Mixture, compositions containing said mixture and use thereof in the treatment and / or prevention of peripheral neuropathies and neuropathic pain

Abstract

The present invention relates to a mixture, compositions containing said mixture, and the use thereof in the treatment and / or prevention of correct peripheral nervous system function, for counteracting and / or treating peripheral neuropathies and neuropathic pain, caused by caused by compression, metabolic imbalances, pathogens, toxic agents, drugs, systemic inflammatory diseases and genetic systemic diseases. In greater detail, the present invention refers to a mixture comprising or, alternatively, consisting of: i) an extract of turmeric and / or one or more of its active ingredients; ii) L-acetyl carnitine and / or a salt thereof; iii) a bergamot extract and / or one or more of its active ingredients; preferably belonging to the flavonoid category, wherein said mixture is for use in a method for the prevention or treatment of peripheral neuropathies and neuropathic pain.

Description

[0001] MIXTURE, COMPOSITIONS CONTAINING SAID MIXTURE AND USE THEREOF IN THE TREATMENT AND / OR PREVENTION OF PERIPHERAL NEUROPATHIES AND NEUROPATHIC PAIN

[0002] ***

[0003] DESCRIPTION

[0004] The present invention relates to a mixture, compositions containing said mixture, and the use thereof in the treatment and / or prevention of peripheral neuropathies and pain of neuropathic origin.

[0005] In greater detail, the present invention relates to a mixture comprising or, alternatively, consisting of: i) an extract of turmeric and / or one or more of its active ingredients; ii) L-acetyl carnitine and / or a salt thereof; and iii) a bergamot extract and / or one or more of its active ingredients; preferably belonging to the flavonoid category; wherein said mixture is for use in a method for the prevention or treatment of peripheral neuropathies and neuropathic pain.

[0006] BACKGROUND OF THE INVENTION

[0007] The nerves of the peripheral nervous system are susceptible to toxic agents, inflammations, infections, hereditary diseases and metabolic alterations, which could damage them and give rise to clinical manifestations referred to as peripheral neuropathies. These may involve a single nerve (mononeuropathies) or more than one (polyneuropathies) and can also be distinguished between neuropathies affecting the peripheral nerves of the upper or lower extremities according to the location of the nerve fibre damage. Examples of peripheral neuropathies in upper extremities are the carpal tunnel syndrome (entrapment of the median nerve at the level of the carpal tunnel), ulnar neuropathy (entrapment of the ulnar nerve at the level of the elbow), and radiculopathy at the cervical level. Examples of localised neuropathies at the level of the lower limbs are tarsal tunnel syndrome (due to compression of the tibial nerve at the level of the ankle), and sciatic or crural radiculopathy.

[0008] From an etiological viewpoint, mononeuropathies can be caused by various factors. One of the most common is undoubtedly compression, which can occur at the level of the most distal nerve segment, generally due to entrapment of the nerve in a ligamentous canal, or at a more proximal level, i.e. in the area of the nerve root, typically due to a disk herniation. The pathological process resulting from compression is identical, irrespective of the site of damage: a condition of ischaemia comes to be created at the level of the nerve fibre every time that, based on posture, the nerve is compressed. The ischaemia triggers the release of inflammation and oxidative stress factors, which cause fibre hypersensitisation and hyperexcitation. When the compression becomes more substantial and chronic, it gives rise to a process of demyelination. At this point the symptoms become persistent and can be worsened by movement. Whereas initially the main symptom was numbness, in this stage pain and weakness also manifest themselves.

[0009] However, neuropathies can also be caused by exposure to toxic agents (alcohol or toxic metals), the use of some drugs, above all chemotherapeutics, or metabolic alterations such as diabetes mellitus, hypothyroidism and porphyria. They can be of inflammatory and demyelinating origin, as in the case of Guillain-Barre syndrome, caused by infectious agents as in the case of HIV, the Epstein-Barr virus, leprosy or sarcoidosis, or due to severe vitamin deficiencies. There also exist neuropathies associated with paraproteinemia (gammopathies, cryoglobulinemia, amyloidosis), or hereditary disorders such as Charcot-Marie-Tooth disease.

[0010] In all these cases, the involvement of several nerves simultaneously is most common, thus giving rise to a polyneuropathy. In these cases, the damage occurs mainly at the axonal level, but a certain degree of demyelination can also occur, and the degeneration is mainly caused by an inflammatory and metabolic state with ischaemic consequences. For example, in diabetic polyneuropathy the damage could be caused by metabolic deterioration and loss of the energy necessary for the distal sensory axons, due to the alteration at the level of the sodium channels. The damage thereof results in a loss of distal sensitivity and onset of widespread pain.

[0011] The diagnosis must be made in such a way as to ensure that the nerve damage is at a peripheral and not central level and, for this reason, all the signs and symptoms the patient manifests should be taken into consideration.

[0012] A peripheral injury, for example, is often asymmetrical and the earliest symptoms also include sensory alterations such as numbness, burning, electric shock sensation, tingling, weakness, allodynia, hyperalgesia and hyperaesthesia. In about one third of the cases of peripheral neuropathy, pain also occurs. Furthermore, pain of neuropathic origin has different characteristics compared to nociception: it is an actual disease and does not constitute a response mechanism of the body but is rather characterised by a process of amplification of the nociceptive message which can manifest itself at both a peripheral and central level. The speed of onset and the beginning of symptoms often depend on the triggering cause; for example, if the neuropathy is the consequence of exposure to a toxin, the onset will be immediate, whereas if it is the consequence of a pharmacological treatment, it will take on chronic characteristics, as in the case where it derives from a metabolic imbalance. Neuropathies deriving from injuries or wounds, by contrast, have a very acute onset and greater severity.

[0013] Generally, these problems are managed from pharmacological viewpoint through the prescription of gabapentinoids, pregabalin and / or antidepressant drugs, such as tricyclic antidepressants. These drugs are moderately effective and are recommended as the first line of treatment; they are exclusively symptomatic, because they are aimed at reducing the symptoms and not at repairing the nerve damage. Furthermore, they are characterised by numerous side effects, also serious ones, which precludes their prolonged use.

[0014] Other types of approaches may regard the use of topical medications, including lidocaine and capsaicin, which can be used in addition to the oral treatment. As the last available approach, there is the prescription of opioids, which are advised against, as they have shown little evidence of actual effectiveness, while posing serious problems in terms of both safety and abuse.

[0015] It is thus necessary to provide a mixture and / or a composition useful for preventing, reducing and treating peripheral neuropathies.

[0016] It is desirable to be able to have a mixture and / or a composition that do not have the sole objective of reducing pain, but which also act on the inflammation and oxidative stress triggered by nerve damage, so as to reduce them, and on the repair of the nerve structure.

[0017] Furthermore, it is necessary to provide a mixture and / or a composition useful to this end for all categories of individuals to be treated, which are easy to prepare and free of side effects, and which do not require the use of costly machinery and processes.

[0018] These aims and still others, which will be clear from the detailed description below, are achieved by the mixtures and compositions comprising said mixtures (mixtures and / or compositions of the invention) having the technical features claimed in the appended claims.

[0019] SUMMARY OF THE INVENTION

[0020] Following an intense research activity, the Applicant has developed and prepared a mixture comprising or, alternatively, consisting of specific active components which are all natural ingredients and thus make both the mixture and the pharmaceutical composition or nutraceutical composition or supplement composition comprising said mixture free of side effects and characterised by high tolerability.

[0021] In fact, the mixture for use according to the invention or the composition comprising it has no significant adverse effects. Precisely for these reasons, it can be advantageously administered to a broad category of individuals, including immunocompromised individuals.

[0022] A first aspect of the present invention relates to a mixture (in short, Mix 1) comprising or, alternatively, consisting of:

[0023] I) an extract of turmeric and / or one or more of its active ingredients; ii) L-acetyl carnitine or a salt thereof; and ill) a bergamot extract and / or one or more of its active ingredients; preferably belonging to the flavonoid category; wherein said mixture is for use in a method for the prevention or treatment of peripheral neuropathies and neuropathic pain.

[0024] A second aspect of the present invention relates to a composition comprising said mixture Mix 1 , according to said first aspect of the invention, and food or pharmaceutical grade excipients and / or additives, for use in a method for the prevention or treatment of peripheral neuropathies and neuropathic pain.

[0025] Said composition is, for example, a pharmaceutical composition or a nutraceutical composition or a supplement composition or a food composition or a composition for medical devices, for example according to Reg. (EU) 745 / 2017, or a composition for foods for special medical purposes, for example according to Reg. (EU) 609 / 2013 (in short, the compositions of the invention).

[0026] Preferably, the mixture of the invention may also comprise at least one further ingredient selected from the group comprising or, alternatively, consisting of at least one vitamin selected in the group comprising or, alternatively, consisting of vitamin C, vitamin E, vitamin B1 , vitamin B2, vitamin B6 and vitamin B12 or mixtures thereof.

[0027] The mixture of the invention, Mix 1, and the pharmaceutical and / or nutraceutical composition comprising said mixture Mix 1 are particularly useful for preventing, reducing and treating peripheral neuropathies (for example, nerve damage at the peripheral and not central level) and counteracting the onset of neuropathic pain, inflammation and oxidative stress at the level of the peripheral nervous system.

[0028] Advantageously, the mixture of the invention and the pharmaceutical and / or nutraceutical composition comprising said mixture can be used in the prevention and / or treatment of peripheral neuropathies, both mononeuropathies and polyneuropathies, and in the prevention and / or treatment of the neuropathic pain.

[0029] Preferably, the mixture of the invention, Mix 1 , and the pharmaceutical and / or nutraceutical composition comprising said mixture Mix 1 can be used in the prevention and / or treatment of peripheral neuropathies and neuropathic pain caused by compression, metabolic imbalance, infection, a toxic agent, a pathogen, drugs, or by the presence of a systemic inflammatory and / or genetic disease.

[0030] Preferably, the mixture of the invention, Mix 1 , and the pharmaceutical and / or nutraceutical composition comprising said mixture Mix 1 are used in a method for protecting peripheral nervous system function and / or for use in a method for counteracting inflammation and oxidative stress and / or for use in a method for the prevention and / or treatment of peripheral neuropathies of different origin and causes and neuropathic pain, such as, for example, neuropathies caused by compression, such as carpal tunnel syndrome and lumbosciatica, and / or metabolic neuropathies, such as diabetic neuropathy and / or iatrogenic neuropathies, such as that caused by Guillain-Barre syndrome or other genetic / hereditary disorders such as Charcot-Marie-Toot disease.

[0031] DESCRIPTION OF THE FIGURES

[0032] Figure 1 shows an analysis of the cell viability of CaCo-2 cells subjected to treatment with the experimental groups described in example 3. At 1h and 2h the Mix is not significant compared to XINEPA OL, but it is significant compared to XINEPA. From 3h onwards, the Mix is significant compared to both. In all cases p<0.05.

[0033] Figure 2 shows a TEER analysis of CaCo-2 cells subjected to treatment with the experimental groups described in example 3. At 1 h and 2h the Mix is not significant compared to XI NEPA OL, but it is significant compared to XINEPA. From 3h onwards, the Mix is significant compared to both. At 6h, the significance is again lost. In all cases p<0.05. Figure 3 shows the level of expression of claudin detected in the CaCo-2 cells subjected to treatment with the experimental groups described in example 3. MIX vs XINEPA OL p<0.05; MIX vs XINEPA p<0.05; XINEPA OL vs XINEPA p<0.05.

[0034] Figure 4 shows the occludin expression level detected in the CaCo-2 cells subjected to treatment with the experimental groups described in example 3. MIX vs XINEPA OL p<0.05; MIX vs XINEPA p<0.05; XINEPA OL vs XINEPA p<0.05.

[0035] Figure 5 shows the Zonula occludens-1 expression level detected in the CaCo-2 cells subjected to treatment with the experimental groups described in example 3. MIX vs XINEPA OL p<0.05; MIX vs XINEPA p<0.05; XINEPA OL vs XINEPA p<0.05.

[0036] Figure 6 shows the rate of absorption over time of the experimental groups according to example 3. At 1 h the Mix is not significant compared to XINEPA OL, but it is significant compared to XINEPA. From 2h onwards, the Mix is significant compared to both. Figure 7 shows the cell viability of the engineered neural tissue subjected to treatment with the experimental groups described in example 3 - phase 2. MIX vs XINEPA OL p<0.05; MIX vs XINEPA p<0.05; XINEPA OL vs XINEPA p<0.05.

[0037] Figure 8 shows the % of ROS production in the engineered neural tissue subjected to treatment with the experimental groups described in example 3 - phase 2. MIX vs XINEPA OL not significant; MIX vs XINEPA p<0.05 XINEPA OL vs XINEPA p<0.05.

[0038] Figure 9 shows the p75 expression levels detected in engineered neural tissue subjected to treatment with the experimental groups described in example 3 - phase 2. MIX vs XINEPA OL p<0.05; MIX vs XINEPA p<0.05; XINEPA OL vs XINEPA p<0.05.

[0039] Figure 10 shows the MPZ expression levels detected in engineered neural tissue subjected to treatment with the experimental groups described in example 3 - phase 2. MIX vs XINEPA OL p<0.05; MIX vs XINEPA p<0.05; XINEPA OL vs XINEPA p<0.05.

[0040] Figure 11 shows the NRG1 expression levels detected in engineered neural tissue subjected to treatment with the experimental groups described in example 3 - phase 2. MIX vs XINEPA OL p<0.05; MIX vs XINEPA p<0.05; XINEPA OL vs XINEPA p<0.05.

[0041] Figure 12 shows the of ERB3 expression levels detected in engineered neural tissue subjected to treatment with the experimental groups described in example 3 - phase 2. MIX vs XINEPA OL p<0.05; MIX vs XINEPA p<0.05; XINEPA OL vs XINEPA p<0.05.

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043] The first aspect of the present invention relates to a mixture (for the sake of brevity also, but not only, indicated as Mix 1) comprising or, alternatively, consisting of i) an extract of turmeric and / or one or more of its active ingredients; ii) L-acetyl carnitine and / or a salt thereof; and iii) a bergamot extract and / or one or more of its active ingredients; preferably belonging to the flavonoid category. wherein said mixture is for use in a method for the prevention or treatment of peripheral neuropathies and neuropathic pain.

[0044] The mixture of the present invention, Mix 1 , comprises I) an extract of turmeric and / or one or more of its active ingredients.

[0045] Preferably, the mixture of the present invention, Mix 1 , comprises I) a dry extract of turmeric and / or one or more of its active ingredients.

[0046] In the context of the present invention, extract of turmeric is understood to include all types of turmeric root extracts comprising, for example, curcuminoids as active ingredients.

[0047] Preferably, the extract of turmeric is a root extract from the plant Curcuma longa. Preferably, said extract of turmeric, preferably a dry extract of Curcuma longa, is a dry extract preferably titrated in curcuminoids, with a minimum curcuminoid titre > 30% w / w as measured by HPLC.

[0048] Preferably, said dry extract of turmeric preferably has a curcuminoid titre comprised from 30% to 50% by weight, more preferably comprised from 35% to 45%, for example 40% by weight, relative to the total weight of the dry extract. For example, the extract of turmeric present in the mixture for use according to the invention can be the product CurQfen® Powder NF, for example sold by Akay Flavours & Aromatics Pvt. Ltd. Malaidamthuruthu P. 0. This product contains an extract of turmeric obtained from the rhizome and seeds. The product appears as a yellow / orange-coloured powder, with a particle size of 90% pass 60 mesh, bulk density of 0.3 to 0.7 g / ml, measured as per USP 29 <616>.

[0049] CurQfen® Powder NF has a curcuminoid titre (curcumin, DMC, BDMC) of 35% as measured by HPLC.

[0050] The mixture of the invention, Mix 1 , comprises, in addition to i) an extract of turmeric and / or one or more of its active ingredients, also ii) L-acetyl carnitine and / or a salt thereof.

[0051] L-acetyl carnitine, IUPAC name (3R)-3-acetyloxy-4-(trimethylazaniumyl)butanoate hydrochloride (CAS: 3040-38- 8), also known as LAC, acetyl-L-carnitine, levacecarnine or ALCAR, is an acetylated form of L-carnitine or carnitine. In the context of the present invention the terms "L-acetyl carnitine” or "acetyl-L-carnitine” are meant to refer to, and include, in general, L-acetyl carnitine as such and / or in the form of a salt thereof and / or mixtures thereof, and / or L- carnitine and / or carnitine.

[0052] More preferably, the mixture for use according to the invention comprises L-acetyl carnitine in salt form, preferably L-acetyl carnitine hydrochloride.

[0053] Preferably, the mixture can comprise i) an extract of turmeric, as described above, and ii) a L-acetyl carnitine in salt form, preferably L-acetyl carnitine hydrochloride.

[0054] For example, the L-acetyl carnitine present in the mixture is the commercial product having the name ACETYL-L- CARNITINE HCI MATRIS®, sold by the firm IPS.

[0055] The mixture of the invention, Mix 1 , comprises or, alternatively, consists of, in addition to i) an extract of turmeric and / or one or more of its active ingredients, for example curcuminoids, ii) L-acetyl carnitine, preferably L-acetyl carnitine in salt form, preferably L-acetyl carnitine hydrochloride, also iii) a bergamot extract and / or one or more of its active ingredients; preferably belonging to the flavonoid category.

[0056] Preferably, the bergamot extract present in the mixture of the invention, Mix 1 , is a bergamot extract of the type extracted from Citrus Bergamia Risso & Poit.

[0057] In the context of the present invention, "bergamot extract” is understood to include all types of extracts of Citrus Bergamia Risso & Poit comprising at least one flavonoid selected from: naringin, (neo)hesperidin, neoeriocitrin, melitidin, brutieridin, or mixtures thereof.

[0058] Preferably, the bergamot extract present in the mixture of the invention, Mix 1 , comprises an amount of total flavonoids comprised from 10% to 50%, preferably from 35% to 45%, more preferably from 38% to 40% by weight, relative to the total weight of the extract, wherein said total flavonoids are selected from the group comprising or, alternatively, consisting of naringin, (neo)hesperidin, neoeriocitrin, melitidin, brutieridin, or mixtures thereof.

[0059] In the context of the present invention, the bergamot extract has a total flavonoid titre comprised from 10% to 50%, preferably from 25% to 45%, more preferably from 30% to 40%, for example 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% by weight, relative to the total weight of the extract.

[0060] The bergamot extract can also be represented by the phytocomplex comprising polysaccharides and total flavonoids; preferably, said phytocomplex can comprise polysaccharides in an amount by weight comprised from 10% to 50%, preferably from 20% to 40% by weight, relative to the weight of the phytocomplex, and total flavonoids in an amount by weight comprised from 10% to 45%, preferably from 25% to 40% by weight, relative to the weight of the phytocomplex. For example, a phytocomplex may be a phytocomplex extracted from the whole fruit of Citrus bergamia var. Risso containing no less than 10% polysaccharides, for example 18% total polysaccharides, and no less than 10% total flavonoids.

[0061] Preferably, said bergamot extract present in the mixture of the invention, Mix 1 , comprises the active compound naringin, among others.

[0062] Preferably, naringin is present in said bergamot extract in an amount by weight comprised from 6% to 14%, preferably from 8% to 13%, more preferably from 10% to 12%, for example 11 % by weight, relative to the weight of total flavonoids present in the extract.

[0063] Preferably, in addition to naringin, said bergamot extract present in the mixture of the invention, Mix 1 , also comprises the active compound (neo)hesperidin.

[0064] Preferably, (neo)hesperidin is present in said bergamot extract in an amount by weight comprised from 6% to 14%, preferably from 8% to 13%, more preferably from 11 % to 12% by weight, relative to the weight of total flavonoids present in the extract.

[0065] More preferably, said bergamot extract present in the mixture of the invention, Mix 1 ((i)+(ii)+(iii)), comprises naringin in an amount by weight comprised from 6% to 14%, preferably from 8% to 13%, more preferably from 10% to 12%, for example 11 %, by weight, relative to the weight of total flavonoids, and (neo)hesperidin in an amount by weight comprised from 6% to 14%, preferably from 8% to 13%, more preferably from 11 % to 12% by weight, relative to the weight of total flavonoids.

[0066] Preferably, said bergamot extract present in the mixture of the invention, Mix 1 , comprises, in addition to naringin and (neo)hesperidin, preferably in the percentage amounts specified above, also neoeriocitrin.

[0067] Preferably, neoeriocitrin is present in the bergamot extract in an amount by weight comprised from 6% to 14%, preferably from 8% to 12%, more preferably from 10% to 11 % by weight, relative to the weight of total flavonoids present in the extract.

[0068] More preferably, said bergamot extract present in the mixture of the invention, Mix 1 ((i)+(ii)+(iii)), comprises:

[0069] - naringin in an amount by weight comprised from 6% to 14%, preferably from 8% to 13%, more preferably from 10% to 12%, for example 11 %, by weight, relative to the weight of total flavonoids, and

[0070] - (neo)hesperidin in an amount by weight comprised from 6% to 14%, preferably from 8% to 13%, more preferably from 11 % to 12% by weight, relative to the weight of total flavonoids, and

[0071] - neoeriocitrin in an amount by weight comprised from 6% to 14%, preferably from 8% to 12%, more preferably from 10% to 11 % by weight relative to the weight of total flavonoids.

[0072] Preferably, said bergamot extract present in the mixture of the invention, Mix 1 , comprises, in addition to naringin, (neo)hesperidin and neoeriocitrin, preferably in the percentage amounts specified above, also melitidin.

[0073] Preferably, melitidin is present in the bergamot extract in the mixture of the invention, Mix 1 , in an amount by weight comprised from 0.5% to 3%, preferably from 1 % to 2%, for example 2% by weight, relative to the weight of total flavonoids present in the extract.

[0074] More preferably, said bergamot extract in the mixture of the invention, Mix 1 ((i)+(ii)+(iii)), comprises:

[0075] - naringin in an amount by weight comprised from 6% to 14%, preferably from 8% to 13%, more preferably from 10% to 12%, for example 11 %, by weight, relative to the weight of total flavonoids, and

[0076] - (neo)hesperidin in an amount by weight comprised from 6% to 14%, preferably from 8% to 13%, more preferably from 11 % to 12% by weight, relative to the weight of total flavonoids, and

[0077] - neoeriocitrin in an amount by weight comprised from 6% to 14%, preferably from 8% to 12%, more preferably from 10% to 11 % by weight relative to the weight of total flavonoids, and

[0078] - melitidin in an amount by weight comprised from 0.5% to 3%, preferably from 1 % to 2%, for example 2% by weight relative to the weight of total flavonoids.

[0079] Preferably, said bergamot extract comprises in the mixture of the invention, Mix 1 , in addition to naringin, (neo)hesperidin, neoeriocitrin and melitidin, preferably in the percentage amounts specified above, also brutieridin. Preferably, brutieridin is present in the bergamot extract in the mixture of the invention, Mix 1 , in an amount by weight comprised from 2% to 8%, preferably from 3% to 6%, more preferably from 4% to 5% by weight, relative to the weight of total flavonoids present in the extract.

[0080] More preferably, said bergamot extract in the mixture of the invention, Mix 1 ((i)+(ii)+(iii)), comprises:

[0081] - naringin in an amount by weight comprised from 6% to 14%, preferably from 8% to 13%, more preferably from 10% to 12%, for example 11 %, by weight, relative to the weight of total flavonoids, and

[0082] - (neo)hesperidin in an amount by weight comprised from 6% to 14%, preferably from 8% to 13%, more preferably from 11 % to 12% by weight, relative to the weight of total flavonoids, and

[0083] - neoeriocitrin in an amount by weight comprised from 6% to 14%, preferably from 8% to 12%, more preferably from 10% to 11 % by weight relative to the weight of total flavonoids, and

[0084] - melitidin in an amount by weight comprised from 0.5% to 3%, preferably from 1 % to 2%, for example 2% by weight relative to the weight of total flavonoids, and

[0085] - brutieridin in an amount by weight comprised from 2% to 8%, preferably from 3% to 6%, more preferably from 4% to 5% by weight, relative to the weight of total flavonoids present in the extract.

[0086] More preferably, the bergamot extract present in Mix 1 comprises in an amount by weight, relative to the weight of total flavonoids: from 11 % to 12% naringin, for example 11 .4%; and / or from 11 % to 12% (neo)hesperidin, for example 11.6%; and / or from 10% to 11 % neoeriocitrin, for example 10.2%; and / or from 1 % to 2% melitidin, for example 1 .9%; and / or from 4% to 5% brutieridin, for example 4.5%.

[0087] More preferably, said bergamot extract in the mixture of the invention, Mix 1 ((i)+(ii)+(iii)), comprises:

[0088] - naringin in an amount by weight comprised from 6% to 40%, preferably from 15% to 35%, more preferably from 20% to 30%, for example 28% or 29%, by weight, relative to the weight of total flavonoids, and

[0089] - (neo)hesperidin in an amount by weight comprised from 6% to 40%, preferably from 15% to 35%, more preferably from 20% to 30%, for example 29% or 30% by weight, relative to the weight of total flavonoids, and

[0090] - neoeriocitrin in an amount by weight comprised from 6% to 40%, preferably from 15% to 35%, more preferably from 20% to 30%, for example 26%, by weight relative to the weight of total flavonoids, and

[0091] - melitidin in an amount by weight comprised from 0.5% to 10%, preferably from 1 % to 8%, more preferably from 3% to 6%, for example 5% by weight relative to the weight of total flavonoids, and

[0092] - brutieridin in an amount by weight comprised from 0.5% to 25%, preferably from 5% to 20%, more preferably from 10% to 15%, for example 11 % by weight, relative to the weight of total flavonoids present in the extract.

[0093] More preferably, the bergamot extract present in Mix 1 comprises in an amount by weight, relative to the weight of total flavonoids: from 28% to 29% naringin, for example 28.7%; and / or from 29% to 30% (neo)hesperidin, for example 29.2%; and / or from 24% to 26% neoeriocitrin, for example 25.6%; and / or from 3% to 6% melitidin, for example 4.7%; and / or from 10% to 15% brutieridin, for example 11 .3%.

[0094] An example of a commercial product of a Citrus Bergamia Risso & Poit. extract is the BERGAMOT POLYPHENOLIC FRACTION™ (BPF™), for example sold by H&AD S.r.l. It is an extract from juice of the fruit of Citrus Bergamia Risso & Poit, comprising a total flavonoid titre, as measured by HPLC, comprised from 20% to 50%, preferably from 35% to 45%, more preferably from 38% to 40%, for example 39%, of which preferably: from 6% to 14%, preferably from 8% to 12%, more preferably 10.2% neoeriocitrin; from 6% to 14%, preferably from 8% to 13%, more preferably 11 % naringin; from 6% to 14%, preferably from 8% to 13%, more preferably from 11 % to 12% (neo)hesperidin; from 0.5% to 3%, preferably from 1 % to 2%, more preferably 2% melitidin and from 2% to 8%, preferably from 3% to 6%, more preferably from 4% to 5% brutieridin.

[0095] In other words, if the total amount of flavonoids in the bergamot extract is, for example, equal to about 40%, this may, for example, be thus subdivided: 10% is the amount of neoeriocitrin, 12% is the amount of naringin, 12% is the amount of neohesperidin, 2% is the amount of melitidin, and 4% the amount of brutieridin.

[0096] More preferably, the bergamot extract in Mix 1 comprises by weight, relative to the weight of total flavonoids: from 6% to 40%, preferably from 15% to 35%, more preferably from 20% to 30%, for example 28% or 29% naringin, from 6% to 40%, preferably from 15% to 35%, more preferably from 20% to 30%, for example 29% or 30% neohesperidin, from 6% to 40%, preferably from 15% to 35%, more preferably from 20% to 30%, for example 26% neoeriocitrin, from 0.5% to 10%, preferably from 1 % to 8%, more preferably from 3% to 6%, for example 5% melitidin, and from 0.5% to 25%, preferably from 5% to 20%, more preferably from 10% to 15%, for example 11 % brutieridin.

[0097] The bergamot extract appears as a yellow-coloured powder having a particle size passing through a 60 mesh sieve and a bulk density comprised, for example, from 30 to 70 g / 100 ml, preferably from 40 to 60 g / 100 ml, more preferably 55 g / 100 ml, 56 g / 100 ml, 57 g / 100 ml, 58 g / 100 ml, 59 g / 100 ml (DIN / ISO 697). Preferably, said bergamot extract has pH comprised from 3 to 4, preferably from 3.1 to 3.8, for example pH 3.5.

[0098] In particular, the BERGAMOT POLYPHENOLIC FRACTION™ (BPF™), for example sold by H&AD S.r.l., comprises a total flavonoid titre, as measured by HPLC, of 39.7%, of which 10.2% neoeriocitrin, 11.4% naringin, 11.6% (neo)hesperidin, 1.9% melitidin and 4.5% brutieridin. This product contains a bergamot extract obtained from the juice of the fruit, but it could also be obtained from the peel, tree and flavedo. It appears in the form of a yellowcoloured powder with a typically citrusy odour and flavour, with a particle size of pass 60 mesh.

[0099] Another example of a commercial bergamot extract product is represented by the product Bergavit™ sold by Bionap, consisting of a fruit extract obtained from Citrus aurantium Bergamia and having CAS number 89957-91-5 and maltodextrins (CAS number 9050-36-6). The bergamot extract present in said product has a flavonoid titre (neoeriocitrin, naringin, (neo)hesperidin) comprised from 20% to 35% w / w, preferably from 25% to 28% w / w as measured by HPLC.

[0100] A further example of a commercial bergamot extract product is represented by the product KALITA sold by Giellepi, consisting of a phytocomplex extracted from the whole fruit of Citrus bergamia var. Risso containing no less than 18% total polysaccharides and 10% total flavonoids.

[0101] The mixture for use according to the invention possesses a noteworthy activity in preventing and repairing damage to the peripheral nervous system, in particular in counteracting the onset of peripheral neuropathies caused by nerve damage due to compression, injury, trauma or metabolic imbalance and neuropathic pain.

[0102] In particular, the effect exerted by the mixture of the invention is not tied to the extract but to the active compounds present in the extract, preferably the active compounds present in the phytocomplex of said extracts.

[0103] Nature-identical molecules of said active compounds can be present in the mixture for use according to the invention, Mix 1 (Regulation (EC) N 1334 / 2008).

[0104] In the context of the present invention, the expression "nature-identical molecules” is understood to indicate and include molecules equal to the active compounds present in the natural extracts or phytocomplexes but produced through chemical synthesis.

[0105] For example, the active compounds naringin, (neo)hesperidin, neoeriocitrin, melitidin, and brutieridin may be present as nature-identical molecules. In one embodiment, in the mixture for use according to the invention, Mix 1 , naringin and / or (neo)hesperidin and / or neoeriocitrin can be present as nature-identical molecules. In other words, the mixture for use according to the invention, Mix 1 , may comprise naringin and / or (neo)hesperidin produced through chemical synthesis.

[0106] For example, the active ingredients present in the turmeric extract, namely the curcuminoids, can be present as nature-identical molecules.

[0107] Preferably, the mixture of the invention, Mix 1 ((i)+(ii)+(iii)), can further comprise at least a) a vitamin, preferably selected from the group comprising or, alternatively, consisting of vitamin C, vitamin E, vitamin B1 , vitamin B2, vitamin B6 and vitamin B12 or mixtures thereof.

[0108] In the context of the present invention a) vitamin E is understood to include any form of vitamin E, a pharmaceutically acceptable salt thereof and mixtures thereof.

[0109] In the context of the present invention with a) vitamin C is understood to include any form of vitamin C, a pharmaceutically acceptable salt thereof and mixtures thereof.

[0110] In addition to or as a replacement for vitamin C and / or vitamin E, the mixture for use according to the invention, Mix 1 , further comprises at least a) vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B6 (pyridoxine), vitamin B12 and mixtures thereof.

[0111] Preferably, the mixture of the invention comprises components (i)+(ii)+(iii) and all the vitamins C, E, B1 , B2, B6 and B12 (see example 2, table 2).

[0112] A further aspect of the present invention relates to a composition comprising the mixture as defined above and food or pharmaceutical grade excipients and / or additives, for use in a method for the prevention or treatment of peripheral neuropathies and neuropathic pain.

[0113] Preferably, the composition comprises: from 30 to 200 mg, preferably from 50 to 160 mg, even more preferably from 60 to 100 mg of a dry extract of Curcuma longa titrated in curcuminoids (minimum titre > 30% w / w; wherein the curcuminoid titre is preferably comprised from 30% to 50%, preferably from 35% to 45%, more preferably 35% by weight relative to the total weight of the dry extract); from 200 to 2,000 mg, preferably from 300 to 1 ,000 mg, more preferably from 400 to 500 mg of L-acetyl carnitine (L-carnitine and / or carnitine) or a pharmaceutically acceptable salt thereof and / or mixtures thereof; from 10 to 1,000 mg, preferably from 200 to 600 mg, even more preferably from 300 to 400 mg of bergamot extract (wherein said bergamot extract preferably has a total flavonoid titre (neoeriocitrin, naringin, (neo)hesperidin, melitidin, brutieridin) comprised from 10% to 50%, preferably from 25% to 45%, more preferably from 30% to 40% w / w), and at least one acceptable food or pharmaceutical grade excipient and / or additive.

[0114] Preferably, in addition to components (i)+(ii)+(iii), the composition comprises: from 50 to 500 mg, preferably from 80 to 400 mg, even more preferably from 125 to 200 mg of vitamin C; and / or from 2 to 50 mg, preferably from 5 to 30 mg, even more preferably from 9 to 20 mg of vitamin E; and / or from 1 to 50 mg, preferably from 3 to 30 mg, even more preferably from 6 to 20 mg, for example 6.25 mg of vitamin B1; and / or from 1 to 50 mg, preferably from 3 to 30 mg, even more preferably from 6 to 20 mg of vitamin B2; and / or from 0.5 to 30 mg, preferably from 1 to 15 mg, even more preferably from 2 to 6 mg, for example 2.38 mg of vitamin B6; and / or from 1 to 50 g, preferably from 3 to 30 pg, even more preferably from 6 to 20 pg, for example 6.25 pg of vitamin B12; and at least one acceptable food or pharmaceutical grade excipient and / or additive.

[0115] The dosages indicated above are to be understood as a dosage unit and not as the daily amount.

[0116] The compositions of the invention can be prepared by mixing the single components, and any conventional excipients and / or vehicles.

[0117] The composition of the invention is a pharmaceutical and / or nutraceutical composition for oral use, preferably a composition in a solid state, preferably formulated in dosage units. "Solid state” means that the composition can exist in the form of granules or powders. The granular or powder compositions are mixed with pharmaceutically acceptable additives and excipients to provide a final product such as, for example, a supplement product, a medical device or a pharmaceutical composition.

[0118] The final product may be in pharmaceutical dosage units such as, for example, granules in a sachet, a stick, orosoluble stick, tablet, gel or capsule.

[0119] The tablets may have different shapes among those known in the field of pharmaceutical forms, such as, for example, a cylindrical or spheroidal shape. The tablets may be coated or film-coated with one or more coating or film layers capable of passing through the gastric barrier, according to known methods.

[0120] The gel capsules may consist of hard gelatine or soft gelatine or soft gel.

[0121] Preferably, the oral composition of the invention is a solid or semi-solid (gel) composition, as described above. However, if desired or necessary, the composition may be formulated in liquid form, for example by dissolution or suspension in water.

[0122] The solid compositions of the invention may contain, as mentioned, physiologically acceptable conventional excipients and / or vehicles, such as diluents, bulking agents, binders, disaggregating agents, flow aids, lubricants, etc. Non-limiting examples of suitable vehicles and excipients are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins. Compositions of the invention may, for example, include cellulose derivatives, glucose, lactose, sucrose, gelatine, malt, rice, flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, glycol, water, ethanol, and the like. The composition may also contain pH buffering reagents and wetting or emulsifying agents.

[0123] Preferably, the compositions of the present invention may be in the form of a capsule, a tablet, a sachet, a stick, an orosoluble stick, an oral gel or granules. The composition of the invention, preferably formulated in dosage units, may be administered once or several times a day, for example once or twice a day, preferably twice a day.

[0124] In particular, both the mixture of the invention and the compositions comprising them are easy to prepare and inexpensive, considering that they can be prepared using the apparatus and preparation processes known to the person skilled in the art and in pharmaceutical practice or in the sector of nutritional supplements.

[0125] The daily dosage depends on the patient's health status, weight, gender and age. In general, the compositions of the invention are well tolerated and can be administered once or several times a day, preferably twice a day, even over an extended period of time.

[0126] The Applicant has found that the mixture of the invention and / or the pharmaceutical and / or nutraceutical compositions containing them are useful for protecting peripheral nervous system function and counteracting the onset of peripheral neuropathies and neuropathic pain.

[0127] The mixture for use according to the invention is capable of counteracting the onset of neuropathic pain, by acting on inflammation and oxidative stress at the level of the peripheral nervous system. The composition is a pharmaceutical and / or nutraceutical composition comprising the mixture for use according to the invention, which may be used in a method of treatment, therapeutic or non-therapeutic, with the aim of ensuring the maintenance of peripheral nervous system function and / or in a method of preventing and / or treating peripheral neuropathies and neuropathic pain of varying origin, preferably caused by compression, metabolic imbalances, infections, toxic agents or pathogens and systemic inflammatory and / or genetic diseases.

[0128] Advantageously, the mixture and the pharmaceutical and / or nutraceutical composition as described above may be used in the prevention and / or treatment of peripheral neuropathies, both mononeuropathies and polyneuropathies, and of neuropathic pain. Preferably, the mixture Mix 1 for use according to the invention and the pharmaceutical and / or nutraceutical composition comprising said mixture can be used in the prevention and / or treatment of peripheral neuropathies and neuropathic pain, wherein said peripheral neuropathies are preferably selected from mononeuropathies and polyneuropathies.

[0129] Advantageously, the mixture and the pharmaceutical and / or nutraceutical composition comprising it as described above are used in a method for the prevention or treatment of peripheral neuropathies and neuropathic pain preferably caused by compression, metabolic imbalance, infection, a toxic agent, a pathogen, drugs, or caused by the presence of a systemic inflammatory and / or genetic disease.

[0130] Preferably, the mixture and the pharmaceutical and / or nutraceutical composition comprising said mixture, as described above, are used in a method for protecting peripheral nervous system function and / or for use in a method for counteracting inflammation and oxidative stress.

[0131] More preferably, the mixture and the pharmaceutical and / or nutraceutical composition comprising said mixture, as described above, are advantageously used in a method for the prevention and / or treatment of peripheral neuropathies of different origin and causes and neuropathic pain, such as, for example, neuropathies caused by compression, such as carpal tunnel syndrome and lumbosciatica, and / or metabolic neuropathies such as diabetic neuropathy and / or iatrogenic neuropathies such as that caused by Guillain-Barre syndrome, or other genetic / hereditary disorders such as Charcot-Marie-Toot disease.

[0132] Said mixture and said composition can also be used in a method for the prevention and / or treatment of ulnar neuropathy, radiculopathy at the cervical level, tarsal tunnel syndrome, and sciatic or crural radiculopathy.

[0133] The present description relates to a method for preventing and repairing damage to the peripheral nervous system, in particular for counteracting peripheral neuropathies and the associated pain, the method comprising administering the mixture and / or the composition of the invention to an individual in need thereof, preferably in a dose effective for the purpose.

[0134] Advantageously, the mixture and / or the composition according to the invention can be administered on their own or together with drugs and / or food supplements commonly used for preventing and repairing damage to the peripheral nervous system.

[0135] For example, the mixture and / or the composition according to the invention can be administered together with drugs commonly used to manage neuropathic pain.

[0136] Preferably, they can be administered together with gabapentinoids, pregabalin, tricyclic antidepressants and opioids.

[0137] Preferably, by means of the composition of the present invention, a daily dose of a dry extract of Curcuma longa titrated in curcuminoids (titre 35% w / w) equal to 120 mg (42 mg of curcuminoids), is administered, for example, by means of one administration or two administrations in a tablet or sachet or orosoluble stick or gel stick.

[0138] Preferably, by means of the composition of the present invention, a daily dose of L-acetyl carnitine or L-carnitine or carnitine equal to 800 mg is administered, for example, by means of one administration or two administrations in a tablet or sachet or orosoluble stick or gel stick.

[0139] Preferably, by means of the composition of the present invention, a daily dose of bergamot extract equal to 600 mg is administered, for example, by means of one administration or two administrations in a tablet or sachet or orosoluble stick or gel stick.

[0140] Preferably, by means of the composition of the present invention, a daily dose of vitamin C equal to 250 mg is administered, for example, by means of one administration or two administrations in a tablet or sachet or orosoluble stick or gel stick or stick in gel.

[0141] Preferably, by means of the composition of the present invention, a daily dose of vitamin E equal to 18 mg is administered, for example, by means of one administration or two administrations in a tablet or sachet or orosoluble stick or gel stick or stick in gel.

[0142] Preferably, by means of the composition of the present invention, a daily dose of vitamin B1 equal to 12.5 mg is administered, for example, by means of one administration or two administrations in a tablet or sachet or orosoluble stick or gel stick or stick in gel.

[0143] Preferably, by means of the composition of the present invention a daily dose of vitamin B2, for example equal to 12.5 mg, is administered, for example, by means of one administration or two administrations in a tablet or sachet or orosoluble stick or gel stick or stick in gel.

[0144] Preferably, by means of the composition of the present invention a daily dose of vitamin B6, for example equal to 4.75 mg, is administered, for example, by means of one administration or two administrations in a tablet or sachet or orosoluble stick or gel stick or stick in gel.

[0145] Preferably, by means of the composition of the present invention, a daily dose of vitamin B12, for example equal to 12.55 g, is administered, for example, by means of one administration or two administrations in a tablet or sachet or orosoluble stick or gel stick or stick in gel.

[0146] Furthermore, the mixture of the invention and the pharmaceutical and / or nutraceutical compositions containing it, due to the presence of natural ingredients, do not have significant adverse effects, are free of side effects and have high tolerability, and can be administered to a broad category of individuals.

[0147] Finally, the mixture and / or the compositions of the invention are easy to prepare and inexpensive.

[0148] Some representative embodiments of the compositions of the invention are given in the Experimental Section below solely by way of illustration and are in no way limiting.

[0149] EXAMPLES

[0150] Example 1

[0151] Composition in the form of a tablet or sachet or orosoluble stick or gel stick (1 dosage form twice a day) containing:

[0152] Table 1 together with food or pharmaceutical grade excipients and / or additives.

[0153] Example 2

[0154] Composition in the form of a tablet or sachet or orosoluble stick or gel stick (1 dosage form twice a day) containing:

[0155] Table 2 together with food or pharmaceutical grade excipients and / or additives.

[0156] Example 3

[0157] The activity of the mixture and of the compositions containing them was assessed on the basis of various in vitro experimental assays; the experimental protocol, divided into different experimental phases, and the results obtained are described below.

[0158] 3.1. Experimental phases

[0159] Phase 1. Analysis of the absorption and bioavailability of the mixture through the intestinal barrier

[0160] For the purpose of conducting an absorption and bioavailability study, it is envisaged to use a 3D barrier model validated in the literature (doi:10.3390 / biomedicines9111543) as the best experimental strategy. The study was conducted on well-designed in vitro models called Transwell® which provide for the use of human intestinal epithelial cells for studies on the absorption of orally administered compounds, as they have 90% compatibility with humans. Therefore, the experimental model provides for the use of the CaCo2 cell line, widely used and validated, as a model of human intestinal epithelial cells for studies on the absorption of orally administered compounds (doi: 10.1007 / s00394-014-0815-8). When cultured on Transwell® supports for 21 days, the cells become polarised and differentiate to form a continuous epithelium (monolayer) with functional tight junctions and microvilli at the apical level (brush border). The cell monolayer provides a physical and biochemical barrier to the passage of ions and small molecules, separating the model into two distinct compartments: an apical one, corresponding to the human intestinal lumen, and a basolateral one which corresponds to the compartment of the body's blood circulation (pH 7.4). This model will be used to assess the degree of permeability and rule out irritability or damage of the intestinal epithelium, both before and after administration of the substances under examination, and to analyse the possible ROS production and inflammatory pathways. In particular, permeability will be analysed by measuring the transepithelial / transendothelial electrical resistance (TEER), a widely accepted quantitative technique that uses a voltmeter (EVOM3) to measure the integrity of tight junction dynamics so as to assess the integrity of the cellular barriers to the passage of the substances to be tested (doi:10.1177 / 2211068214561025). Furthermore, changes in the expression of tight junction (TJ) proteins are crucial and typically evaluated in order to analyse the barrier function, since, as they behave like multiple protein complexes, they form a selectively permeable seal between adjacent epithelial cells and, for this reason, they will be analysed as indicators of epithelial integrity, in particular by analysing occludin, claudin and zonula occludens (doi: 10.3390 / molecules24010148). Experimental phase 1 provides for:

[0161] • MTT cell viability assays with treatment with the single active compounds, the combination thereof, and the mixture of the invention;

[0162] • Analysis of intestinal barrier integrity (TEER, Claudin-4, Occludin and Zo-1);

[0163] • Analysis of intestinal absorption (Jmax). Phase 2. Analysis of the main mechanisms involved in neuropathies

[0164] Starting from the intestinal passage, a further 3D in vitro model will be created to study the peripheral nerve. This model, called 3D "engineered neural tissue” (EngNT), enables researchers to build a bridge between the results obtained in the in vitro monolayer models and studies on humans with greater success, so much so that preclinical studies with 3D models are the basis for determining the effectiveness and safety of compounds as required by regulatory bodies, including, for example, the Medicines and Healthcare Products Regulatory Agency (MHRA) or the US Food and Drug Administration (FDA). It should be considered that in order to have a successful regeneration following nerve injuries, Schwann cells must provide support to neurons and, therefore, this cell-cell interaction is a key feature that must be recreated in order to build more representative in vitro models. With this method, one can understand the effect of supplementation in the treatment of peripheral nerve injuries and seek to increase the rate of regeneration of the neurites extending through the site of the injury, where they are supported and guided by Schwann cells (doi: 10.1002 / ar.23918). Therefore, it was envisaged to recreate a culture model that simulates 3D neuroglial interaction in a reliable and reproducible manner, as reported in the literature (doi: 10.1002 / ar.23918). This growth of neurites in vitro imitates the key characteristics of distal peripheral nerve physiology during a repair following damage to the peripheral nerve. Therefore, this second part of the analysis is aimed at examining any direct effects on the peripheral nerve, following the intestinal passage, by analysing survival understood as mitochondrial activity (viability) and the oxidative state, fundamental for reducing chronic pain. Furthermore, the main pathways involved in myelin sheath protection processes and for the formation of neurites, such as, for example, NRG1 , MPZ, p75 and ERB3, will be analysed. For this purpose, peripheral nerve damage was mimicked using the glial growth factor (GGF), a model for simulating peripheral nerve injuries that is well established in the literature, as it is capable of reproducing a robust demyelination (doi: 10.1016 / j.actbio.2018.07.048).

[0165] To summarize, in phase 2 the product metabolised by the intestinal cells in phase 1 was placed directly in contact with an engineered neural tissue, an in vitro model of peripheral nerve damage (by administration of Glial Growth Factor).

[0166] The following were analysed in this phase:

[0167] • cell viability;

[0168] • mitochondrial activity and analysis of ROS production;

[0169] • the main pathways involved in myelin sheath protection processes and the formation of neurites, namely NRG1 , MPZ, p75 and ERB3.

[0170] Experimental groups:

[0171] Single active components: Bergamot (BPF) - N-acetyl-L-carnitine (ALC) - Turmeric d.e. (CUR) MIX: Bergamot + N-acetyl-L-carnitine + Turmeric Xinepa: Lipoic acid + N-acetyl-L-carnitine + Turmeric Xinepa OL: N-acetyl-L-carnitine + Turmeric The analysis was carried out at 1 , 2, 3, 4, 5, 6 h.

[0172] 3.2. Results

[0173] Phase 1

[0174] Viability

[0175] The MIX shows to be completely safe; in fact, the viability of the CaCo2 cells of the intestinal model is improved by treatment with the mixture of active components, in a synergistic manner compared to the individual administration thereof (Figure 1 , Table 3).

[0176] The formulation containing bergamot (MIX) is statistically superior both to current formulation of Xinepa and to the formulation without lipoic acid (p<0.05).

[0177] Table 3

[0178] TEER

[0179] In order to assess the safety aspect of the mixture in greater depth, other markers were investigated at the intestinal level. Figure 2 represents the analysis of transepithelial electrical resistance (TEER), which may be reduced in case of toxicity. As may be seen, all the single compounds and the Mix reveal to be safe, since at every time point taken into consideration, their TEER value is higher compared to the control. The mixture is statistically superior compared to the single active components (Figure 2).

[0180] Furthermore, when the TEER of the Mix with bergamot is compared with the present formulation of Xinepa and the formulation without lipoic acid, a statistical significance (p<0.05) of the Mix under examination compared to the others is demonstrated.

[0181] Tight junctions

[0182] Claudin

[0183] Claudin contributes to maintaining the structure of the tight junctions. All the active components demonstrate their safety by improving the expression of claudin. It should be noted that the mix demonstrates a synergistic action compared to the single components and is statistically superior (p<0.05) compared to the other two formulations with and without lipoic acid (Figure 3, Table 4).

[0184] Table 4

[0185] Occludin

[0186] Occludin contributes to stabilising the structure of the tight junctions. All the active components demonstrate their safety by improving the expression of occludin, with the action of the mix showing to be statistically superior both compared to the single active components and compared to other two formulations (p<0.05) (Figure 4).

[0187] Zonula occludens -1

[0188] Zonula occludens is the protein that mediates the adhesion of the tight junctions. Its correct expression is thus an indicator that the membrane is maintained in a physiological state. The safety of all the components is demonstrated by the good expression of ZO-1 , with the mix showing to be statistically superior and synergistic compared to the single components. Furthermore, the mix composed of bergamot, carnitine and turmeric is also statistically superior to the other two tested formulations (Figure 5).

[0189] Absorption

[0190] It is fundamental that a compound be absorbed in order to be able to perform its biological action. All the active components show low bioavailability; the Mix, by contrast, is absorbed with statistically higher values, also compared to the other two tested formulations with and without lipoic acid (p<0.05) (Figure 6, Table 5). Furthermore, at all time points, the mixture reveals to be synergistic compared to the single components.

[0191] Table 5

[0192] Phase 2

[0193] Viability

[0194] In this phase of the experiments, GGF was used as a toxic stimulus to induce neurodegeneration and then the death of the cellular model. The single active components counteract the toxic action of GGF, but only the mixture is capable of bringing viability back to positive levels. In particular, the Mix under examination shows to be statistically superior also compared to the formulations with and without lipoic acid (p<0.05) (Figure 7; Table 6).

[0195] Table 6

[0196] ROS production

[0197] Compared to the healthy control, GGF causes a 24.2% increase in ROS production. Bergamot is capable of reducing production to 12.5%, whereas carnitine and turmeric stand at around 22-23%. The mix shows its strong antioxidant power, as it brings ROS production to barely 4% (Figure 8).

[0198] Starting from this consideration, the antioxidant power of each active component and of the mix with respect to the damage caused by GGF was calculated by subtracting the power of each from the activity of GGF. Subsequently, the reductions were combined and the sum thereof was lower than the reduction brought about by the mix, which can thus be considered synergistic (Table 7). Furthermore, the power of the Mix under examination is statistically significant compared to the formulation with lipoic acid.

[0199] Table 7

[0200] Markers of neuroprotection p75

[0201] P75 is a neurotrophin receptor that controls neuron survival. Following the damage caused by GGF, the expression of the receptor is reduced. As may be observed in Figure 9, the single active components are capable of counteracting the damage, though only the mix is capable of restoring expression to levels comparable to the basal level (see also Table 8).

[0202] In this case as well, the Mix under examination is statistically significant compared to the other two formulations with and without lipoic acid.

[0203] Table 8

[0204] MPZ

[0205] MPZ is a myelin sheath protein which is inhibited by the degradation caused by GGF. The active components are able to reduce the inhibition, but only the mix is able to bring the activity back to basal values (Figure 10; Table 9). In this case as well, when the actions of the different mixtures are compared to each other, the Mix under examination containing bergamot is the one that demonstrates statistical significance (p<0.05) versus the others.

[0206] Table 9

[0207] NRG1

[0208] The condition of peripheral neuropathy caused by GGF negatively influenced the expression of neuregulin 1. All the active compounds effectively reduced the damage, confirming their neuroprotective potential. Only the Mix is capable of restoring the levels of NRG1 expression to the basal value (Figure 11; Table 10).

[0209] The Mix with bergamot is statistically significant compared to the other two formulations with and without lipoic acid (p<0.05).

[0210] Table 10

[0211] ERB3

[0212] The condition of peripheral neuropathy caused by GGF negatively influenced the activity of the epidermal receptor p (ERB3). All the active compounds and the mix effectively reduced the damage, confirming their neuroprotective potential. The mix is capable of bring the expression of ERB3 back to basal values (Figure 12; Table 11).

[0213] A comparison between the Mix with bergamot and other two formulations with and without lipoic acid demonstrates that the action of the Mix under examination is significantly greater compared to the other two (p<0.05).

[0214] Table 11 3.3. Conclusions

[0215] The data obtained demonstrated that:

[0216] • the mixture according to the invention can be considered safe at the intestinal level, as it is not toxic, nor did it show to cause alterations at the level of the tight junctions. Furthermore, the mixture is also absorbed to a greater degree, thus assuring bioavailability and the reaching of the target tissue;

[0217] • at the level of peripheral nerve tissue, following the induced damage, the mixture according to the invention shows a strong neuroprotective action. In particular, in most of the markers taken into consideration, the mix shows a statistically significant superiority, being capable of bringing the levels of the markers back into physiological conditions; and • in the in vitro model of GGF-induced neurodegeneration, the mix shows to be synergistic in terms of viability and in counteracting the production of oxidative stress.

Claims

CLAIMS1. A mixture comprising or, alternatively, consisting of: i) an extract of turmeric and / or one or more of its active ingredients; ii) L-acetyl carnitine and / or a salt thereof; and iii) a bergamot extract and / or one or more of its active ingredients; wherein said mixture is for use in a method for the prevention or treatment of peripheral neuropathies and neuropathic pain.

2. The mixture for use according to claim 1 , wherein said peripheral neuropathies are preferably selected from mononeuropathies and polyneuropathies.

3. The mixture for use according to claim 1 or 2, wherein said peripheral neuropathies and said neuropathic pain are preferably selected from those caused by compression, metabolic imbalance, infection, a toxic agent, a pathogen, drugs, or caused by the presence of a systemic inflammatory and / or genetic disease.

4. The mixture for use according to any one of the preceding claims, wherein said mixture is for use in a method of treatment of neuropathies selected from those caused by compression, preferably carpal tunnel syndrome and lumbosciatica; in a method of treatment of metabolic neuropathies, preferably diabetic neuropathy; in a method of treatment of iatrogenic neuropathies, preferably that caused by Guillain-Barre syndrome, or other genetic / hereditary disorders such as Charcot-Marie-Toot disease.

5. The mixture for use according to any one of the preceding claims, wherein said I) turmeric extract is preferably a dry extract of Curcuma longa titrated in curcuminoids, with a minimum curcuminoid titre > 30% w / w.

6. The mixture for use according to any one of the preceding claims, wherein said I) turmeric extract has a curcuminoid titre comprised from 30% to 50% by weight, more preferably comprised from 35% to 45%, for example 40% by weight, relative to the total weight of the dry extract.

7. The mixture for use according to any one of the preceding claims, wherein said ii) L-acetyl carnitine is in salt form, preferably L-acetyl carnitine hydrochloride.

8. The mixture for use according to any one of the preceding claims, wherein said iii) bergamot extract is preferably a dry extract of Citrus Bergamia Risso & Poit, titrated in flavonoids, with a minimum total flavonoid titre > 10%, wherein said total flavonoids are selected from the group comprising or, alternatively, consisting of naringin, (neo)hesperidin, neoeriocitrin, melitidin, brutieridin, or mixtures thereof.

9. The mixture according to any one of the preceding claims, wherein said iii) bergamot extract comprises an amount of total flavonoids comprised from 10% to 50%, preferably from 35% to 45%, more preferably from 38% to 40%, for example 39%, by weight relative to the total weight of the extract, wherein said flavonoids comprise naringin, (neo)hesperidin, neoeriocitrin, melitidine, brutieridin.

10. The mixture according to claim 9, wherein said iii) bergamot extract comprises naringin in an amount by weight comprised from 6% to 40%, preferably from 15% to 35%, more preferably from 20% to 30%, for example 28% or 29%, by weight, relative to the weight of total flavonoids, and (neo)hesperidin in an amount by weight comprisedfrom 6% to 40%, preferably from 15% to 35%, more preferably from 20% to 30%, for example 29% or 30%, by weight, relative to the weight of total flavonoids; or preferably, said ill) bergamot extract comprises naringin in an amount by weight comprised from 6% to 14%, preferably from 8% to 13%, more preferably from 10% to 12%, for example 11 %, by weight, relative to the weight of total flavonoids, and (neo)hesperidin in an amount by weight comprised from 6% to 14%, preferably comprised from 8% to 13%, more preferably comprised from 11 % to 12% by weight, relative to the weight of total flavonoids.

11. The mixture for use according to any one of the preceding claims, further comprising at least a) a vitamin, preferably selected from the group comprising or, alternatively, consisting of vitamin C, vitamin E, vitamin B1, vitamin B2, vitamin B6 and vitamin B12 or mixtures thereof.

12. A composition comprising a mixture according to any one of claims 1 to 11 and at least one acceptable pharmaceutical or food grade additive and / or excipient, for use in a method for the prevention or treatment of peripheral neuropathies and neuropathic pain.

13. The composition for use according to claim 12, wherein said composition comprises or, alternatively, consists of: from 30 to 200 mg, preferably from 50 to 160 mg, even more preferably from 60 to 100 mg of a dry extract of Curcuma longa titrated in curcuminoids (minimum titre > 30% w / w; wherein preferably the curcuminoid titre is comprised from 30% to 50%, preferably from 35% to 45%, more preferably 35% by weight relative to the total weight of the dry extract); from 200 to 2,000 mg, preferably from 300 to 1000 mg, more preferably from 400 to 500 mg of L-acetyl carnitine (L-carnitine and / or carnitine) or a pharmaceutically acceptable salt thereof and / or mixtures thereof; from 10 to 1000 mg, preferably from 200 to 600 mg, even more preferably from 300 to 400 mg of bergamot extract (wherein said bergamot extract preferably has a total flavonoid titre (neoeriocitrin, naringin, (neo)hesperidin, melitidin, brutieridin) comprised from 10% to 50%, preferably from 35% to 45%, more preferably from 38% to 40% w / w), and at least one acceptable pharmaceutical or food grade additive and / or excipient.

14. The composition for use according to any one of claims 12 or 13 that further comprises: from 50 to 500 mg, preferably from 80 to 400 mg, even more preferably from 125 to 200 mg of a vitamin C; and / or from 2 to 50 mg, preferably from 5 to 30 mg, even more preferably from 9 to 20 mg of a vitamin E; and / or from 1 to 50 mg, preferably from 3 to 30 mg, even more preferably from 6 to 20 mg, for example 6.25 mg of a vitamin B1; and / or from 1 to 50 mg, preferably from 3 to 30 mg, even more preferably from 6 to 20 mg of a vitamin B2; and / or from 0.5 to 30 mg, preferably from 1 to 15 mg, even more preferably from 2 to 6 mg, for example 2.38 mg of a vitamin B6; and / or from 1 to 50 pig, preferably from 3 to 30 pig, even more preferably from 6 to 20 pig, for example 6.25 pigof a vitamin B12; and at least one acceptable pharmaceutical or food grade additive and / or excipient.

15. The composition for use according to any one of claims 12 to 14, wherein said peripheral neuropathies and said neuropathic pain are preferably selected from those caused by compression, metabolic imbalance, infection, a toxic agent, a pathogen, drugs, or caused by the presence of a systemic inflammatory and / or genetic disease.

16. The composition for use according to any one of claims 12 to 15, for use in a method of treating neuropathies selected from those caused by compression, preferably carpal tunnel syndrome and lumbosciatica; in a method of treating metabolic neuropathies, preferably diabetic neuropathy; in a method of treating iatrogenic neuropathies, preferably that caused by Guillain-Barre syndrome, or other genetic / hereditary disorders such as Charcot-Marie- Toot disease.

17. The composition for use according to any one of claims 12 to 16, for oral use, preferably in the form of a capsule, tablet, sachet, stick, orosoluble stick, oral gel, or granules.

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