the attached drawings, by way of a non-limiting illustration. The phraseology and terminology used here is also for the purposes of providing non-limiting examples.

It is also understood that elements and characteristics of one embodiment can conveniently be combined or incorporated into other embodiments without further clarifications.

All measurements are carried out, unless otherwise indicated, at 25°C and at atmospheric pressure. All temperatures, unless otherwise indicated, are expressed in degrees Celsius.

All percentages and ratios indicated refer to the weight of the total composition (w/w), unless otherwise indicated.

All the percentage intervals reported here are provided with the provision that the sum with respect to the overall composition is 100%, unless otherwise indicated.

All the intervals reported here shall be understood to include the extremes, including those that report an interval “between” two values, unless otherwise indicated.

The present description also includes the intervals that derive from uniting or overlapping two or more intervals described, unless otherwise indicated.

The present description also includes the intervals that can derive from the combination of two or more values taken at different points, unless otherwise indicated.

Some embodiments described here concern a formulation or composition for oral administration able to increase the bioavailability of apolar or moderately apolar compounds with a generally low bioavailability, in particular highly hydrophilic, because for example ionized, contained in the formulation or composition. Highly hydrophilic compounds, also called lipophobic compounds, in particular, are active substances that are not soluble in lipids, or in non-polar solvents, generally highly water-soluble, or substances that are in any case highly ionized.

In some embodiments, the active compounds are selected from a group comprising, or consisting of, Berberine, Curcumin, Diosgenin, lipophilic vitamins (D, E and K), water-soluble vitamins (e.g. Bl, B2, folates, etc.), flavonoids, palmitoylethanolamide (PEA), Resveratrol, oleoresins, gingerols and shogaols, Melatonin.

The Applicant, starting from experimental studies conducted on Berberine, has discovered that its bioavailability is significantly increased if formulated in association with lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters.

Therefore, some embodiments concern a formulation as indicated above, which comprises one or more of the highly hydrophilic or apolar or moderately apolar active compounds as above, and one or more pharmacologically acceptable lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters.

In some embodiments, the fatty acids are, or the corresponding esters derive from, fatty acids with a chain of 12 to 30 carbon atoms. These fatty acids can be medium and/or long chain. Furthermore, these fatty acids can be saturated or mono-, poly-unsaturated.

The fatty acid esters can be obtained from fatty acids esterified for example and not only with glycerin (mono-, di-, tri-glycerides), sugars (e.g. sucrose esters) of natural or artificial origin (e.g. sucralose and its esters), polyols (e.g. sorbitans). Another example of fatty acid esters usable in the embodiments described here is glyceryl dibehenate. In some embodiments, therefore, the fatty acid esters comprise, or consist of, glyceryl dibehenate.

As stated, the Applicant initially studied Berberine (BBR), which is a natural hydrophilic, ionized compound isolated from the rhizome of the traditional Chinese herb Coptidis, identified for example as a promising cholesterol- lowering agent with satisfactory clinical efficacy and safety.

Berberine, however, is generally poorly absorbed in the intestinal tract, resulting in low bioavailability after oral administration. In particular, the bioavailability of Berberine is generally very low, around 0.7%.

The Applicant has found that, due to its poor solubility in lipids, the main constituents of cell membranes, the passage of Berberine through the membranes of intestinal cells is reduced, in particular. Furthermore, after oral administration, part of the Berberine remains intact through the gastrointestinal tract while the other part is metabolized through the small intestine.

In particular, the Applicant has devised an approach to increase the bioavailability of Berberine which, in some embodiments, contemplates the presence, in the formulation, of the lipid excipients as above, in particular phospholipids and/or fatty acids and/or fatty acid esters, as agents to increase the bioavailability of Berberine. It has been found that, in this way, the liposolubility of Berberine, and therefore its bioavailability, is significantly increased. A particularly advantageous example of fatty acid esters is glyceryl dibehenate. The latter derives from the esterification of glycerin with behenic or docosanoic acid, which is a linear long-chain (22 carbon atoms) saturated fatty acid.

The Applicant has noted that the complexation of Berberine with the lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters described here, significantly increases its intestinal absorption.

The Applicant believes that it is plausible to also extend the scientific rationale indicated above to other active compounds with chemical-physical characteristics similar to those of Berberine, that is, very polar, or in any case ionized substances, the bioavailability of which is normally low due to lipophobicity and high water-solubility and, in some cases, also to their high molecular weight. In addition to these, the scientific rationale can also be extended to apolar or moderately apolar compounds such as Diosgenin, which due to their hydrophobicity are poorly soluble in biological fluids.

The Applicant therefore believes that, similarly to what developed for Berberine, it is possible to significantly increase the bioavailability of the above compounds by providing to use the lipid excipients described here, in particular phospholipids and/or fatty acids and/or fatty acid esters, as complexing agents able to facilitate the passage both of the more polar ones through the membranes of intestinal cells, and also of the apolar or moderately apolar ones, thus increasing their intestinal absorption and consequently their bioavailability.

In some embodiments, the formulation described here comprises one or more pharmacologically acceptable adjuvants and/or excipients.

In particular, among the excipients there can be one or more of either diluents, absorbents, adsorbents, lubricants, binders, disintegrants, emulsifiers or surfactants, in particular surfactants, dyes, sweeteners, antioxidants or antimicrobials, polymers to modify the time or site of release, coating agents.

In specific embodiments, the formulation comprises one or more of such surfactant or emulsifying agents, in particular phospholipid emulsifiers. An example of a phospholipid emulsifier is lecithin, in particular soy lecithin or sunflower lecithin.

In other embodiments, among the excipients present in the formulation described here are the lipid excipients as above, in particular phospholipids and/or fatty acids and/or fatty acid esters. For example, the medium- or long- chain fatty acids and/or fatty acid esters with glycerin, such as mono-, di-, tri glycerides, sugars, such as sucroesters, or polyols, such as sorbitans.

Advantageously, the lipid excipients are present at a concentration comprised between 5 and 95% weight/weight with respect to the weight of the formulation, preferably between 10 and 90%, more preferably between 16 and 85%.

Another possible example of fatty acid esters is glyceryl dibehenate. In some embodiments, the glyceryl dibehenate is present between 5 and 50% weight/weight with respect to the weight of the formulation, preferably between 10 and 50%, more preferably between 16 and 50%.

In other embodiments, the glyceryl dibehenate is present between 5 and 80% (w/w) with respect to the weight of the formulation, preferably between 10 and 80%, more preferably between 16 and 80%.

In other embodiments, another possible example of fatty acid esters is glyceryl dibehenate. In some embodiments, the glyceryl dibehenate is present between 5 and 95% weight/weight with respect to the weight of the formulation, preferably between 10 and 90%, more preferably between 16 and 85%.

In some embodiments, the formulation described here comprises the one or more active compounds between 0.01 and 50% weight/weight, preferably between 2 and 48%, more preferably between 3.5 and 45%.

For example, if the active compound is Berberine, the formulation described here comprises Berberine between 1 and 50% weight/ weight, preferably between 2 and 48%, more preferably between 3.5 and 45%.

In some embodiments, the weight ratio between the lipid excipients as above, in particular phospholipids and/or fatty acids and/or fatty acid esters, and the one or more active compounds present in the formulation is between 1 : 1 and 20: 1.

For example, in the case of Berberine and glyceryl dibehenate, their ratio is between 1:20 and 1:1.

The presence of lipid excipients allows to increase the bioavailability of Berberine, which allows to decrease its concentration in the formulation. For example, with this solution, it is possible to provide a concentration of Berberine lower than 45% weight/weight with respect to the weight of the formulation, even lower than 30%, for example comprised between 4 and 15%.

Other embodiments described here concern a method to produce a formulation or composition for oral administration in accordance with the present description, able to increase the bioavailability of compounds with generally low bioavailability, in particular both very polar and apolar or moderately apolar, contained therein. In particular, the method includes a preparation step in which lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters, and one or more active compounds are associated. After which this association can possibly be reduced to a fine powder.

In possible embodiments, the preparation step as above is carried out by means of a technique selected from: extrusion, dry granulation, wet granulation or by means of fluid bed granulators, kneading, spray-drying, dry co-grinding. It has been observed that fluid bed granulators are particularly effective in obtaining the desired granulate.

In possible embodiments, the preparation step as above is carried out hot or cold. In the event that it is carried out hot, the preparation step provides that the lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters, are heated and, subjected to stirring, at least the one or more active compounds as above are then added. After this, the mixture is stirred and, finally, a slow cooling of the mixture itself is determined, in accordance with a desired cooling gradient. Once a desired temperature has been reached, the mixture is reduced to a fine powder.

Possibly, the fine powder can be processed to obtain the desired form of the formulation described here, for example tablet, differentiated release tablet, multilayer tablet, differentiated release multilayer tablet, filmed or coated tablet, gastro-resistant tablet, time or pH-dependent controlled release tablet, capsule or powder for extemporaneous suspension or liquid dispersion.

In possible embodiments, the temperature to which the lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters, are heated is between 60°C and 85°C, in particular between 65°C and 75°C.

In possible embodiments, the stirring time of the mixture obtained by adding the one or more active compounds as above to the heated lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters, is between 5 min and 25 min.

In possible embodiments, the stirring speed is between 3000 and 12000 rpm.

In possible embodiments, the cooling gradient of the mixture is 1-4 °C/min.

EXPERIMENTAL DATA

Transport experiments in Caco-2 cell model The Applicant has carried out transport experiments in a Caco-2 cell model to demonstrate that the association of polar compounds with lipid excipients, in particular phospholipids and/or fatty acids and/or fatty acid esters, increases their intestinal absorption and therefore improves bioavailability. The Applicant has carried out such transport experiments in a Caco-2 cell model using Berberine, a naturally positively ionized molecule, as an example of hydrophilic active compound and fatty acid esters, for example glyceryl dibehenate, as lipid excipient complexing Berberine. The fatty acid esters are of the food grade or food supplement grade type. The experiments carried out allowed the Applicant to demonstrate that it is possible to increase the intestinal absorption of Berberine, improving its bioavailability. It is believed that, in consideration of the scientific rationale explained above, it is plausible to also extend this result to other hydrophilic or in any case highly ionized compounds, for which, therefore, it is possible to increase intestinal absorption, improving their bioavailability.

For the purposes of the experimental tests, a system (BBR-ES) for delivery in emulsion (ES) for Berberine (BBR) was prepared and its effect on absorption of BBR was evaluated by means of a Caco-2 cell transport method. The following formulations were tested, each with a total weight of 1000 mg.

(*) In Test 4 (T4) a hot preparation technology was used, in which the fatty acids and/or fatty acid esters were heated to about 70 °C and, subjected to stirring, Berberine was added. The mixture was stirred for 10 minutes, slowly cooled and then reduced to a fine powder. Glyceryl dibehenate is a possible example of a fatty acid ester used in the experimental tests described here.

Transcellular transport of BBR was performed in accordance with a published study (Volpe 2011) with slight modifications. Each experiment was conducted in triplicate. The Caco-2 cells were supplied by the molecular biological laboratory of DeFENS, Universita degli Studi di Milano (I).

The cells were grown in T-75 culture flasks in a C0 ₂ :0 ₂ atmosphere (5:95 %, v/v) at 37°C, and cultured in a Dulbecco culture medium also containing 10% (v/v) FBS, 90 U/mL penicillin, 90 pg/mL streptomycin, 1% non-essential amino acids and L-glutamine. The Caco-2 model was tested by seeding the cells with 80% degree of confluence on Transwell® 24- well permeable supports at a density of 2x10 ⁵ cells per well. The permeability of the monolayers was evaluated by means of a transepithelial electrical resistance method and experiments were conducted when the resistance values were above 300 W-cm ² . In the experiments from apical (AP) to basolateral (BP) direction, 0.5 mL of test solution (5, 20 and 50 pg/mL of BBR) diluted by a pH 6.8 buffer was added to the AP side of the monolayer.

Aliquots (50 pL) were taken from the BP side at 30, 60, 90, 120 and 180 minutes and after centrifugation at 6000 x g, all samples were stored at -20 °C prior to Liquid Chromatography-High Resolution-Mass Spectrometry (LC-HR- MS) analysis.

At the end of the experiment, after 180 minutes, the cells were removed, counted and washed with pH 6.8 buffer, removing the adsorbed BBR. The washing solution was removed, and the cells treated with trypsin to separate the cells, which were lysed with Triton® lysis buffer. 50 pL of methanol was added to the lysate and the suspension centrifuged at 6000 x g for 1 min. The clear solution was transferred to a bottle, analyzed with LC-HR-MS and the quantity of Berberine expressed as ng/10 ⁶ cells.

The determination of the Berberine in all the samples was carried out by means of Acquity model Ultra Performance Liquid Chromatography (UPLC) (Waters, Milford, US) coupled to an E-Lambda model diode array detector (Waters) and to an Exactive model high resolution Fourier transform mass spectrometer (HR-FT-MS) (Thermo Scientific, San Jose, CA, USA) equipped with a HESI-II probe for electrospray ionization and a collision cell (HCD). The operating conditions were: spray voltage +4.0 kV, primary gas flow rate 55, auxiliary gas flow rate 10, capillary temperature 320°C, capillary +37.5V, lens +10 V, skimmer +26 V, and probe temperature 130°C. 5 pL was injected onto a 1.7 pm Kinetex XB g column (100x2.1 mm, Phenomenex) maintained at 40°C and flow 0.7 ml/min. The eluents were 0.05% formic acid in MilliQ (solvent A) and acetonitrile (solvent B) treated water. The chromatographic separation was carried out by means of the following linear elution gradient: from 5 to 50% of solvent B for 5 min and then from 50 to 90% for 5 min at a flow rate of 0.7 mL/min.

The identification of the BBR was carried out in full-scan mode in the range (m/z) ⁺ 100-1000 u, using an isolation window of ±2 ppm. The AGC target, injection time, mass resolution and energy in the collision cell were lxlO ⁶ , 100 ms, 50 K and 30 V respectively. The MS data was processed using the software Xcalibur (Thermo Scientific). The identity of the peak was also ascertained by evaluating the accurate mass of the fragments obtained in the collision cell. The calibration was in the range 0.01-10 pg/ml.

The results obtained seem to suggest that in particular the fatty acid esters (for example, glyceryl dibehenate) present in the formula could significantly change the transport of Berberine. In fact, the values of apical absorbtive transport (AP) compared to basolateral (BL) of formulations 1, 2, 3 and 4 are larger than those of the respective controls, as shown in fig. 1.

As expected, and as shown in fig. 2, among the test formulations prepared in the same way, the largest quantity of Berberine in the basolateral solution was T1>T2>T3. On the other hand, among the formulations containing the same quantity of Berberine (T3 and T4), that is, 50 mg, the formulation prepared by heating the solution of fatty acid esters (T4) showed a better absorption of the active ingredients. Fig. 2 shows the concentration of Berberine in the basolateral solution after 180 minutes of incubation with Caco-2 cells.

It should be noted that the relative percentage of Berberine permeated through the Caco-2 cells, compared with the quantity initially present in the apical solution was T4>T3>T2>T1, as seen in fig. 3. The formulations Test 1, Test 2, Test 3, Test 4 are as in Table 1.

Overall, the formulation containing fatty acid esters, for example glyceryl dibehenate, significantly increased the permeability of Berberine through the Caco-2 monolayer. In particular, a significant increase was measured in the quantity of Berberine absorbed by the Caco-2 cells as the Berberine Tatty acid esters ratio increased from 1:1 to 1:20, as shown in fig. 4. Particularly interesting is the fact that, considering the absorption percentages determined in the in vitro tests, approximately 75 mg of the T3 and T4 formulations correspond to 500 mg of the control formulation Cl .

Some examples of pharmacologically acceptable excipients and/or other ingredients that can be present in the embodiments of formulation described here are one or more of:

- cellulose, magnesium stearate, sodium bicarbonate, sodium silicate, silicon dioxide, talcum powder, bentonite, stearic acid, polyvinylpyrrolidone, polysorbates, polydimethylsiloxane, cross-linked sodium carboxymethyl cellulose, calcium phosphate, hydroxypropyl methylcellulose;

- steviol glycosides, erythritol, maltodextrin, sucralose, neohesperidin, polyols (for example xylitol, mannitol, sorbitol ...), sugars (for example fructose, glucose, sucrose);

- citric acid, lactic acid, tartaric acid;

- emulsifiers and thickeners (for example lecithin, gums, alginates, mono-, di-, tri-glycerides, fatty acids, phospholipids, fatty acid esters with sugars or polyols...);

- flavoring compounds (for example vanilla, strawberry, citrus, lemon, ...);

- dyes;

- vitamins, such as one or more of: Vitamin A, Vitamin Bl, Vitamin B2, Vitamin B3 (PP, niacin), Vitamin B5 (Pantothenic Acid), Vitamin B6, Vitamin B12, Vitamin C, Vitamin D, Vitamin E, Vitamin H, folates, vitamin K, in particular MK-7;

- minerals or metals such as one or more of: Magnesium, Potassium, Zinc, Selenium, Calcium, Fluorine, Phosphorus, Iron, Iodine, - natural extracts that provide active compounds, such as antioxidants, vitamins, minerals or other complementary nutrients such as for example one or more of: fermented red rice extract (RYR) as a source of Monacolin K, or Bergamot extract, propolis, berries (blueberry, bilberry, cranberry, currant, blackberry, raspberry, etc.), aronia (Chokeberry), mulberry, elder, hibiscus, orange, green tea, vitis vinifera, spices (rosemary, thyme, oregano, cumin, cinnamon or other), olives ( Olea europea ), as a source of flavonoids, Lactoferrin, Dioscorea villosa as a source of Diosgenin, Silymarin, coenzyme Q10, Folates, Astaxanthin, Policosanol/s, Sinensetin, omega-3 essential fatty acids, for example EPA and/or DHA, and/or omega-6 essential fatty acids, E-Camitine, L-acetyl-Camitine, Propionyl-L-Camitine, Acetyl-L-camitine taurinate, L-Camitine tartrate, creatine, carnosine, L-aspartic acid, L-asparagine, Diosmin, Hesperidin, Troxerutin, Glutamine, Phosphoserine, Ginkgo biloba ES (dry extract), Ginseng, Caffeine, choline or cytylcholine, L-arginine;

- essential oils. In some embodiments, the formulation described here, packaged as such or mixed with acceptable excipients and conveniently formulated, can be used in any form suitable for pharmaceutical use, possibly also for veterinary use, or in any form suitable for food and diet supplementation, or also in any form suitable for cosmetic use. Some embodiments of formulations in accordance with the following examples are described below, developed on the basis of experimental data and which are intended for illustrative and non-limiting purposes.

Example 1 - Three-layer prolonged-release tablet

The formulation described here can for example be formulated as a three-layer prolonged-release tablet, as exemplified below.

An example of fatty acid esters is glyceryl dibehenate. Example 2 - Tablet for oral use

The formulation described here can for example be formulated as a tablet for oral use, as exemplified below. Also in this case, an example of fatty acid esters is glyceryl dibehenate. Example 3 - Formulation obtained by means of hot preparation

About 700 mg of excipients, fatty acid esters and 100 mg of lecithin are heated at 70°C until

12000 rpm for 5 min. Add 100 mg of inert excipient and stir for 5 min at 12000 rpm. Allow to cool until the mixture solidifies, about 2°C/min. Reduce the mixture into a fine powder to obtain the semi-finished product to be used to make the final product.

Example 4 - Formulation obtained by means of spray-drying

The preparation obtained in example 1 or 2 is dissolved in an ethanohwater solution and maltodextrins and/or gums are added to the preparation thus obtained. The mixture is then subjected to spray-drying.

Example 5 - Formulation obtained by means of a fluid bed granulator

The only functional active ingredients in the form of powder present in the preparation in examples 1, 2 and 3 are loaded into the fluid bed granulator, brought to a temperature comprised between 50 and 85 °C. The fatty acid esters are dispersed in an ethanol: water:gum arabic and/or maltodextrins solution subjected to stirring and the dispersion obtained used as a granulating solution to be injected into the fluid bed.

It is clear that modifications and/or additions of parts and/or steps may be made to the formulation and to the production method as described heretofore, without departing from the field and scope of the present invention as defined by the claims.

REFERENCES

Volpe DA. Drug-permeability and transporter assays in Caco-2 and MDCK cell lines. Future Med. Chem. 3; 2011: 2063-2077.