The present invention relates to a mixture consisting of or alternatively comprising (I) at least one cannabinoid, such as a cannabidiol-CBD, of synthetic or natural origin preferably from Cannabis sativa, (ii) at least one terpene, such as a beta-caryophyllene BCP, of synthetic or natural origin preferably from Eugenia caryophyllus, and (ill) at least one sesquiterpene, such as a sesquiterpene with furanodiene structure, of synthetic or natural origin preferably from Commyphora myrrha. The present invention further relates to a composition comprising said mixture and optionally additives and/or excipients of pharmaceutical or food or cosmetic grade. The present invention also relates to a form of administration of said composition in the form of a cream, or transdermal patch or patch, preferably for topical use.

Further, the present invention relates to said mixture and said composition containing said mixture, for use in a non-therapeutic treatment, for example for cosmetic use, or for use in a method of treatment of peripheral neuropathic pain. Finally, the present invention relates to a bandage or transdermal patch made of nonwoven fabric comprising said mixture, or said composition containing said mixture, for nontherapeutic use, e.g. for cosmetic use, or for use in a method of treatment of peripheral neuropathic pain.

STATE OF THE ART

Peripheral neuropathic pain is pain caused by various types of nerve damage. Some examples of neuropathic pain conditions include, but are not limited to, trigeminal neuralgia, complex regional pain syndrome, sciatic inflammation, carpal tunnel, lumbosacral radiculopathy, cervical radiculopathy, lumbosciatica, ulnar neuropathy, and low back pain.

These inflammatory conditions are extremely common among the adult population, and there is an increasing demand for remedies, to provide relief from this type of pain/inflammatory condition, that are as effective, natural and easy to administer as possible without giving rise to side effects.

Pharmaceutical compositions (drugs) or compositions for medical devices, dietary supplements, or nutraceutical products currently available on the market for the treatment, therapeutic or nontherapeutic, of diseases, symptoms, and/or disorders associated with inflammation or neuropathic pain are sometimes ineffective or only partially effective. In addition, said pharmaceutical compositions may cause even severe side effects due to the fact that they contain active pharmaceutical ingredients, such as painkillers or antiinflammatories, which may be poorly tolerated by some categories of people.

The technical problem that the present invention addresses and solves is to provide an efficient solution for the effective treatment, both therapeutic and non-therapeutic, of pathologies, symptoms and/or disorders associated with peripheral neuropathic pain, particularly for the treatment of neuropathic diseases, such as complex regional pain syndrome, sciatic inflammation, carpal tunnel, lumbosacral radiculopathy, cervical radiculopathy, lumbosciatalgia, ulnar neuropathy, and low back pain, which overcomes the currently unresolved drawbacks of the known technique, particularly with regard to efficacy and/or the presence of undesirable side effects. Furthermore, the technical problem that the present invention addresses and solves is also to provide a efficient solution for the nontherapeutic treatment of inflamed/painful muscles that relaxes tense muscle conditions by acting as a myorelaxant effectively and in the absence of side effects.

The Applicant after extensive and intensive research and development activity, has found that the combination or association of: (I) at least one cannabinoid, such as a cannabidiol-CBD, (II) at least one terpene, such as a beta-caryophyllene BCP, and (ill) at least one sesquiterpene, such as a sesquiterpene with a furanodiene structure, is capable of performing and providing, in a useful and beneficial manner, benefit when applied, preferably topically, to a subject in need thereof.

One purpose of the present invention is to make available a mixture M consisting of or alternatively comprising

(I) at least one cannabinoid, such as a cannabidiol-CBD, of synthetic or natural origin preferably from Cannabis sativa,

(II) at least one terpene, such as a beta-caryophyllene BCP, of synthetic or natural origin preferably from Eugenia caryophyllus, and (ill) at least one sesquiterpene, such as a sesquiterpene with furanodiene structure, of synthetic or natural origin, preferably from Commyphora myrrha.

Another purpose of the present invention is to make available a mixture M1 consisting of or alternatively comprising (I) at least one cannabinoid, such as a cannabidiol-CBD, of synthetic or natural origin preferably from Cannabis sativa,

(II) at least one terpene, such as a beta-caryophyllene BCP, of synthetic or natural origin preferably from Eugenia caryophyllus, and (ill) at least one sesquiterpene, such as a sesquiterpene with furanodiene structure, of synthetic or natural origin preferably from Commyphora myrrha, and optionally additives or excipients of pharmaceutical or food or cosmetic grade.

Preferably, M1 may, in addition, include lecithin or the ingredient copaifera reticulata balsam oil (essential oil, fragrance agent) CAS No. 8001-61-4; EINECS/ELINCS No.: 232-288-0.

Another purpose of the present invention is to make available a mixture M or M1 for use in a nontherapeutic method of treatment, e.g. for cosmetic use, or for use in a method of treatment of peripheral neuropathic pain.

Another purpose of the present invention is to make available a composition C (pharmaceutical composition, cosmetic composition, nutraceutical composition, dietary supplement or medical device composition, in short the compositions of the present invention) comprising said M or M1 mixture, in addition to at least one essential oil selected from the group comprising or alternatively consisting of: a) at least one lavandin grosso essential oil; b) at least one rosemary essential oil; c) at least one pinus mugo essential oil; d) at least one hemp sativa essential oil and, optionally, additives or excipients of pharmaceutical or food or cosmetic grade.

Another purpose of the present invention is to make available a composition C for use in a nontherapeutic method of treatment, e.g. for cosmetic use, or for use in a method of treatment of peripheral neuropathic pain.

Another purpose of the present invention is to provide a bandage or transdermal patch made of nonwoven fabric comprising said mixture M or M1, or said composition C containing said mixture M or M1, for nontherapeutic use, e.g. for cosmetic use, or for use in a method of treatment of peripheral neuropathic pain, particularly in the treatment of peripheral neuropathic diseases, such as complex regional pain syndrome, sciatic inflammation, carpal tunnel, lumbosacral radiculopathy, cervical radiculopathy, lumbosciatica, ulnar neuropathy, and low back pain.

Finally, another purpose of the present invention relates to the use of said mixture M or M1, or said composition C containing said mixture M or M1, to prepare a cosmetic composition, or for the treatment of peripheral neuropathic pain.

Said mixture M or M1, said composition comprising said mixture M or M1, and the transdermal patch, which are objects of the present invention, are advantageously free of undesirable side effects, stable, easy to prepare, and cost-effective.

These purposes and others, which will be clear from the detailed description that follows, are achieved by the mixtures M (e.g., M or M1) and compositions C, which are objects of the present invention, by the technical features claimed in the united claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Representation of a transdermal patch according to a preferred embodiment of the present invention. Figure 2: Representation of a cross section of a transdermal patch according to a preferred embodiment of the present invention.

Figures 3 and 4 refer to the efficacy of a transdermal patch according to a preferred embodiment of the present invention (Capidol NERV patch) in the treatment of neuropathic and neuralgic pain: an evident pain relief was verified in all patients with an average decrease of 59.3% in NRS from the initial detection, stable during the twelve-week follow-up period.

DETAILED DESCRIPTION OF THE INVENTION

The Applicant has found that the specific and selected combination (or association) consisting of: (I) at least one cannabinoid, such as a cannabidiol-CBD, (II) at least one terpene, such as a beta-caryophyllene BOP, and (ill) at least one sesquiterpene, such as a sesquiterpene with a furanodiene structure, is capable of performing and providing, in a useful and beneficial manner, benefit when applied, preferably topically, to a subject in need thereof.

Said (I) at least one cannabinoid, such as a cannabidiol-CBD, may be of synthetic or natural origin. In case it is of natural origin, said (I) at least one cannabinoid, such as a cannabidiol-CBD, can be preferably obtained from Cannabis sativa.

Said (II) at least one terpene, such as a caryophyllene or beta-caryophyllene BOP, may be of synthetic or natural origin. In case it is of natural origin, said (II) at least one terpene, such as a caryophyllene or beta- caryophyllene-BCP, may be preferably obtained from Eugenia caryophyllus, or from Syzygium aromaticum (cloves), Piper nigrum (black pepper), Salvia rosmarinus (rosemary) or from Cannabis sativa (hemp).

Terpenes are aromatic compounds that characterize the smell and fragrance of many plants. Terpenes are defined as molecules containing 10 carbon atoms (two isoprene base units) and at least one double bond. Chemically, terpenes have 5-carbon-atom isoprene base units. Terpenes generally consist of two, three, four, or six isoprene base units. These terpenes are called monoterpenes, sesquiterpenes, diterpenes and triterpenes, respectively.

Said (ill) at least one sesquiterpene with furanodiene structure, such as a bioactive sesquiterpene selected from curzerene, furanoeudesma-1,3-diene and lindestrene (furanosesquiterpenes), can be of synthetic or natural origin. In case it is of natural origin, said

(ill) at least one sesquiterpene with furanodiene structure can be preferably obtained from Commyphora myrrha.

It is an object of the present invention to make a mixture M or M1 comprising or alternatively consisting of:

(i) at least one cannabinoid, such as a cannabidiol-CBD, preferably extracted from Cannabis sativa,'

(ii) at least one terpene or terpenoid, such as a caryophyllene or beta-caryophyllene BCP, preferably extracted from Eugenia caryophyllus] and

(ill) at least one sesquiterpene with furanodiene structure selected from curzerene, furanoeudesma- 1 ,3-diene and lindestrene (furanosesquiterpenes), extracted from Commyphora myrrha.

It is an object of the present invention to provide a mixture M1 comprising said mixture M [(i)+(ii)+(iii)] and, optionally, additives or excipients or carriers of pharmaceutical or food or cosmetic grade.

With reference to said (i), at least one cannabinoid, such as a cannabidiol-CBD, this may be preferably extracted from Cannabis sativa, the extract is preferably an extract from Cannabis sativa leaves and preferably represents a source of cannabidiol (CBD). In such an extract, the presence of CBD, together with the other compounds present in the extract from leaves (phytocomplex) of Cannabis sativa, preferably has an analgesic, anti-inflammatory and myorelaxant action.

Cannabis sativa extract is preferably an extract from leaves and does not contain THC, that is, THC is not detectable using the standard analytical methods used to determine its THC concentration.

The Cannabis sativa extract preferably used in the present context does not contain THC in amounts detectable by standard analytical methods; therefore, it is not classifiable as a opiate.

The Cannabis sativa extract that can be used in this context is preferably an extract obtained from the leaf.

In an embodiment, said (i) is an extract from Cannabis sativa (7.1), extract (i.1) is preferably an extract from Cannabis sativa leaves. Said extract (i.1), usable in the present context, is preferably a phytocomplex characterized by a Cannabidiol titer < 50% by weight with respect to the total weight of the phytocomplex obtained by the extraction.

Ethanol can be used as the extraction solvent, and the extraction method that can be used can be any of the standard extraction methods known in the industry.

Extract (i.1 ) at room temperature (about 20°C-25°C) can be in the form of a resinous flaky compound.

In a preferred embodiment, said Cannabis sativa extract (i.1) is concentrated after extraction to give a Cannabis sativa extract (i.1 concentrate) characterized by a CBD concentration by weight (titer) ranging from 55% to 99%, preferably ranging from 60% to 98.5% with respect to the total weight of the extract, even more preferably ranging from 85% to 98% with respect to the total weight of the extract.

Cannabis sativa extract (i.1) can also be purchased commercially. An example of Cannabis sativa extract that can be used in the context of the present invention is the following commercial product:

Cannabis sativa Leaf oil (50% CBD), THC-free, marketed by Materia medica processing. The extract is prepared using the leaves of the plant Cannabis sativa L (synonym Hemp), grown in Italy. The plant used for extraction belongs to the Cannabaceae family, the INCI name is Cannabis sativa leaf extract, CAs No. 89958- 21-4, EC No.289-644-3. The extraction solvent used is ethanol. The appearance at room temperature (about 20°C-25°C) is that of a resin.

Alternatively, a cannabis sativa extract produced and marketed by Pura cannabis italiana srl, TCH free, with a CBD titer >=80% by weight with respect to the total weight of the extract, ca be used.

In a preferred embodiment, said (II) is at least one extract of Eugenia caryophyllus (II.1); preferably this is an oily extract and is a source of BCP. The source of BCP, together with the other compounds present in the oily extract (phytocomplex) of Eugenia caryophyllus, preferably have an analgesic and anti-inflammatory action.

Eugenia caryophyllus extract can also be purchased commercially.

In a preferred embodiment, said (ill) is an extract of Commyphora myrrha (iii.1), preferably, this is an oily extract and is a source of terpenes. The source of terpenes, together with the other compounds present in the oily extract (phytocomplex) of Commyphora myrrha, preferably has an analgesic and anesthetic action.

Commyphora myrrha extract can also be purchased commercially.

In a preferred embodiment said mixture M or M1 comprises or, alternatively, consists of:

(1.1) at least one extract of Cannabis sativa,' and (II.1) at least one extract of Eugenia caryophyllus,' and (ill.1) at least one extract of Commyphora myrrha,' and optionally, additives or excipients or carriers of pharmaceutical or cosmetic grade.

Preferably, said (I) at least one cannabinoid, such as a cannabidiol-CBD, is present in said mixture M or M1 in an amount by weight ranging from 5% to 80%, preferably from 10% to 70%, even more preferably from 20% to 60% from with respect to the total weight of M or M1, e.g. (20%, 30%, 40%, 50%, 60%).

Preferably, said (II) at least one terpene, such as a beta-caryophyllene BCP is present in said mixture M or M1 in an amount by weight ranging from 5% to 80%, preferably from 10% to 70% even more preferably from 20% to 60% with respect to the total weight of M or M1, e.g. (20%, 30%, 40%, 50%, 60%) with respect to the total weight of M or M1.

Preferably, said (ill) at least one sesquiterpene, such as a sesquiterpene with a furanodiene structure, is present in said mixture M or M1 in an amount by weight ranging from 5% to 80%, preferably from 10% to 70%, even more preferably from 20% to 60% with respect to the total weight of M or M1, e.g. (20%, 30%, 40%, 50%, 60%) with respect to the total weight M or M1. In a preferred embodiment said (i)+(ii)+(iii) are included in a weight ratio of 1 :1:1.

In a preferred embodiment said (ib)+(iib)+(iiib) are included in a weight ratio of 1 :1 :1.

In a preferred embodiment said mixture M or M1 comprises an amount in grams of CBD ranging from 40 mg to 70 mg, preferably ranging from 35 mg to 50 mg with respect to the total weight of the mixture, e.g., 20 mg.

In a preferred embodiment said mixture M or M1 comprises an amount in grams of BCP ranging from 40 mg to 70 mg, preferably ranging from 35 mg to 50 mg with respect to the total weight of the mixture, e.g., 20 mg.

In a preferred embodiment said mixture M or M1 comprises an amount in grams of Myrrh ranging from 40 mg to 70 mg, preferably ranging from 35 mg to 50 mg with respect to the total weight of the mixture, e.g., 20 mg.

In a preferred embodiment, the mixture M is coated with a lipid (microencapsulated) coating matrix. Said coating matrix comprises or, alternatively, consists of at least one lipid, preferably of plant origin, and wherein, preferably, said at least one lipid has a lamellar configuration, more preferably a multilayer lamellar configuration.

Preferably said lipid-coating matrix, it is a liposome. In the present context, the term "liposome" refers to a three-dimensional lipid vesicle in the micron range in size, consisting of at least one phospholipid bilayer membrane (lamella) surrounding and separating an inner aqueous compartment.

The size of the lipid matrix according to the present invention, preferably of the liposomes according to the present invention, is 20 nm - 1000 nm, preferably ranging from 50 nm to 400 nm, even more preferably ranging from 100 nm to 200 nm.

The lipid coating matrix according to the present invention can be obtained using any lipid capable of forming a bilayer. Preferably, phospholipids, sphingolipids, glycosphingolipids and ceramides can be used.

In the present context, the term phospholipid refers to a lipid whose molecule has a hydrophilic "head" containing a phosphate group, and two hydrophobic "tails" derived from fatty acids, joined by a glycerol molecule.

Preferably said phospholipid used in the present context may be a glycerophospholipid, e.g. it may be selected from the group comprising or alternatively consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, lecithin, phosphatidic acid, and mixtures thereof. Preferably, said lipid coating matrix having a multilamellar structure includes at least one phosphatidylcholine.

Phosphatidylcholine (PC) refers to a class of phospholipids that incorporate choline as their head group.

Phosphatidylcholine that can be used in the present context can also be purchased commercially. For example, a phosphatidylcholine as produced and marketed by Lipoid GmbH, under the trade name Lipoid S 75 (Item. no. 577600), can be used.

Preferably, phosphatidylcholine used in the present context can be selected from the group comprising or, alternatively, consisting of: phosphaditylcholine LPC, phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine, and mixtures thereof.

Thus, a preferred embodiment according to the present invention relates to a mixture M or M1 wherein said mixture is coated/microencapsulated within a lipid coating matrix in a multilayer lamellar configuration.

Preferably, said mixture M or M1 is microencapsulated within a lipid coating matrix in a multilayer lamellar configuration, wherein said lipid matrix comprises or, alternatively, consists of at least one phosphatidylcholine selected from the group comprising or, alternatively, consisting of phosphaditylcholine LPC, phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine, and mixtures thereof.

Preferably the mixture M or M1 according to the present invention is microencapsulated within liposomes.

In addition, the lipid matrix that can be used in the present context advantageously allows for improved penetration of the mixture M or M1 into the dermal layer. Furthermore, it advantageously allows said mixture M or M1 to be dispersible in water or water-based liquids and optimizes its processing. Finally, it allows the mixture to be protected from thermal shock due to temperature rise.

In an alternative embodiment, individual components (i), (ii), (iii) can be coated/microencapsulated individually/separately within the multilamellar lipid matrix, preferably within a liposomal structure (liposome).

In an embodiment, the mixture M or M1 according to the present invention is for cosmetic use as a myorelaxant, muscle relaxant.

In an embodiment, the mixture M or M1 according to the present invention is for use as a medicament.

In an embodiment, the mixture M or M1 according to the present invention is for use in a method of treatment of peripheral neuropathic pain.

Preferably, said neuropathic pain is selected from the group comprising or alternatively consisting of: complex regional pain syndrome, sciatic inflammation, carpal tunnel, lumbosacral radiculopathy, cervical radiculopathy, lumbosciatica, ulnar neuropathy, and low back pain.

COMPOSITION

A composition C (pharmaceutical composition, cosmetic composition, nutraceutical composition, dietary supplement or medical device composition, in short the compositions of the present invention) comprising said mixture M or M1, and also at least one essential oil selected from the group comprising or, alternatively, consisting of: a) at least one lavandin grosso essential oil ; b) at least one rosemary essential oil; c) at least one pinus mugo essential oil; d) at least one hemp sativa essential oil and, optionally, additives or excipients of pharmaceutical or food or cosmetic grade.

Preferably, said composition C comprises M or M1.

Preferably, said (i) at least one cannabinoid, such as a cannabidiol-CBD, preferably extracted from leaves of Cannabis sativa, is present in said composition C, comprising M or M1, in an amount by weight ranging from 0.05% to 5%, preferably from 0.1% to 3.5%, even more preferably from 1% to 3%, e.g. 1.5%, or 2%, or 2.5%, with respect to the total weight of C.

Preferably, said (ii) at least one terpene, such as a beta-caryophyllene BCP, of synthetic or natural origin preferably from Eugenia caryophyllus, is present in said composition C, comprising M or M1, in an amount by weight ranging from 0.05% to 5%, preferably from 0.1% to 3.5%, even more preferably from 1% to 3%, e.g. 1.5%, or 2%, or 2.5%, with respect to the total weight of C.

Preferably, said (iii) at least one sesquiterpene, such as a sesquiterpene with furanodiene structure, of synthetic or natural origin preferably from Commyphora myrrha, is present in said composition C, comprising M or M1, in an amount by weight ranging from 0.05% to 5%, preferably from 0.1% to 3.5%, even more preferably from 1% to 3%, e.g. 1.5%, or 1.6%, or 1.7%, or 1.8%, or 1.9%, or 2%, or 2.5%, with respect to the total weight of C.

Preferably, in M1 and, therefore, in said composition C, there may, in addition, be present a lecithin preferably from soybean or corn or sunflower in an amount by weight preferably ranging from 2% to 10%, even more preferably from 4% to 8%, e.g. 5%, or 6%, or 7%, with respect to total C; and/or an ingredient such as copaifera reticulata balsam oil (essential oil, fragrance agent) CAS No.° 8001-61-4; EINECS/ELINCS No.: 232-288-0, in an amount by weight preferably ranging from 1% to 5%, even more preferably from 2% to 4%, e.g. 3%, with respect to the total weight of C.

Preferably, said (a) at least one essential oil of lavandin grosso is present in said composition C in an amount by weight ranging from 0.05% to 3%, preferably from 0.1% to 2%, even more preferably from 0.2% to 1 %, e.g., 0.25%, or 0.5%, with respect to the total weight of C.

Preferably, said (b) at least one essential oil of rosemary is present in said composition C in an amount by weight of 0.05% to 3%, preferably 0.1% to 2%, even more preferably 0.2% to 1%, e.g., 0.25%, or 0.5%, relative to the total weight of C.

Preferably, said (c) at least one essential oil of pinus mugo is present in said composition C in an amount by weight ranging from 0.05% to 3%, preferably from 0.1% to 2%, even more preferably from 0.2% to 1 %, e.g., 0.25%, or 0.5%, with respect to the total weight of C.

Preferably, said (d) at least one essential oil of hemp sativa is present in said composition C in an amount by weight ranging from 0.05% to 3%, preferably from 0.1% to 2%, even more preferably from 0.2% to 1 %, e.g., 0.25%, or 0.5%, with respect to the total weight of C.

Preferably, said composition C may further comprise in addition to (a)+(b)+(c) and (d) also a lecithin (e.g., from soybean, sunflower, or corn) in an amount by weight ranging from 0.05% to 5%, preferably from 0.1% to 3%, even more preferably from 0.15% to 2%, e.g., 0.2%, or 0.3%, or 0.5%, with respect to the total weight of C.

Preferably, said C composition may further include in addition to (a)+(b)+(c)+(d) and lecithin, also borneol in an amount by weight ranging from 0.001% to 1 %, preferably from 0.01% to 0.5%, even more preferably from 0.05% to 0.1%, e.g., 0.06%, with respect to the total weight of C.

Preferably, said composition C comprises M or M1 and (a)+(b).

Preferably, said composition C comprises M or M1 and (a)+(c).

Preferably, said composition C comprises M or M1 and (a)+(d).

Preferably, said composition C comprises M or M1 and (b)+(c).

Preferably, said composition C comprises M or M1 and (b)+(d).

Preferably, said composition C comprises M or M1 and (c)+(d).

Preferably, said composition C comprises M or M1 and (a)+(b)+(c).

Preferably, said composition C comprises M or M1 and (a)+(b)+(d).

Preferably, said composition C comprises M or M1 and (b)+(c)+(d).

Preferably, said composition C comprises M or M1 and (a)+(c)+(d).

In a preferred embodiment, said composition C comprises said mixture M or M1 and

(a) at least one lavandin grosso essential oil, and

(b) at least one rosemary essential oil, and

(c) at least one pinus mugo essential oil, and

(d) at least one hemp sativa essential oil, and optionally, additives or excipients or carriers of pharmaceutical or cosmetic grade.

With reference to said (a) at least one lavandin grosso essential oil, this is an essential oil obtained from the lavandin grosso plant which is a lavender hybrid halfway between true lavender (angustifolia) and lavandula latifolia (latifolia).

This oil is in a liquid form, can be presented as a colorless/yellowish liquid, and can be obtained by steam distillation from the flowering spikes of the lavandin grosso plant; it has an intense odorous tone, with an herbaceous touch and a delicate floral side.

Lavandin grosso essential oil (a) that can be used in the present context can be purchased commercially. For example, a lavandin grosso essential oil produced and marketed by Exentiae (Exentiae Ltd., soc. agricola) CAS no. 93455-97-1 may be used.

Said lavandin grosso essential oil (a) preferably comprises linalool in a weight % with respect to the total weight of the essential oil ranging from 10% to 40%, linalyl acetate in a weight % with respect to the total weight of the essential oil ranging from 10% to 40%, terpinen-4-ol in a weight % with respect to the total weight of the essential oil ranging from 1% to 10%.

With reference to said (b) at least one essential oil of rosemary, this is an essential oil of rosemary obtained by distillation of the leaves of rosmarinus officinalis L, a plant in the Lamiaceae family.

Essential oil (b) can be obtained by distillation of the flowering plant and has balsamic characteristics.

Said rosemary essential oil (b) preferably comprises 1,8-cineole in a % by weight with respect to the total weight of the essential oil ranging from 10% to 50%. (e.g., 44%), camphor in a % by weight with respect to the total weight of the essential oil ranging from 1% to 20%. (e.g., 13%) and o-pinene % by weight with respect to the total weight of the essential oil ranging from 1% to 20%. (e.g., 12%).

Rosemary essential oil (b) that can be used in the present context can be purchased commercially. For example, an essential oil of rosemary produced and marketed by Exentiae (Exentiae Ltd., soc. agricola) CAS no. 8000-25-7 may be used.

With reference to said (c) at least one essential oil of pinus mugo, this is an essential oil obtained by steam distillation from the needles and twigs of the Pinus Pumilio plant, (common name: pinus mugo) a plant belonging to the Pinaceae family. Preferably, said pinus mugo essential oil (c) comprises:

Delta-3-carotene, preferably in a weight concentration from 10% to 30%, e.g. 20%;

Beta-fellandrene, preferably in a weight concentration from 10 to 20%, e.g. 16%;

Alpha-pinene, preferably in a weight concentration from 10 to 20 percent, e.g. 16 percent;

Limonene, preferably in a weight concentration from 5% to 13%, e.g. 8%;

Beta-caryophyllene, preferably in a weight concentration from 1% to 13%, e.g., 4%;

Bornyl acetate, preferably in a weight concentration from 1% to 10%, e.g., 3%; with respect to the total weight of the composition.

Pinus mugo essential oil (b) that can be used in the present context can be purchased commercially. For example, an essential oil Pinus Mugo leaf oil produced and marketed by Bergila (Bergila Ltd.) CAS no. 90082- 73-8 may be used.

With reference to said (d) at least one hemp sativa essential oil, this is a concentrated hemp extract, free of THC.

Said (d) at least one hemp sativa essential oil can be purchased commercially.

In a preferred embodiment, said essential oils (a)-(d) are encapsulated in lipid micelles.

Lipid micelles, in the present context means a system of lipid molecules arranged in spherical form in aqueous solutions.

Preferably said lipid micelles comprise at least one phospholipid.

Preferably, said lipid micelles comprise at least one phosphatidylcholine.

A phosphatidylcholine that can be used in the present context can also be purchased commercially. For example, a phosphatidylcholine as produced and marketed by Lipoid GmbH, under the trade name Lipoid S 75 (Art. no. 577600), may be used.

Preferably, the phosphatidylcholine included in said lipid micelles may be selected from the group comprising or, alternatively, consisting of: phosphaditylcholine LPC, phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine, and mixtures thereof.

In an embodiment, said lipid micelles preferably may be formed from phospholipids, sphingolipids, glycosphingolipids ceramides or mixtures thereof. In a preferred embodiment, said lipid micelles comprise at least one phospholipid and borneol.

Borneol is a bicyclic organic compound belonging to the terpene family. One of its historical names is "camphor from Borneo".

There are two borneol enantiomers, in the present context a racemic mixtureof the two enantiomers is used. Borneol used in the present context can be purchased commercially.

Advantageously, the Applicant found that said micelles comprising at least one lecithin and borneol allow for increased transdermal permeation.

The composition and mixture according to the present invention can be prepared in gel formulations, cream preparations or they can be dispensed on dry transdermal patches.

In an embodiment, composition C according to the present invention is for cosmetic use as a myorelaxant, muscle relaxant.

In an embodiment, composition C according to the present invention is for use as a medicament.

In an embodiment, composition C according to the present invention is for use in a method of treatment of neuropathic pain.

Preferably, said neuropathic pain is selected from the group comprising or alternatively consisting of: complex regional pain syndrome, sciatic inflammation, carpal tunnel, lumbosacral radiculopathy, cervical radiculopathy, lumbosciatica, ulnar neuropathy, and low back pain.

TRANSDERMAL PATCH

In an embodiment, the mixture M or M1 or the composition C are adsorbed/deposited onto a bandage or transdermal patch made of nonwoven fabric.

The transdermal patch made of nonwoven fabric according to the present invention comprises a structure, such as a skin patch, bandage, covering, or set of related materials, that can contain and deliver an effective amount of mixture M or M1 according to the present invention or composition C according to the present invention during a predetermined period of time.

Advantageously, administration of the mixture M or M1 or composition C according to the present invention through a transdermal patch allows for controlled release of the active ingredients contained therein. The transdermal patch according to the present invention allows the active ingredients to permeate through the stratum corneum.

By optimizing the structure of the patch and the amount of active material, nonsignificant skin permeation can be achieved, that is, activity at the skin level and not systemically. Or sufficient skin permeation can be achieved to provide systemic release.

A transdermal patch according to the present invention is a passively diffusing patch made of nonwoven fabric. Passively diffusing transdermal patch made of nonwoven fabric means a patch in which the active ingredient diffuses through intact skin as a result of a solubility or concentration gradient.

Advantageously, the Applicant found that microencapsulated mixture M or M1 and composition C comprising said microencapsulated mixture M or M1 allows optimal release and improves transdermal penetration.

Preferably said mixture M or M1 or said composition C are deposited on the transdermal patch in such an amount as to have an amount of (I) ranging from 10 mg to 40 mg, preferably iranging from 15 mg to 30 mg, e.g, 20 mg.

Preferably said mixture M or M1 or said composition C are deposited on the transdermal patch in such an amount as to have an amount of (ii) from 10 mg to 40 mg, preferably ranging from 15 mg to 30 mg, e.g., 20 mg.

Preferably said mixture M or M1 or said composition C are deposited on the transdermal patch in such an amount as to have an amount of (ill) ranging from 10 mg to 40 mg, preferably ranging from 15 mg to 30 mg, e.g., 20 mg.

In a preferred embodiment, (I), (ii), (ill) are included on the transdermal patch in an amount of 20mg, 20mg, and 20mg.

Passive transdermal patches, called reservoir systems, may be used in the context of the present invention; polymer matrix systems, or microreservoir systems, may also be used.

A preferred embodiment relates to a transdermal patch comprising:

A backing (2), preferably a backing made of nonwoven fabric; and

An adhesive mixture comprising the mixture according to the present invention or composition C according to the present invention, and an adhesive compound selected from the group comprising or alternatively consisting of: acrylic polymers, polyisobutenic polymers (pib), silicone polymers, and mixtures thereof.

In a preferred embodiment, the transdermal patch is a passive diffusion transdermal patch made of nonwoven fabric, said patch compriseing: a backing (2), preferably a backing made of nonwoven fabric, an active surface (3) a protective coating that covers the adhesive and is removed before application.

Figure 1, shows a representation of said transdermal patch (plan view). Figure 2 shows a cross section along the transverse plane ll-ll, wherein the layers of said patch are visible. List of reference numbers: (1) Patch; (2) Backing made of nonwoven fabric; and (3) Active surface.

The mixture M or M1 according to the present invention, or composition C according to the present invention are mixed with an adhesive formulation, preferably comprising acrylates, preferably polyacrylates, to form an adhesive mixture comprising the active ingredients. Said adhesive mixture is spread/deposited on the backing (2) to form said active surface (3).

Preferably, said adhesive formulation comprises at least one adhesive compound, preferably selected from the group comprising or alternatively consisting of: acrylic polymers, polyacrylates, polyisobutenic polymers (pib), silicone polymers, and mixtures thereof.

In an embodiment, the transdermal patch comprising the mixture M or M1 or composition C according to the present invention is for cosmetic use as a myorelaxant, muscle relaxant.

In an embodiment, the transdermal patch comprising the mixture M or M1 or composition C according to the present invention according to the present invention is for use as a medicament.

In an embodiment, the transdermal patch comprising the mixture M or M1 or composition C according to the present invention is for use in a method of treatment of neuropathic pain.

Preferably, said neuropathic pain is selected from the group comprising or alternatively consisting of: complex regional pain syndrome, sciatic inflammation, carpal tunnel, lumbosacral radiculopathy, cervical radiculopathy, lumbosciatica, ulnar neuropathy, and low back pain. The transdermal patch, which is an object of the present invention, is marketed under the name Capidol NERV Patch and is a patch with topical activity having analgesic action with specific formulation for the treatment of neuropathic pain. Preferably, its main components are (I) CBD - Cannabis sativa leaf extract, (ii) BCP - Eugenia caryophyllus bud oil, and (ill) Myrrh - Commyphora myrrha gum oil; the combination of said (i)+ii)+iii) acts on cannabinoid receptors in the peripheral nervous system, also interacts with peripheral opioid receptors and has anti-inflammatory activity. In addition, ancillary substances such as extracts of Lavender, Rosemary and Pinus mugo are also present in the composition that is an object of the present invention (Capidol NERV Plaster), which may have an effective synergistic action on pain control. Cannabidiol (CBD) interacts with CB1 and CB2 cannabinoid receptors in the peripheral nervous system, controls pain and inflammation also through a special interaction with opioid receptors. Topical use has no psychoactive activity and does not alter perceptual, psychological, or psychomotor functions. Beta-caryophyllene (BCP) is present in concentrations greater than 35% in Cannabis sativa essential oil in the form of its isocaryophyllene and umulene isomers.

As a selective CB2 cannabinoid receptor ligand, it has marked anti-inflammatory and analgesic activities. Myrrh is an aromatic gummoresin secreted from the trunk and branches of an air-hardened Commiphora species tree. Myrrh is credited with disinfectant, anti-inflammatory and analgesic, and antioxidant properties. The analgesic action is made possible by furanodiene-structured sesquiterpenes capable of activating opioid receptors. Other classes of furanodienes exhibit local anesthetic properties due to selective and reversible blockade of sodium channels. Myrrh extract also inhibits IL-6 production, blocking the inflammatory cascade.

Regarding the ancillary components present in the composition, the activity of Lavender is traced to the presence of linalool and linalyl acetate, which have anti-inflammatory and analgesic properties involving the endogenous opioid system and glutamate modulation. Rosemary is recognized to have anti-inflammatory, antioxidant and antiradical activity. Pinus mugo contains terpene compounds such as bornyl acetate, and esters, resins and glucosides are contained in the leaves. Compounds such as a-pinene, 5-3-carene, limonene and p-pinene, p-caryophy llene and p-phellandrene, have been further isolated as major components with monoterpene activity.

In order to evaluate the analgesic efficacy of Capidol NERV patch, 20 patients with neuropathic pain were observed during the treatment: 6 patients had cervical radiculopathy and 6 patients had lumbar radiculopathy resulting from osteoarthritis of the spine, 4 patients had postchemotherapy neuropathy algias, 2 had carpal tunnel syndrome, and 2 had Morton's neuroma (TAB. 1).

In patients with cervical and lumbar radiculopathy and postchemotherapy neuropathy, systemic treatment with neuromodulators or tapentadol with stable dosages was ongoing during treatment with Capidol NERV patch. In patients with carpal tunnel syndrome and Morton's neuroma, Capidol NERV patch was the only proposed antalgic treatment. Hyperalgesia, never allodynia, was present in all patients. Pain intensity was recorded by NRS scale with range of values from 1 to 10, considering time 0 the application of the device, and times 1 and 2 at 5 and 10 days after the first application. The transdermal Capidol NERV patch was replaced every 24 hours and kept continuously applied to the site of pain throughout the observation period.

The efficacy of Capidol NERV patch in the treatment of neuropathic and neuralgic pain was confirmed. Evident pain relief was verified in all patients with an average 59.3% decrease in NRS from the initial detection (FIGURE 3 - FIGURE 4), stable during the 12-week follow-up period.

Treatment with Capidol Nerv patches (composition (i)+ii)+iii) performed direct analgesic action in some cases, and potentiated the action of systemically administered analgesics. The efficacy and absence of major side effects make Capidol NERV patch a useful solution in the treatment of neurogenic pain.

Table 1

Preferably, composition C (Capidol Nerv Patch transdermal patch) object of the present invention, may comprise:

Table 2