“COMPOSITION FOR THE TREATMENT OF PAINFUL AND/OR INFLAMMATORY STATES”

FIELD OF THE INVENTION

Embodiments described here concern a composition based on cannabidiol (CBD), in particular for the therapeutic treatment of painful and/or inflammatory states. More specifically, the embodiments described here concern a composition comprising a synergistic combination of CBD or an extract containing CBD and one or more natural ingredients that help the pain relief and/or anti-inflammatory activity. The composition described here can be formulated, for example, as a pharmaceutical composition or as a food supplement composition.

BACKGROUND OF THE INVENTION

It is known that humans and animals suffering from chronic and severe pain require good clinical management. The pharmacological agents generally used to treat the different types of painful states are many and include, for example, opiates, non-steroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, antidepressants and ketamine. However, the negative side effects of these drugs limit their therapeutic dosage, and in the final analysis reduce their therapeutic efficacy.

In recent years there have been considerable improvements in the understanding of the pathophysiological mechanisms that underlie the manifestations of chronic pain and various other molecules have been tested that have been found to be effective in treating pain and free from unwanted side effects.

Document US-A-2021/015774 describes a tablet or composition comprising N-acyl ethanolamine or PEA, a cannabinoid and a terpene.

Document EP- A- 1.542.657 describes a liquid formulation of cannabinoid for administration via the mucosa, in particular by spraying.

There is therefore a need to provide a composition for the therapeutic treatment, in particular of painful and/or inflammatory states, which overcomes one or more of the disadvantages of the state of the art.

In particular, one purpose of the present invention is to provide a composition in particular for the therapeutic treatment of painful and/or inflammatory states which prevents the side effects typical of synthetic painkillers.

The Applicant has devised, tested and embodied the present invention to overcome the shortcomings of the state of the art and to obtain these and other purposes and advantages.

SUMMARY OF THE INVENTION

The present invention is set forth and characterized in the independent claim. The dependent claims describe other characteristics of the present invention or variants to the main inventive idea.

In accordance with the above purposes, the embodiments concern a composition comprising a synergistic combination of Cannabidiol (CBD), or an extract containing CBD, with one or more substances or molecules, and/or respective natural dry extracts, with pain-relieving and/or anti-inflammatory activity.

The present inventors have discovered that the therapeutic action of CBD increases if associated with other molecules and/or natural extracts with pain- relieving and/or anti-inflammatory activity. In summary, the various associations provided here were found to be more effective against pain and inflammatory situations than the action of the individual functional principles.

According to some embodiments, the composition described here is a pharmaceutical composition.

According to some embodiments, the pharmaceutical composition also comprises one or more pharmaceutically acceptable excipients.

According to other embodiments, the composition described here is a food supplement.

According to other embodiments, the composition described here also comprises dry extracts, coenzymes or a combination thereof.

According to other embodiments, the composition described here is free of terpenes.

In accordance with still other embodiments, the natural pain-relieving, antiinflammatory agents and the respective dry extracts present in the composition described here are selected from Palmitoylethanolamide (PEA) and/or L- acetylcamitine (LAC) and/or Boswellic acids from Boswellia serrata and/or Lipoic acid and/or furanodienes from Chommiphora myrrha and/or harpagoside from Harphagophytum Procumbens, and/or gingerols and shogaols from ginger and/or curcumin or a combination thereof.

In accordance with still other embodiments, the composition as above comprises CBD and at least two natural pain-relieving and/or anti-inflammatory substances. One of these two substances can for example be PEA and the other can be, for example, a plant-derived anti-inflammatory substance.

In accordance with still other embodiments, the composition as above comprises CBD and Palmitoylethanolamide (PEA), wherein the weight ratio of PEA:CBD in said composition is from 5:1 to 1:1, in particular from 3:1 to 1:1, more in particular from 2:1 to 1:1. An example of implementation can be 1 : 1.

In accordance with still other embodiments, the composition as above comprises CBD, Palmitoylethanolamide (PEA) and one or more plant-derived anti-inflammatory substances.

In possible implementations, the plant-derived anti-inflammatory substances can be selected from gingerols and shogaols from ginger Zingiber officinale), curcumin from Curcuma longa, harpagoside from Harphagophytum Procumbens.

In other possible implementations, such plant-derived anti-inflammatory substances can be standardized plant extracts.

In accordance with other embodiments, the composition as above comprises CBD and PEA and is free of other plant-derived anti-inflammatory and/or pain- relieving substances and/or other active principles or substances, such composition possibly including suitable and pharmaceutically acceptable excipients. Also in this case, for example, the weight ratio of PEA:CBD in such composition is from 5:1 to 1 :1, in particular from 3:1 to 1:1, more in particular from 2:1 to 1 : 1. An example of implementation can be 1:1.

The composition that provides the association of the substances described above can be made in the form of powder, for example single- or multi-layer tablets, single- or multi-layer tablets with differentiated release, soluble sachets, hard gelatin capsules or softgels or any other form suitable for oral intake.

Furthermore, the composition according to the embodiments described here can be made available, as well as in powder form, also in liquid form. For example, the liquid form can be made in the form of simple syrups, emulsified syrups, suspensions or preparations for extemporaneous use.

DESCRIPTION OF SOME EMBODIMENTS

We will now refer in detail to the possible embodiments of the present invention, of which one or more examples are described below, by way of a non- limiting illustration. The phraseology and terminology used here is also for the purposes of providing non-limiting examples.

It is also understood that elements and characteristics of one embodiment can be conveniently combined or incorporated into other embodiments without further clarifications. All the percentages and ratios indicated shall be understood to refer to the weight of the total composition (w/w), unless otherwise indicated.

All the percentage intervals reported here are provided with the provision that the sum with respect to the overall composition is 100%, unless otherwise indicated. All the intervals reported here shall be understood to include the extremes, including those that report an interval “between” two values, unless otherwise indicated.

The present description also includes the intervals that derive from uniting or overlapping two or more intervals described, unless otherwise indicated. The present description also includes the intervals that can derive from the combination of two or more values taken at different points, unless otherwise indicated.

The embodiments described here concern a composition comprising Cannabidiol (CBD) or an extract containing CBD. CBD is a cannabinoid found in Cannabis sativa. The term cannabinoid refers to compounds that activate G-protein coupled to cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 receptors, located mainly on the neurons of the hippocampus and basal ganglia, mediate the psychoactive actions of cannabinoids. CB2 receptors are found mainly on tissues and circulating cells of the immune system. Unlike the psychoactive constituent Tetrahydrocannabinol (THC), CBD does not exhibit psychoactive activity because it has no direct effect on CB1 and CB2 receptors, but it modulates the effect of the agonists, suggesting an allosteric function. Furthermore, CBD binds to PPARy, GPR3/6/12/18/55, TRPV1/2, TRPA1, to the 5-hydroxytryptamine receptor and to mitochondrial proteins. Furthermore, CBD is well tolerated even when administered in high concentrations and the therapeutic benefits it brings in the treatment of childhood epilepsy are well documented. On the contrary, until now its effects on inflammation have been mainly studied on animal models. Studies on rodents with osteoarthritis or collagen-induced arthritis have demonstrated the antiinflammatory and analgesic effects of CBD, but, to date, these studies have not yet clarified the mechanism of action. Several studies report that CBD reduces the production of pro-inflammatory cytokines, such as TNF-a, IL-6, IL- 10, and induces the reduction of fatty acid amide hydrolase (FAAH) activity, thus increasing the production of Anandamide, an anti-inflammatory endocannabinoid.

Furthermore, and just as importantly, CBD also counteracts THC-induced psychoactivity, sedation and tachycardia.

In summary, CBD comes with a long list of medical properties. The main one among these is the ability to relieve the symptoms of various ailments, such as chronic pain, inflammation, migraines, arthritis, spasms, epilepsy and schizophrenia. Furthermore, it has been proven that CBD has some anti-cancer properties, and new uses and applications are constantly being discovered thanks to medical research.

The Applicant has found for the first time that the association of CBD with one or more natural ingredients or substances that act as agents with pain- relieving and/or anti-inflammatory properties, in particular molecules, and/or respective natural pain-relieving and/or anti-inflammatory dry extracts, more in particular one or more pain-relieving and anti-inflammatory substances present in nature, results in a synergistic combination between CBD and the above natural ingredients or substances that act as agents with pain-relieving and/or antiinflammatory properties. The Applicant has found that this synergistic combination is particularly effective for therapeutic treatment, in particular of painful and/or inflammatory states.

The embodiments described here therefore provide a safe composition of CBD or a CBD-containing extract with one or more molecules and/or natural extracts with pain-relieving and/or anti-inflammatory properties, such composition exhibiting ameliorative and synergistic effects in therapeutic treatment, in particular of painful or inflammatory states, compared to CBD alone.

In some embodiments, the composition described here comprises CBD from 5 to 90% w/w of the composition.

In some embodiments, the composition described here comprises the one or more natural pain-relieving and/or anti-inflammatory substances as above from 0.5 to 90% w/w of the composition.

The composition described here can be for human or veterinary use.

In some embodiments, the composition described here can be, in particular, a pharmaceutical composition.

In some embodiments, the composition as above can be provided or used in both powder and also liquid form.

In some embodiments, the composition described here comprises CBD in liquid or solid form, wherein the quantity of CBD in the composition is from 5 to 1000 mg per unit dose.

In some embodiments, the one or more natural pain-relieving and/or antiinflammatory substances as above are one or more selected from Palmitoylethanolamide (PEA) or L-acetylcamitine (LAC) and/or Boswellic acids from Boswellia serrata and/or Lipoic acid and/or a mixture of antioxidant substances extracted mainly from the bark of Maritime Pine (Pinus pinaster) and/or from the seeds of Vitis vinifera (for example Pycnogenol) and/or furanodienes from Chommiphora myrrha, or extract of Chommiphora myrrha as a source of furanodienes and/or harpagoside from Harphagophytum Procumbens, and/or gingerols and shogaols from ginger and/or curcumin from Curcuma longa, or a combination thereof. In possible embodiments, the quantity of the natural pain-relieving and/or anti-inflammatory substances as above in the composition described here is from 2 to 2000 mg per unit dose.

According to one possible embodiment, the composition described here comprises CBD and PEA.

According to other embodiments, the composition described here is free of terpenes.

In accordance with still other embodiments, which can be combined with all the embodiments described here, the composition as above comprises CBD and Palmitoylethanolamide (PEA), wherein the weight ratio of PEA:CBD in such composition is from 5:1 to 1:1, in particular from 3:1 to 1:1, more in particular from 2: 1 to 1 : 1. An example of implementation can be 1:1.

In accordance with still other embodiments, which can be combined with all the embodiments described here, the composition as above comprises CBD, Palmitoylethanolamide (PEA) and one or more plant-derived anti-inflammatory substances.

In some embodiments, which can be combined with all the embodiments described here, such plant-derived anti-inflammatory substances are selected from gingerols and shogaols from ginger (Zingiber officinale , curcumin from Curcuma longa, harpagoside from Harphagophytum Procumbens.

In other embodiments, which can be combined with all the embodiments described here, such plant-derived anti-inflammatory substances are standardized plant extracts.

According to another possible embodiment, which can be combined with all the embodiments described here, the composition described here comprises CBD, PEA and titrated dry extract of Commiphora myrrha.

In accordance with another possible embodiment, which can be combined with all the embodiments described here, the composition described here comprises CBD, PEA and curcumin or an extract containing curcumin.

In accordance with another possible embodiment, which can be combined with all the embodiments described here, the composition described here comprises CBD, titrated dry extract of Boswellia s errata and LAC.

According to another possible embodiment, which can be combined with all the embodiments described here, the composition described here comprises CBD and Lipoic acid.

According to a possible embodiment, which can be combined with all the embodiments described here, the composition described here comprises CBD and a mixture of antioxidant substances extracted mainly from the bark of Maritime Pine (Pinus pinaster) and/or from the seeds of Vitis vinifera (for example Pycnogenol).

In accordance with another possible embodiment, which can be combined with all the embodiments described here, the composition described here comprises CBD, PEA and ginger or an extract containing ginger.

In accordance with another possible embodiment, which can be combined with all the embodiments described here, the composition described here comprises CBD, PEA and Harphagophytum Procumbens or an extract containing harpagoside from Harphagophytum Procumbens.

In accordance with still another possible embodiment, which can be combined with all the embodiments described here, the composition described here comprises CBD and LAC.

According to another possible embodiment, which can be combined with all the embodiments described here, the composition described here comprises CBD, PEA and LAC.

According to another possible embodiment, which can be combined with all the embodiments described here, the composition described here can include one or more compounds with antioxidant activity, for example selected from a mixture of antioxidant substances extracted mainly from the bark of maritime pine Pinus pinaster) and/or from the seeds of Vitis vinifera (for example Pycnogenol), Lipoic acid, n-Acetyl cysteine, Polyphenols, Resveratrol, Polydatin, Quercetin, Rutin, Luteolin, or a combination thereof. Such one or more compounds with antioxidant activity can for example be present between 5 and 60% w/w of the composition.

In particular, both the mixture of antioxidants extracted from Pinus pinaster and/or from Vitis vinifera (for example Pycnogenol) and also Lipoic acid are strong antioxidants that also have pain-relieving and/or anti-inflammatory properties and therefore can act as natural pain-relieving and/or antiinflammatory substances in the composition in accordance with the present description. Accordingly, as indicated above, in some embodiments the composition described here can include CBD together with the mixture of antioxidants extracted from Pinus pinaster and/or from Vitis vinifera (for example Pycnogenol) and/or Lipoic acid.

In some embodiments, which can be combined with all the embodiments described here, the composition described here can be made or supplied in the form of single- or multi-layer tablets, capsules, softgels, granules, powder, sachets, suspensions, solutions, formulations with modified release, double chamber sachets, topical formulations such as creams, ointments, emulsions and dispersions.

In some embodiments, which can be combined with all of the embodiments described here, the composition described here can comprise suitable and pharmaceutically acceptable excipients, such as diluents, disintegrants, binders, solubilizing agents, lubricants, sliding agents, solvents, desiccants, etc., or a combination thereof.

In some embodiments, the composition described here can comprise, in addition or as a replacement, further additives and/or excipients of pharmaceutical or food grade, that is, substances without therapeutic activity suitable for pharmaceutical or food use. In the context of the present description, the ingredients acceptable for pharmaceutical or food use comprise all the auxiliary substances known to the person of skill in the art such as, as a nonlimiting example, diluents, solvents, solubilizers, thickeners, sweeteners, flavorings, dyes, lubricants, surfactants, antimicrobials, antioxidants, preservatives, buffers to stabilize the pH and mixtures thereof.

In some embodiments, the excipients can be in powder form. Examples of powdered excipients are selected from microcrystalline cellulose, lactose, starch, silica, ammonium alginate, calcium carbonate, calcium lactate, di- or tri-basic calcium phosphate, calcium silicate, calcium sulphate, com starch, pregelatinized starch, erythritol, ethyl cellulose, fructose, glyceryl palmitostearate, isomalt, kaolin, sugar alcohols, lactitol, magnesium carbonate, magnesium oxide, maltose, mannitol, medium chain triglycerides, sodium alginate, sodium chloride, sorbitol, P-cyclodextrins, talc, trehalose. The quantity of excipient in the composition described here can, for example, be from 5 to 50% w/w of the composition.

In the embodiments in which the composition described here can be in liquid form, the excipients can be liquid. Favorably, such liquid excipients act as a solvent of the substances present, that is, the CBD and the natural substances with pain-relieving and/or anti-inflammatory properties, for example PEA and the plant-derived anti-inflammatory substances described above. Such liquid excipients can for example be selected from water, ethyl alcohol, isopropyl alcohol, propylene glycol, almond oil, benzyl alcohol, benzyl benzoate, butylene glycol, carbon dioxide, castor oil, com oil, cottonseed oil, dimethyl ether, albumin, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, ethyl acetate, ethyl lactate, ethyl oleate, glycerin, glycofurol, isopropyl myristate, isopropyl palmitate, light mineral oil, medium chain triglycerides, methyl lactate, mineral oil, monoethanolamine, olive oil, peanut oil, polyethylene glycol, poly oxy 1 35 castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, triacetin, tricaprilin, triethanolamine, triethyl citrate, triolein, water-miscible solvents or suchlike. The quantity of liquid excipient used in the composition described here is typically the quantity required to make the composition in liquid form.

The composition in accordance with the embodiments described here can be used for the therapeutic treatment of one or more of the following forms of pain:

- somatic pain

- visceral pain

- non-nociceptive pain

- neuropathic pain

- sympathetic pain.

EXAMPLES

Some examples of compositions in accordance with the embodiments described here are described below.

Example of composition 1

Cannabidiol (CBD): 5-90% (w/w)

PEA: 0.5-90% (w/w)

Example of composition 2

Cannabidiol (CBD): 5-90% (w/w)

PEA: 0.5-90% (w/w)

Titrated dry extract of Commiphora myrra: 0.5-90% (w/w)

Example of composition 3

Cannabidiol (CBD): 5-90% (w/w)

PEA: 0.5-90% (w/w)

Curcumin or extract containing curcumin: 1-90% (w/w)

Example of composition 4

Cannabidiol (CBD): 5-90% (w/w) Titrated dry extract of Boswellia serrata 0.5-90% (w/w)

L- Acetyl Carnitine: 1-90% (w/w)

Example of composition 5

Cannabidiol (CBD): 5-90% (w/w)

L-Acetyl Carnitine: 0.5-90% (w/w)

Example of composition 6

Cannabidiol (CBD): 5-90% (w/w)

Lipoic Acid: 0.5-90% (w/w)

Example of composition 7

Cannabidiol (CBD): 5-90% (w/w)

Pycnogenol: 0.5-90% (w/w)

Example of composition 8

Cannabidiol (CBD): 5-90% (w/w)

PEA: 0.5-90% (w/w)

Gingerols and shogaols from ginger (Zingiber officinale), dry extract: 1-90% (w/w)

Example of composition 9

Cannabidiol (CBD): 5-90% (w/w)

PEA: 0.5-90% (w/w)

Harpagoside from Harphagophytum Procumbens, dry extract: 1-90% (w/w)

It is understood that, depending on the applications, intended use or physical forms provided, the compositions of the examples described above could include suitable excipients, as described above.

CBD and PEA EXPERIMENTAL TRIALS

The Applicant carried out a study to verify the synergistic action of a formulation containing CBD and PEA in reducing the levels of some pro- inflammatory cytokines in an in vitro model consisting of human leukocytes.

Cells were seeded at approximately 5><10 ⁵ cells per well in 24-well polystyrene plates, into which the following treatments were pipetted (n=3):

1) carrier (buffers)

2) inflammatory protocol - IFN-y (10 ng/ml) for 8 h, followed by TNF-a (10 ng/ml) for 16 h

3) test 1 - inflammatory protocol + CBD (5pM) 4) test 2 - inflammatory protocol + PEA (5pM)

5) test 3 - inflammatory protocol + CBD + PEA (5pM)

IFN-y: Interferon y; TNF-a: Tumor Necrosis Factor a

RESULTS

To quantify the effects of CBD and its association with PEA on the inflammatory response, the concentration of interleukin-6 (IL-6) was measured, normalized for the protein content determined by means of BCA assay. The experimental conditions were mediated by tripled readings. Table 1 below summarizes the effects of the different treatments on the production of IL-6 in human leukocytes stimulated with TNF-a.

Table 1: Effect of the different treatments on the production of IL-6 caused by inflammation induced by TNF-a in human leukocyte cells.

Test IL-6

% Increase

Carrier 25+1

IFN-y + TNF-a 330+17

IFN-y + TNF-a + CBD (5 pM) 180±15 ^a

IFN-y + TNF-a + PEA (5 pM) 175±10 ^a

IFN-y + TNF-a + CBD + PEA (5 pM) 147+1 l ^b

Results are the mean of 3 wells in triplicate ± S.D. The values with different letters within the same column in Table 1 are significantly different (P <0.05).

Based on the data reported above in Table 1, it can be deduced that the CBD+PEA association, in particular at low concentrations (in the example provided 5pM), has significantly suppressed the release of the pro-inflammatory cytokine, IL-6, induced by TNF-a, in significantly greater quantities than single treatments with CBD and PEA, demonstrating the presence of a synergistic effect. This datum is particularly important for the formulation of CBD+PEA based products used as anti-inflammatories.

Although the embodiments of the composition have been described and shown here with reference to some of its uses and to various associations with the indicated components mentioned above, the person of skill in the art will appreciate that it is possible to make different adaptations, changes, modifications, substitutions, deletions or additions of components, procedures and protocols without departing from the spirit and scope of the invention. For example, dosages other than those indicated can in particular be applicable as a consequence of variations in the response of the treated subject for any of the indications listed above. The specific pharmacological responses observed may vary depending on the particular active compounds selected along with the pharmaceutical carriers mentioned. Furthermore, responses may vary depending on the type of formulation and mode of administration employed, and such expected variations or differences in results are contemplated in accordance with the purposes and practices of the present invention.

CBD, PEA AND PLANT EXTRACT EXPERIMENTAL TESTS

The Applicant carried out a study to verify the synergistic action of a formulation containing CBD, PEA and a Standardized Plant Extract (SPE) in reducing the levels of some pro-inflammatory cytokines in an in vitro model consisting of human leukocytes. The plant extracts evaluated were: Curcuma longa - standardized in curcumin

Harpagophytum Procumbens - standardized in harpagoside Zingiber officinale - standardized in gingerols and shogaols

Cells were seeded at approximately 5><10 ⁵ cells per well in 24- well polystyrene plates, into which the following treatments were pipetted (n=3):

1) carrier (buffers)

2) inflammatory protocol - IFN-y (10 ng/ml) for 8 h, followed by TNF-a (10 ng/ml) for 16 h

3) test 1 - inflammatory protocol + CBD (5 pM)

4) test 2 - inflammatory protocol + PEA (5 pM)

5) test 3 - inflammatory protocol + CBD + PEA (5 pM, 1:1)

6) test 3 - inflammatory protocol + CBD + PEA + Standardized extract (5 pM, 1:1:1)

IFN-y, Interferon y; TNF-a, Tumor Necrosis Factor a

RESULTS To quantify the effects of CBD, PEA and SPV on the inflammatory response, the concentration of interleukin-6 (IL-6) was measured, normalized for the protein content determined by means of BCA assay. The experimental conditions were mediated by tripled readings. Table 2 below summarizes the effects of the different treatments on the production of IL- 6 in human leukocytes stimulated with TNF-a.

Table 2: Effect of CBD on the production of IL-6 caused by inflammation induced by TNF-a in human leukocyte cells.

Test IL-6

% Increase

Carrier 25±1

IFN-y + TNF-a 315±15

IFN-y + TNF-a + CBD (5 pM) 178± 14 ^a

IFN-y + TNF-a + PEA (5 pM, 1 : 1 ) 172± 10 ^a

IFN-y + TNF-a + CBD + PEA (5 pM) 151±6 ^b

IFN-Y + TNF-a + Curcuma ES (5pM 160±7 ^b curcumin)

IFN-Y + TNF-a + CBD + PEA + 121±12 ^c

Curcuma ES (5pM, 1:1:1)

IFN-y ⁺ TNF-a + Harphagophytum ES 141±7 ^b

(5 pM harpagoside)

Results are the mean of 3 wells in triplicate ± S.D. The values with different letters within the same column are significantly different (P <0.05).

From what is reported in Table 2, it can be deduced that the addition of standardized extract of Curcuma longa or Harpagophytum Procumbens or Zingiber officinale to the mixture of CBD+PEA significantly increases the antiinflammatory action of the preparation.

It is interesting to note that the Applicant found that the CBD+PEA combination, at low concentrations, significantly suppressed the release of the pro-inflammatory cytokine, IL-6, induced by TNF-a, in significantly greater quantities than single treatments with CBD and PEA. Furthermore, it has been found that some dry plant extracts, such as those mentioned above, in association with CBD and PEA, increase the anti-inflammatory effect of the preparation. This datum will be particularly important for the formulation of CBD+PEA+ SPV based products used as anti-inflammatories and/or pain relievers.

It is clear that modifications and/or additions of parts and/or steps may be made to the composition as described heretofore, without departing from the field and scope of the present invention as defined by the claims.