WO2022264058A1

WO2022264058A1 - Composition for the prevention and/or treatment of inflammatory diseases

Info

Publication number: WO2022264058A1
Application number: PCT/IB2022/055541
Authority: WO
Inventors: Umberto DI MAIO
Original assignee: Neilos S.r.l.
Priority date: 2021-06-16
Filing date: 2022-06-15
Publication date: 2022-12-22
Also published as: IT202100015704A1; EP4355347A1

Abstract

A composition containing a combination of an extract of Mangifera indica, bromelain and an extract of Salvia officinalis is described, which is useful for the prevention and/or treatment of inflammatory diseases and in particular osteoarticular, urogenital, dental, and gynecological inflammatory diseases in both humans and animals. The composition is particularly effective due to the synergistic action of its components.

Description

“Composition for the prevention and/or treatment of inflammatory diseases”

DESCRIPTION

The present invention relates to a composition containing a combination of an extract of Mangifera indica, bromelain and an extract of Salvia officinalis useful for the prevention and/or treatment of inflammatory diseases.

The composition is particularly effective due to the synergistic action of its components. Background of the invention

INFLAMMATION

Inflammation, also known as phlogosis, is the ensemble of changes and variations that occur in a specific region or in a wider area of the body following damage. It is an adaptive response usually triggered by noxious stimuli or conditions. Physical agents such as trauma or heat, chemical agents such as acid substances, or still biological agents such as bacteria and viruses may play a role in the genesis of pro-inflammatory conditions. Therefore, it is appreciated as an important defence mechanism in case of tissue damage or during infections, which acts with the aim of restoring homeostasis. Inflammation, in general, is a predominantly acute and local reaction but in various cases can become chronic and affect larger and larger areas of the body.

The pivotal points of inflammation are five and are defined as calor, increased temperature of the affected area caused by increased vascularization, tumor, swelling of the affected area due to the formation of exudate following vasodilation, rubor, redness resulting from hyperaemia, dolor, a painful sensation triggered by the stimulation of sensory endings by the inflammatory agent or by the components of the inflammatory response, and finally, the functio laesa, which consists in the functional impairment of the affected area. Inflammation may be induced by either endogenous or exogenous factors.

In the case of exogenous factors, these may be further divided into two groups, microbial factors and non-microbial factors. Microbial factors that induce inflammation are PAMPs (Pathogen- Associated Molecular Patterns) and virulence factors, whereas non-microbial factors include allergens, irritants, foreign bodies, and toxic compounds.

Instead, endogenous inflammation inducers are signals produced by stressed and damaged cells, or by tissues with impaired function.

These inflammation inducers trigger the production of numerous mediators that primarily act on vascularization and leukocyte attraction. Some mediators such as histamine and serotonin are preformed and stored in mast cells, basophils, and platelets, ready for use when needed, while others are synthesized de novo. Inflammation mediators are divided into 7 groups according to their biochemical properties into: vasoactive amines, vasoactive peptides, lipid mediators, fragments forming part of the complement system, cytokines, chemokines, and proteolytic enzymes.

Vasoactive substances play a complex and major role in vascularization causing vasodilation and increased vascular permeability. Lipid mediators derive from the phospholipids of the cell membrane and have arachidonic acid as the main component, which can be metabolized by cyclooxygenases (COX-1 and COX-2) into prostaglandins, thereby acting as an important algesic agent and fever inducer, or be metabolized by lipoxygenases into leukotrienes and lipoxins.

Fragments forming part of the complement system act by promoting granulocyte and monocyte recruitment and induce mast cell degranulation. Pro-inflammatory cytokines such as TNF-a, IL-6, IL-1 and many others are produced by several cell types, particularly mast cells and macrophages, and are important in the inflammatory response as they are involved in endothelial and leukocyte activation. Chemokines, on the other hand, control leukocyte extravasation and chemotaxis. Finally, proteolytic enzymes have different roles ranging from the body's defence to tissue remodelling.

All these components contribute to eliminating noxious stimuli and work together to restore physiological tissue conditions.

However, under certain conditions, the inflammatory response may go out of control and may turn from a defence, homeostasis-restoring mechanism into a cause triggering or even exacerbating a disease.

The mechanism underlying inflammation as well as all the components taking part in it are not yet fully known, but major advances have been made especially with regard to the control of the inflammatory response.

To date, a wide variety of anti-inflammatory agents are available on the market, which have shown great efficacy but nevertheless their use is not free from side effects.

The best known and widely used anti-inflammatory drugs are the so-called NSAIDs (Non- Steroidal Anti-Inflammatory Drugs) which act by inhibiting the two isoforms of the COX enzyme (COX-1 and COX-2). This mechanism prevents the formation of prostaglandins and thromboxane, which are major pro-inflammatory factors. However, despite their extensive and proven effectiveness, prolonged use of this class of drugs is accompanied by non-negligible side effects, the most frequent of which are at the gastrointestinal and cardiovascular levels.

Another class of drugs classically used in the treatment of inflammation is that of SAIDs (Steroidal Anti-Inflammatory Drugs), also known as glucocorticoids. Anti-inflammatory activity is mediated through various mechanisms of action, but the major mechanism of action is thought to be cytokine-induced gene transcription inhibition. SAIDs can enter the cell and bind the cytoplasmic steroid receptor; subsequently, this complex migrates within the nucleus and recognizes and binds specific sequences on the DNA. This prevents NF- kB and AP-1 transcription factors from acting.

Although glucocorticoids are widely used in the treatment of inflammatory and autoimmune chronic diseases, their use is related to annoying and in some cases serious side effects such as carbohydrate metabolism alteration, osteoporosis, menstrual abnormalities, hyperlipidemia, decreased GH secretion, and they also have important interactions with other classes of drugs. The side effects are usually directly proportional to the duration of treatment and the dosage used.

New drugs, designated as monoclonal antibodies or more simply biologies, can act and inhibit the diverse activities of the various pro-inflammatory agents in a highly selective manner. However, even these are not free from side effects, indeed the major side effect consists precisely in reducing the body’s defences against other noxious stimuli and infections.

Inflammation therefore occurs in a wide range of diseases that can affect all areas of the body.

Of particular interest for this patent application are inflammatory diseases at the osteoarticular, urogenital, dental and gynecological levels in both humans and animals. One of the classic diseases associated with a high inflammatory state is osteoarthritis. After a trauma, the classic signs of inflammation are easily visible and detectable within the tissues and in the synovial fluid of the joints. If inflammation, which initially plays an important role in optimal healing, does not resolve on its own, it can be an important risk factor for the development of post-traumatic osteoarthritis. In addition, inflammation can lead to progressive cartilage degeneration and subsequent development of chronic post- injury symptoms.

The urogenital tract is also often subject to inflammatory states, especially with advancing age. Frequently, the pro-inflammatory state is associated with infections caused by bacteria and viruses, but also with a wide range of non-infectious processes. The most common inflammatory processes are vulvovaginitis, metritis, endometritis, prostatitis, epididymitis, orchitis. These are all diseases which, if not treated properly and correctly, can lead to infertility.

In dentistry, inflammation plays a major role in various fields, whether in the case of infections, systemic diseases, or damage caused by a physical agent. Inflammation is the basis of stomatitis, which is a widespread inflammation of the oral cavity, but periodontitis, gingivitis and canker sores can also occur. Furthermore, the role of inflammation in the case of tooth extraction is not to be underestimated, as pain and swelling are important limiting factors for this procedure.

GLOSSARY

The terms used in this description are as generally understood by the person skilled in the art, unless otherwise stated.

The term “extract”, in the context of this description, means any product referable to a plant drug including all products derived from mechanical treatments (pulverization, grinding, mixing and/or other methods) or extractive treatments (solvent extraction, distillation, and/or other specific methods) performed on a drug.

Detailed description of the invention

Therefore, the object of the present invention is a composition containing a combination of an extract of Mangifera indica, bromelain and an extract of Salvia officinalis useful for the prevention and/or treatment of inflammatory diseases in both humans and animals, and in particular osteo articular, urogenital, dental, and gynecological inflammatory diseases. MANGIFERA INDICA

Mangifera indica, known by the common name of mango, is a tree belonging to the Anacardiaceae family, native to India but now cultivated in all tropical areas of the world. Since ancient times, it has been used in Ayurvedic and indigenous medicine, and different pharmacological properties are attributed to the different parts of the tree.

All parts of this tree are used, in fact the fruits, root, bark, leaves and flowers are used. Today, mango is one of the most famous and used tropical fruits, second only to bananas. It contains mangiferin, a glycosidic xanthone, which is attributed with high antioxidant activity, ability to inhibit lipid peroxidation, immunomodulation, and cardiotonic, hypotensive, anti-degenerative and hypoglycemic activities.

The seeds are used to treat asthma and as astringents. Inhalation of smoke from the burning of leaves is used to treat upper respiratory tract diseases. The bark has astringent abilities and is used in diphtheria and rheumatism, and is believed to have a tonic action on the mucous membranes.

Many chemical compounds have been recognized within M. indica, among these the most important and at the same time those that are attributed with the greatest anti-inflammatory and antioxidant activity are phenolic acids, phenolic esters, flavonoids, and triterpenes. Polyphenols and in particular mangiferin are reported to have anti-inflammatory activity through the inhibition of nuclear factor-kappa B (NF-kB).

In particular, mangiferin has been shown to have the ability to suppress the activation of the transcription factor NF-kB, which in turn controls the production of pro-inflammatory cytokines.

Numerous studies have been performed on an aqueous extract of the stems and bark of M. indica containing a large amount of mangiferin, widely used in Cuba as a supplement.

An in vitro study has shown that the extract can inhibit the production of prostaglandins E2 and leukotrienes B4 in macrophages in which a pro-inflammatory stimulus has been induced, probably by inhibiting the enzymes COX-2 and 5-LOX. Studies in mice have shown that it reduces arachidonic acid levels, PMA-induced ear edema, myeloperoxidase activity, and a substantial decrease in serum TNF-a levels has also been achieved.

In addition, it has been shown to block the release of TNF-a and inhibit NO production in macrophages and in a murine model of septic shock.

The effect of the extract and mangiferin on COX-2 and on the expression of inducible nitric oxide synthase (iNOS) was investigated in smooth muscle cells of mesenteric arteries of normotensive rats, with or without stimulation through administration of IL-Ib. When IL- 1b was not administered, the extract at a dose of 0.5 mg/ml and mangiferin at a dose of 0.025 mg/ml had no effect on the expression of iNOS and COX-2. In contrast, following stimulation by IL-Ib, they were able to prevent the expression of iNOS and COX-2, demonstrating that they possess an important anti-inflammatory activity.

Through in vitro studies, the extract obtained from the bark of M. indica was found to have a strong antioxidant activity; a significant decrease in phospholipid peroxidation in rat brain was obtained, demonstrating its effectiveness as a scavenger of radicals responsible for oxidative stress. This supports the hypothesis of its possible use as a highly antioxidant substance that promotes the elimination of radicals produced during the inflammatory phase, resulting in the promotion of healing. This is because a high oxidative state can induce significant damage to biological molecules, such as proteins, lipids, and DNA, with a corresponding change in their structure and function.

By virtue of the important activities demonstrated in vitro by the extracts of Mangifera indica or the individual compounds contained therein, several clinical studies have been carried out to demonstrate its effectiveness and evaluate its use as a supplement.

The use and possible benefit of a supplement containing an extract of M. indica has been assessed in patients with rheumatoid arthritis.

The study was performed on a total sample of 20 patients, divided into two groups, one of which followed a conventional therapy with methotrexate and non-steroidal anti inflammatory drugs (NSAIDs), whereas the other group, in addition to the conventional therapy, was administered with the supplement of M. indica containing 300 mg of 15% titrated extract in mangiferin, 3 times a day before meals, for a total dose of 900 mg supplement per day.

The study lasted 180 days and at the end a significant improvement in the condition of the disease was achieved in the group treated with the supplement. 100% of patients treated with the supplement decreased the dose of NSAIDs and 70% obtained a significant improvement in gastro-intestinal symptoms associated with past treatments.

A further study evaluated the possible use of a supplement containing mangiferin and quercetin in 48 athletes as a means of reducing inflammation and muscle fatigue.

The athletes were divided into two groups, one was given the supplement (140 mg containing mangiferin in a quantity greater than or equal to 60% + 140 mg quercetin), while the other was given a placebo.

The supplement or placebo was administered one hour before the competition, and then one tablet was administered every 8 h for the next 24 h. At the end of the study, the group receiving the supplement exhibited a decrease in pain sensation, less muscle damage caused by physical exercise and also improved muscle recovery.

All these elements reveal the true value and potential of the various extracts of M. indica in the field of prevention and treatment of diseases related to an excessive inflammatory state, and justify their use in traditional medicine.

Bromelain

Bromelain is the generic name for a family of proteolytic enzymes containing the sulfhydryl group. However, the beneficial effects of bromelain are also attributable to the constituents that are not part of the proteolytic fraction such as peroxidase, acid phosphatase, various protein inhibitors, and organic calcium.

Different measurement units may be used to assess the enzymatic activity of bromelain, but the most used are gelatin dissolving units (g.d.u.) and generally one gram of bromelain has an activity of 1,200 g.d.u.

By virtue of its historical and wide use, numerous tests have been carried out both in vitro and in vivo, in order to assess its pharmacokinetics, but above all to assess the mechanism of action through which it can act and play such an important role in the treatment of various diseases.

Oral absorption is high, especially bromelain is absorbed intact, and the plasma peak is approximately one hour after administration. However, the proteolytic activity is rapidly inactivated.

To date, the mechanism of action is not yet fully clarified, but certainly several routes and various mediators are involved.

Its anti-inflammatory activity is mainly due to its ability to inhibit bradykinin formation at the site of inflammation through action on the kinin-kallikrein system, and it is also able to limit fibrin production, thus decreasing the intermediates of the coagulation cascade.

In vivo studies in a murine model of carrageenan-induced inflammation showed that bromelain had the ability to significantly decrease the production of prostaglandins and substance P, two important mediators of the inflammatory and pain response. Bromelain was already effective at a dose of 10 mg/kg. In addition, the above study also assessed the activity of bromelain in vitw, however, it had no effect, indeed the value of substance P increased. This shows that bromelain does not act directly on these mediators, but implicitly, resulting in a decrease in the two inflammatory markers.

Furthermore, bromelain by acting as a signalling molecule appears to have the ability to intervene in and affect different cell signalling cascades, many of which are involved in cell survival.

A mouse carcinogenesis model showed that treatment with 1 mg/animal of bromelain caused increased regulation of p53 and Bax, two important transcription factors involved in the apoptosis process, and subsequent activation of caspase 3 and caspase 9 with concomitant decrease in Bcl-2.

In addition, the expression of COX-2 and of the transcription factor NF-kB were significantly inhibited due to the fact that bromelain showed the ability to block phosphorylation and subsequent degradation of IkBa, an important factor that inhibits NF- kB activity. This results in marked anti-inflammatory and preventive activity on carcinogenesis.

In addition, in vitro, bromelain at a dose of 5 mg/ml demonstrated the ability to decrease platelet activity and aggregation in blood samples taken from 10 healthy, non-smoking male volunteers (Glaser et ah).

In addition, treatment with bromelain in vitro has shown the ability to decrease platelet adhesion to endothelial cells, and probably its activity as an anti-platelet aggregation agent is mainly related to this ability.

The anti-thrombotic ability of bromelain when administered orally at a dose of 60 mg/kg was assessed in a mouse laser-induced thrombosis model. Under these conditions, bromelain showed the ability to significantly inhibit the formation of thrombi in rat mesenteric vessels. The above in vitro and in vivo scientific evidence was later also confirmed in clinical studies. Bromelain has actually been shown to be effective in treating inflammatory diseases.

In a study on 84 patients subjected to surgical removal of the third mandibular molar, administration of 40 mg bromelain every 6 hours for 6 days in combination with an injection of 4 mg dexamethasone has been shown to be effective in significantly reducing the intake of anti-inflammatory drugs and it also reduced, although not significantly, post operative swelling. Bromelain has been shown to be a valuable ingredient in post-operative inflammation conditions in clinical trials; one study demonstrated effective improvement in swelling, pain, and swallowing difficulties in groups treated with various doses of bromelain compared to the placebo group.

SALVIA OFFICINALIS

Salvia officinalis is a perennial aromatic plant belonging to the Laminaceae family and is widely spread throughout the world, although it is native to the Middle east and the Mediterranean area. The aerial parts of S. officinalis have been commonly used for centuries for food purposes and in traditional medicine. In Asian and Latin American popular medicine, it has been widely used for a long time as a remedy in the treatment of different diseases such as ulcers, rheumatism, tremors, gout, vertigo, inflammation, and diarrhoea. In traditional European medicine S. officinalis is used to treat moderate dyspepsia such as gastroesophageal reflux or the sense of swelling, excessive sweating, age-related cognitive decline, and inflammation of the upper respiratory tract and skin. Recently, more and more studies have been developed and conducted to document and support the traditional use of S. officinalis. These studies led to the discovery of a wide variety of pharmacological activities including the anticancer, anti-inflammatory, anti- nociceptive, antioxidant, antimicrobial, cognitive-protective, hypoglycemic and lipid lowering activities.

Inside the flowers and especially the leaves, which is the most widely used drug, there are a wide range of constituents including alkaloids, fatty acids, glycosidic derivatives such as flavonoid glycosides and saponins, phenolic compounds such as coumarins, flavonoids and tannins, and lastly terpenes and terpenoids in the form of monoterpenes, diterpenes, triterpenoids and sesquiterpenes. In total, over 120 components have been isolated and characterized.

Oxidative stress plays a pivotal role in the early stages and progression of several diseases. High oxidative stress occurs when the production of reactive oxygen species (ROS) through the mitochondrial electron transport chain, NAPDH oxidase activity and xanthine oxidase activity exceeds the antioxidant activity of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD).

Natural substances with antioxidant activity can protect cells from excessive ROS production and possibly prevent tissue damage caused by high oxidative stress.

Various studies have shown that extracts obtained from S. officinalis have a potent antioxidant effect. Components with the greatest antioxidant capacity contained in S. officinalis are camosol, rosmarinic acid, and camosic acid with an activity comparable to that of a-tocopherol.

Other studies have highlighted the ability of the aqueous extract of the aerial parts of S. officinalis to significantly increase the enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), all important enzymes involved in the response to oxidative stress. In addition, nitric oxide (NO) levels were also significantly decreased.

In this study, carried out on 36 rats, inflammation was induced by using E. coli LPS and the response was assessed after treatment with 10 or 30 mg/kg of S. officinalis extract. As mentioned above, the treatment increased the enzymes involved in the response to oxidative stress and a consequent improvement in the inflammatory state was achieved. Pharmacological studies have shown that S. officinalis has anti-inflammatory and anti nociceptive activities.

The anti-inflammatory and anti-nociceptive potential of a hydro alcoholic extract of S. officinalis leaves and specific isolated substances (camosol and ursolic acid/oleanic acid) was assessed.

The extract, when administered orally at a dose of 10, 30 and 100 mg/kg was shown to significantly decrease leukocyte and plasma extravasation induced by acetic acid administration. Furthermore, in the formalin test, the extract showed a significant decrease in pain both in the initial phase, known as neurological pain, and in the subsequent phase, known as inflammatory pain.

Moreover, camosol at a dose of 10 mg/kg and ursolic acid/oleanic acid at a dose of 30 mg/kg significantly inhibited the inflammatory phase induced by the formalin test and the nociceptive and mechanical pain caused by cinnamaldehyde.

The S. officinalis extract, and specifically camosic acid and camosol, can inhibit the production of prostaglandins by selective inhibition of mPGES-1 (microsomal Prostaglandin E Synthase- 1) with an IC50 value of 5.0 mM.

Furthermore, other studies have shown that both camosic acid and camosol, in addition to acting efficiently on mPGES-1 inhibition, act on 5-lipoxygenase (5-LOX), resulting in significant and dose-dependent anti-inflammatory and anti-nociceptive activity. All this was demonstrated through a murine carrageenan-induced hyperalgesia model.

Finally, various clinical studies were performed to evaluate its use as an anti-inflammatory and pain relief product.

The use of a supplement containing 500 mg S. officinalis has been assessed to combat the symptoms of premenstrual pain. The study was carried out on a sample of 90 patients divided into two groups, one was given placebo and the other was given a tablet containing 500 mg of S. officinalis extract.

The treatment consisted of taking one tablet per day for 2 months. At the end of the study, a significant decrease in physical and psychological symptoms in premenstrual pain was achieved in the group treated with the product obtained from S. officinalis.

A clinical study assessed its use as a possible pain reliever in viral pharyngitis, and the use of a spray containing 15% S. officinalis extract was shown to be more effective than the placebo after 3 days of treatment.

In a preferred embodiment, the composition object of the present invention contains the combination of an extract of Mangifera indica, bromelain and an extract of Salvia officinalis in admixture with a suitable pharmaceutically acceptable carrier.

Suitable pharmaceutically acceptable carriers are those commonly known to those skilled in the art for the preparation of pharmaceutical compositions for oral administration such as solutions, suspensions, powders or granules, tablets, capsules, pellets.

By way of non-limiting example, such pharmaceutically acceptable carriers may consist of binders, diluents, lubricants, glidants, disintegrants, solubilisers (wetting agents), stabilizers, dyes, anti-caking agents, emulsifiers, thickeners and gelling agents, coating agents, humectants, sequestrants, sweeteners. Specifically, examples of diluents can be: magnesium carbonate, microcrystalline cellulose, starch, lactose, sucrose; mainly used lubricants are magnesium stearate, stearic acid, sodium stearyl fumarate. Colloidal silica and magnesium silicate may be mentioned as glidants, cross-linked polyvinylpyrrolidones and sodium starch glycolate may be mentioned as disintegrants, surfactants such as TWEEN or sodium lauryl sulphate may be mentioned as solubilisers, and all classes of preservatives (sorbic acid and derivatives, benzoic acid and derivatives, parabens), antioxidants (ascorbic acid and derivatives, tocopherol), acidifiers (phosphoric acid, tartaric acid) may be mentioned as stabilizers. Thickeners and gelling agents can be carrageenan, pectins, starches; coating agents include, e.g., waxes and derivatives; anti-caking agents include calcium or magnesium carbonate; humectants include sorbitol, mannitol; sequestrants include EDTA and derivatives; dyes include aspartame, potassium acesulfame.

The composition object of the present invention is preferably a solid, liquid or semi-solid composition for oral use, still more preferably powder or granules, a capsule, a tablet, an aqueous solution, a suspension, a buccal powder, a pellet.

The composition object of the present invention contains an extract of Mangifera indica, bromelain and an extract of Salvia officinalis.

The extract of Mangifera indica is present in an amount between 1 mg and 5000 mg, preferably between 5 mg and 4000 mg, still more preferably between 10 mg and 2000 mg. Bromelain is present in an amount between 5 mg and 10000 mg, preferably between 10 mg and 7000 mg, still more preferably between 20 mg and 5000 mg. The extract of Salvia officinalis is present in an amount between 1 mg and 5000 mg, preferably between 5 mg and 4000 mg, still more preferably between 10 mg and 2000 mg.

Thanks to the properties of the active ingredients, the composition object of the present invention is particularly effective in the prevention and/or treatment of inflammatory diseases.

The compositions object of the present invention are particularly effective in the prevention and/or treatment of inflammatory diseases, in particular at the osteoarticular, urogenital, dental and gynecological levels.

The compositions object of the present invention are particularly effective in the prevention and/or treatment of osteoarthritis, arthritis, arthrosis, vulvovaginitis, metritis, mastitis, endometritis, prostatitis, epididymitis, orchitis, periodontitis, gingivitis, canker sores, stomatitis, inflammation following dental procedures, soft tissue inflammation. The composition object of the present invention simultaneously allows:

- anti-inflammatory action

- antioxidant action

- anti-edema action thanks to the synergistic action of its components.

Therefore, a further object of the present invention is a composition containing the combination of an extract of Mangifera indica, bromelain and an extract of Salvia officinalis in admixture with a suitable pharmaceutically acceptable carrier for use in the prevention and/or treatment of inflammatory diseases.

The composition can be a medical device, a food supplement, a nutraceutic, dietetic and nutritional composition, a food product, a beverage, a nutraceutic product, a medicament, a medicated food, a pharmaceutical composition, a food for special medical purposes, a complementary feed, a complete feed, a feed intended for particular nutritional purposes, or a medicated feed.

Without wishing to be bound to a specific theory, the inventors believe that the synergistic effect of the combination in the composition object of the present invention derives from the following actions of the components of the combination.

The extract of Mangifera indica has a strong anti-inflammatory activity by inhibiting the NfKB factor and a good antioxidant activity.

Bromelain provides anti-inflammatory efficacy, prevents the phosphorylation and degradation of IKB-a related to the activity of NfKb, and inhibits bradykinin activity.

The extract of Salvia officinalis, thanks to components such as carnosol and camosic acid, acts by inhibiting 5-LOX and mPGES-1, ensuring anti-inflammatory activity.

The synergistic activity of the aforementioned active ingredients is investigated through the use of in vitro and/or in vivo tests capable of assessing the anti-inflammatory and antioxidant activity of the compositions according to the present invention and/or of comparative compositions. Tests and experimental models known in the literature are used for the evaluation of these activities.

Several cell studies can provide information on the anti-inflammatory efficacy of the combination object of the present invention by assessing the expression of cytokines. Models with macrophages, and/or the Whole Blood Assay (WBA), or testing with Peripheral Blood Mononuclear Cells (PBMC), or other similar experimental models known to those skilled in the art are used to assess in more detail the response (inhibition/activation) of cytokines characterizing the inflammatory process (such as, for example, TNF-a, IL-1, IL-4, IL-6, IL-8, IL-10, IL-17, INF-Y, COMP) during inflammatory processes induced by LPS or another pro-inflammatory agent.

As an in vivo test, a simple model of general inflammation is the carrageenan-induced edema model induced in mice or rats. In this test, the injection of carrageenan into the animal's paw causes an acute inflammatory reaction of the paw with the appearance of the classic signs of inflammation; this reaction reaches its maximum within 3 hours of inoculation. This test can assess the ability of the composition object of the present invention to reduce paw edema induced by carrageenan injection.

The above examples are only exemplary and non-limiting examples of possible experimental models; other models known in the scientific literature are also used to demonstrate the synergistic activity of the composition object of the present invention.

Examples

Some non-limiting examples of doses per dosage unit of the active components of the compositions object of the present invention are now provided for illustrative purposes. Daily doses are intended to be administered in a suitable oral dosage form and divided into one or more dosage units.

EXAMPLE 1 (powder for oral suspension solution)

EXAMPLE 2 (powder or granules for oral solution/suspension)

EXAMPLE 3 (capsule)

EXAMPLE 4 (oral solution)

EXAMPLE 5 (tablet)

The compositions are prepared according to conventional techniques.

Claims

1) A composition containing a combination of an extract of Mangifera indica, bromelain and an extract of Salvia officinalis in admixture with a suitable pharmaceutically acceptable carrier.

2) The composition according to claim 1 in the form of a solid, liquid, or semi-solid composition for oral use.

3) The composition according to claim 1 or 2 wherein the extract of Mangifera indica is present in an amount between 1 mg and 5000 mg, preferably between 5 mg and 4000 mg, still more preferably between 10 mg and 2000 mg.

4) The composition according to any one of the previous claims wherein bromelain is present in an amount between 5 mg and 10000 mg, preferably between 10 mg and 7000 mg, still more preferably between 20 mg and 5000 mg.

5) The composition according to any one of the previous claims wherein the extract of Salvia officinalis is present in an amount between 1 mg and 5000 mg, preferably between 5 mg and 4000 mg, still more preferably between 10 mg and 2000 mg.

6) The composition according to any one of the previous claims wherein the composition is a medical device, a food supplement, a nutraceutic, dietetic and nutritional composition, a food product, a beverage, a nutraceutic product, a medicament, a medicated food, a pharmaceutical composition, a food for special medical purposes, a complementary feed, a complete feed, a feed intended for particular nutritional purposes, or a medicated feed.

7) The composition according to any one of the previous claims for use in the prevention and/or treatment of inflammatory diseases in both humans and animals.

8) The composition according to any one of the previous claims for use in the prevention and/or treatment of osteoarticular, urogenital, dental, gynecological inflammatory diseases in both humans and animals.

9) The composition according to claim 8 for use in the prevention and/or treatment of osteoarthritis, arthritis, arthrosis, vulvovaginitis, metritis, mastitis, endometritis, prostatitis, epididymitis, orchitis, periodontitis, gingivitis, canker sores, stomatitis, inflammation following dental procedures, soft tissue inflammation.