IT202100006893A1 - A FORMULATION IN THE FORM OF MICROGRANULES INCLUDING AN EXTRACT OR MOLECULE OF VEGETABLE ORIGIN HAVING GASTROLESIVE EFFECTS OR INSTABILITY TO ACID PH, AND A GASTRO-RESISTANT MATRIX - Google Patents

Description

DESCRIPTION of the invention entitled:

?A FORMULATION IN THE FORM OF MICROGRANULES INCLUDING AN EXTRACT OR MOLECULE OF VEGETABLE ORIGIN HAVING GASTROLESIVE EFFECTS OR INSTABILITY? WITH ACID PH, AND A GASTRO-RESISTANT MATRIX?.

The present invention refers to formulations in the form of microgranules for gastro-resistant oral administration comprising at least one extract of plant origin (botanical) or at least one molecule of plant origin, having gastro-damaging effects and/or instability? with acid pH, and a gastro-resistant (enteric) matrix, in which said matrix coats and/or incorporates (coat and/or embed) said extract of vegetable origin. The presence of said gastro-resistant matrix allows said at least one extract or molecule of vegetable origin to pass the gastric tract without generating undesirable effects and without undergoing modifications, and furthermore allows said at least one extract to be released mainly in the intestinal tract.

Said formulations in the form of microgranules comprising at least one gastro-protected vegetable extract or molecule according to the present invention can be used for the preparation of food supplements, foods for special medical purposes (AFMS), compositions for medical devices or pharmaceutical compositions.

Furthermore, the present invention relates to a process for the preparation of said formulations in the form of microgranules for gastro-resistant oral administration, said microgranules comprising at least one extract, or a molecule of vegetable origin, said process being capable of conferring protection, said at least one extract, or a molecule of vegetable origin, at the gastric level (gastric = relative or inherent to the stomach) and the gastric wall (gastric wall, the surface that delimits the stomach cavity). The process gives gastroprotection to said at least one extract, or a molecule of vegetable origin, making them gastroprotective.

Extracts of plant origin (or botanicals), such as extracts of portions of plants such as leaves, seeds, roots and/or rhizomes, or molecules of plant origin are widely used as active ingredients both in food supplements (or AFMS) and in compositions for medical devices or pharmaceutical compositions, for the therapeutic or non-therapeutic (for example cosmetic) treatment of various problems.

Despite this, some extracts or molecules of plant origin can cause unpleasant side effects for those who use them, so as to determine the suspension of their intake.

In most cases, said side effects are stomach and/or intestinal disorders due to the presence of molecules which have a detrimental effect on the gastric mucosa. Said harmful effect on the gastric mucosa can? cause acidity? gastric, have effects on motility? gastrointestinal tract and/or cause nausea, vomiting and/or gastric discomfort.

Further side effects caused by extracts or molecules of vegetable origin, or by compounds containing them, are gastric disturbances caused by their bitter taste, such as nausea, vomiting, loss of appetite and/or gastric discomfort.

Gastrolesive or gastrolesivit? are these terms that are found with reference to drugs, for example a gastrolesive drug (from the Greek gastros, gaster = stomach)? a drug that causes inflammatory processes in the stomach or in subjects who already? suffer from gastric ulcer even bleeding. ? note the gastrolesivit? of non-steroidal anti-inflammatory drugs (NSAIDs), but also of other substances (non-drugs). In general, the gastrolesivit? weakens the ability defense and functional recovery of the gastric mucosa. Numerous studies show that the acidity gastric can? play an important role in promoting this toxicity? gastrointestinal. However, as mentioned above, gastrolesivity? can? also be caused, or caused, by other substances, not drugs. ? therefore it is important to be able to act to reduce gastrolesivit? caused by non-drug substances, substances that may be present in compositions for food supplements, medical devices (Reg. 745/20017) or foods for special medical purposes (AFMS).

In the context of the present invention, with the term extract or molecule of vegetable origin with ?gastrolesive effects? an extract or molecule of vegetable origin is understood which, at the doses used in the treated subject, causes not only beneficial effects but also undesirable side effects on the gastric system as defined in the context of the present invention (side effects known in the literature or not). These side effects may be due to the extract as a whole or to one or more components or molecules present in said extract.

In the context of the present invention, with the term extract or molecule of vegetable origin with ?instability? at acidic pH? an extract of vegetable origin is understood which at the acidic pH of the stomach (for example, pH ranging from 1 to 3, preferably ranging from 1.5 to 2.5) undergoes a structural modification such as to alter or reduce its properties. beneficial (the effectiveness) for which ? administered to the subject (instability known in the literature or not). This structural modification pu? be referred to? extract or one or more? components of the extract.

Among the molecules which cause or mostly cause gastric problems, tannins and triterpene saponins are preferably of interest for the present invention.

Tannins are polyphenols with an?affinity? high for protein. They are classified into hydrolysable tannins, condensed tannins (procyanidins, proanthocyanidins) and tannoids. In contact with the mucous membrane of the gastrointestinal tract, the tannins exert an astringent function, making the mucosa itself not very permeable and reducing its enzymatic secretion. In particular, at the gastric level the tannins reduce secretions and inhibit the activity of hyaluronidase (enzyme that participates in the inflammatory process by releasing histamine). In the long run these activities? of the tannins on the gastrointestinal mucous membranes can be irritating at the level of the digestive tract and can cause hepatotoxicity. Tannins are contained, for example, in two extracts widely used in food supplements or foods for special medical purposes (AFMS), such as the extract of Arctostaphylos uva-ursi (Linnaeus) (or bearberry) and the extract of Thea sinensis (Linnaeus) (or tea plant?).

Triterpene saponins are among the most widespread saponins in the plant kingdom. The triterpenic saponins, when administered in small quantities, thanks to their ability surfactant, dissolve and stimulate the secretion of a fluid bronchial mucus, facilitating expectoration and causing cough. In particular, this last effect seems to be due to an irritating action of the saponins at the level of the gastric mucosa which, by reflex action, determines an increase in bronchial secretion. The irritating effect of saponins on the mucous membranes of the gastrointestinal tract is also exploited to improve the absorption of some drugs: the irritation caused causes an imbalance in the intestinal mucosa, decreasing its barrier effect of resistance and filter towards exogenous substances. Disadvantageously, in large quantities? saponins have a purgative and/or unwanted emetic effect (emetic, which causes ?emesis? that is, capable of stimulating vomiting).

Triterpenic saponins are contained, for example, in extracts of vegetable origin widely used in the food and pharmacological fields, such as, for example, the extract of Bacopa munnieri, the extract of Aesculus hippocastanum (L.) and the extract of a ginseng (for example, Panax ginseng (C.)).

Further extracts of vegetable origin which cause gastric problems, of interest for the present invention, are for example the extracts of Zingiber officinale and Andrographis paniculata.

The technical problem that the present invention faces and solves? that of providing formulations for oral use comprising extracts or molecules of vegetable origin (botanicals) having undesirable gastrolesive effects or an instability? at acidic pH, in which said formulations are capable of releasing said extracts or molecules directly into the intestinal tract (controlled release with gastric tract bypass) in the absence of side effects at the gastric level (for example due to the bitter taste or a harmful effect of ?extracted on the gastric mucosa) and/or in the absence of degradation or modifications of the active molecules (for example modifications due to the acidic pH of the gastric tract or to specific enzymes present in the gastric tract).

To overcome said technical problems, the Applicant, in the face of an intense activity? of research and development, provides formulations in the form of microgranules for oral administration comprising at least one extract or molecule of plant origin (botanical) and a gastro-resistant matrix, in which said matrix coats (coats) or incorporates (embeds) said extract or molecule, allowing said at least one extract or molecule of vegetable origin to pass the gastric tract without generating undesirable effects and without undergoing modifications, and allowing said at least one extract or molecule of vegetable origin to be released directly into the intestinal tract, preferably in the intestinal tract. digestive system.

The formulations of the invention in the form of microgranules comprising gastro-protected extracts or molecules of vegetable origin, showing a high safety profile, can be used by a wide category of subjects, such as adults, the elderly, subjects of pediatric, subjects with comorbidity? and sportsmen.

Said formulations of the present invention are easy to prepare and economically advantageous, in particular the microencapsulation step.

These aims, and others which will become clear from the detailed description which follows, are achieved by the formulations and processes of the present invention thanks to the technical characteristics present in the description and in the appended claims.

FIGURES

Figure 1 graphically represents the structure of a microgranule of the formulation object of the present invention: core/shell structure A and structure B of microspheres dispersed in the matrix.

SUMMARY OF THE INVENTION

A first aspect of the present invention relates to a formulation in the form of gastro-resistant microgranules for oral administration, in which a microgranule comprises at least one extract or a molecule of vegetable origin having gastro-damaging effects (or a composition thereof) and a gastro-resistant matrix in which said gastro-resistant matrix coats and/or incorporates said at least one extract or molecule of vegetable origin (or a composition thereof).

A second aspect of the present invention relates to a composition comprising at least one formulation in the form of microgranules of the present invention and at least one additive and/or excipient of acceptable pharmaceutical or food grade.

A third aspect of the present invention relates to said formulation or composition of the present invention for use as a medicament, such as a formulation or composition for use in a method of treatment or a method of treatment by administration to a subject having of said formulation or composition.

A fourth aspect of the present invention relates to the non-therapeutic (or cosmetic) use of the formulation or composition of the present invention in a healthy subject.

A fifth aspect of the present invention relates to a process for the preparation of said formulation in the form of microgranules of the present invention.

A sixth aspect of the present invention relates to said formulation in the form of microgranules of the present invention which can be obtained by the process of the invention.

A last aspect of the present invention relates to the use of said formulation or composition of the present invention for the preparation of a food supplement, a food for special medical purposes (AFMS), a composition for medical devices and/or a pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is a formulation in the form of microgranules (or a microgranule) for gastro-resistant oral administration (in brief formulation of the present invention), in which a microgranule comprises:

(a) a mixture (or nucleus) which comprises or, alternatively, consists of (a.1) at least one extract of vegetable origin or a molecule of vegetable origin having gastrolesive effects and/or instability? at acidic pH, e

(b) a gastro-resistant matrix, wherein said gastro-resistant matrix coats and/or incorporates said (a) blend (or core).

In the formulation of the present invention, said (a.1) at least one extract or molecule of vegetable origin can be selected from the group which includes or alternatively consists of: Arctostaphylos uva-ursi extract, Thea sinensis extract, Bacopa munnieri extract, Aesculus hippocastanum extract, Ginseng or Panax extract (e.g. Panax ginseng), Zingiber officinale extract , Andrographis paniculata extract, and a mixture thereof; preferably Arctostaphylos uva-ursi, Thea sinensis, Bacopa munnieri, Aesculus hippocastanum, Zingiber officinale, Andrographis paniculata; more preferably Arctostaphylos uva-ursi, Thea sinensis, Bacopa munnieri, Zingiber officinale, Andrographis paniculata.

Furthermore, in the formulation of the present invention, said (a.1) at least one extract of vegetable origin can be selected from an extract comprising or alternatively consisting of at least one triterpene saponin (e.g. escin or ginsenosides) and/or at least one tannin.

Alternatively, in the formulation of the present invention, said (a.1) at least one molecule of vegetable origin can be selected from at least one triterpene saponin (e.g. escin or ginsenosides) and/or at least one tannin.

The extract of Arctostaphylos uva-ursi (L.) (or bearberry)? mainly a leaf extract. The main components of Arctostaphylos uva-ursi are: phenolic glycosides, in particular arbutin and methylarbutin, tannins (about 15-20%), flavonoids (about 1-2% of which quercetin and isoquercitrin), triterpenes (for example, ursolic acid and the corresponding grape alcohol). According to the official pharmacopoeia, the drug should contain not less than 6% (w/w) of hydroquinone derivatives, calculated as arbutoside. The Arctostaphylos uva-ursi extract? traditionally used for the relief of symptoms associated with lower urinary tract infections in women, such as a burning sensation when urinating and/or frequent urination. The dosage? variable and depends both from? entity? of the symptom to be alleviated, both on the type of preparation and extraction to be used (for example, in the case of dry extract, about 400 mg of extract in 60% v/v ethanol up to 3-4 times a day). The Arctostaphylos uva-ursi extract? considered a safe substance for the subjects to whom ? administered, however, given the high tannin content, adverse events such as nausea, vomiting and cramps due to irritation of the stomach mucous membranes could occur, especially in particularly sensitive and predisposed subjects (for example, subjects with gastric-type pathologies or disorders such as, for example, indigestion, heartburn, nausea, cramps or vomiting etc.). For these reasons, the use of an extract of Arctostaphylos uva-ursi for prolonged periods (for example, more than seven days) is not recommended.

The extract of leaves and/or flowers of Thea sinensis (Linnaeus) (or tea plant?). Classically the Thea sinensis is consumed in infusion, and traditionally its use? associated with resistance to fatigue and to combat the feeling of discomfort. The tea contains tannins (approx. 8 to 20%) including epigallocatechin-3-O-gallate (EGCG), caffeine (approx. 2.5-5.5%), theobromine (approx. 0.07-0.17%), theophylline (about 0.002-0.013%), a volatile oil; also vitamins (of group B), polyflavonic compounds (for example theoflavine and thearubigin). Possible side effects at the level of the gastrointestinal tract or the gastrointestinal tract following the intake of tea? are attributable to the high tannic content, such as stomach ailments and cramps, nausea, flatulence, dyspepsia and abdominal pain, while disturbances such as dizziness, headache and increased heart rate are attributable to the caffeine content.

The extract of Bacopa munnieri (plant belongs to the botanical family of Scrofulariaceae) includes, as active compounds responsible for its activity? biologic, alkaloids (e.g. brahmine, nicotine and herpestine), triterpene saponins (e.g. bacosides A and B) and sterols (e.g. beta-sitosterol and stigmasterol). The standardized extract of Bacopa munnieri ? used in traditional medicine to counteract anxiety disorders, depression and improve cognitive functions. The use of Bacopa munnieri extract is not free of side effects. Subjects involved in clinical studies, subjected to treatments with preparations based on Bacopa munnieri have often experienced adverse effects at the level of the gastrointestinal tract, mainly diarrhoea, nausea and abdominal cramps. These adverse effects have been associated with some specific characteristics of Bacopa munnieri: its cholinergic action in the intestine exerts a spasmolytic action, a relaxation of the smooth muscles, contractions with more intense tone. wide correlated to a stimulation of the? activity? secretory, that in some subjects you can? translate into nausea, constipation or diarrhea due to relaxation of the sphincters. As regards the adverse effect at the gastric level, ? It has been demonstrated that the extract of Bacopa munnieri has a direct effect on the modulation of astric secretions, mainly due to the high content of aponins, and this effect could irritate the stomach.

Aesculus hippocastanum (L.) seed extract includes escin, a triterpenic saponin. The extract from the seeds of Aesculus hippocastanum authorized to date by the EMA (European Medicines Agency) ? a standardized dry extract of hydroalcoholic derivation (40-80% v/v) containing from 6.5% to 10% (w/w) of riterpenic glycosides, calculated as protoescigenin. The main components of Aesculus hippocastanum are triterpene saponins (whose mixture takes the name of escin), flavonoids (for example quercetin, aempferol and rutin), coumarins and tannins (present in the bark and in the trunk and are therefore lost during the process of seed extraction). are traditionally recognized all?escina ropriet? anti-inflammatory, anti-oedema, venotonic anti-exudative, with particular effectiveness in the early stages of the inflammatory process. Experimental evidence demonstrates an interference of the extract with isosomal enzymes, by hindering the activity of aluronidase, but not of elastase, and with the synthesis of autacoids (eicosanoids and serotonin). According to the monograph prepared by the World Health Organization, the clinically recognized uses of aescin are for the treatment of symptoms of chronic venous insufficiency, including pain, heavy legs, nocturnal calf cramps, stinging and oedema. The recommended dosage? 250 mg to 312 mg twice daily of standardized powdered extract of crude drug (corresponding to 100 mg escin) containing 16%-20% (w/w) triterpene saponins calculated as escin. In Italy, to date, the content in escin cannot? exceed 75 mg as a daily dosage. In fact, escin has shown undesirable effects on the gastrointestinal tract, in particular nausea and stomach upset. As known, a high content of triterpenic saponins can cause irritation of the gastric mucosa.

With the term ?ginseng extract? or ?Panax extract? describes the extract obtained from the root of at least one of the eleven different species of plants belonging to the genus Panax, each typical of a different region of the world. The ginseng more derives from the root of Panax ginseng (C. Meyer). L? Ginseng root extract (or Panax root extract) or Panax ginseng comprises triterpenic or pentacyclic saponins, related to oleanoic acid (e.g. ginsenosides, panaxosides, chikusetsusaponins), polysaccharides (e.g. panaxanes), sterols and vitamin D. The ginseng ? useful in case of asthenia, tiredness, malaise, to improve concentration in work and study and in periods of convalescence (dose 1-2 g per day for a maximum period of 3 months). Traditionally it is also used to treat impotence, lower diabetes, prevent hepatotoxicity and and treat ulcers and gastritis. The side effects observed following the use of a ginseng extract are mainly borne by the gastrointestinal system, such as nausea, irritation of the gastric mucosa, epigastric pain, vomiting, diarrhea, constipation. These gastrointestinal disturbances are attributable to the high triterpene saponin content of ginseng extract, which are called ginsenosides. The terms ?ginseng? and ?Panax? are used in the context of this description as interchangeable synonyms.

Zingiber officinale (Roscoe, 1807; common name ginger or ginger) ? a herbaceous plant of the Zingiberaceae family. Ginger or Zingiber officinale extract comes from the rhizome of the plant. The main components of ginger are contained in oleoresin which contains gingerols (about 30-35%), shogaols and zingerone. The other components of ginger are carbohydrates (starch about 50%), lipids (fatty acids 6-8%) and essential oil (about 1-3%). In the monograph drawn up by the EMA (European Medicines Agency) it is indicated that the oral consumption of ginger is? useful for preventing disorders associated with nausea and vomiting in motion sickness. Furthermore, its traditional use ? also associated with mild intestinal disturbances such as flatulence and bloating. Said functions of ginger are mainly due to 6-gingerol and shogaols. It seems that these compounds are able to inhibit nausea and vomiting, as they normalize the motility stomach and inhibit the release of vasopressin. These gastric effects for? they also manifest as side effects. In the monograph edited by the EMA it is reported that the use of ginger can cause minor gastrointestinal disturbances such as in particular stomach pain, eructation, dyspepsia and nausea.

Andrographis paniculata (Burm. f.; Wall. ex Nees) ? an annual herbaceous plant of the Acanthaceae family used to reduce the duration and symptoms of the common cold and in the treatment of symptoms of upper respiratory tract infections. ? it is known that high oral doses of dry extract of Andrographidis paniculata can cause gastric disturbances, vomiting and loss of appetite. These side effects appear to be due to its bitter taste.

The content of tannins and/or triterpene saponins or any other molecule of interest (i.e. active or active molecule) in one of said extracts of vegetable origin can be determined by titration methods (for example titration by UV or HPLC technique) and standard equipment known to the person skilled in the art.

The extracts of vegetable origin of the present invention are preferably dry extracts.

For ?dry extract? In the context of the present invention, a powdered extract having a weight percent water content of 0.05% to 15% (e.g., 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, or 14%), preferably 0.05% to 10% or 0 .05% to 5%.

The extracts of vegetable origin of the present invention can be extracted from one or more plant parts, such as leaves, roots, seeds, pistils, bark, and/or fruit.

The extracts (or dry extracts) of vegetable origin which can be used in the formulations of the present invention are extracts obtained and identified according to methods and equipment known to those skilled in the art.

For example, an Arctostaphylos uvaursi leaf extract (bearberry leaf extract) can be obtained as a dry extract by extraction in aqueous solvent or in alcoholic solvent (for example 60% v/v ethanol) or as a liquid extract by extraction in alcoholic solvent (for example 25% v/v ethanol), and identified by spectroscopic techniques; an extract of Bacopa munnieri leaves or an extract of Zingiber officinale can be obtained by extraction in an alcoholic solvent (for example ethanol); an extract of ginseng or Panax ginseng roots is produced by standard extraction methods using alcoholic solvents (for example ethanol or methanol) in different concentration ratios with water; an extract of seeds of Aesculus hippocastanum can? be obtained by extraction in alcoholic solvent (e.g. 40% v/v ethanol); an extract of Panax ginseng roots can? be obtained by extraction in alcoholic solvent (e.g. 95% v/v ethanol); an extract of Andrographis paniculata roots can? be obtained by extraction in a water/ethanol solvent (e.g. water 20/ethanol 80 v/v).

Advantageously, the microgranules of the formulation object of the present invention have an average particle diameter ranging from about 1 µm to about 950 µm (for example 10 µm, 20 µm, 50 µm, 80 µm, 100 µm, 200 µm, ?m, 300 ?m, 400 ?m, 500 ?m, 600 ?m, 700 ?m, 800 ?m or 900 ?m), preferably from 100 ?m to 600 ?m, more? preferably from about 150?m to about 400?m.

Microencapsulation or coating, in general, refers to technologies that allow for the incorporation/coating of one or more? composed in an individualized particle structure having an average diameter in the range of about 1 µm to about 1000 µm (e.g., 10 µm, 50 µm, 100 µm, 200 µm, 400 µm, 600 µm , or 800 ?m). Depending on the applied process, these microparticles obtained from the encapsulation or coating process can have different specific sizes, shapes and structures. The advantage of microencapsulation lies in the fact that the core material ? completely coated and isolated from the external environment (for example the acidic pH environment of the stomach). Furthermore, microencapsulation potentially does not affect the properties? of the core materials.

The microgranules of the formulation object of the present invention can have a core/shell structure A or a matrix structure B or a mixed A+B structure.

In the core/shell A structure, the mixture (a) comprising or, alternatively, consisting of (a.1) at least one extract or mixture of vegetable origin constitutes the core, while the gastro-resistant matrix (b) constitutes the shell which covers (a ).

In the matrix structure B, a multitude of microgranules of mixture (a) comprising or, alternatively, consisting of (a.1) at least one extract or mixture of vegetable origin? dispersed or incorporated in the gastro-resistant matrix (b) (i.e. microgranules of active principle incorporated in the gastro-resistant matrix to form a microgranule of the invention).

In structure A+B, a multitude of core/shell A structures ? dispersed or incorporated into the gastro-resistant matrix (b).

The microgranules of the formulation object of the present invention can have various shapes without any limitation such as, for example, spherical, ellipsoid, cubic, parallelepiped, or in flakes or pellets.

In the formulation of the present invention, said (b) gastro-resistant matrix can comprising or, alternatively, consisting of (b.1) at least one gastro-resistant component selected from the group comprising or, alternatively, consisting of: a lipid, an alginate salt, a polymer other than an alginate salt, and a mixture thereof.

According to one aspect, in the formulation in the form of microgranules comprising (a) and (b), object of the present invention, said (b.1) at least one gastro-resistant component consists of a lipid selected from the group comprising or, alternatively, consisting of: 1 ) a phospholipid, preferably a phosphoglyceride, pi? preferably a phosphoglyceride selected from the group comprising or alternatively consisting of 1,2-diacyl phospholipid, 1-alkyl-2-acyl phospholipid, 1-alkenyl-2-acyl phospholipid; even more preferably a diacylphospholipid selected from the group comprising or alternatively consisting of: phosphatidylcholine or lecithin for example (E322), phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid and mixtures thereof; preferably phosphatidylcholine or lecithin for example (E322), are advantageously allergen free and/or in powder or granules; more preferably ? choose lecithin, for example (E322) from sunflower, corn or soy; And

2) a lipid of vegetable origin selected from the group comprising or, alternatively, consisting of:

- glycerols or mono-alcohols or di-alcohols mono-, di- or triesterified with saturated or unsaturated fatty acids (e.g. monounsaturated);

- saturated or unsaturated free fatty acids (e.g. monounsaturated);

- sucrose esters of fatty acids (sucresters), preferably mixtures of mono-di- or tri- esters of sucrose of fatty acids;

in which said fatty acids, saturated or unsaturated, both free and esterified with glycerol or mono-alcohols or dialcohols or sucrose, have a carbon number in the range from C12 to C28, plus? preferably from C14 to C24, for example C16, C18, C20 and/or C22.

According to another aspect, in the formulation in the form of microgranules comprising (a) and (b) object of the present invention, said (b.1) at least one gastro-resistant component consists of a salt of an alginate selected from the group comprising or, alternatively, consisting of: sodium alginate, potassium alginate, magnesium alginate, ammonium alginate, calcium alginate and their mixtures; preferably sodium alginate. Preferably, said alginate salt, present in (b) gastro-resistant matrix, has an average molecular weight in the range from 10,000 Da to 600,000 Da (for example, 50,000 Da, 100,000 Da, 150,000 Da, 200,000 Da, 250,000 Da, 300,000 Da, 350,000 Da, 400,000 Da, 450,000 Da, 500,000 Da, or 550,000 Da; Da = Dalton), preferably from 100,000 Da to 400,000 Da, plus? preferably from 150,000 Da to 300,000 Da.

Sodium alginate? a chemical compound formed from the sodium salt of alginic acid, with the minimum formula NaC6H7O6. Sodium alginate? extracted from the cell walls of algae, it has the appearance of a rubber. The sodium alginate generally used in the food or pharmaceutical field? an E401 alginate (E401 means: food additive allowed by European legislation and regulated by the Italian ministerial decree D.M.1996).

Alginic acid, also called algin, is a polysaccharide found widely in the cell walls of brown algae (e.g., gross or molecular formula (C6H8O6)n, molecular mass (u or Da) 10,000 to 600,000).

According to one aspect, in the formulation in the form of microgranules comprising (a) and (b) object of the present invention, said (b.1) at least one gastro-resistant component consists of a polymer other than an alginate, in which said polymer has the technical characteristics suitable for coating and/or incorporating said (a) mixture and guaranteeing gastro-protection. Examples of a polymer other than an alginate, usable in the context of the present invention ? ethyl cellulose and polyvinyl alcohol.

In the formulation of the present invention, said (a) mixture (or core) can? comprise, in addition to said (a.1) at least one extract or molecule of vegetable origin, furthermore (a.2) at least one additive and/or blend excipient of acceptable pharmaceutical or food grade known to the person skilled in the art.

In the formulation of the present invention, said (b) gastro-resistant matrix can comprising, in addition to said (b.1) at least one gastro-resistant component, furthermore (b.2) at least one additive and/or matrix excipient of acceptable pharmaceutical or food grade known to the person skilled in the art.

Said (a.2) at least one additive and/or excipient of pharmaceutical or food grade, included in (a) mixture/core of the invention together with said (a.1) at least one extract or molecule of plant origin (botanical), or said (b.2) at least one additive and/or excipient of pharmaceutical or food grade, included in the (b) gastro-resistant matrix together with said (b.1) gastro-resistant component, consist of substances without activity? therapeutic or cosmetic (or non-therapeutic) suitable for pharmaceutical or food use selected from the group of auxiliary substances known to the person skilled in the art such as, for example, diluents, solvents, solubilizers, thickeners, sweeteners, flavourings, colourants, lubricants, surfactants, antimicrobials, antioxidants, preservatives, pH stabilizing buffers, and mixtures thereof. Examples (non-limiting) of such substances are phosphate buffers (e.g. dicalcium phosphate), stearate of an alkali or alkaline earth metal (e.g. magnesium), silicon dioxide, mono and diglycerides of fatty acids, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch or corn starch, natural or artificial flavors.

In the formulation of the present invention, said (a) mixture or core (for example (a.1) or (a.1)+(a.2)) and said (b) gastro-resistant matrix (for example (b.1) or (b.1)+(b.2)) may be in a weight ratio [(a):(b)] of 100:1 to 1:1 (for example, 90:1, 80:1, 70: 1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2:1) or 1:1 to 1:100 (for example, 1:2, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80 or 1:90).

In the formulation of the present invention, said (a.1) at least one extract of vegetable origin and said (b.1) gastro-resistant component can be in a weight ratio [(a.1):(b.1)] of 100: 1 to 1:1 (for example, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2 :1) or 1:1 to 1:100 (for example, 5:1, 2:1, 1:2, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50 , 1:60, 1:70, 1:80 or 1:90).

The microgranule formulation of the present invention ((a) (b)) can comprising said (a) mixture, which comprises or consists of (a.1) at least one extract or molecule of vegetable origin, in a percentage by weight, with respect to the total weight of the formulation, ranging from 1% to 90% (for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85 %), preferably from 20% to 40% (e.g., about 25-30%).

The microgranule formulation of the present invention ((a) (b)) can comprising said (b) gastro-resistant matrix in a percentage by weight, with respect to the total weight of the formulation, ranging from 10% to 99% (for example, 15%, 20%, 25%, 30%, 35%, 40%, 45 %, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%), preferably 60% to 80% (e.g., about 70-85%) .

It is understood that the percentages of said (a) mixture and of said (b) gastro-resistant matrix shown above are mutually connected and interdependent.

The microgranule formulation of the present invention ((a) (b)) can comprising said (a.1) at least one extract of vegetable origin in a percentage by weight, with respect to the total weight of the formulation, ranging from 1% to 90% (for example, 5%, 10%, 15%, 20%, 25 %, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%), preferably 20% to 40% (e.g. , about 25-30%).

The microgranule formulation of the present invention ((a) (b)) can comprising said (b.1) at least one gastro-resistant component (for example a lipid or an alginate salt or a polymer) in a percentage by weight, with respect to the total weight of the formulation, ranging from 10% to 99% (for example, 15 %, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) , preferably 60% to 80% (e.g., about 70-85%).

It is understood that the percentages of said (a.1) at least one extract of vegetable origin and of said (b.1) at least one gastro-resistant component shown above are mutually connected and interdependent.

The formulations in the form of microgranules of the invention are suitable for oral administration.

The oral dosage form of said formulations in the form of microgranules of the invention can be in a solid form, such as a capsule comprising microgranules, microgranules to be dissolved in water or in a water-based liquid, or buccal microgranules; or a semi-solid form, such as a soft-gel capsule comprising the microgranules; or a liquid form, such as a suspension or dispersion comprising or deriving from the microgranules; preferably the composition of? invention ? for oral use in solid form.

The object of the present invention is compositions (in short, compositions of the present invention) comprising at least one formulation in the form of microgranules of the present invention and at least one additive and/or excipient of acceptable pharmaceutical or food grade.

Said formulations in the form of microgranules or the related compositions of the present invention can consist of or, alternatively, be included in a food supplement, a food for special medical purposes (AFMS), a composition for medical devices (Medical Devices Regulation (EU) 2017/ 745 (MDR)), and/or a pharmaceutical composition.

The object of the present invention is the use of the formulation in the form of microgranules of the present invention comprising said at least one extract or molecule of vegetable origin (botanical) and said gastro-resistant matrix (according to any one of the embodiments or aspects described) or of the compositions of the present invention for preparing a dietary supplement, a food for special medical purposes (AFMS), a composition for medical devices (Medical Device Regulation (EU) 2017/745 (MDR)), and/or a pharmaceutical composition.

The object of the present invention is the formulation in the form of microgranules of the present invention comprising said at least one extract or molecule of plant origin (botanical) and said gastro-resistant matrix (according to any of the embodiments or aspects described) or the compositions of the present invention for use as a medicine in a person in need.

Advantageously, the formulations in the form of microgranules of the present invention comprising said at least one extract or molecule of vegetable origin (botanical) and said gastro-resistant matrix (according to any of the embodiments or aspects described) or the compositions of the present invention are formulations or compositions for use in a method of treating a disease and/or symptom defined on the basis of the properties? of said extract or molecule of vegetable origin, in which said method of treatment provides for the administration of a quantity therapeutically effective to a subject in need.

Examples of pathologies or symptoms that can be treated by the formulations of the present invention are for example: muscle pain, joint pain, circadian cycle disturbances (sleep disturbances), menstrual disturbances, gastrointestinal disturbances (nausea, diarrhea, vomiting, stomach discomfort and/or or of the intestine), gastric reflux disease (GERD or from the English GERD), metabolic dysfunctions (obesity, overweight, diabetes).

Furthermore, the present invention provides methods of treating a pathology and/or symptom by administering an amount therapeutically effective of a formulation or composition of the present invention to a subject in need, in which said pathology and/or symptom are defined on the basis of the properties? of said extract or molecule of vegetable origin.

The formulations of the present invention may be for use in the treatment of a disease or symptom or disorder either as a sole treatment or as an adjuvant to further treatments.

The object of the present invention is the cosmetic use or non-therapeutic use of the formulations in the form of microgranules or of the relative compositions according to the present invention, in which said non-therapeutic use is use on healthy subjects to enhance or enhance or enhance physical and/or mental performance.

The subject of the present invention is a process (in short microencapsulation process of the invention) for the preparation of said formulation in the form of microgranules of the invention comprising said at least one extract or molecule of vegetable origin (botanical) and said gastro-resistant matrix (according to a any of the embodiments or aspects described) comprising the steps of: (1) preparing the mixture (a) to be microencapsulated and the gastro-resistant matrix (b) as coating matrix of the mixture (a); (2) coating (a) with (b) or incorporating (a) in (b) according to the structure A or B or A+B, wherein said structures are as described in the present invention, to obtain microgranules of (a) coated or incorporated in (b) (or formulations in the form of microgranules of the present invention); (3) optionally, applying a drying step to the microgranules obtained from step 2, to obtain the formulations in the form of microgranules of the present invention.

Said microencapsulation process of the present invention can be achieved by means of methods and procedures known to the person skilled in the art.

According to a preferred aspect, the microencapsulation process of the present invention is carried out by means of a fluidized bed system, i.e. a microencapsulation system comprising a fluidized bed process chamber (for example, a fluidized bed chamber according to standard processes and machinery ). In said fluidized bed chamber the particles (or microparticles) of the mixture (a) (which comprises or consists of (a.1) at least one extract of vegetable origin) to be microencapsulated are in movement in a flow of a gas and, at the same time, the gastro-resistant matrix (b) of the present invention is applied on said mixture particles (a) in said fluidized bed chamber, for example by spray method (for example, spray emitted from a nozzle located in the fluidized bed chamber). The result ? the microencapsulation of the mixture (a) in the gastro-resistant matrix (b) to give the formulation in the form of microgranules according to the invention. Said fluid bed microencapsulation is preferably performed at a process temperature ranging from 20?C to 80?C (for example 25?C, 35?C, 40?C, 50?C, 60?C, or 70?C) , preferably from 30?C to 60?C.

The formulation in the form of microgranules of the present invention ? obtainable by the process of the present invention.

With the term ?subject/s? within the scope of the present invention mammalian subjects (animals and/or humans), preferably human subjects, are indicated.

The term ?quantity? therapeutically effective? does it refer to the quantity? of mixture or compound or formulation that elicits the biological or medicinal response in a tissue, system or subject that is researched and defined by an expert in the art.

Unless otherwise specified, the expression mixture or composition includes a component in an amount? ?in the range from x to y? do you mean that this component can? be present in the composition in all quantities? present in said range, even if not explicit, including extremes of the range.

Claims (10)

1. A microbead formulation for oral gastro-resistant administration, wherein a microbead comprises: (a) a mixture (or nucleus) comprising or, alternatively, consisting of (a.1) at least one extract of vegetable origin or at least one molecule of vegetable origin having at least one gastrolesive effect and/or instability? at acidic pH, e (b) a gastro-resistant matrix, wherein said gastro-resistant matrix coats and/or incorporates said (a) mixture. 2. The formulation according to claim 1, wherein said microgranules have an average particle diameter ranging from about 100 µm to about 600 µm, preferably ranging from about 150 µm to about 400 µm. 3. The formulation according to claim 1 or 2, wherein said (a.1) at least one extract of vegetable origin ? selected from the group which includes or alternatively consists of: Arctostaphylos uva-ursi extract, Thea sinensis extract, Bacopa munnieri, Aesculus hippocastanum extract, Ginseng or Panax extract, preferably Panax ginseng, Zingiber officinale extract, Andrographis extract paniculata, an extract comprising at least one triterpene saponin, preferably escin or ginsenosides, an extract comprising at least one tannin, and a mixture thereof; preferably Arctostaphylos uva-ursi, Thea sinensis, Bacopa munnieri, Aesculus hippocastanum, Zingiber officinale, Andrographis paniculata. 4. The formulation according to any one of claims 1-3, wherein said (b) gastro-resistant matrix can comprising or, alternatively, consisting of (b.1) at least one gastro-resistant component selected from the group comprising or, alternatively, consisting of: a lipid, an alginate salt, a polymer other than an alginate salt, and a mixture thereof; preferably a lipid, pi? preferably a phospholipid. 5. The formulation according to any one of claims 1-4, wherein said microgranules have a core/shell structure, wherein the core comprises or, alternatively, consists of said mixture (a) and wherein the shell comprises or, alternatively, it consists of said gastro-resistant matrix (b). 6. The formulation according to any one of claims 1-5, wherein said microgranules have a matrix structure, wherein a multitude of microgranules of said mixture (a) ? dispersed or incorporated in said gastro-resistant matrix (b). 7. A composition comprising: at least one formulation in the form of microgranules according to any of the preceding claims, and at least one additive and/or excipient of acceptable pharmaceutical or food grade; preferably in which said composition? a dietary supplement composition, a food for special medical purposes (AFMS), a medical device composition, and/or a pharmaceutical composition. 8. The formulation in the form of microgranules or the composition according to any one of the preceding claims for use as a medicament. 9. Cosmetic use or non-therapeutic use on healthy subjects to enhance physical and/or mental performance of the formulation according to any one of claims 1-6 or of the composition according to claim 7. The use of the formulation in the form of microgranules according to any one of claims 1-6 or of the composition according to claim 7 to prepare a composition for a dietary supplement, a food for special medical purposes (AFMS), a composition for medical devices and/ or a pharmaceutical composition.