WO2015000064A1

WO2015000064A1 - Composition for treating pain and/or inflammation comprising eugenol and beta-caryophyllene

Info

Publication number: WO2015000064A1
Application number: PCT/CA2014/000545
Authority: WO
Inventors: Donna EVANS; Sean Evans
Original assignee: Evans Donna; Sean Evans
Priority date: 2013-07-05
Filing date: 2014-07-04
Publication date: 2015-01-08

Abstract

A novel pharmaceutical composition is provided comprising beta--caryophyllene or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof, and eugenol or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof. The composition is useful to treat pain and/or inflammation.

Description

COMPOSITION FOR TREATING PAIN AND/OR INFLAMMATION COMPRISING EUGENOL AND BETA-CARYOPHYLLENE

Field of the Invention

[0001] The present invention generally relates to pain and/or inflammation relief, and in particular, relates to a composition useful to treat pain and/or inflammation.

Background of the Invention

[0002] A wide range of inter-individual variability exists for the perception of pain affected, in part, by age, gender, race, ethnicity, mood states, and stress. Additionally, the pathophysiology of different pain types such as inflammatory, neuropathic and cancer-related pain is distinct. This understanding coupled with the understanding that disease is rarely a simple consequence of an abnormality in a single effector gene product favours the use of multi- targeting strategies in addressing pain.

[0003] Multicomponent therapeutics, in which two or more agents interact simultaneously with multiple targets is a rational and efficient form of therapy designed to control complex diseases. One of the advantages of multicomponent therapeutics is the potential synergistic effect of the combination, e.g. an effect which is greater than the sum of the expected individual effects. A multimodal therapeutic approach is best suited to target the complex mechanisms leading to the transition from acute to chronic pain. Multi-target drugs may overcome system robustness and result in reduced side-effects and reduced toxicity that may be associated with high doses of single drugs.

[0004] It would be desirable to develop a multi-component therapeutic for the treatment of pain and/or inflammation.

Summary of the Invention

[0005] A novel composition has now been developed for the treatment of pain and/or inflammation.

[0006] Accordingly, in one aspect of the invention, a composition is provided comprising beta-caryophyllene or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof, and eugenol or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof.

[0007] In another aspect of the invention, a method of treating pain and/or inflammation in a mammal is provided comprising administering to the mammal a composition comprising beta-caryophyllene or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof, and eugenol or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof.

[0008] In another aspect, an article of manufacture is provided comprising packaging and a composition, wherein the composition comprises beta-caryophyllene or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof, and eugenol or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof, and the packaging indicates that the composition is useful to treat pain and/or inflammation.

[0009] These and other aspects of the invention will become apparent in the following detailed description and examples.

Detailed Description of the Invention

[0010] A composition for use in treating pain and/or inflammation is provided comprising beta-caryophyllene or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof, and eugenol or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof.

[0011] The term "beta-caryophyllene" is used herein to encompass the secondary metabolite, bicyclic sesquiterpene,-4, 1 1,11 -trimethyl-8-methylene-bicyclo[7.2.0]undec-4-ene, which is present in, for example, plant-derived oleoresins, essential oils, solutes, distillates, extracts, fermentations, infusions and leaching, from plants including, but not limited to, Cannabis spp. including Cannabis sativa, Cannabis indica and Cannabis ruderalis, Humulus lupulus, Carum nigrum, Eugenia caryophyllata, Ocimum micranthum, Origanum vulgare, Piper guineense, Cinnamomum zeylanicum, Carthamus tinctorius, Helichrysum italicum, Copaifera spp. including Copaiba officinalis, Copaibaguianensis, Copaiba martii hayne, Copaiba Duckei, Copaiba reticulata, Copaiba multijuga, Copaiba confertiflora, Copaiba langsdorffii, Copaiba coriacea, Copaiba trapezifolia, Copaiba lucens, Copaiba paupera and Copaiba cearensis, Syzygium aromaticum (clove), piper nigrum (black pepper), Zingiber nimmoni, Zingiber officinale, Ocimum canum, Ocimum selloi, Piper cubeba, Aframomum melegueta, Panax ginseng, Zanthoxylum piperitum, Zanthoxylum simulans, Zanthoxylum bungeanum, Zanthoxylum rhesta, Zanthoxylum acanthopodium, Zanthoxylum piperitum, Syzgium aromaticum, Mentha longifolia, Ocimum tenuiflorum, Micromeria fruticosa, Salvia triloba, Salvia canariensis, Rosmarinus officinalis, Satureja thymbra, Satureja montana, Micromeria fruticosa subsp. Barbata, Piper longum, Piper retrofractum, Satureja obovata, Schinus terebinthifolius, Spilanthes acmella, Spilanthes oleracea, Persicaria hydropiper, Artemisia abrotanum, Persicaria odorata, Rhus coriaria, Xylopia aethiopica, Cymbopogon citratis, Pandanus amaryllifolius, Myrica gale, Myrica cerifera, Myrica pensylvanica, Origanum heracleoticum, Ocimum kilimandscharicum, Melissa officinalis, Mentha acquatica, Salvia officinalis, Salvia gillesii, Hyssopus officinalis, Thymus vulgaris, Teucrium cyprium, Teucrium divaricatum var. canescens, Artemisia salsoloides, Thymus zygis subsp. Sylvestris, Teucrium chamaedrys, Origanum minutiflorum, Ocimum basilicum, Thymus x citriodorus, Micromeria Juliana, Origanum onites, Origanum vulgare subsp. hirtum, Rosmarinus tomentosus, Lippia alba, Thymus riatarum, Rosemarinus eriocalyx, Ageratum conyzoides, Teucrium arduini, Teucrium kotschyanum, Nepeta racemosa, Rosmariunus x lavandulaceus, Thymus funkii, Coridothymus capitatus, Origanum syriacum, Thymus cilicicus, Eucalyptus porosa, Laurus nobilis, Daucas carota, Eucalyptus leucoxylon, Teucrium micropodioides, Leonotis leonurus, Micromeria varia subsp. thymoides, Hyptis suaveolens, Plectranthus coleoides, Vitex agnus-castus, Calamintha nepeta, Micromeria myrtifolia, Mentha aquatic, Salvia dorisiana, Ocimum suave, Sideritis scardica, Plectranthus incanus, Mentha x piperita, Hyssopus officinalis subsp. aristatus, Rosmarinus x mendizabalii, Satureja subspicata subsp. librnica, Sideritis mugronesis, Eucalyoptus fasiculosa, Teucrium gnaphalodes, Dictamnus albus, Satureja cilicica, Monardia citriodora, Sideritis germanicolpitana, Zingiber officinale, Eucalyptus sparsa, Thymus longicaulis, Origanum vulgare var. gracile, Minthostachys mollis, Monardia didyma, Salvia sclarea, Eucalyptus melanophloia, Elsholtzia blanda, Eucalyptus desquamate, Teucrium pseudoscorodonia, Eucalyptus cuprea, Sideritis pauli, Eucalyptus lansdowneana, Teucrium salviastrum, Teucrium scorodonia, Elsholtzia eriostachya var. pusilla, Sideritis athoa, Aralia cordata, Eucalyptus intertexta, Teurcrium oxylepis subsp. oxylepis, Cleaonia lusitanica, Satureja cuneifolia, Eucalyptus largisparsa, Eucalyptus odorata, Teurcrium polium var. valentinum, Eucalyptus behriana, Eucalyptus populnea, Teurcrium oxylepis subsp. marianum, Origanum vulgare var. viride, Eucalyptus ochrophloia, Eucalyptus viridis, Teucrium asiaticum, Thymus zygis, Lonicera japonica, Achillea millefolium, Aesculus hippocastanum, Agastache rugosa, Alpinia galangal, Anethum graveolens, Angelica archangelica, Annona squamosal, Apium graveolens, Artemisia absinithium, Artemisia annua, Artemisia capillaris, Bidens pilosa, Boswellia sacra, Camellia sinensis, Carum carvi, Centella asiatica, Chamaemelum nobile, Chrysanthemum parthenium, Chrysanthemum x morifolium, Cinnamomum aromaticum, Cinnamomum camphora, Cinnamomum verum, Citrus limon, Citrus paradise, Citrus reticulate, Citrus sinensis, Coleus barbatus, Coriandrum sativum, Croton eluteria, Croton lechleri, Ellettaria cardamomum, Ephedra sinica, Eruca sativa, Eucalyptus albens, Eucalyptus angulosa, Eucalyptus astringens, Eucalyptus blakelyi, Eucalyptus bosistoana, Eucalyptus botryoides, Eucalyptus brassiana, Eucalyptus camaldulensis, Eucalyptus ceratocorys, Eucalyptus cladocalyx, Eucalyptus dealbata, Eucalyptus diversicolor, Eucalyptus dolichorhyncha, Eucalyptus erythrandra, Eucalyptus forrestiana, Eucalyptus globulus, Eucalyptus grandis, Eucalyptus incrassate, Eucalyptus maculata, Eucalyptus maiden, Eucalyptus melliodora, Eucalyptus moluccana, Eucalyptus occidentalis, Eucalyptus oviformis, Eucalyptus polyanthemos, Eucalyptus puncata, Eucalyptus siderophloia, Eucalyptus sideroxylon, Eucalyptus stoatei, Eucalyptus tereticornis, Eucalyptus tetraptera, Foeniculum vulgare, Hedychium flavum, Houttuynia cordata, Lantana camara, Leptospermum scoparium, Lindera benzoin, Magnolia denudate, Matricaria recutita, Malaleuca altemifolia, Melia azedarach, Mentha arvensis var. piperascens, Mentha pulegium, Mentha rotundifolia, Mentha spicata, Montanoa tomentosa, Murraya koenigii, Myrciaria dubia, Myristica fragrans, Myrrhis odorata, Nepeta cataria, Ocimum gratissimum, Panax ginseng, Pelargonium citrosum, Perilla frutescens, Petroselinum crispum, Pimenta dioica, Pimenta racemosa, Pimpinella anisum, Pinus strobus, Piper nigrum, Pistacia lentiscus, Populus tacamahacca, Psidium guajava, Ptychopetalum olacoides, Ravensara aromatic, Sambucus nigra, Vaccinium myrtillus, Sassafras albidum, Satureja hortensis, Stevia rebaudiana, Illicium verum, Gossypium sp., Tagetes filifolia, Tagetes lucida, Tagetes minuta, Tamarindus indica, Tanacetum parthenium, Teucrium polium, Trifolium pretense, Valeriana officinalis, Zea mays, Piper betel, Pycnanthemum tenuifolium, Thymus serpyllum, Pycnanthemum setosum, Pycnanthemum pycnanthemoides, Pycnanthemum virginianum, Thymus orospedanus, Pycnanthemum clinopodioides, Pycnanthemum loomisii, Pilocarpus microphyllus, Hedeoma hispida, Lavandula x intermedia, Cymbopogon nardus, Pycnanthemum pilosum, Cuminum cyminum, Pycnanthemum verticillatum, Thymus capitatus, Pycnanthemum muticum, Lepechinia calycina, Aloysia citrodora, Dracocephalum thymiflora, Leonurus cardiac, Lepechinia schiediana, Scutellaria galericulata, Hedeoma pulegioides, Micromeria croatica, Pycnanthemum californicum, Cunila origanoides, Pycnanthemum torreyi, Thymus mastichina, Lycopus europeus, Moldavica thymiflora, Juniperis communis, Satureja vulgaris, Elsholtzia polystachya, Lycopus virginicus, Scutellaria churchilliana, Pycnanthemum montanum, Agastache foeniculum, Agastache nepetoides, Carthamus tinctorius, Dracocephalum parviflora, Pycnanthemum beadle, Scutellaria parvula, Echinacea spp, Galeopsis tetrahit, Satureja douglasii, Balotta nigra, Ribes nigrum, Isanthus brachiatus, Moldavica parviflora, Elsholtzia cristata, Elsholtzia pilosa, Myrtus communis, Cordia verbenacea, Ferula galbaniflua, Commiphora gileadensis, Populus balsamifera, Citrus bergamia, Tanacetum annum, Abies balsamea, Ocimum basilicum ct linalool, Mentha citrate, Picea mariana, Malaleuca leucadendron var. cajuputi, Eriocephalus punctulatus, Cymbopogon winterianus, Pinus nigra laricio, Cupressus sempervirens, Psudotsuga menzies, Canarium luzonicum, Eucalyptus citriodora, Eucalypotus dives, Eucalyptus radiata, Agonis fragrans, Bowsellia carterii, Pelargonium roseum x asperum, Helichrysum bracteiferum, Helichrysum gymnocephalum, Helichrysum odoratissimum, Tsuga Canadensis, Malaleuca teretifolia, Citrus hystrix, Kunzea ambigua, Larix laricina, Lavendula angustifolia, Lavendula officinalis, Cymbopogon citradis, Cymbopogon citratus ct rhodinol, Citrus aurantifolia, Bursera delpechiana, Origanum marjorana, Litsea cubeba, Citrus aurantium var. amara, Malaleuca quinquenervia ct 1 ,8 cineole, Pinus resinosa, Cymbopogon martini var. motia, Pogostemom cablin, Citrus aurantium var. bigardia, Pinus edulis, Pinus ponderosa, Cinnamomum camphor act 1,8 cineole, Rhododendron anthopogon, Rose damascena, Rosa damascena/Pelargonium Roseum x asperum, Rosmarinus officinalis ct camphor, Rosmarinus officinalis ct verbenone, Aniba rosaeodora, Cinnamosma fragrans, Pinus sylvestris, Abies sibirica, Abies alba, Lavandula latifolia, Hypericum perforatum, Cinnamomum glaucescens, Cinnamomum tamala, Thymus zygis \., Thymus vulgaris ct linalool, Ocimum sanctum ct eugenol, Thymus vulgaris ct thymol, Curcuma longa, Picea glance, Zanthoxylum armatum, Cananga odorata, Ocimum mircanthum, Ocimum selloi, Citrus junos, and all Plantae taxa thereof, including, life, domain, kingdom, phylum, class, order, family, genus, species, super-species, sub-species, varieties, hybrids and chemotypes, phenotypes and genotypes, whether naturally occurring or genetically modified. Preferred plant sources of beta-caryophyllene include at least about 20% beta-caryophyllene, such as, at least about 25%, 30%, 35%, 40%, 45% or 50% beta-caryophyllene.

[0012] Functionally equivalent derivatives, analogues or salts of beta-caryophyllene, which are pharmaceutically acceptable, may replace beta-caryophyllene in the present composition. The term "functionally equivalent" as used with respect to derivatives, analogues and salts of beta-caryophyllene, refers to compounds which possess the activity or function of beta-caryophyllene, at least in part, to treat pain and/or inflammation. The term

"pharmaceutically acceptable" refers to derivatives, analogues and salts which are

physiologically acceptable for use in mammals, and which are not unduly toxic or otherwise unacceptable for such use. The term "mammals" includes human and non-human mammals, including domestic animals, e.g. cats, dogs, rodents, cattle, horses and the like, as well as non- domesticated animals.

[0013] Functionally equivalent derivatives or analogues, including structural and functional analogues, of beta-caryophyllene include compounds derived from beta-caryophyllene or a precursor thereof, including isomers thereof. Examples of functionally equivalent derivatives or analogues include, but are not limited to, alpha-humulene, 9-epi-(E)- Caryophyllene, [-] -Caryophyllene oxide or (-)-Epoxycaryophyllene, (li?,4i?,6 ?,10S)-9- Methylene-4,12,12-trimethyl-5-oxatricyclo[8.2.0.0^]Caryophyllene, 9-epi-Caryophyllene or (E)- Caryophyllene, epi-, cis-Caryophyllene, (+)(E)-Caryophyllene or 2-epi-(E)- β-Caryophyllene, and Isocaryophyllene (or (Z)- -Caryophyllene or β-cis-Caryophyllene or (Z)-Caryophyllene or Bicyclo(7.2.0)undec-4-ene, 4,1 1,1 l-trimethyl-8-methylene-, (1R,4Z,9S)- or cis-Caryophyllene or γ-Caryophyllene or [1R-(1R*,4Z,9S*)]-4,1 1, 1 l-trimethyl-8-methylenebicyclo[7.2.0]undec-4- ene).

[0014] Functionally equivalent salts which are pharmaceutically acceptable salts of beta- caryophyllene are also encompassed herein for use to treat pain and/or inflammation. The term "salts" refers to salts or esters of beta-caryophyllene that retain the desired biological activity of the parent compound to treat pain and/or inflammation, at least in part. Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as Ν,Ν'-dibenzylethylenediamine, N- methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.

[0015] Although various natural sources of beta-caryophyllene exist which may be incorporated into the present composition, it will be appreciated that beta-caryophyllene for use in the present composition may also be synthetically derived.

[0016] The term "eugenol" is used herein to encompass the secondary metabolite, phenylpropene, 4-allyl-2-methoxyphenol, which is present in plant-derived oleoresins, essential oils, solutes, distillates, extracts, fermentations, infusions and leaching, from, for example, plants including, but not limited to, Eugenia caryophyllus, Syzygium aromaticum, Cinnamomum tamala, Ocimum spp. such as Ocimum basilicum, Ocimum kilimandscharicum, Ocimum suave, Ocimum selloi., Ocimum gratissimum, Foeniculum vulgare, Sassafras albidum, Cinnamomum loureiroi, Cinnamomum burmannii, Eugenia polyantha, Zanthoxylum piperitum, Zanthoxylum simulans, Zanthoxylum bungeanum, Zanthoxylum rhesta, Zanthoxylum acanthopodium, Zanthoxylum piperitum, Ocimum tenuiflorum, Ocimum sanctum, Ocimum campechianum, Ocimum basilicumvar. feuilles de laitre, Ocimum basilicum var. grand vert, Ocimum basilicum var. minimum, Euphorbia spp., Aspalathus linearis, Humulus lupus, Lavendula officinalis, Lavendula angustifolia, Panax ginseng, Vaccinium macrocarpon, Vaccinium myrtillus Ocimum gratissimum var. thymoliferum and Ocimum santum ct. eugenol, Pimenta racemosa, Pimenta dioica, Pimenta officinalis, Piper betel, Alpinia galangal, Daucus carota, Cinnamomum verum, Curcuma longa, Origanum marjorana, Cistus ladaniferus, Hyssopus officinalis, Ageratum conyzoides, Alpinia officinarum, Viola odorata, Mentha pulegium, Myristica fragrans,

Cymbopogon winterianus, Pycnanthemum setosum, Origanum minutiflorum, Micromeria fruticosa subsp. barbata, Thymus capitatus, Jasminum officinale, Lavandula latifolia, Micromeria congesta, Calamintha nepeta subsp. glandulosa, Rosa gallica, Glycyrrhiza glabra, Elsholtzia blanda, Ocimum basilicum ct linalool, Cinnamomum zeylanicum, Artemisia pallens, Homalomena aromatic, Jasminum grandiflorum, Larix laricina, Cymbopogon citratus ct rhodinol, Mentha x piperita, Artemisia dracunculus, Cananga odorata, Malaleuca bracteata, Acorus calamus, Cymbopogon flexuosus, Canarium indicum, Cymbopogon nardus, Peumus boldus, Umbellularia californica, Pycnanthemum clinopodioides, Satureja subspicata subsp. liburnica, Hyacinthus orientalis, Metrosideros sclerocarpa, Acacia farnesiana, Artemisia capillaris, Asarum canadense, Asiasarum heterotropoides, Asiasarum sieboldii, Cinnamomum aromaticum, Cinnamomum camphora, Citrullus colocynthis, Ephedra sinica, Eruca sativa, Eucalyptus brassiana, Juniperus virginiana, Melissa officinalis, Ocimum canum, Piper nigrum, Pycnanthemum pycnanthemoides, Rheum palmatum, Rosa damascena, Rosmarinus officinalis, Stevia rebaudiana, Syringa vulgaris, Tagetes lucida, Aniba rosaedora, Canarium lucozonium, Cananga odorata subsp. macrophylla, Cananga odorata subsp. genuine, Croton elutaria,

Cinnamomum cassia, Citrus paradisi, Citrus sinensis, Cymbopogon citratus, Cympbopogon spp. Dacrydium franklinii, Echinophora tenuifolia, Elettaria cardamomum, Eucalyptus spp. Hyssop officinalis, Illicium verum, Laurus nobilis, Levisticum officinale, Lippia citriodora, Magnolia spp. Malaleuca spp. Malaleuca bracteata, Malaleuca leucadendron, Michelia alba, Myrtus communis, Ocotea pretiosa, Pelargonium graveolens, Pelargonium odoratissum, Peumus boldus,, Pimpinella anisum, Piper cubeba, Ravensara aromatic, Rosa centifolia, Rosa spp. Satureia hortensis, Rosa rugosa, Satureia montana, Tagetes minuta, Trachyspermum ammi and all Plantae taxa thereof including life, domain, kingdom, phylum, class, order, family, genus, species, super- species, sub-species, varieties, hybrids and chemotypes, phenotypes and genotypes, whether naturally occuring or genetically modified.

[0017] Functionally equivalent derivatives, analogues or salts of eugenol, which are pharmaceutically acceptable and which possess the activity of eugenol, at least in part, to treat pain and/or inflammation, may replace eugenol in the present composition. Functionally equivalent derivatives or analogues, including structural and functional analogues, of eugenol include compounds derived from eugenol or a precursor thereof, including isomers thereof. Examples of functionally equivalent derivatives or analogues of eugenol (or 4-allyl-2-methoxy- phenol; eugenic acid; Caryophyllic acid; allylguaiacol; 2-methoxy-4-allylphenol; 2-methoxy-4- (2-propen-l-yl)-phenol; 4-allylcatechol-2 -methyl ether; 2-methoxy-4-(2-propenyl)-phenol;

engenol, p-allylguaiacol; p-eugenol; 2-methoxy-l-hydroxy-4-allylbenzene; 4-allylguaiacol; 4- hydroxy-3-methoxyallylbenzene; NCI-C50453; l-hydroxy-2-methoxy-4-allylbenzene; 1- hydroxy-2-methoxy-4-prop-2-enylbenzene; 2-methoxy-4-(2- propenyl)phenol; 2-methoxy-4- prop-2-enylphenol; 4-allyl-l-hydroxy-2-methoxybenzene; 1,3,4-eugenol; FA 100; FEMA No. 2467; 2-metoksy-4-allilofenol; 2-hydroxy-5-allylanisole; NSC 209525; 4-(2-propenyl)-2- methoxyphenol) include, but are not limited to, 2-methoxyphenol; methyl eugenol; and isoeugenol. Pharmaceutically acceptable salts include acid and base addition salts of eugenol. Although there are various natural sources of eugenol which may be incorporated into the present composition, it will be appreciated that eugenol for use in the present composition may also be synthetically derived.

[0018] The present composition comprises a mixture of eugenol and beta-caryophyllene.

The amount of eugenol in the composition ranges from about 0.001 mg/ml to about 4 mg/ml, and the amount of beta-caryophyllene in the composition ranges about 0.01 mg/ml to about 1.5 mg/ml. Preferably, the amount of eugenol in the composition ranges from about 0.005 mg/ml to about 1 mg/ml, and the amount of beta-caryophyllene in the composition ranges from about 0.01 mg/ml to about 1 mg/ml. More preferably, the amount of eugenol in the composition ranges from about 0.01 mg/ml to about 0.5 mg/ml, e.g. 0.01 - 0.05 mg/ml, and the amount of beta- caryophyllene in the composition is in the range of about 0.02 - 0.5 mg/ml, e.g. 0.02 - 0.05 mg/ml. The beta-caryophyllene and eugenol content of the composition may be from a single source or from a combination of different sources. For example, the beta-caryophyllene content in the composition may be achieved by the inclusion of essential oil from Cannabis spp. alone, or alternatively, may be achieved by a combination of two or more essential oils, for example, from Syzygium aromaticum (clove). Cannabis sativa, piper nigrum (black pepper) and/or, copaiba spp. Similarly, the eugenol content may be achieved by inclusion of essential oil from Syzygium aromaticum alone, or from a combination of sources of eugenol.

[0019] The present composition may include one or more additional active ingredients that are suitable for topical, sublingual, transdermal, rectal, oral, nasal or inhalation applications. Examples of such additional active ingredients include anti-inflammatory, analgesic, rubefacient, antiseptic, anti-rheumatic, bruise-, swollen vein- and oedema- reducing, antineuralgic, antiphlogistic, antioxidant, immunomodulatory, cicatrisation (scab forming) and regenerative compounds. Preferably, any additional active ingredient is also a plant-derived essential oil. In one embodiment, essential oil of ginger {Zingiber officinalis) is incorporated in the present composition, preferably in an amount ranging from about 2 to about 22 % by wt, preferably from about 2.7% to about 20.36% by wt of the formulation.

[0020] The present composition may also be combined with one or more pharmaceutically acceptable adjuvants. The expression "pharmaceutically acceptable" means physiologically acceptable for use in the pharmaceutical and veterinary arts, i.e. not being unacceptably toxic or otherwise unsuitable. Examples of pharmaceutically acceptable adjuvants for inclusion in the present composition include those that are suitable for combination with the essential oil active ingredients. Reference may be made to "Remington's: The Science and Practice of Pharmacy", 21st Ed., Lippincott Williams & Wilkins, 2005, for guidance on drug formulations generally. The selection of adjuvant depends on the intended mode of administration of the composition. In one embodiment of the invention, the active ingredients are formulated for oral administration via tablet, capsule, lozenge or suspension. Suitable adjuvants include sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and derivatives thereof, including sodium carboxymethylcellulose, ethylcellulose and cellulose acetates; powdered tragancanth; malt; gelatin; talc; stearic acids; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oils, cotton seed oil, sesame oil, olive oil, and corn oil; polyols such as propylene glycol, glycerine, sorbital, mannitol and polyethylene glycol; agar; alginic acids; water; isotonic saline and phosphate buffer solutions. Wetting agents, lubricants such as sodium lauryl sulfate, stabilizers, tableting agents, antioxidants, preservatives, colouring agents and flavouring agents may also be present. Aduvants for a topical, sublingual, transdermal, rectal, oral, nasal or inhalant composition include compounds that may facilitate delivery of plant-derived essential oils, oleoresins, solutes, distillates, extracts, fermentations, infusions and leaching such as meadowfoam seed oil (Limnanthes alba), sweet almond (Amygdalus communis var. dulcis), arnica (Arnica montana), argan (Argania spinosa Skeels), avocado (Persea grattissima), borage (Borrago officinalis), calendula (Calendula officinalis), tamanu (Calophyllum inophyllum), carrot (Daucus carota), wheat germ (Triticum vulgare), cocoa butter (Theobroma cacao), cottonseed oil (Gossypium barbadense), evening primrose (Oenothera biennis, O. glazioviana, O. lamardiana, O. riparia), grapeseed oil (Vitis vinifera), hemp (Cannabis sativa), jojoba (Simmondsia sinensis), macadamia (Macadamia tetraphylla), St. John's wort (Hypericum perforatum), apricot (Prunus armeniaca ), hazel (Corylus avellana), olive (Olea europea), rosehip (Rosa spp.), sunflower (Helianthus annuus), sesame (Sesamum indicum), Carthamus tinctorius and wheatgerm (Triticum vulgare, Triticum durum, Triticum aestivum) and all Plantae taxa thereof including life, domain, kingdom, phylum, class, order, family, genus, species, genetically modified super-species, subspecies, varieties, hybrids and chemotypes, phenotypes and genotypes thereof. Other exemplary adjuvants include skin conditioning agents, stabilizers, anti-oxidants, anti-microbial agents, preservatives, colouring agents, fragrance, fixatives, solvent and surface active agents.

[0021] In one embodiment, the present composition comprises, as a source of beta- caryophyllene, the essential oils of Clove (Eugenia caryophyllata) ("clove"); Balsam Copaiba; and Black Pepper (Piper nigrum) ("pepper"). Clove bud oil is also the source of eugenol. The amounts of each may be within the following ranges in the composition: clove about 0.194% to 14%, copaiba about 0.005%) to 36%) and pepper about 0.003%> to 25%. These active ingredients may optionally be combined with ginger essential oil in an amount ranging from about 2.7% to 20% and with a non-active ingredient carrier, e.g. Meadowfoam oil, in an amount ranging from about 5% to about 97.098%.

[0022] A method of treating pain and/or inflammation in a mammal is provided in another aspect of the invention. The method comprises administering a composition comprising a therapeutically effective amount of beta-caryophyllene and eugenol. The terms "treat", "treating" and "treatment" are used broadly herein to denote methods that moderate, ameliorate, reverse the progression of, reduce the severity of, or prevent pain and/or inflammation. In this regard it is noted that because a wide range of inter-individual variability exists in the perception of pain, the perceived result of the present treatment may vary from mammal to mammal.

[0023] The term "pain" is used broadly herein to refer to any neural or non-neural pain including, for example, cancer pain, multiple sclerosis pain, HIV pain, diabetic pain, chemotherapeutic pain, ischemic pain, arthritic pain and pain from inflammation. Neural or neuropathic pain refers to pain resulting from an injury to or malfunction in the peripheral or central nervous system. Neural pain may be triggered by an injury, but does not necessarily involve actual damage to the nervous system. Neuropathic pain is frequently chronic. Examples of neuropathic pain include, but are not limited to, lower back pain, repetitive strain injury, migraine and headache, and pain resulting from a disease state such as any type of cancer and/or from other substances to treat said disease state such as chemotherapeutic substances doxorubicin, cisplatin, paclitaxel and any neuroinflammatory pain, disease associated with the immune system, multiple sclerosis, arthritis, trigeminal neuralgia, peripheral neuropathy, complex regional pain syndrome (CRPS), fibromyalgia, TMJ (temporal mandibular joint) pain and inflammatory myopathy. Non-neural or nociceptive pain refers to pain from tissue injury, including for example, sprains, bone breaks or fractures, burns, bumps, bruises, inflammation, obstructions and myofascial pain.

[0024] The term "inflammation" refers to a complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Signs of inflammation include pain, redness, swelling and/or loss of function. Types of inflammation include, but are not limited to, localized inflammation, systemic inflammation, neuroinflammation, appendicitis, bursitis, colitis, cystitis, dermatitis, phlebitis, rhinitis, tendonitis, tonsillitis and vasculitis.

[0025] The present method includes administration of the composition using any suitable administrable form, formulated accordingly, including one or more appropriate carriers and/or adjuvants. Suitable administrable forms include, for example, by oral, subcutaneous, intravenous, intraperitoneal, intranasal, enteral, topical, sublingual, intramuscular, intra-arterial, intramedullary, intrathecal, inhalation, ocular, transdermal, vaginal or rectal forms.

[0026] In one embodiment, the method includes topical application of the composition to a mammal in need of pain and/or inflammation treatment. The composition may be applied to an affected area on the skin of the mammal, or to a site appropriate to target an affected area, e.g. an affected internal area such as the sciatic nerve, joints, muscle, brain (migraine), liver (hepatitis pain), ischemic pain, etc. The composition is preferably rubbed into the skin to promote absorption of the active ingredients. The composition is administered at a dosage suitable to treat pain and/or inflammation. In one embodiment, the dosage administered is generally in the range of between about 1 to 2 ml of a composition comprising from about O.OOlmg/ml to about 4mg/ml eugenol, and from about 0.01 mg/ml to about 1.5mg/ml beta-carophyllene. As one of skill in the art will appreciate, the dosage may be adjusted upwards or downwards to address the severity of the pain and/or inflammation, or the size of an affected area. The composition is generally applied one to two times a day for a period of time sufficient to treat pain and/or inflammation. For more severe cases, however, the composition may be applied more frequently, e.g. three or more times a day for a period of time sufficient to treat the pain and/or inflammation.

[0027] While not wishing to be limited to a particular mode of action, it is believed that the activity of the present composition is specific to the cannabinoid-2 receptor (CB2 receptor), and thus, functions as a CB2 agonist, selectively targeting the CB2 receptor, while not interacting with the psychoactive cannabinoid 1 -receptor (CBl receptor). This selectivity of the present composition renders it very effective to treat pain and/or inflammation with minimal side effects. Moreover, the combination of components unexpectedly result in a high degree of pain relief and inflammation reduction, e.g. greater than 80%, for example, greater than 90%, including essentially complete pain relief.

[0028] In addition to alleviating pain and/or inflammation, the present composition may also provide, or be adapted to provide, one or more of neuroprotective, chemoprotective, DNA protective, hepatoprotective, cardioprotective, blood brain barrier protective, antiproliferative, antimetastatic, glial protective, neurogenerative, nephroprotective, immunomodulatory, anticarcinogenic, anti-ischemic, anti-neuroinflammatory or anti-nociceptive properties. In this regard, it is noted that components of the present composition, namely essential oils that comprise beta-caryophyllene and eugenol, may exhibit one or more of such properties.

Additional components may also be added to the present composition to impart one or more of such properties.

[0029] Embodiments of the present invention are described in the following specific examples which are not to be construed as limiting.

Example 1: Formula

[0030] A formulation, herein termed "EXPIAN", was prepared including the essential oil of clove (Eugenia caryophyllata or Syzygium aromaticum), balsam copaiba (Copaiba martii haynes), and black pepper (Piper nigrum) in the amounts shown in Table 1. Table 1.

[0031] The essential oils comprised the following percentages of beta-caryophyllene:

3.66% in clove oil, 20.84% in pepper oil, and 55.01% in copaiba oil; and eugenol: 81.81% in clove oil. Thus, the concentration of beta-caryophyllene was 0.03 mg/ml in the final formulation. The concentration of eugenol was 0.016 mg/ml in the final formulation, and the concentration of ginger was 0.02 mg/ml in the final formulation. The balance of the formulation was Meadowfoam seed oil obtained from Elementis.

[0032] The oils were combined to form a homogeneous mixture ready for use.

Example 2: Back Pain Resulting from Scoliosis

[0033] EXPIAN was used to treat back pain resulting from scoliosis. EXPIAN was applied in an amount of about l-2ml to the area in need of treatment on the back. Pain reduction was noted within a very short period of time (e.g. within the hour) following application, with complete relief from pain resulting with further application of EXPIAN 1-3 times a day. Example 3: Overnight Back Pain from Mild to Severe

[0034] EXPIAN was topically applied in an amount of about 1-2 ml to the affected area of the back to treat overnight back pain. Pain relief was noted shortly following the application of EXPIAN, with complete relief from pain resulting with further applications of EXPIAN 1 -3 times a day.

Example 4: Sciatica

[0035] EXPIAN was also used to treat sciatica pain. Sciatic pain was treated with a single topical application of EXPIAN (1-2 ml) to the affected area to result in relief of pain, with complete relief from pain with further application of EXPIAN 1-3 times a day. .

Example 5 - Knee Pain Resulting from Long-Term Cartilage Damage

[0036] Knee pain resulting from long-term cartilage damage was treated by topical application of 1 -2 ml of EXPIAN to the affected area of the knee. This treatment resulted in pain relief, with complete relief from pain with further application of EXPIAN 1 -3 times a day.

Example 6 - General Joint Pain Resulting from Overuse

[0037] Joint pain in swollen ankles was treated using EXPIAN as described above for treatment of knee pain, and pain relief was achieved following a single application. Complete pain relief was achieved following additional applications of EXPIAN.

Example 7; Arthritis

[0038] Arthritic pain and inflammation in hands was treated with EXPIAN using single

1 -2 ml applications per day for several days to achieve pain relief and inflammation reduction.

Example 8: Muscular Aches and Strains from Mild to Debilitating

[0039] Muscle ache and strain was treated with EXPIAN as described in Example 6. Pain relief was achieved following a single application, with complete pain relief resulting after further EXPIAN applications. Example 9: Knee Pain Resulting from Long-Term Sport Abuse

[0040] EXPIAN was used as described in Example 5 to treat knee pain resulting from strain due to sports. As described, pain relief was achieved following a single application, with complete pain relief resulting following further applications.

Example 10: Knee Pain Resulting from Lateral Meniscus Tear, Chondromalacia Patellae, Bakers and Popliteal Cysts

[0041] EXPIAN was used as described in Example 5 to treat chronic knee pain resulting from cartilage damage. Pain relief was achieved within 48 hours, with complete pain relief resulting following further applications.

Example 11: Acute, Debilitating Back Pain

[0042] To treat acute lower back pain resulting in immobility and collapse, Expian was applied in the amount of 2 mL, three times in a period of 30 minutes. Approximately 30% mobility was restored and approximately 40% pain reduction was noted after 30 minutes following application was noted. Mobility of approximately 60% was seen after 2.5 hours and pain reduction of approximately 80% was noted.

Example 12 - Treatment of Knee Pain with modified formulations

[0043] The EXPIAN formulation described in Example lwas modifed to exclude ginger, and this formulation was found to be as effective as EXPIAN in the treatment of knee pain.

[0044] The EXPIAN formulation was also modified to replace the beta-caryophyllene source, the essential oil of Copaiba martii haynes, with a different beta-caryophyllene source, namely, the essential oil of Copaiba officinalis. The modified formulation included an amount of the latter essential oil that was about the same as that of the former in the EXPIAN formulation (as shown in Example 1). This modified formulation was used as described in Example 5 and was found to be similarly effective in achieving pain relief of chronic knee pain. Example 13 - Comparison of Formulations

[0045] The efficacy of the EXP IAN formulation, comprising beta-caryophyllene in the amount of 0.03 mg/ml, eugenol in the amount of 0.016 mg/ml and ginger in the amount of 0.02 mg/ml in Meadowfoam seed oil, was compared to a similar formulation comprising clove, pepper and ginger oils in Meadowfoam seed oil but lacking copaiba oil.

[0046] Each formulation was used as described in Example 5 to treat knee pain. While the latter composition provided only partial pain relief (approximately 50%) over the treatment period, EXPIAN provided complete relief of pain (100%). The EXPIAN formulation exhibited an unexpectedly greater effect than the comparison formulation in its complete treatment of the pain indicating that the components of the formulation, when combined, exhibited a synergistic effect.

Claims

CLAIMS We claim:

1. A pharmaceutical composition comprising beta-caryophyllene or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof, and eugenol or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof.

2. The composition of claim 1, wherein eugenol is in an amount ranging from about O.OOlmg/ml to about 4mg/ml, and beta-caryophyllene is in an amount ranging from about 0.01 mg/ml to about 1.5 mg/ml.

3. The composition of claim 2, wherein the amount of eugenol in the composition ranges from about 0.005 mg/ml to about 1 mg/ml, and the amount of beta-caryophyllene in the composition ranges from about 0.01 mg/ml to about 1 mg/ml.

4. The composition of claim 1, wherein the beta-caryophyllene and eugenol are each provided in a plant-derived essential oil, oleoresin, solute, extract, fermentation, infusion, leaching and/or distillate.

5. The composition of claim 4, further comprising a mixture of plant-derived essential oils.

6. The composition of claim 1, further comprising a pharmaceutically acceptable adjuvant.

7. The composition of claim 6, wherein the adjuvant facilitates topical delivery.

8. The composition of claim 6, wherein the adjuvant is selected from the group consisting of meadowfoam seed, sweet almond, arnica, argan, avocado, borage, calendula, calophyllum, carrot, wheat germ, jojoba, macadamia, St. John's wort, apricot, hazel, olive, rosehip, sunflower, cocoa butter, cottonseed oil, evening primrose, grapeseed oil, wheatgerm, hemp, tamanu, macadamia, olive and sesame.

9. The composition of claim 1, additionally comprising ginger oil.

10. The composition of claim 1, comprising essential oils from clove, copaiba and pepper in combination with a pharmaceutically acceptable adjuvant.

11. The composition of claim 10, comprising about 0.194% to 14% by wt clove oil, about 0.005% to 36% by wt copaiba oil and about 0.003%) to 25% by wt pepper oil.

12. A method of treating pain and/or inflammation in a mammal comprising administering to the mammal a composition as defined in claim 1.

13. The method of claim 12, wherein the composition is topically applied.

14. The method of claim 12, wherein the composition comprises eugenol in an amount ranging from about 0.001 mg/ml to about 4 mg/ml, and beta-caryophyllene in an amount ranging from about 0.01 mg/ml to about 1.5 mg/ml.

15. The method of claim 12, wherein each of beta-caryophyllene and eugenol are provided as at least one of a plant-derived essential oil, oleoresin, solute, extract, fermentation, infusion, leaching and/or distillate.

16. The method of claim 12, wherein the composition further comprises ginger essential oil.

17. The method of claim 12, wherein the composition comprises essential oils from clove, copaiba, and pepper in combination with a pharmaceutically acceptable adjuvant.

18. The method of claim 12, wherein the adjuvant is selected from the group consisting of meadowfoam seed, sweet almond, arnica, argan, avocado, borage, calendula, calophyllum, carrot, wheat germ jojoba, macadamia, St. John's wort, apricot, hazel, olive, rosehip, sunflower, cocoa butter, cottonseed oil, evening primrose, grapeseed oil, wheatgerm, hemp, tamanu, macadamia, olive and sesame.

19. The use of the composition of claim 1 to treat pain and/or inflammation.

20. A composition comprising beta-caryophyllene or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof, and eugenol or a functionally equivalent derivative, analogue or pharmaceutically acceptable salt thereof for use in the manufacture of a medicament to treat pain and/or inflammation.