EP3773525A1

EP3773525A1 - Composition for the treatment of inflammatory diseases

Info

Publication number: EP3773525A1
Application number: EP19721069.3A
Authority: EP
Inventors: Giulio Bianchini; Chiara CECCONELLO; Lanfranco Callegaro
Original assignee: Jointherapeutics SRL
Current assignee: Jointherapeutics SRL
Priority date: 2018-03-28
Filing date: 2019-03-25
Publication date: 2021-02-17
Also published as: WO2019186355A1; IT201800004027A1

Abstract

A composition is disclosed comprising at least one cannabinoid receptor type-2 selective agonist, at least one substance having antioxidant properties, and at least one tissue function modulator. Said composition has proved to effectively treat diseases characterised by high oxidative stress, inflammatory state, and tissue dysfunction.

Description

COMPOSITION FOR THE TREATMENT OF INFLAMMATORY DISEASES

FIELD OF INVENTION

The present invention relates to a composition comprising at least one cannabinoid receptor type-2 selective agonist, at least one substance having antioxidant properties, and at least one tissue function modulator. Said composition has proved to effectively treat diseases characterised by high oxidative stress, inflammatory state, and tissue dysfunction.

The use of this composition is particularly indicated in people suffering from at least one of the following diseases: metabolic diseases, peripheral neurological diseases, diseases of the circulatory system, musculoskeletal diseases, diseases of the central and peripheral nervous system, gastrointestinal tract diseases, and urinary tract diseases.

BACKGROUND ART

One of the features underlying many diseases, including metabolic diseases, peripheral neurological diseases, diseases of the circulatory system, musculoskeletal diseases, diseases of the central and peripheral nervous system, gastrointestinal tract diseases, and urinary tract diseases, is the presence of an inflammatory state and/or oxidative stress associated with a tissue dysfunction.

Frequently, the association of inflammatory state and/or oxidative stress and tissue dysfunction can worsen the pathological condition, increasing expansion of the immune response, with possible involvement of and damage to healthy tissues. Elements responsible for the expansion of the inflammatory response include diffusion of proinflammatory cytokines and the recruitment and migration of immune system cells in tissues.

For example, the neuropathic pain is associated with an inflammatory state expressed as hyperalgesia and allodynia. Neuropathy can arise following an injury to peripheral nerves, caused by metabolic or vascular illnesses, cancer, or infections. Regardless of the cause of the nerve injury, the inflammatory response is characterised by the activation of the microglia and astrocytes, and by an increase in production of proinflammatory cytokines, often associated with structural damage of neurons. This damage can lead to demyelination, and axonal degeneration, and therefore a dysfunction of the neuronal cell. Furthermore, recently, neuropathic pain has also been associated with a mitochondrial dysfunction caused by oxidative stress. In the case of peripheral neurological diseases, there is, therefore, a chronic inflammatory state accompanied by high oxidative stress and by neuronal dysfunction.

Considering, instead, the phenomenon of varicose veins, connected to venous insufficiency, one notes a high presence of proinflammatory cytokines IL-6, IL-8, and MCP-17. The factor which triggers the inflammatory state appears to be, above all, anomalous venous flow, often caused by endothelial dysfunction. In addition, oxidative stress is one of the factors which triggers endothelial dysfunction and it has recently been demonstrated that a reduction in oxidative state leads to an improvement in endothelial dysfunction, and therefore in venous insufficiency. Also in this case, the disease is characterised by oxidative stress, inflammatory state, and vascular endothelial tissue dysfunction.

Nowadays, there are food supplements available on the market for the treatment of diseases characterised by high oxidative stress, inflammation, and tissue dysfunction. Nevertheless, one of the limits of the conventional treatments is that they require the prolonged intake of active antioxidant components and/or anti-inflammatory components and tissue function-modulating components. Since they do not act on the pathological and immune response mechanisms, these products offer patients merely a temporary improvement in symptoms and, consequently, any interruption in the treatment leads to the reappearance of the symptoms. In addition, recent studies have shown that abuse of vitamin supplements and plant-based supplements can cause liver damage and hypervitaminosis. In particular, a recent study revealed that in the United States, 20% of cases of liver damage are attributable to the abuse of food supplements and natural remedies. According to the American Association of Poison Control Centers (AAPCC), over 50,000 cases of severe intoxication due to abuse of food supplements were registered in the USA in 2016.

For these reasons, there is a need to provide an effective, specific treatment to treat a series of diseases which have in common an inflammatory state and oxidative stress associated with a tissue dysfunction, by treating both the symptoms and the causes, in particular, by modulating the immune response.

The object of the present invention is therefore to offer said remedy.

SUMMARY OF THE INVENTION Said object is achieved by a composition as stated in Claim 1.

In another aspect, the present invention concerns a food supplement comprising the above composition and suitable dietary ingredients.

In a further aspect, the present invention concerns the use of said composition in the treatment of diseases characterised by high oxidative stress, inflammatory state, and tissue dysfunction such as, at least one of the following: metabolic diseases, peripheral neurological diseases, diseases of the circulatory system, musculoskeletal diseases, diseases of the central and peripheral nervous system, gastrointestinal tract diseases, and urinary tract diseases.

The composition of the invention supplements the immunomodulating effects in combination and in synergy with the anti-inflammatory, antioxidant and tissue function- modulating effects, allowing effective treatment of diseases characterised by high oxidative stress, inflammatory state, and tissue dysfunction.

DETAILED DESCRIPTION OF THE INVENTION

The invention therefore relates to a composition comprising:

- a cannabinoid receptor type-2 selective agonist component, comprising b- caryophyllene,

- an antioxidant component, comprising vitamin C, and

- a tissue function-modulating component, comprising a compound selected from at least one B -group vitamin, at least one essential amino acid, calcium, citicoline, chondroitin, D-mannose, at least one phytosterol, glucosamine, lycopene, magnesium, proanthocyanidins, at least one D-group vitamin, zinc, and mixtures thereof.

It has surprisingly been found that the composition of the invention advantageously combines these three actions, thus obtaining a synergic effect for the treatment of the different diseases.

The term“cannabinoid receptor type-2 selective agonist component”, or briefly“CB2 receptor agonist component”, means a substance or a mixture of substances of natural origin, as such or in the form of essential oils or in the form of extracts, which act on type 2 cannabinoids, or briefly “CB2”, determining an immunomodulating and anti inflammatory effect. This component comprises b-caryophyllene. b-caryophyllene is a natural bicyclic sesquiterpene present in many essential oils and extracts from a broad variety of plants, including cannabis sativa, hemp, black cumin, cloves, hops, basil, oregano, black pepper, lavender, rosemary, cinnamon, ylang-ylang, and copaiba. Therefore, for the purposes of the present invention, b-caryophyllene can be supplied as such or in the form of essential oil or in the form of an extract of one or more of the plants listed above. In preferred embodiments, b-caryophyllene is in the form of powdered extract or liquid extract of black pepper. Preferably, the extraction solvent is water. In more preferable embodiments, b-caryophyllene is in the form of 30% powdered extract or extract in a fluid form of 80% titre oil.

Advantageously, said cannabinoid receptor type-2 selective agonist component may also comprise other cannabinoid receptor type-2 selective agonist compounds, such as:

- dodeca-2E, 4E, 8Z, lOZ-tetraenoic acid isobutylamide,

- dodeca-2E, 4E-dienoic acid isobutylamide,

- rutamarin,

- diindolylmethane, and

mixtures thereof.

Dodeca-2E, 4E, 8Z, lOZ-tetraenoic acid isobutylamide and dodeca-2E, 4E-dienoic acid isobutylamide are polyunsaturated fatty acid alkylamides present in plant varieties belonging to the Echinacea genus. Therefore, for the purposes of the present invention, said alkylamides may be supplied as such or in the form of a hydroalcoholic extract of Echinacea containing the same.

Rutamarin is a furanocoumarin from Ruta Graveolens L.

Diindolylmethane (DIM) is an indole-3-carbinol metabolite obtained from Brassicacea. In preferred embodiments, said cannabinoid receptor type-2 selective agonist component consists of b-caryophyllene.

The term“antioxidant component” means a substance or a mixture of substances of natural and/or synthetic origin as such or in the form of essential oils or in the form of extracts, having an antioxidant - but also preferably an anti-inflammatory - effect. This component comprises vitamin C. It is believed, indeed, that the latter is able to preserve b-caryophyllene against oxidative stress, thus hindering its oxidation to b-caryophyllene oxide, which conversely is not active on CB2.

Preferably, the vitamin C is in an amount of 1-70 wt%, based on the weight of the antioxidant component, more preferably 5-60 wt%.

Advantageously, said antioxidant component may also comprise other antioxidant compounds, such as:

- Omega-3 polyunsaturated fatty acids, preferably docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA),

- lipoic acid,

- ajoene,

- allicin,

- L-arginine,

- N-acetylcysteine,

- carnitine, L-acetyl carnitine, propionyl L-carnitine,

- catechins, preferably epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), epicatechin (EC) or a mixture thereof,

- coenzyme Q10,

- curcumin,

- ellagitannins, preferably punicalagin, gallagic acid, ellagic acid, ellagitannin, vescalagin, castalagin, punicalin, rhoipteleanin H, rhoipteleanin I, rhoipteleanin J, tellimagrandin I, tellimagrandin II (eugeniin), pterocarianin C, sanguin H-4, sanguin H- 5, casuarictin, potentillin, pedunculagin, davidiin, corilagin, geraniin, carpinusin, chebulinic acid, chebulagic acid, elaeocarpusin, repandusinic acid, repandusinin, stachiurin, casuarinin, 5-desgalloyl-stachiurin, casuariin, roburin A, roburin D, cercidinin A, cercidinin B, cuspinin, platicarianin D, nufarin A, sanguiin H-6, grandinin, coriariin, agrimoniin, rugosin D, oenothein B, woodfordin C, strictinin, trapanin B, or a mixture thereof,

- Furanodienes, preferably in the form of a dry or liquid extract of gum resin of Commiphora myrrha,

- boswellic acids, preferably in the form of dry or fluid extract of gum resin of Boswellia serrata,

- acetyl- l l-keto-P-boswellic acid (AKBA), preferably in the form of dry or fluid extract of gum resin of Boswellia sacra,

- phytoestrogens, preferably silymarin, silibinin, isosilibinin, silidianin, silicristin, genistein, baicalein, apigenin, daidzein, neoxanthn, spinacetin, patuletin, luteolin, resveratrol, biochanin A, formononetin, or a mixture thereof,

- flavonoids and flavonols, preferably quercetin, rutin, crisin, kaempferol, myricetin, rhamnetin, apigenin, luteolin, naringin, hesperidin, naringenin, hesperitin, morin, phloridzin, diosmin, troxerutin, fisetin, vitexin, neohesperidin dihydrochalcone, flavone, rutin, genistein, or a mixture thereof,

- terpene trilactones extracted from ginkgo biloba, such as ginkgolides and bilobalides,

- saponins, preferably escin, sericoside, ginsenosides, ariunetin, ariunglicoside, asiaticoside, asiatic acid, madecassic acid, hederin, glycyrrhetic acid, or a mixture thereof,

- E-group vitamins, such as tocotrienols, tocopherols, or mixtures thereof,

- K-group vitamins, such as vitamin Kl, vitamin K2, vitamin K3, or a mixture thereof, and mixtures thereof.

Preferably, said antioxidant component furthermore comprises:

- lipoic acid,

- L-arginine,

- N-acetylcysteine,

- carnitine, L-acetyl carnitine, propionyl L-carnitine,

- coenzyme Q10,

- curcumin,

- furanodienes, preferably in the form of dry or liquid extract of gum resin of Commiphora myrrha,

- acetyl- 1 l-keto-P-boswellic acid (AKBA), preferably in the form of dry or fluid extract of gum resin of Boswellia sacra,

- E-group vitamins, such as tocotrienols, tocopherols, or a mixture thereof,

- K-group vitamins, such as vitamin Kl, vitamin K2, vitamin K3, or a mixture thereof, or a mixture thereof.

In certain preferred embodiments, said antioxidant component furthermore comprises:

- lipoic acid,

- N-acetylcysteine,

- troxerutin,

- quercetin,

- diosmin,

- escin,

- E-group vitamins, such as tocotrienols, tocopherols, or a mixture thereof,

- carnitine, L-acetyl carnitine, propionyl L-carnitine,

- coenzyme Q10,

or a mixture thereof.

In other preferred embodiments, said antioxidant component consists of vitamin C.

The term“tissue function-modulating component” means a substance or a mixture of substances of natural and/or synthetic origin, as such or in the form of essential oils or in the form of extracts, having a tissue function-modulating effect. Indeed, said tissue function modulators are able to act on the cell metabolism, contributing to the restoration of normal tissue function.

This component comprises a compound selected from at least one B -group vitamin, at least one essential amino acid, calcium, citicoline, chondroitin, D-mannose, at least one phytosterol, glucosamine, lycopene, magnesium, proanthocyanidins, at least one D-group vitamin, zinc, and mixtures thereof.

The B-group vitamins comprise vitamin B 1 or thiamine, vitamin B2 or riboflavin, vitamin B3 or niacin, vitamin B5 or pantothenic acid, vitamin B6 or pyridoxine, vitamin B8 or biotin, vitamin B9 or folic acid, vitamin B 12 or cobalamin, or mixtures thereof.

Preferably, this component comprises at least one B-group vitamin in amounts up to 50 wt%, in relation to the weight of the tissue function-modulating component, more preferably up to 30 wt%. It is believed, indeed, that the latter supports the prevention of mitochondrial function damage, often associated with a tissue dysfunction such as, for example, altered metabolic activity.

Said essential amino acids comprise histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), threonine (T), tryptophan (W), valine (V).

Said at least one phytosterol preferably comprises b-sitosterol, brassicasterol, campesterol, delta-5-avenasterol, or a mixture thereof, more preferably extracts of Serenoa repens,

The term“chondroitin” means chondroitin sulphate or a pharmaceutically acceptable salt thereof. Preferably, said salt is sodium chondroitin sulphate.

The term“glucosamine” means 2-D-(+)-glucosamine (or 2-amino-2-deoxy-D-glucose, or chitosamine) or a pharmaceutically acceptable salt thereof. Salts of glucosamine comprise preferably glucosamine sulphate, glucosamine hydrochloride, acetyl-glucosamine and mixtures thereof.

Said proanthocyanidins preferably comprise proanthocyanidin A2 or procyanidolic oligomers extracted from Vitis vinifera, Vaccinium vitis-idaea, Camellia sinensis, Vaccinium Macrocarpon, or Oxycoccus Palustris Pers..

Said at least one D-group vitamin comprises vitamin Dl, vitamin D2, vitamin D3, vitamin D4, vitamin D5, or a mixture thereof.

Said tissue function-modulating component may also advantageously comprise other tissue function-modulating compounds, such as:

- hyaluronic acid or the salt thereof, such as sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, ammonium hyaluronate, tetrabutylammonium hyaluronate and mixtures thereof,

- arbutin and methylarbutin,

- collagen,

- creatin,

- phosphatidylserine,

- monacolin K, extracted from fermented red rice, - anthocyanidins, preferably selected from aurantinidin, cyanidin, delphinidin, europinidin, luteolinidin, pelargonidin, malvidin, peonidin, petunidin, rosinidin, and mixtures thereof,

- S-adenosylmethionine

- selenium,

- silicon, preferably extracted from equisetum,

- oxotriterpene esters, such as asiaticoside and madecassoside,

- free triterpene acids , such as asiatic acid and madecassic acid, preferably extracted from Centella Asiatica,

- sulphur,

and mixtures thereof.

The term“collagen” means the various kinds of collagen, in addition to hydrolysates of collagen. Preferably, the collagen is collagen of type I or type II collagen; more preferably it is type II collagen.

In preferred embodiments, said tissue function-modulating component comprises:

- tryptophan (W), leucine (L),

- proanthocyanidins, such as proanthocyanidin A2, procyanidolic oligomers extracted from Vitis vinifera, Vaccinium vitis-idaea, Camellia sinensis, Vaccinium Macrocarpon, or Oxy coccus Palustris Pers. ,

- D-mannose,

- phytosterols, preferably b-sitosterol, brassicasterol, campesterol, delta-5-avenasterol, more preferably extracted from Serenoa repens,

- calcium,

- citicoline,

- chondroitin sulphate or a pharmaceutically acceptable salt thereof,

- lycopene,

- magnesium,

- glucosamine, such as 2-D-(+)-glucosamine or a pharmaceutically acceptable salt thereof,

- vitamin D3,

- zinc,

or a mixture thereof. In other preferred embodiments, said tissue function-modulating component consists of at least one B -group vitamin.

In certain embodiments, the by weight ratio of said CB2 selective agonist component and said antioxidant component is of 1:0.1 to 1:150.

Preferably, said CB2 receptor agonist component is in smaller amount than said antioxidant component.

More preferably, the by weight ratio of said CB2 receptor agonist component and said antioxidant component ranges from 1:2 to 1:120.

In preferred embodiments, the weight ratio of said CB2 receptor agonist component to said antioxidant component is of 1:5 to 1:50.

In other embodiments, the weight ratio of said CB2 receptor agonist component to said tissue function-modulating component is of 1:0.1 to 1: 130.

Preferably, said CB2 receptor agonist component is in a smaller amount than said tissue function-modulating component.

More preferably, the weight ratio of said CB2 receptor agonist component to said tissue function-modulating component is of 1:5 to 1:50.

In preferred embodiments, the weight ratio of said CB2 receptor agonist component to said tissue function-modulating component is of 1 :10 to 1:35.

In further embodiments, the weight ratio of said antioxidant component to said tissue function-modulating component is of 10: 1 to 1: 10.

Preferably, the weight ratio of said antioxidant component to said tissue function- modulating component is of 5: 1 to 1:5.

For the purposes of the present invention, the weight percentages of the individual components should be understood as based on the sum of the weights of the CB2 receptor agonist, antioxidant and tissue function-modulating components, or briefly the sum of the “active components”.

Preferably, the CB2 receptor agonist component is in an amount of 0.1-20 wt%, preferably of 0.25-10 wt%, and more preferably of 0.5-5 wt%.

Preferably, the antioxidant component is in an amount of 1-95 wt%, preferably of 5-85 wt%, and more preferably of 15-75 wt%.

Preferably, the tissue function-modulating component is in an amount of 0.1-95 wt%, preferably of 2-90 wt%, and more preferably of 15-80 wt%. In preferred embodiments, the composition of the invention comprises:

- 0.1-20 wt% of CB2 receptor agonist component,

- 1-95 wt% of antioxidant component, and

-0.1-95 wt% of tissue function-modulating component.

More preferably, the composition of the invention comprises:

- 0.25-10 wt% of CB2 receptor agonist component,

- 5-85 wt% of antioxidant component, and

- 2-90 wt% of tissue function-modulating component.

Particularly preferred are those embodiments wherein the composition of the invention comprises:

- 0.5-5 wt% of CB2 receptor agonist component,

- 15-75 wt% of antioxidant component, and

- 15-80 wt% of tissue function-modulating component.

It should also be understood that all possible combinations of the preferred aspects of the components of the composition described above should also be deemed as hereby disclosed and therefore similarly preferable.

The composition of the invention may furthermore comprise pharmaceutically acceptable excipients, such as acidifiers, acidity regulators, bulking agents, coating agents, anti caking agents, emulsifiers, antioxidants, tone regulators, preservatives, flavourings, sweeteners, diluents, glidants, colourings, binders, adsorbents, release retardants and mixtures thereof.

Suitable excipients may be potassium sorbate, sodium benzoate, e-polylysine, sucralose, maltodextrin, citric acid, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium stearate, stearic, polyethylene glycol, natural starch, partially hydrolysed starch, lactose, phosphate of calcium, carbonate of calcium, sulphate of calcium, 5 polyvinylpyrrolidone, silica, colloidal silica, precipitated silica , silicates of magnesium, silicates of aluminium, sodium lauryl sulphate, magnesium lauryl sulphate, methacrylate copolymers, sodium dehydroacetate, xanthan gum, guar gum , tara gum, locust bean gum, fenugreek gum, gum arabic, alginic acid, sodium alginate, propylene glycol alginate , sodium croscarmellose, polyvinylpolypyrrolidone, glyceryl behenate, titanium dioxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, ethylcellulose, gelatine, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polydextrose, carrageenan, methylcellulose, saccharose, esters of saccharose, sorbitol, xylitol, dextrose, fructose, maltitol, tragacanth gum, pectin, agar- agar, carboxypolymethylene, hydroxypropylmethylcellulose, and mixtures thereof.

In certain embodiments, the composition of the invention consists essentially of:

- an antioxidant component, comprising vitamin C, and

The expression“consists essentially of’ means the CB2 agonist component, antioxidant component, and tissue function-modulating component are, in the composition of the invention, the sole ingredients to be active in the treatment of diseases characterised by high oxidative stress, inflammatory state, and tissue dysfunction, such as metabolic diseases, peripheral neurological diseases, diseases of the circulatory system, musculoskeletal diseases, diseases of the central and peripheral nervous system, gastrointestinal tract diseases, and urinary tract diseases, while any further components or excipients do not interfere with the action thereof.

In other embodiments, the composition of the invention consists of:

- an antioxidant component, comprising vitamin C,

- a tissue function-modulating component, comprising a compound selected from at least one B -group vitamin, at least one essential amino acid, calcium, citicoline, chondroitin, D-mannose, at least one phytosterol, glucosamine, lycopene, magnesium, proanthocyanidins, at least one D-group vitamin, zinc, and mixtures thereof, and optionally, pharmaceutically acceptable excipients.

The composition of the invention can be in the form of a unit dose.

Preferably, said unit dose comprises:

- up to 100 mg of cannabinoid receptor type-2 selective agonist component, comprising b-caryophyllene, - up to 5000 mg of antioxidant component, comprising vitamin C,

- up to 2000 mg of tissue function-modulating component, comprising a compound with components selected from: at least one B-group vitamin, at least one essential amino acid, calcium, citicoline, chondroitin, D-mannose, at least one phytosterol, glucosamine, lycopene, magnesium, proanthocyanidins, at least one D-group vitamin, zinc, and mixtures thereof.

More preferably, said unit dose comprises:

- 5-50 mg of a cannabinoid receptor type-2 selective agonist component, comprising b- caryophyllene,

- 85-2000 mg of antioxidant component, comprising vitamin C,

- 10-1950 mg of tissue function-modulating component, comprising a compound with components selected from: at least one B-group vitamin, at least one essential amino acid, calcium, citicoline, chondroitin, D-mannose, at least one phytosterol, glucosamine, lycopene, magnesium, proanthocyanidins, at least one D-group vitamin, zinc, and mixtures thereof.

The composition of the present invention may be prepared by using methods known to those skilled in the art. Indeed, for oral administration, the components may, for example, be mixed as they stand or with one or more excipients, enclosed in soft-gel capsules or in a solid form, such as a tablet, mini-tablet, micro-tablet, granule, micro-granule, pellet, multiparticulate, or micronized particulate, or powder or in the form of a solution, emulsion, gel, vial, drops, or spray.

In another aspect, the present invention concerns a food supplement comprising the composition described above and suitable dietary ingredients.

Said supplement may be intended for either human or animal food supplementation.

In a further aspect, the present invention concerns the use of the composition described above in the treatment of diseases characterised by high oxidative stress, inflammatory state, and tissue dysfunction, such as metabolic diseases, peripheral neurological diseases, diseases of the circulatory system, musculoskeletal diseases, diseases of the central and peripheral nervous system, gastrointestinal tract diseases, and urinary tract diseases, in addition to comorbidity thereof due to an inflammatory and/or oxidative state, also associated with an immune response.

Comorbidity, within a clinical context, refers to both an independent co-existence of multiple different diseases within a single individual, and the presence of diseases which onset at different times from and as a consequence of a primary background disease. Indeed, advantageously, the composition of the invention enables a noticeable improvement in function and symptoms in at least one of the following diseases: metabolic diseases, peripheral neurological diseases, diseases of the circulatory system, musculoskeletal diseases, diseases of the central and peripheral nervous system, gastrointestinal tract diseases, and urinary tract diseases.

In particular, the CB2 receptor agonist component and the antioxidant component enable modulation of oxidative and/or inflammatory stress, promoting the improvement of at least one of the diseases stated above. In addition, the tissue function-modulating component can act as a adjuvant in the treatment of at least one of the diseases stated above, therefore promoting restored function of the damaged tissue.

The composition of the invention therefore integrates all these effects enabling a synergic action for the treatment of at least one of the diseases stated above, since it promotes both treatment of the symptoms and the restoration of the damaged tissue to a healthy condition.

Preferably, the composition of the invention is administered orally.

More preferably, the composition of the invention is in the form of a unit dose for oral administration, comprising active components, namely the CB2 receptor agonist component, antioxidant component, and tissue function-modulating component, amounting to a total weight of 50-4500 mg.

More preferably, the composition of the invention is in the form of a unit dose for oral administration, comprising active components amounting to a total weight of 75-4000 mg.

It should also be understood that all possible combinations of preferred aspects of the components of the composition, the unit doses, the supplement, the preparation and the uses of the said composition should also be deemed as hereby disclosed and therefore similarly preferable.

It should also be understood that all aspects identified as preferable and advantageous for the composition and the components thereof should be deemed to be equally preferable and advantageous also for the unit dose, the supplement, the preparation and the uses of the said composition. Below are working examples of the present invention provided for illustrative purposes. EXAMPLES

In the examples,‘BCP’ denotes b-caryophyllene,‘CB2 AGO’ denotes the cannabinoid receptor type-2 selective agonist component, ‘ANTIOX’ denotes the antioxidant component;‘MODULATOR’ denotes the tissue function-modulating component.

Example 1.

A composition was prepared comprising the following active components:

* cranberry extract

Example 2.

A composition was prepared comprising the following active components:

* cranberry extract

Example 3.

A composition was prepared comprising the following active components:

* cranberry extract

The compositions of Examples 1-3 are suitable for the treatment of diseases concerning the urinary tract. The latter comprise, for example, cystitis and benign prostatic hyperplasia, and are characterised by a local inflammatory state also associated, in the case of cystitis, with an infection. The compositions of the invention are able to reduce the inflammatory state associated with cystitis. The D-mannose, in particular, modulates bacterial infection and the tissue damage associated therewith. Example 4.

A composition was prepared comprising the following active components:

Example 5.

A composition was prepared comprising the following active components: Example 6.

A composition was prepared comprising the following active components:

The compositions of Examples 4-6 are suitable for the treatment of the diseases concerning the circulatory system, in particular the venous system.

In the inflammatory state associated with the circulatory system, the anti-inflammatory and immunomodulating effect of the CB2 agonists in the modulation of vascular inflammation should be noted, together with the promising application in the case of chronic venous insufficiency, cardiovascular diseases, and avascular necrosis (osteonecrosis). The BCP promotes a reduction in the development of atherosclerosis, by intervening precisely in the vascular inflammation and inhibiting attachment of the leucocytes to the endothelial wall.

Recently, it has been demonstrated that a reduction in the oxidative state leads to an improvement in endothelial dysfunction, the latter also causing abnormal venous and/or arterial flow. In this sense, the contemporaneous presence of BCP, antioxidants, such as vitamin C and troxerutin, and vitamin B6 offer an advantageous effect for venous tone and an anti-oedematous effect, promoting microcirculation locally. It should be noted that low levels of vitamin B6 are associated with a higher risk of developing venous thrombosis, therefore, the compositions of the invention also offer an antithrombotic action. Example 7.

A composition was prepared comprising the following active components:

Example 8.

A composition was prepared comprising the following active components:

Example 9.

A composition was prepared comprising the following active components:

The compositions of Examples 7-9 are suitable for the treatment of diseases concerning the urinary tract. The latter comprise, for example, cystitis and benign prostatic hyperplasia and are characterised by an associated local inflammatory state.

In benign prostatic hyperplasia, high oxidative stress values are encountered and therefore the compositions of the invention, by providing antioxidants such as vitamin C, vitamins E, and phytosterols, offer a direct benefit in the treatment of urinary tract diseases.

Furthermore, the use of b-sitosterol (extracted from Serenoa repens ) and lycopene have been associated with better urinary flow and improvement in benign prostatic hyperplasia. Furthermore, it has been found that the association of Serenoa repens and lycopene promotes a decrease in cellular proliferation, promoting a return to normality in the prostate. Example 10.

A composition was prepared comprising the following active components:

Example 11.

A composition was prepared comprising the following active components:

Example 12.

A composition was prepared comprising the following active components:

Example 13.

A composition was prepared comprising the following active components:

Example 14.

A composition was prepared comprising the following active components:

* extract of Commiphora myrrha

The compositions of Examples 10-14 are suitable for the treatment of peripheral neurological diseases.

In peripheral neurological diseases, it has been found that BCP can reduce the inflammatory state and the neuropathic pain symptoms. Furthermore, it has recently been found that in the treatment of neuropathic pain, the use of BCP demonstrates a greater beneficial effect than other CB2 selective agonists. The use of BCP for the treatment of neuropathy enables a decrease not only in the inflammatory state, but also in the hyperalgesia and allodynia, which are characteristic symptoms of neuropathic pain. Furthermore, the crucial role of CB2 receptors in the modulation of neuropathic pain takes the form of the immune modulation of IFN-g activity.

In the case of peripheral neurological diseases, there is therefore a chronic inflammatory state accompanied by high oxidative stress and by neuronal dysfunction. Recent studies have demonstrated that the use of antioxidants can alleviate neuropathic pain. Fipoic acid can protect neuronal cells against oxidative damage, and the intake of Coenzyme Q10 is related to low oxidative stress and a decrease in neuropathic pain. In addition, use of antioxidants such as, for example vitamins E and vitamin C, administered individually or in association, helps reduce oxidative stress in the spinal cord, reducing nociceptive pain. In this context, B-group vitamins and citicoline act as neurotrophic agents and adjuvants of neuronal structural integrity, intervening actively in the treatment of the damage caused by peripheral neurological diseases.

Example 15.

A composition was prepared comprising the following active components:

Example 16.

A composition was prepared comprising the following active components:

Example 17.

A composition was prepared comprising the following active components:

The compositions of Examples 15-17 are suitable for the treatment of diseases concerning the CNS, such as, for example, Alzheimer's and Parkinson's diseases, which are characterised by cognitive decline.

Cognitive decline is often associated with various factors, including oxidative stress and a state of chronic low-grade inflammation.

Use of CB2 agonists has an anti-inflammatory and neuroprotective effect, while the antioxidants, such as vitamin C and polyphenols extracted from blueberries, have a positive effect on memory and learning. Furthermore, omega 3 (DHA and EPA) improve neuronal structure and activity and have an effect on inflammatory response, by modulating microglia activity.

In addition, cognitive decline is also characterised by deterioration of neuronal and mitochondrial membranes, which leads to a loss of cell integrity and neuronal dysfunction. Since a low level of B-group vitamins is related to a neurological dysfunction, the compositions of the invention also enable restoration of correct neuronal function. Example 18.

A composition was prepared comprising the following active components:

Example 19.

A composition was prepared comprising the following active components: Example 20.

A composition was prepared comprising the following active components:

The compositions of Examples 18-20 are suitable for the treatment of musculoskeletal diseases in the presence of comorbidity, such as obesity.

Through its anti-inflammatory activity, BCP, can also have a therapeutic effect in the case of obesity, a disease - characterised by a chronic inflammatory state - which involves cells belonging to both the innate and the adaptive immune response, in particular NK cells and T lymphocytes. Furthermore, CB2 receptors are involved in the oxidation of fatty acids, intervening therefore in lipid metabolism. One use of CB2 agonists enables therefore modulation of inflammation and of the recruitment of immune cells, intervening also in lipid oxidation.

In this sense, the contemporaneous presence of vitamin C further increases effectiveness, as it has a beneficial action on the modulation of various mechanisms, including adipocyte lipolysis, and the secretion of leptin, i.e. a hormone involved in appetite regulation. Finally, it should also be noted that vitamin B2 (riboflavin) inhibits the proinflammatory activity of the adipocytes and macrophages, re-establishing the physiological function of adipose tissue. Example 21.

A composition was prepared comprising the following active components:

Example 22.

A composition was prepared comprising the following active components: Example 23.

A composition was prepared comprising the following active components:

* cranberry extract

Example 24.

A composition was prepared comprising the following active components:

The compositions of Examples 21-24 are suitable for the treatment of bone diseases, such as osteoarthritis, osteoporosis, and osteonecrosis.

These diseases are caused by an inflammatory state, bone and cartilage damage, and/or insufficient bone circulation.

The BCP ha an anti-inflammatory and anti-catabolic effect in human chondrocytes, finding therefore application in the treatment of osteoarthritis. Osteoarthritis is a disease which is also characterised by the recruitment of various immune cells, including T lymphocytes. The use of CB2 agonists allows intervention involving the modulation of both the inflammatory response and the immune response.

Osteonecrosis (avascular necrosis) is a disease characterised by bone tissue death due to a deficit in blood circulation. This disease is characterised by high levels of proinflammatory cytokines, such as, for example, IL-6, and recruitment of the cells involved the inflammatory response. As anti-inflammatory and immune-modulating agents, CB2 agonists help bring the illness to an end. Furthermore, BCP also acts as a promoter of bone health, since it promotes osteoblastic mineralisation and suppresses osteoclastogenesis, which is useful in the treatment of both osteoporosis and osteonecrosis. BCP is furthermore associated with a significant increase in collagen content, one of the main components of joints.

In addition, the protective effect of BCP on bone function should be noted: in particular the presence of BCP is related to an increase in collagen, alkaline phosphatase, production of osteocalcin and bone mineralisation, which is expressed as promotion of osteoblastic differentiation. Furthermore, by also reducing the oxidative stress, BCP inhibits possible osteoblastic dysfunction.

In osteoarthritis, oxidative stress is held to be a major cause of chondrocyte dysfunction and of the deterioration of cartilage in joints. The use of antioxidants, such as, for example, vitamin C provides protection for the chondrocytes, reducing the oxidative stress of the inflamed joint. In the case of osteonecrosis, the antioxidants modulate angiogenesis, facilitating therefore blood circulation and therefore recovery of tissue health. Indeed, the use of vitamins E and lipoic acid reduces the rate of osteonecrosis, thanks to their antioxidant effect.

In addition, the positive correlation between vitamin C intake and bone mineral density should be noted.

Furthermore, it should be stressed that, in the case of osteoporosis, treatment with magnesium, calcium, vitamin D and/or associations thereof, results in modulation of the bone metabolism and density, suggesting a key role in the treatment of osteoporosis. Treatment with joint protectors, such as chondroitin sulphate and glucosamine, reduces pain and joint stiffness, therefore promoting joint function.

Furthermore, glucosamine appears to contribute to the suppression of osteoclastogenesis, finding therefore possible application in people suffering from osteonecrosis.

In addition to the foregoing, supplementation with B -group vitamins could modulate the development of avascular necrosis (osteonecrosis). Various polyphenols have pro- angiogenic properties and could therefore promote the bone circulation and therefore correct bone trophism in the event of osteonecrosis.

Finally, vitamin B12 is also involved in bone formation, acting as an adjuvant in the growth of bone mass. Example 25.

A composition was prepared comprising the following active components:

* cranberry extract

Example 26.

A composition was prepared comprising the following active components:

* cranberry extract

Example 27.

A composition was prepared comprising the following active components:

The compositions of Examples 25-27 are suitable for the treatment of gastrointestinal tract diseases.

CB2 receptor agonists also appear to play a protective role in the gastrointestinal tract. For example, it has been found that BCP ha a beneficial effect in the case of IBD ( inflammatory bowel disease), a group of chronic inflammatory disorders which comprise Crohn's disease and ulcerative colitis. These chronic inflammatory diseases are also characterised by high oxidative stress which contributes to both the onset and the continuation of the pathological state, leading also to mucosa tissue damage. Often, Furthermore, IBD is associated with an alteration of bone growth. It has been found that BCP attenuates the inflammatory state associated with the colitis, having modulated the levels of inflammatory cytokines. Furthermore, BCP has been associated with both anti inflammatory and cytoprotective effects in the gastric mucosa, suggesting possible use in the case of gastric ulcers. Furthermore, it has been found that the receptorial system of the endocannabinoids plays a key role in physiological gastrointestinal modulation, mucosa integrity, sense of satiety, immune function, motility and secretion, all of which are highly significant aspects of diseases of the gastrointestinal tract characterised by an inflammatory state.

It has been found that people suffering from IBD have low levels of vitamin C, suggesting the key role of this vitamin in countering the oxidative stress of the disease. In addition, recent studies suggest that use of Omega 3 has beneficial effects in both preventing and treating IBD.

Furthermore, it would appear that use of B-group vitamins, vitamin D and cranberry extracts have beneficial effects in gastrointestinal diseases, in particular IBD. Furthermore, a recent study has demonstrated that IBD is associated with low levels of tryptophan, which appears to have both protective and remedial effects for colitis, contributing also to the regulation of epithelial integrity and homeostasis.

Example 28.

A composition was prepared comprising the following active components:

The composition of Example 28 is suitable for the treatment of sarcopenia.

Sarcopenia, disease characterised by a loss of muscle mass, is often associated with an inflammatory state in the patient. Treatment with a CB2 agonist can alleviate the inflammatory state, and therefore reduce existing muscle mass damage, resulting in efficient muscular regeneration.

In sarcopenia, it has been highlighted that the cell damage and muscular deficit are associated with a chronic oxidative stress and inflammatory state. It has been demonstrated that supplementation of Omega 3 (such as EPA and/or DHA) can reduce mitochondrial oxidative stress and increase muscle protein synthesis, suggesting a beneficial role in people suffering from sarcopenia. It has been found that a diet rich in antioxidant substances, such Vitamin C and vitamin E, would appear to prevent loss of muscle mass, which is associated with sarcopenia. Supplementation of amino acids (such as, for example, leucine) is used widely in the treatment of sarcopenia. Furthermore, it appears that vitamin D is involved in muscular metabolism and has beneficial effects on muscular strength. Furthermore, vitamin B6 appears to modulate gene expression which promotes the growth and repair of skeletal muscle, finding potential application for muscle health in sarcopenia.

Example 29.

In vitro cell viability test

Materials and method:

1. Cultivation of human monocytes U937 and activation thereof with phorbol myristate acetate (PMA) and lipopolysaccaride (LPS).

The monocytes were cultivated in RPMI 1640 medium with 2 mM l-glutamine, 100 U/ml penicillin, 100 pg/ml streptomycin, 10% FBS. Next, they were activated with PMA 50 ng/ml for 48h and subsequently stimulated with LPS 1 pg/ml for lh. The conditioned culture medium (CCM) was then sampled, centrifuged, filtered, and used to treat the NIH- 3T3 and imitate a pro-inflammatory effect.

The differentiation of the monocytes into macrophages was observed under optical microscope and through analysis of the gene expression of the cells treated.

2. Cell proliferation test (MTT)

The NIH-3T3 cells were sown on a 48-well plate (1000 cells/well) and treated with b- caryophyllene, glucosamine hydrochloride, ascorbic acid, and a combination thereof for 24h.

24h after sowing, the cells were treated with the substances under examination at different concentrations in triplicate, in the presence or absence of the conditioned culture obtained from the activated U937. Cell proliferation was assayed by MTT (3-4,5-dimethylthiazol- 2-il-2, 5-diphenyl tetrazolium bromide): an MTT solution was added to each well and after incubation for 3h at 37°C absorbance at 595 nm was measured with a TECAN INFINITE PRO 200. Statistical analysis was performed with a two-tail t-test and the differences were considerate significant with a t-test value of <0.05. The experiments were performed in triplicate. Tests carried out:

Cell viability test (proliferation): if viability >70%, the concentration of the substance used is not cytotoxic.

Compared with non-treated (NT) samples, the following substances were tested individually and in association: beta-caryophyllene (BCP) as an example of cannabinoid receptor type-2 selective agonist (CB2); vitamin C (VIT C) as an example of a substance endowed with antioxidant properties; glucosamine (GLN) as an example of a tissue function modulator.

The performance of the aforesaid substances was measured in normal culture conditions and in conditioned culture conditions in order to simulate an inflammatory state.

BETA-CARYOPHYLLENE (BCP) NORMAL CULTURE - 24 hours

BCP INFLAMED CULTURE - 24 hours

VITAMIN C (VIT C) NORMAL CULTURE - 24 hours

VIT C INFLAMED CULTURE - 24 hours

GLUCOSAMINE (GLN) NORMAL CULTURE- 24 hours

GLN INFLAMED CULTURE - 24 hours

Viability of the cells treated with the individual substances (BCP, VIT C, and GLN) was maintained in both of normal and inflamed culture conditions, at all the concentrations tested.

Counter to expectations, the combination of the three substances maintains an excellent cell viability, which is comparable - if not better - than that of the individual components:

TREATMENT normal culture - 24 hours

In the inflamed culture conditions, the association of the three substances maintained good cell viability. Surprisingly, the association of the three substances provides better cell viability results than treatment with the individual substances.

TREATMENT inflamed culture - 24 HOURS

The compositions according to the present invention proved particularly effective in ensuring cell viability in inflammatory stress conditions. Similar results were not found, meanwhile, when using solely BCP or solely glucosamine.

In conclusion, the invention allows treatments with active substances characterised by low risks with equivalent benefits. This factor proves extremely significant in the non- pharmacological treatment of diseases characterised by high oxidative stress, inflammatory state, and tissue dysfunction.

Claims

1. A composition comprising:

- an antioxidant component, comprising vitamin C, and

- a tissue function-modulating component, comprising a compound selected from at least one vitamin of group B, at least one essential amino acid, calcium, citicoline, chondroitin, D-mannose, at least one phytosterol, glucosamine, lycopene, magnesium, proanthocyanidins, at least one vitamin of group D, zinc, and mixtures thereof.

2. The composition of claim 1, wherein the weight ratio of said cannabinoid receptor type- 2 selective agonist component to said antioxidant component is 1:0.1 to 1: 150, preferably 1:2 to 1: 120, more preferably 1:5 to 1:50.

3. The composition of claim 1 or 2, wherein the weight ratio of said cannabinoid receptor type-2 selective agonist component to said tissue function-modulating component is 1:0.1 to 1: 130, preferably 1:5 to 1:50, more preferably 1: 10 to 1:35.

4. The composition of any one of claims 1-3, wherein the weight ratio of said antioxidant component to said tissue function-modulating component is 10: 1 to 1: 10, preferably 5: 1 to 1:5.

5. The composition of any one of claims 1-4, wherein the cannabinoid receptor type-2 selective agonist component is in an amount of 0.1-20 wt%, preferably 0.25-10 wt%, and more preferably 0.5-5 wt%, based on the sum of the components' weights.

6. The composition of any one of claims 1-5, wherein the antioxidant component is in amounts of 1-95 wt%, preferably 5-85 wt%, and more preferably 15-75 wt%, on the sum of the components’ weights.

7. The composition of any one of claims 1-6, wherein the tissue function-modulating component is in an amount of 0.1-95 wt%, preferably 2-90 wt%, and more preferably of 15-80 wt%, on the sum of the components' weights.

8. The composition of any one of claims 1-7, wherein said composition is in the form of a unit dose comprising:

- up to 100 mg of cannabinoid receptor type-2 selective agonist component, comprising b-caryophyllene,

- up to 5000 mg of antioxidant component, comprising vitamin C,

- up to 2000 mg of tissue function-modulating component, comprising a compound selected from at least one vitamin of group B, at least one essential amino acid, calcium, citicoline, chondroitin, D-mannose, at least one phytosterol, glucosamine, lycopene, magnesium, proanthocyanidins, at least one vitamin of group D, zinc, and mixtures thereof.

9. A food supplement comprising the composition of any one of claims 1-8 and suitable food ingredients.

10. The composition of any one of the claims 1-8 for use in the treatment of diseases characterized by high oxidative stress, inflammatory state, and dysfunction of tissue function, said pathologies comprising metabolic diseases, peripheral neuropathies, circulatory system diseases, musculoskeletal disorders, diseases of the central and peripheral nervous system, diseases of the gastrointestinal tract, and pathologies of the urinary tract, as well as their comorbidity due to an inflammatory and/or oxidative state, possibly associated with an immune response.