AU2021107265A4 - A composition and uses thereof - Google Patents
A composition and uses thereof Download PDFInfo
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- AU2021107265A4 AU2021107265A4 AU2021107265A AU2021107265A AU2021107265A4 AU 2021107265 A4 AU2021107265 A4 AU 2021107265A4 AU 2021107265 A AU2021107265 A AU 2021107265A AU 2021107265 A AU2021107265 A AU 2021107265A AU 2021107265 A4 AU2021107265 A4 AU 2021107265A4
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- cbd
- caryophyllene
- cbda
- eudesmol
- myrcene
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Abstract
The present invention relates to a pharmaceutical composition comprising a cannabinoid and a terpene,
wherein the cannabinoid is selected from cannabidiol (CBD) or cannabidiolic acid (CBDA) and the terpene is
enriched for eudesmol. The composition is useful for the treatment or prevention of an inflammatory
condition.
Description
[0001] The present application claims priority from Australian Provisional Patent Application No. 2021902682 filed 24 August 2021, the disclosure of which is hereby expressly incorporated herein by reference in its entirety.
[0002] The present disclosure relates generally to a composition comprising a cannabinoid and a terpene, wherein the cannabinoid is selected from cannabidiol (CBD) and cannabidiolic acid (CBDA) and wherein the terpene is enriched for eudesmol. In some embodiments, the composition is useful for the treatment or prevention of an inflammatory condition.
[0003] Cannabis has been widely used throughout history for its medicinal properties. More recently, however, cannabis has been regarded as an illicit recreational drug. Selective breeding for this purpose has led to the development of Cannabis sativa cultivars that produce high levels of A 9-tetrahydrocannabinol (THC), being the main psychoactive component of cannabis. As the medicinal properties of cannabis are becoming clearer, other cannabinoids and different classes of molecules produced by Cannabis sativa are emerging as compounds that may elicit significant therapeutic effects.
[0004] Whilst the effects of individual compounds in cannabis are important for the development of isolated drug products and to scientifically justify the effects of complex extracts, this is removed from the traditional use of cannabis (e.g., consumption of whole plant extracts). There is growing anecdotal evidence that the interactions between the chemical components of cannabis enhances their biological effect synergistically, in what has been termed "the entourage effect". However, there is currently limited and contradictory scientific evidence to support the entourage effect in cannabis. For example, it has been demonstrated that the use of a botanical drug preparation results in an improvement in the potency of anti-tumor effects as compared to that use of pure THC (Blasco-Benito et al.,
2018, Biochemical Pharmacology, 157: 285-293). By contrast, it has also been shown that terpenes commonly found in Cannabis sativa do not potentiate cannabinoid receptor signaling (via the CB 1 and CB 2 receptors) when combined with THC (Santiago et al., 2019, Cannabis and CannabinoidResearch, 4(3): 165-176).
[0005] Given the diversity and therapeutic potential of cannabis, it has been suggested that cannabis, or cannabis-derived compounds, may be used for the treatment of a broad range of conditions, such as multiple sclerosis, cancer, pain and epilepsy. In particular, there is significant therapeutic potential for the use of cannabis-derived compounds for the treatment of chronic conditions that currently have limited or no pharmacological treatment options.
[0006] Chronic inflammation is a contributing factor to many prevalent ageing-related diseases, such as acute and chronic neurodegenerative diseases, degenerative musculoskeletal diseases, cardiovascular diseases, diabetes and cancer. Currently, pharmacotherapy of inflammatory conditions is largely based on the use of non-steroidal anti-inflammatory drugs (NSAIDs). However, these therapies are often unsatisfactory, as treatment is required over extended periods due to adverse side effects. In addition, extended administration typically leads to drug tolerance, resulting in the need for administration of increased levels of drugs, thereby further exacerbating the side effects of the drugs.
[0007] Therefore, there remains an urgent need for the development of pharmacological approaches for the treatment or prevention of inflammatory conditions.
[0008] In an aspect of the present disclosure, there is provided a pharmaceutical composition comprising a cannabinoid and a terpene, wherein:
a. the cannabinoid is selected from cannabidiol (CBD) or a pharmaceutically acceptable salt or functional derivative thereof, and cannabidiolic acid (CBDA) or a pharmaceutically acceptable salt or functional derivative thereof; and b. wherein the terpene is enriched for eudesmol or a pharmaceutically acceptable salt or functional derivative thereof.
[0009] In another aspect of the present disclosure, there is provided a method for the treatment or prevention of an inflammatory condition, the method comprising administering a therapeutically effective amount of the pharmaceutical composition described herein to a subject in need thereof.
[0010] Embodiments of the disclosure are described herein, by way of non-limiting example only, with reference to the accompanying drawings.
[0011] Figure 1 shows the dose response of CBD, CBDA, 3-caryophyllene, caryophyllene oxide, myrcene and eudesmol (pg/mL; x-axis) on nitric oxide (NO) release (%, y-axis) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages.
[0012] Figure 2 shows the dose response of CBD and -caryophyllene (pg/mL; x-axis) on NO release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0013] Figure 3 shows the dose response of CBD and caryophyllene oxide (pg/mL; x axis) on NO release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0014] Figure 4 shows the dose response of CBD and myrcene (pg/mL; x-axis) on NO release (%,y-axis) in LPS-stimulated RAW264.7 macrophages.
[0015] Figure 5 shows the dose response of CBD and eudesmol (p g/mL; x-axis) on NO release (%,y-axis) in LPS-stimulated RAW264.7 macrophages.
[0016] Figure 6 shows the dose response of CBDA and -caryophyllene (pg/mL; x axis) on NO release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0017] Figure 7 shows the dose response of CBDA and caryophyllene oxide (pg/mL; x-axis) on NO release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0018] Figure 8 shows the dose response of CBDA and myrcene (pg/mL; x-axis) on NO release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0019] Figure 9 shows the dose response of CBDA and eudesmol (pg/mL; x-axis) on NO release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0020] Figure 10 shows the dose response of CBD and caryophyllene oxide (pg/mL; x-axis) on NO release (%, y-axis) as compared to the combination of CBD and caryophyllene oxide at a 3:4 ratio in LPS-stimulated RAW264.7 macrophages.
[0021] Figure 11 shows an example of the interpretation of an isobologram, reproduced from Biavatti (2009, BrazilianJournalof PharmaceuticalSciences, 45(3): 371-378).
[0022] Figure 12 shows the isobologram for NO release resulting from combinations of CBD and caryophyllene oxide (CBD: CO) based on CO IC5 0 (pg/mL; y-axis) and CBD
IC50 (pg/mL; x-axis).
[0023] Figure 13 shows the dose response of CBD, CBDA, 3-caryophyllene, caryophyllene oxide, myrcene and eudesmol (pg/mL; x-axis) on TNF-a release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0024] Figure 14 shows the dose response of CBD and -caryophyllene (pg/mL; x axis) on TNF-a release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0025] Figure 15 shows the dose response of CBD and caryophyllene oxide (pg/mL; x-axis) on TNF-a release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0026] Figure 16 shows the dose response of CBD and myrcene (pg/mL; x-axis) on TNF-a release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0027] Figure 17 shows the dose response of CBD and eudesmol (pg/mL; x-axis) on TNF-a release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0028] Figure 18 shows the dose response of CBDA and -caryophyllene (pg/mL; x axis) on TNF-a release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0029] Figure 19 shows the dose response of CBDA and caryophyllene oxide (pg/mL; x-axis) on TNF-a release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0030] Figure 20 shows the dose response of CBDA and myrcene (pg/mL; x-axis) on TNF-a release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0031] Figure 21 shows the dose response of CBDA and eudesmol (pg/mL; x-axis) on TNF-a release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0032] Figure 22 shows the dose response of CBD, CBDA, 3-caryophyllene, caryophyllene oxide, myrcene and eudesmol (pg/mL; x-axis) on IL-6 release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0033] Figure 23 shows the dose response of CBD and -caryophyllene (pg/mL; x axis) on IL-6 release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0034] Figure 24 shows the dose response of CBD and caryophyllene oxide (pg/mL; x-axis) on IL-6 release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0035] Figure 25 shows the dose response of CBD and myrcene (pg/mL; x-axis) on IL 6 release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0036] Figure 26 shows the dose response of CBD and eudesmol (pg/mL; x-axis) on IL-6 release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0037] Figure 27 shows the dose response of CBDA and -caryophyllene (pg/mL; x axis) on IL-6 release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0038] Figure 28 shows the dose response of CBDA and caryophyllene oxide (pg/mL; x-axis) on IL-6 release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0039] Figure 29 shows the dose response of CBDA and myrcene (pg/mL; x-axis) on IL-6 release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0040] Figure 30 shows the dose response of CBDA and eudesmol (pg/mL; x-axis) on IL-6 release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0041] Figure 31 shows the dose response of CBD, eudesmol, myrcene and/or caryophyllene oxide (pg/mL; x-axis) on prostaglandin release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0042] Figure 32 shows the dose response of CBD, eudesmol, myrcene and/or caryophyllene oxide (pg/mL; x-axis) on prostaglandin release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0043] Figure 33 shows the dose response of CBD and/or -caryophyllene (pg/mL; x axis) on prostaglandin release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0044] Figure 34 shows the dose response of CBD, eudesmol, myrcene and/or caryophyllene oxide (pg/mL; x-axis) on prostaglandin release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0045] Figure 35 shows the dose response of CBD, eudesmol, myrcene and/or caryophyllene oxide (pg/mL; x-axis) on prostaglandin release (%, y-axis) in LPS-stimulated RAW264.7 macrophages.
[0046] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the disclosure belongs. Any materials and method similar or equivalent to those described herein can be used to practice the present invention.
[0047] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply
the inclusion of the stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
[0048] The phrase "consisting of" means including, and limited to, whatever follows the phrase "consisting of". Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and that no other elements may be present. The phrase "consisting essentially of" means including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.
[0049] As used herein the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound, as well as two or more compounds; reference to "an agent" includes one agent, as well as two or more agents; and so forth.
[0050] The term "about" will be understood by persons skilled in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are not clear to persons skilled in the art, given the context which it is used, "about" will mean up to plus or minus 10% of the particular value.
[0051] The present disclosure is predicated, at least in part, on the inventors' surprising finding that compositions comprising cannabidiol (CBD) or cannabidiolic acid (CBDA) and a terpene enriched for any one or more or all of -caryophyllene, caryophyllene oxide, myrcene, and eudesmol synergize to provide anti-inflammatory activity, useful for the treatment of sepsis, traumatic injury, ischemia, asthma, burns, irritable bowel syndrome, Alzheimer's disease, cancer, major depression, arthritis, multiple sclerosis and pain. Each of the cannabinoid / terpene combinations disclosed herein exhibited synergistic inhibition of NO, TNF-a and IL-6 across a range of different weight-to-weight (w/w) ratios. For example, the combination of CBD and one or more or all of -caryophyllene, caryophyllene oxide, myrcene, and eudesmol have been shown to synergize to the extent that it makes it possible to reduce the dose of CBD, while still eliciting a therapeutic effect.
[0052] Thus, in an aspect disclosed herein, there is provided a pharmaceutical composition comprising a cannabinoid and a terpene, wherein:
a. the cannabinoid is selected from cannabidiol (CBD) or a pharmaceutically acceptable salt or functional derivative thereof, and cannabidiolic acid
(CBDA) or a pharmaceutically acceptable salt or functional derivative thereof; and b. wherein the terpene is enriched for one or more or all of -caryophyllene or a pharmaceutically acceptable salt or functional derivative thereof, caryophyllene oxide or a pharmaceutically acceptable salt or functional derivative thereof, myrcene or a pharmaceutically acceptable salt or functional derivative thereof, and eudesmol or a pharmaceutically acceptable salt or functional derivative thereof.
Cannabidiol (CBD)
[0053] The terms "cannabidiol", "CBD", or "C" are used interchangeably herein to refer to a cannabinoid produced by plants of the genus Cannabis. CBD has antagonist activity on agonists of the CB1 and CB2 receptors and acts as an inverse agonist of the CB1 and CB2 receptors.
[0054] CBD is synthesized in cannabis plants as cannabidiolic acid (CBDA or A, as used herein), which decarboxylates to CBD (Table 1). While some decarboxylation may occur in the plant, decarboxylation typically occurs post-harvest and is increased by exposing plant material to heat (Sanchez and Verpoote, 2008, PlantCell Physiology, 49(12): 1767-82). Decarboxylation is usually achieved by drying and/or heating the plant material. Persons skilled in the art would be familiar with methods by which decarboxylation of CBDA can be promoted, illustrative examples of which include air-drying, combustion, vaporization, curing, heating and baking. The decarboxylated CBD will typically bind to and/or stimulate, directly or indirectly, cannabinoid receptors including CB1 and/or CB2.
[0055] "Total cannabidiol" or "total CBD" as used herein refers to the total amount of CBD and CBDA in the composition.
Table 1. Cannabidiol and related cannabinoids
Chemical Name Structure properties!
[M+H]+ ESI MS
cannabidiol (CBD) CH 3 decarboxylation product of OH CBDA
H2 C m/z 315.2319 H3 C HO CH 3
cannabidiolic acid CH 3 m/z 359.2217 (CBDA) OH 0 OH H 2C HH2/HO 3CCH CH3
cannabigerolic acid CH 3 CH 3 OH 0 m/z 361.2373 (CBGA) H3C OH HO OH 3
[0056] CBD and CBDA may be extracted from any suitable plant parts including leaves, flowers or stems and may be produced by any suitable means known to those skilled in the art. For example, CBD extracts may be produced by extraction with supercritical or subcritical C0 2 , or by volatilization of plant material with a heated gas. Illustrative examples of methods used to extract CBD, CBDA and other cannabinoids from plant material include the methods described in US Patent No. 10189762 and WO 2004/016277.
[0057] In an embodiment, the CBD is a synthetic CBD. In another embodiment, the CBDA is a synthetic CBDA.
[0058] CBD is a chiral compound, although only the (-) CBD enantiomer is present in cannabis plants.
[0059] The term "enantiomer" as used herein refers to asymmetric molecules that can exist in two different isomeric forms, which have different configurations in space. An enantiomer can rotate plane-polarized light and is, therefore, optically active. Two different enantiomers of the same compound will rotate plane-polarized light in the opposite direction, thus the light can be rotated to the left or counterclockwise for a hypothetical observer (i.e., "levorotatory" or "-") or it can be rotated to the right or clockwise (i.e., "dextrorotatory" or "4+").
[0060] In an embodiment, the synthesized CBD is a racemic mixture, comprising the (-) CBD enantiomer and the (+) CBD enantiomer.
[0061] In an embodiment, the synthetic CBD consists of the (-) CBD enantiomer.
[0062] The present disclosure contemplates the use of pharmaceutically acceptable salts of CBD and CBDA. Suitable pharmaceutically acceptable salts of CBD and CBDA would be known to persons skilled in the art, illustrative examples of which include salts or esters prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids, which would be known to persons skilled in the art.
[0063] The present disclosure further contemplates the use of functional derivatives of CBD and CBDA. Suitable functional derivatives of CBD and CBDA would be known to persons skilled in the art, illustrative examples of which include 7-OH-CBD (7 hydrocannabidiol), methoxylated CBD derivatives (e.g., CBDM, or 2-methoxycannabidiol and CBDD, or 2,6-dimethoxycannabidiol), cannabidiorcol (CBD-C 1 ) and the CBD derivatives described by Morales et al. (2017, Frontiersin Pharmacology,8: 422).
Terpenes
[0064] The term "terpene" as used herein, refers to a class of organic hydrocarbon compounds, which are produced by a variety of plants. Cannabis plants produce and accumulate different terpenes, such as monoterpenes and sesquiterpenes, in the glandular trichomes of the female inflorescence. The term "terpene" includes "terpenoids" or "isoprenoids", which are modified terpenes that contain additional functional groups.
[0065] Terpenes are responsible for much of the scent of cannabis flowers and contribute to the unique flavor qualities of cannabis products. Terpenes will be known to persons skilled in the art, illustrative examples of which are provided in Table 2.
Table 2. Terpenes and their properties
Name Structure
Caryophyllene oxide H3 C H
H 3C
H' H 2C
Myrcene
p-caryophyllene
Eudesmol H
[0066] Monoterpenes consist of two isoprene units and may be liner or contain ring structures. The primary function of monoterpenes is to protect plants from infection by fungal and bacterial pathogens and insect pests. Monoterpenes produced by cannabis plants would be known to persons skilled in the art, illustrative examples of which includep pinene, myrcene, p-phellandrene, cis-ocimene, terpinolene and terpineol.
[0067] Sesquiterpenes differ from other common terpenes as they contain one additional isoprene unit, which creates a 15 carbon structure. The primary function of sesquiterpenes is as a pheromone for the bud and flower. Sesquiterpenes produced by cannabis plants would be known to persons skilled in the art, illustrative examples of which include -caryophyllene, bisabolol, humulene, 6-guaiene, y-cadinene, eudesma-3,7(11) dene and elemene.
[0068] In certain embodiments, the pharmaceutical composition comprises a terpene enriched for one or more or all of -caryophyllene or a pharmaceutically acceptable salt or functional derivative thereof, caryophyllene oxide or a pharmaceutically acceptable salt or functional derivative thereof, myrcene or a pharmaceutically acceptable salt or functional derivative thereof, and eudesmol or a pharmaceutically acceptable salt or functional derivative thereof.
[0069] The terms "-caryophyllene", "beta-caryophyllene", "b-caryophyllene", "B" and "B-Cary" are used interchangeably herein to refer to some of the most abundant sesquiterpenes in cannabis. -caryophyllene has been shown to bind directly to the CB2 receptor. As a result, -caryophyllene has been associated with therapeutic or medicinal effects of cannabis, e.g., as an anti-bacterial and anti-cancer agent.
[0070] The terms "caryophyllene oxide" "0" and "CO" are used interchangeably herein to refer to a sesquiterpene that results from the oxidation of -caryophyllene. Similar to caryophyllene, caryophyllene oxide has been associated with therapeutic or medicinal effects of cannabis, e.g., as an anti-bacterial and anti-cancer agent.
[0071] The terms "myrcene", M" and "Myr" are used interchangeably herein to refer
to a monoterpinoid derivative of -pinene. Myrcene has been associated with the therapeutic or medicinal effects of cannabis and has been suggested for use as a sedative, hypnotic, analgesic and muscle relaxant.
[0072] The terms "eudesmol", "E" and "Eud" are used interchangeably herein to refer to an oxygenized sesquiterpene that is a noncompetitive agonist of nicotinic acetylcholine receptors and has been shown to elicit anti-tumor effects and amelioration of the symptoms associated with migraines. The term "eudesmol" as used herein is intended to encompasses each of the different isomers of eudesmol, i.e., the alpha, beta and gamma isoforms.
Pharmaceutical compositions
[0073] The pharmaceutical compositions of the present disclosure suitably comprise combinations of a cannabinoid (i.e., CBD or CBDA) and a terpene (i.e., one or more or all of -caryophyllene, caryophyllene oxide, myrcene, and eudesmol) that synergize to inhibit the production, release or activity of inflammatory molecules (e.g., NO, TNF-a, IL-6 and PGE2).
[0074] The terms "level", "content", "concentration" and the like, are used interchangeably herein to describe an amount of the referenced compound, and may be represented in absolute terms (e.g., mg/g, mg/mL, etc.) or in relative terms, such as a ratio.
[0075] In accordance with certain embodiments, a ratio of cannabinoid and terpene is intended to encompass a reasonable level of variance, e.g., a ratio of "about" may encompass a level of variation being plus or minus 10%. In certain embodiments, the ratio of cannabinoid and terpene may be presented by reference to decimals of each component, e.g., 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1.1:2.5, 1.2:2.5: 1.3:2.5, 1.4:1.5, 1.5:2.5, and so on and so forth.
[0076] As used herein, the term "enriched for" means that, the3-caryophyllene, caryophyllene oxide, myrcene, and/or eudesmol are substantial components of the terpene fraction of the compositions described herein. In an embodiment, a terpene enriched for one or more or all of -caryophyllene, caryophyllene oxide, myrcene, and eudesmol, comprise at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, or preferably at least 99% of the one or more or all of -caryophyllene, caryophyllene oxide, myrcene, and eudesmol, by weight of total terpenes. It is to be understood that the remainder of the terpene fraction or component of the compositions may comprise other terpenes, as described elsewhere herein.
[0077] For example, a terpene enriched for -caryophyllene typically means that the terpene fraction or component of the composition comprises at least 50% -caryophyllene, preferably at least 60% -caryophyllene, preferably at least 70% -caryophyllene, preferably at least 80% -caryophyllene, preferably at least 90% -caryophyllene, preferably at least % p-caryophyllene, preferably at least 99%, or essentially the entire terpene fraction, i.e., 100% -caryophyllene by weight of total terpenes.
[0078] In an embodiment, the terpene is enriched for 3-caryophyllene or a pharmaceutically acceptable salt or functional derivative thereof.
[0079] In an embodiment, the pharmaceutical composition comprises a cannabinoid: -caryophyllene ratio of from about 1:100 to about 10:1 (w/w).
[0080] Accordingly, in an embodiment, the pharmaceutical composition comprises a cannabinoid : -caryophyllene ratio of from about 1:100 to about 10:1 (w/w), preferably about 1:100, preferably about 1:99, preferably about 1:98, preferably about 1:97, preferably about 1:96, preferably about 1:95, preferably about 1:94, preferably about 1:93, preferably about 1:92, preferably about 1:91, preferably about 1:90, preferably about 1:89, preferably about 1:88, preferably about 1:87, preferably about 1:86, preferably about 1:85, preferably about 1:84, preferably about 1:83, preferably about 1:82, preferably about 1:81, preferably about 1:80, preferably about 1:79, preferably about 1:78, preferably about 1:77, preferably about 1:76, preferably about 1:75, preferably about 1:74, preferably about 1:73, preferably about 1:72, preferably about 1:71, preferably about 1:70, preferably about 1:69, preferably about 1:68, preferably about 1:67, preferably about 1:66, preferably about 1:65, preferably about 1:64, preferably about 1:63, preferably about 1:62, preferably about 1:61, preferably about 1:60, preferably about 1:59, preferably about 1:58, preferably about 1:57, preferably about 1:56, preferably about 1:55, preferably about 1:54, preferably about 1:53, preferably about 1:52, preferably about 1:51, preferably about 1:50, preferably about 1:49, preferably about 1:48, preferably about 1:47, preferably about 1:46, preferably about 1:45, preferably about 1:43, preferably about 1:42, preferably about 1:41, preferably about 1:40, preferably about 1:39, preferably about 1:38, preferably about 1:37, preferably about 1:36, preferably about 1:35, preferably about 1:34, preferably about 1:33, preferably about 1:32, preferably about 1:31, preferably about 1:30, preferably about 1:29, preferably about 1:28, preferably about 1:27, preferably about 1:26, preferably about 1:25, preferably about 1:14, preferably about 1:23, preferably about 1:22, preferably about 1:21, preferably about 1:20, preferably about 1:19, preferably about 1:18, preferably about 1:17, preferably about 1:16, preferably about 1:15, preferably about 1:14, preferably about 1:13, preferably about 1:12, preferably about 1:11, preferably about 1:10, preferably about 1:9, preferably about 1:8, preferably about 1:7, preferably about 1:6, preferably about 1:5, preferably about 1:3, preferably about 1:2, preferably about 1:1, preferably about 2:1, preferably about 3:1, preferably about 4:1, preferably about 5:1, preferably about 6:1, preferably about 7:1, preferably about 8:1, preferably about 9:1, or more preferably about 10:1 (w/w).
[0081] In an embodiment, the pharmaceutical composition comprises a cannabinoid: -caryophyllene ratio of from about 1:72 to about 9:8 (w/w).
[0082] In an embodiment, the pharmaceutical composition comprises a cannabinoid: -caryophyllene ratio of from about 9:8 (w/w).
[0083] In an embodiment, the terpene is enriched for caryophyllene oxide or a pharmaceutically acceptable salt or functional derivative thereof.
[0084] In an embodiment, the pharmaceutical composition comprises a cannabinoid: caryophyllene oxide ratio of from about 1:100 to about 10:1 (w/w).
[0085] Accordingly, in an embodiment, the pharmaceutical composition comprises a cannabinoid : caryophyllene oxide ratio of from about 1:100 to about 10:1 (w/w), preferably about 1:100, preferably about 1:99, preferably about 1:98, preferably about 1:97, preferably about 1:96, preferably about 1:95, preferably about 1:94, preferably about 1:93, preferably about 1:92, preferably about 1:91, preferably about 1:90, preferably about 1:89, preferably about 1:88, preferably about 1:87, preferably about 1:86, preferably about 1:85, preferably about 1:84, preferably about 1:83, preferably about 1:82, preferably about 1:81, preferably about 1:80, preferably about 1:79, preferably about 1:78, preferably about 1:77, preferably about 1:76, preferably about 1:75, preferably about 1:74, preferably about 1:73, preferably about 1:72, preferably about 1:71, preferably about 1:70, preferably about 1:69, preferably about 1:68, preferably about 1:67, preferably about 1:66, preferably about 1:65, preferably about 1:64, preferably about 1:63, preferably about 1:62, preferably about 1:61, preferably about 1:60, preferably about 1:59, preferably about 1:58, preferably about 1:57, preferably about 1:56, preferably about 1:55, preferably about 1:54, preferably about 1:53, preferably about 1:52, preferably about 1:51, preferably about 1:50, preferably about 1:49, preferably about 1:48, preferably about 1:47, preferably about 1:46, preferably about 1:45, preferably about 1:43, preferably about 1:42, preferably about 1:41, preferably about 1:40, preferably about 1:39, preferably about 1:38, preferably about 1:37, preferably about 1:36, preferably about 1:35, preferably about 1:34, preferably about 1:33, preferably about 1:32, preferably about 1:31, preferably about 1:30, preferably about 1:29, preferably about 1:28, preferably about 1:27, preferably about 1:26, preferably about 1:25, preferably about 1:14, preferably about 1:23, preferably about 1:22, preferably about 1:21, preferably about 1:20, preferably about 1:19, preferably about 1:18, preferably about 1:17, preferably about 1:16, preferably about 1:15, preferably about 1:14, preferably about 1:13, preferably about 1:12, preferably about 1:11, preferably about 1:10, preferably about 1:9, preferably about 1:8, preferably about 1:7, preferably about 1:6, preferably about 1:5, preferably about 1:3, preferably about 1:2, preferably about 1:1, preferably about 2:1, preferably about 3:1, preferably about 4:1, preferably about 5:1, preferably about 6:1, preferably about 7:1, preferably about 8:1, preferably about 9:1, or more preferably about 10:1 (w/w).
[0086] In an embodiment, the pharmaceutical composition comprises a cannabinoid: caryophyllene oxide ratio of from about 1:36 to about 9:4 (w/w).
[0087] In an embodiment, the pharmaceutical composition comprises a cannabinoid: caryophyllene oxide ratio of about 1:1 (w/w).
[0088] In an embodiment, the terpene is enriched for myrcene or a pharmaceutically acceptable salt or functional derivative thereof.
[0089] In an embodiment, the pharmaceutical composition comprises a cannabinoid: myrcene ratio of from about 1:100 to about 10:1 (w/w).
[0090] Accordingly, in an embodiment, the pharmaceutical composition comprises a cannabinoid : myrcene ratio of from about 1:100 to about 10:1 (w/w), preferably about 1:100, preferably about 1:99, preferably about 1:98, preferably about 1:97, preferably about 1:96, preferably about 1:95, preferably about 1:94, preferably about 1:93, preferably about 1:92, preferably about 1:91, preferably about 1:90, preferably about 1:89, preferably about 1:88, preferably about 1:87, preferably about 1:86, preferably about 1:85, preferably about 1:84, preferably about 1:83, preferably about 1:82, preferably about 1:81, preferably about 1:80, preferably about 1:79, preferably about 1:78, preferably about 1:77, preferably about 1:76, preferably about 1:75, preferably about 1:74, preferably about 1:73, preferably about 1:72, preferably about 1:71, preferably about 1:70, preferably about 1:69, preferably about 1:68, preferably about 1:67, preferably about 1:66, preferably about 1:65, preferably about
1:64, preferably about 1:63, preferably about 1:62, preferably about 1:61, preferably about 1:60, preferably about 1:59, preferably about 1:58, preferably about 1:57, preferably about 1:56, preferably about 1:55, preferably about 1:54, preferably about 1:53, preferably about 1:52, preferably about 1:51, preferably about 1:50, preferably about 1:49, preferably about 1:48, preferably about 1:47, preferably about 1:46, preferably about 1:45, preferably about 1:43, preferably about 1:42, preferably about 1:41, preferably about 1:40, preferably about 1:39, preferably about 1:38, preferably about 1:37, preferably about 1:36, preferably about 1:35, preferably about 1:34, preferably about 1:33, preferably about 1:32, preferably about 1:31, preferably about 1:30, preferably about 1:29, preferably about 1:28, preferably about 1:27, preferably about 1:26, preferably about 1:25, preferably about 1:14, preferably about 1:23, preferably about 1:22, preferably about 1:21, preferably about 1:20, preferably about 1:19, preferably about 1:18, preferably about 1:17, preferably about 1:16, preferably about 1:15, preferably about 1:14, preferably about 1:13, preferably about 1:12, preferably about 1:11, preferably about 1:10, preferably about 1:9, preferably about 1:8, preferably about 1:7, preferably about 1:6, preferably about 1:5, preferably about 1:3, preferably about 1:2, preferably about 1:1, preferably about 2:1, preferably about 3:1, preferably about 4:1, preferably about 5:1, preferably about 6:1, preferably about 7:1, preferably about 8:1, preferably about 9:1, or more preferably about 10:1 (w/w).
[0091] In an embodiment, the pharmaceutical composition comprises a cannabinoid: myrcene ratio of from about 1:36 to about 9:4 (w/w).
[0092] In an embodiment, the pharmaceutical composition comprises a cannabinoid: myrcene ratio of about 2:1 (w/w).
[0093] In an embodiment, the terpene is enriched for eudesmol or a pharmaceutically acceptable salt or functional derivative thereof.
[0094] In an embodiment, the pharmaceutical composition comprises a cannabinoid: eudesmol ratio of from about 1:100 to about 10:1 (w/w).
[0095] Accordingly, in an embodiment, the pharmaceutical composition comprises a cannabinoid : eudesmol ratio of from about 1:100 to about 10:1 (w/w), preferably about 1:100, preferably about 1:99, preferably about 1:98, preferably about 1:97, preferably about
1:96, preferably about 1:95, preferably about 1:94, preferably about 1:93, preferably about 1:92, preferably about 1:91, preferably about 1:90, preferably about 1:89, preferably about 1:88, preferably about 1:87, preferably about 1:86, preferably about 1:85, preferably about 1:84, preferably about 1:83, preferably about 1:82, preferably about 1:81, preferably about 1:80, preferably about 1:79, preferably about 1:78, preferably about 1:77, preferably about 1:76, preferably about 1:75, preferably about 1:74, preferably about 1:73, preferably about 1:72, preferably about 1:71, preferably about 1:70, preferably about 1:69, preferably about 1:68, preferably about 1:67, preferably about 1:66, preferably about 1:65, preferably about 1:64, preferably about 1:63, preferably about 1:62, preferably about 1:61, preferably about 1:60, preferably about 1:59, preferably about 1:58, preferably about 1:57, preferably about 1:56, preferably about 1:55, preferably about 1:54, preferably about 1:53, preferably about 1:52, preferably about 1:51, preferably about 1:50, preferably about 1:49, preferably about 1:48, preferably about 1:47, preferably about 1:46, preferably about 1:45, preferably about 1:43, preferably about 1:42, preferably about 1:41, preferably about 1:40, preferably about 1:39, preferably about 1:38, preferably about 1:37, preferably about 1:36, preferably about 1:35, preferably about 1:34, preferably about 1:33, preferably about 1:32, preferably about 1:31, preferably about 1:30, preferably about 1:29, preferably about 1:28, preferably about 1:27, preferably about 1:26, preferably about 1:25, preferably about 1:14, preferably about 1:23, preferably about 1:22, preferably about 1:21, preferably about 1:20, preferably about 1:19, preferably about 1:18, preferably about 1:17, preferably about 1:16, preferably about 1:15, preferably about 1:14, preferably about 1:13, preferably about 1:12, preferably about 1:11, preferably about 1:10, preferably about 1:9, preferably about 1:8, preferably about 1:7, preferably about 1:6, preferably about 1:5, preferably about 1:3, preferably about 1:2, preferably about 1:1, preferably about 2:1, preferably about 3:1, preferably about 4:1, preferably about 5:1, preferably about 6:1, preferably about 7:1, preferably about 8:1, preferably about 9:1, or more preferably about 10:1 (w/w).
[0096] In an embodiment, the pharmaceutical composition comprises a cannabinoid: eudesmol ratio of from about 1:36 to about 9:4 (w/w).
[0097] In an embodiment, the pharmaceutical composition comprises a cannabinoid: eudesmol ratio of about 2:1 (w/w).
[0098] In another embodiment, the terpene is enriched for caryophyllene oxide or a pharmaceutically acceptable salt or functional derivative thereof, myrcene or a pharmaceutically acceptable salt or functional derivative thereof, and eudesmol or a pharmaceutically acceptable salt or functional derivative thereof.
[0099] In an embodiment, the pharmaceutical composition comprises a cannabinoid: eudesmol : myrcene : caryophyllene oxide ratio of from about 10:1:1:1 to about 1:1:1:1 (w/w).
[0100] Accordingly, in an embodiment, the pharmaceutical composition comprises a cannabinoid : eudesmol : myrcene : caryophyllene oxide ratio of from about 10:1:1:1 to about 1:1:1:1 (w/w), preferably about 10:1:1:1, preferably about 9:1:1:1, preferably about 8:1:1:1, preferably about 7:1:1:1, preferably about 6:1:1:1, preferably about 5:1: 1:1, preferably about 4:1:1:1, preferably about 3:1:1:1, preferably about 2:1:1:1, or more preferably about 1:1:1:1 (w/w).
[0101] In an embodiment, the pharmaceutical composition comprises a cannabinoid eudesmol : myrcene : caryophyllene oxide ratio of about 3:1:1:1 (w/w).
[0102] As described elsewhere herein, combinations of a cannabinoid (i.e., CBD or CBDA) and a terpene synergistically inhibit inflammatory molecules. In particular, the anti inflammatory effect associated with CBD or CBDA as single agents is maintained, however, with a significantly reduced IC5 o, thereby significantly increasing the potency of the cannabinoids.
[0103] In an embodiment, the cannabinoid is CBD or a pharmaceutically acceptable salt or functional derivative thereof.
[0104] In another embodiment, the cannabinoid is CBDA or a pharmaceutically acceptable salt or functional derivative thereof.
[0105] The pharmaceutical composition may be administered in dosage unit and in formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Formulations include transdermal, aerosol, nasal spray, sublingual spray, liposomal, nanoparticle, microparticle, polymer-based, dispersion, suspension, powder, microspheres, carrier-mediated, and encapsulation.
[0106] Pharmaceutical compositions disclosed herein may be prepared according to conventional methods well known in the pharmaceutical and nutraceutical industries, such as those described in Remington's Pharmaceutical Handbook (Mack Publishing Co., NY, USA).
[0107] In an embodiment, the pharmaceutical composition is formulated for oral administration.
[0108] Pharmaceutical compositions suitable for oral administration would be known to persons skilled in the art, illustrative examples of which include liquid, oil, tablets and capsules. The term "oral administration" as used herein broadly encompasses formulations for sublingual and buccal administration.
[0109] Pharmaceutical compositions for oral administration may contain one or more additional agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavoring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavoring. Suitable preservatives include sodium benzoate, vitamin E, alphatocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
[0110] Pharmaceutical compositions suitable for oral administration may be presented as discrete units (i.e., dosage forms), each containing a predetermined amount of each component of the composition as a powder, tablet, capsule, granules, as a solution or a suspension in an aqueous liquid or non-aqueous liquid, or as an emulsion.
[0111] Oral administration has been demonstrated to be an effective administration route for CBD (reviewed by Millar et al., 2018, Frontiers in Pharmacology, 9: 1365 and Poyatos et al., 2020, Medicina (Kaunas), 56(6): 309).
[0112] In an embodiment, the pharmaceutical composition as disclosed herein is for use in the treatment or prevention of an inflammatory condition.
Inflammatory conditions
[0113] As used herein, the term "inflammatory condition" typically refers to a condition characterized by inflammation, or the complex biological response to a noxious stimulus such as damage, auto-immunity, or an infection by a microbial pathogen and/or virus. The clinical features of an inflammatory condition are likely to depend on the noxious stimulus (or stimuli), but is typically characterized by any one or more of heat, pain, redness and swelling of the affected organ or tissue. The inflammatory condition may be acute or chronic.
[0114] In an embodiment, the inflammatory condition is selected from the group consisting of sepsis, traumatic injury, ischemia, asthma, bums, irritable bowel syndrome, Alzheimer's disease, cancer, major depression, arthritis, multiple sclerosis and pain.
[0115] In an embodiment, the inflammatory condition is associated with an increase or upregulation in the level of an inflammatory cytokine selected from the group consisting of NO, IL-6, TNF-a, PGE2, and combinations of the foregoing.
[0116] Inflammatory conditions associated with an increase or upregulation in the level of NO, IL-6, TNF-a, and/or PGE2 would be known to persons skilled in the art, illustrative examples of which include irritable bowel disease (as described by, e.g., Neurath, 2014, Nature Reviews Immunology, 14: 329-342; Papadakis and Targan, 2000, The Annual Review of Medicine, 51: 289-298) and pain (as described by, e.g., Zhang, 2007, International Anesthesiology Clinics, 45: 27-37), asthma (as described by, e.g., Rincon and Irvin, 2012, InternationalJournalof Biological Sciences, 8: 1281-1290; Thomas, 2001, Immunology &
Cell Biology, 79: 132-140).
Methods of treatment
[0117] In an aspect disclosed herein, there is provided a method for the treatment or prevention of an inflammatory condition, the method comprising administering a therapeutically effective amount of the pharmaceutical composition as disclosed herein to a subject in need thereof.
[0118] The terms "treat", "treating", "treatment", and the like refer to any and all methods that remedy, prevent, hinder, retard, ameliorate, reduce, delay or reverse or otherwise inhibit the severity of the condition (e.g., an inflammatory condition) or of one or more symptoms thereof in a subject. Treatment does not necessarily imply that a patient is treated until total recovery. Inflammatory conditions are characterized by multiple symptoms/comorbidities (e.g., sleep quality, anxiety, quality of life), and thus the treatment need not necessarily remedy, prevent, hinder, retard, ameliorate, reduce, delay or reverse all of said symptoms/comorbidities. Methods of the present disclosure may involve "treating" pain in terms of reducing, preventing or ameliorating the occurrence of a highly undesirable event or symptom associated with an inflammatory condition or an outcome of the progression of the inflammatory condition, but may not of itself prevent the initial occurrence of the event, symptom, comorbidity or outcome. Accordingly, treatment includes amelioration of the symptoms of an inflammatory condition or preventing or otherwise reducing the risk of developing symptoms/comorbidities of an inflammatory condition.
[0119] The term "subject" as used herein refers to any mammal, including livestock and other farm animals (such as cattle, goats, sheep, horses, pigs and chickens), performance animals (such as racehorses), companion animals (such as cats and dogs), laboratory test animals and humans. In an embodiment, the subject is a human.
[0120] Pharmaceutical compositions comprising a cannabinoid (i.e., CBD or CBDA) and a terpene (i.e., 3-caryophyllene, caryophyllene oxide, myrcene, and/or eudesmol) will suitably be administered to the subject in need thereof in a therapeutically effective amount. As used herein, the term "therapeutically effective amount" or "effective amount" typically refers to an amount of the cannabinoid and the terpene that is sufficient to affect one or more beneficial or desired therapeutic outcomes (e.g., reduction or amelioration of the symptoms of an inflammatory condition). Said beneficial or desired therapeutic outcomes may be subjectively measured using clinical instruments known in the art, illustrative examples of which include the detection of altered levels of immunological biomarkers. Subjective measures of said beneficial or desired therapeutic outcomes can also be made using clinical instruments known in the art, illustrative examples of which include the Depression Anxiety Stress Scale (Lovibond and Lovibond, 1995, Manual for the Depression Anxiety Stress Scales, 2 nd edition, Sydney: Psychology Foundation), Medical Outcomes of Sleep Survey (Shahid et al., in Shahid et al. (eds), 2012 STOP, THAT and One Hundred Other Sleep Scales, Springer, New York, pp 219-222), Pittsburgh Sleep Quality Index (Buysse et al., 1989, Psychiatry Research, 28(2): 193-213), Roland Morris Disability Questionnaire (Roland and Morris, 1983, Spine, 8: 141-144), Hospital Anxiety and Depression Scale (Zigmond and Snaith, 1983, Acta Psychiatrica Scandinavia, 67(6): 361-70), EuroQol 5D (EuroQol Research Foundation, 2019, EQ-5D-5L User Guide), Short Form Medical Outcomes 12 (Ware et al., 1996, Med Care, 34: 220-233), and Patient Global Impression of Change (Hurst and Bolton, 2004, Journal of Manipulative & Physiological Therapeutics, 27: 26-35).
[0121] An effective amount can be provided in one or more administrations. The exact amount required may vary depending on factors such as the nature and severity of the pain to be treated, the age and general health of the subject.
[0122] In another aspect disclosed herein, there is provided a use of a cannabinoid and a terpene in the manufacture of a medicament for the treatment or prevention of an inflammatory condition, wherein:
a. the cannabinoid is selected from CBD or a pharmaceutically acceptable salt or functional derivative thereof, and CBDA or a pharmaceutically acceptable salt or functional derivative thereof; and b. wherein the terpene is enriched for one or more or all of -caryophyllene or a pharmaceutically acceptable salt or functional derivative thereof, caryophyllene oxide or a pharmaceutically acceptable salt or functional derivative thereof, myrcene or a pharmaceutically acceptable salt or functional derivative thereof, and eudesmol or a pharmaceutically acceptable salt or functional derivative thereof.
[0123] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.
[0124] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.
[0125] All patents, patent applications and publications mentioned herein are hereby incorporated by reference in their entireties.
[0126] The various embodiments enabled herein are further described by the following non-limiting examples.
Example 1 - Materials and methods
Assays
[0127] Anti-inflammatory activity was determined in lipopolysaccharide (LPS) stimulated murine macrophages, RAW264.7 cells cultured in standard cell culture media (DMEM, Foetal bovine serum 5%) and incubated in the presence or absence of different test compounds/extracts and controls. The production of inflammatory mediators, including NO, cytokines TNFa and IL-6, were measured by established methods using commercial ELISA kits (Table 3). Each sample was tested with at least 6 concentrations (using 3 replicates, maximum concentration was 80jg/mL; n=9), with relevant internal controls (Table 3). The cytotoxicity of each sample tested was determined by MTT assay.
[0128] The assay parameters for each assay are summarised in Table 3. Briefly, for the NO, TNF-a and IL-6 assays the cultured RAW264.7 cells were counted and plated (0.8 x 105 cells/well) in 96 well plates and incubated for 48 hours. The medium was then aspired and replaced with fresh medium followed by the addition of the test compounds. The compounds were incubated for 1 hour prior to the addition of the stimulant. The plates were then incubated for 18 hours and the supernatant analysed for the mediator of interest, the remaining cell viability was determined by MTT.
[0129] The positive controls were selected based on their widespread use in similar assays, including N-(3-(Aminomethyl)benzyl)acetamidine (1400W), a slow, tight binding inhibitor of inducible nitric-oxide synthase (iNOS) (Garvey et al., 1997, Journal of Biological Chemistry, 272(8): 4959-4963), and dexamethasone, a commonly used cytokine inhibitor. The positive controls used or the prostaglandins assay were the mild non-steroidal anti-inflammatory drug (NSAID) aspirin and strong NSAID diclofenac.
Testing ratios
[0130] The ratios were designed to cover a wide range of combinations, where the two compounds contribute equally to the anti-inflammatory effect at the middle ratio. These activity guided ratios are useful when examining synergy between two compounds with mismatched potency. For example, CBD had a cytotoxicity of around 10 g/mL, whereas the terpenes were tested up to 80 g/mL. Testing them at 1:1 would result in cytotoxic dosages for CBD. Preparing the ratio by activity compensates for this and allows an equal contribution to activity to be examined. The corresponding weight-by-weight (w/w) ratios are shown in Table 4.
Data analysis
[0131] The data are presented as mean and standard error of mean (SEM). The dose response curves were fit using Graph Pad Prism. The 95% confidence intervals (CI) were calculated using the whole data set and give an estimate error in the IC5 0 value. The 95% CI for the IC50 where the IC50 was not reached in the testing concentrations require graphical extrapolation to calculate the IC5. Where the IC5o has been estimated by graphical extrapolation "~" is used to indicate that it is an estimate and not experimentally determined, unless otherwise stated. The graphical extrapolation results in a wider 95% confidence interval.
Synergy calculation
[0132] The synergism combination index (CI) and isobologram IC5 0 weightings were calculated using Compsyn software. The dose response curve generated in GraphPad prism was transformed into 15 points representing the curve. These 15 points were then entered into the Compsyn program that generated a curve to fit the data points. This method was preferable to closely replicate the complete dose response curve in the synergy program. The Compsyn fit curve was then used for synergy calculations.
[0133] A CI of less than 1 indicates synergy, and a CI value of less than 0.5 is considered significant synergy. For the isobologram IC5 o weightings, the relative contribution of each component to the activity at the IC5 o. A straight line is drawn between the two drugs being combined. Values below the line indicate synergy, on the line is considered additive and above the line is antagonistic (Figure 11).
Example 2 - Nitric oxide (NO) assay
[0134] NO is a radical metabolite, which has been shown to have numerous physiological functions both as a signalling molecule and as a toxic agent in inflammation (Coleman, 2001, International Immunopharmacology, 1(8): 1397-1406). NO is derived from the oxidation of L-arginine by three types of nitric oxide synthases (NOS); the constitutive forms, neuronal NOS and endothelial NOS, and the inducible form, iNOS, originally described in murine macrophages (Nathan & Xie, 1994, Cell, 78(6): 915-918; Stuehr & Marletta, 1985, Proceedingsof the National Academy of Sciences U.S.A., 82(22): 7738-7742). The inducible form is continually activated once expressed, and is therefore regulated at the transcription level by NF-KB, stimulated by inflammatory molecules like LPS and IFN-. The production of NO by iNOS (due to the time taken for messenger ribonucleic acid (mRNA) and protein synthesis) experiences hours of lag time before NO is produced in much higher (nM) sustained levels (Nathan & Xie, 1994, supra). The inducible form of NOS is most likely implicated in inflammation and due to the higher levels of NO produced it is more easily assessed in-vitro.
[0135] NO is an unusual signalling molecule. As there is no specific cell surface receptor for NO it enters cells indiscriminately, where the effect is dependent on cell type and NO concentration, thus producing a wide range of physiological responses. NO causes increased vascular permeability, vasodilatation and generation of radicals which causes tissue damage and eliminates pathogens (Guzik et al., 2003, Journal of Physiology and Pharmacology, 54(4): 469-487). These physiological changes are associated with inflammation with the increased blood flow, allowing more immune cells to enter affected tissue thereby destroying the pathogen.
[0136] The cannabinoids, terpenes and mixtures were therefore assayed to determine if the blends showed synergistic inhibition on the inflammatory signalling molecule NO. The blends were first tested in 10% increments to determine the optimum combination. The dose dependent effects of the individual cannabinoids and terpenes are shown in Figure 1. The cannabinoids and terpenes tested inhibited NO release in a dose dependent manner. The most active compound for NO inhibition was CBD (Table 5). The cannabinoids were significantly more potent inhibitors of NO compared to the terpenes.
[0137] To investigate if there is a synergistic relationship between the cannabinoids and terpenes they were tested as mixtures. The cannabinoids were combined with terpenes at ratios defined by their activity. The dose response results for the combinations are shown in Figures 2-8.
[0138] The IC 5 0 for each pure compound and combination was calculated and is shown in Table 6. The combination index (CI) also calculated at 75% inhibition (i.e., IC7 5 ) and 90% inhibition (i.e., IC9 o). Many combinations showed synergistic interaction. The 'best' combinations show synergy and high potency. These combinations have been highlighted in bold (Table 6) and the increase in potency of CBD or CBDA in the combinations have been presented by reference to their w/w ratios in Table 7.
[0139] The combination of CBD and caryophyllene oxide at a CBD : caryophyllene oxide ratio of 9:4 (w/w) was the most potent combination (Tables 6 and 7). It produced an
IC5o of 1.4 g/mL which is only slightly more active (not significantly) than CBD alone. However, in this combination the concentration of the CBD at the IC5 0 was 0.96 g/mL.
[0140] The synergistic effect associated with the combination of CBD and caryophyllene oxide can be observed in the isobologram for the CBD and caryophyllene oxide blends also shows the synergistic effect for each combination of CBD and caryophyllene oxide tested in the NO assay (Figure 12).
[0141] The combination with the lowest IC 5 0 for CBD was the CBD and eudesmol combination at a CBD : eudesmol ratio of 3:4 (w/w), where the concentration of CBD at the IC 5 0 was 0.77 g/ml (Table 7). Accordingly, the CBD is nearly double the potency in these optimum combinations.
[0142] The combination of CBDA and myrcene at a CBDA: myrcene ratio of 9:4 (w/w) was most the potent and synergistic combination for the CBDA combinations. At the IC5 0 CBDA concentration is 2.4 tg/mL, well below the IC5 0 of 8.9 tg/mL alone (Table 7).
Summary
[0143] CBD and CBDA each showed a synergistic anti-inflammatory effect on the release of NO from LPS stimulated RAW264.7 cells when combined with terpenes at multiple ratios.
[0144] For CBD, terpene combinations which resulted in a CI less than 1 were: CBD
+ -caryophyllene at ratios ranging from 1:8 to 9:8 (w/w); CBD + caryophyllene oxide at all ratios tested from 1:36 to 9:4 (w/w); CBD + myrcene at ratios from 1:4 to 9:4 (w/w); and CBD + eudesmol at ratios from 1:12 to 9:4 (w/w).
[0145] For CBDA, terpene combinations which resulted in a CI less than 1 were: CBDA + beta-caryophyllene at ratios from 1:24 to 9:8 (w/w); CBDA + caryophyllene oxide at ratios from 1:36 to 9:4 (w/w); CBDA + myrcene at ratios from 1:36 to 9:4 (w/w); and CBDA +
eudesmol at ratios from 1:36 to 9:4 (w/w).
Example 3 - TNF-a assay
[0146] TNF-a is a cell signalling protein (cytokine) involved mainly in the acute phase inflammatory response. Macrophages are the major source of TNF-a, although it can be released by many other cell types such as CD4+ lymphocytes, natural killer (NK) cells, neutrophils, mast cells, eosinophils, and neurons. TNF-a is produced by activation of MAPK and NF-KB. It acts to increase its own production and that of other inflammatory cytokines such as interleukin-1 beta (IL-1). TNF-a induces fever, apoptotic cell death, cachexia, inflammation and inhibits tumorigenesis and viral replication. TNF-a is implicated in many disease states, including, sepsis, traumatic injury, ischemia, asthma, bums, irritable bowel syndrome, Alzheimer's disease, cancer, major depression, arthritis and multiple sclerosis (see, e.g., Cairns et al., 2000, Academic Emergency Medicine, 7(8): 930-941; Dowlati et al., 2010, BiologicalPsychiatry, 67(5): 446-457; Swardfager et al., 2010, BiologicalPsychiatry, 68(10): 930-941).
[0147] The cannabinoid and terpene mixtures were assayed to determine if the blends showed synergistic inhibition on the inflammatory cytokine TNF-a. The dose dependent effects of the individual cannabinoids and terpenes are shown in Figure 13, which demonstrates that the cannabinoids and terpenes tested inhibited TNF-a release in a dose dependent manner. The most active compound for TNF-a inhibition was CBD (Table 9). The cannabinoids were significantly more potent inhibitors of TNF-a compared to the terpenes (Figure 13; Table 9).
[0148] To investigate if there is a synergistic relationship between, the cannabinoids and terpenes they were tested as mixtures. The cannabinoids were combined with terpenes at ratios defined by their activity (Table 4). The dose response results for the combinations are shown in Figures 14-21 and Table 10. Many combinations showed synergistic interactions. The 'best' combinations show synergy and high potency. These combinations have been highlighted in bold (Table 10) and the increase in potency of CBD or CBDA in the combinations have been presented by reference to their w/w ratios in Table 11.
[0149] The combination of CBD and caryophyllene oxide at a CBD : caryophyllene oxide ratio of 9:4 (w/w) was the most potent combination (Table 11). It produced an IC5o of 4.9 g/mL which is only slightly more active (not significantly) than CBD alone. However, in this combination the concentration of the CBD at the IC5o was 3.4 g/ml. Accordingly, the CBD is nearly double the potency in this optimal combination.
[0150] The combination of CBDA and caryophyllene oxide at a CBDA : caryophyllene oxide ratio of 9:4 (w/w) was the most potent CBDA combination (Table 11). The IC5 0 of CBDA in this combination was 4 tg/ml, well below the IC50 of 19.8 tg/ml for CBDA alone.
Summary
[0151] CBD and CBDA each showed a synergistic anti-inflammatory effect on the release of TNF-a from LPS stimulated RAW264.7 cells when combined with terpenes at multiple ratios.
[0152] For CBD, terpene combinations which resulted in a CI less than 1 were: CBD
+ -caryophyllene at a ratio of 9:8 (w/w); and CBD + caryophyllene oxide at ratios from 1:36 to 9:4 (w/w).
[0153] For CBDA, terpene combinations which resulted in a CI less than 1 were: CBDA + beta-caryophyllene at a ratio of 9:8 (w/w) at IC7 5 and IC9 0 ; CBDA + caryophyllene oxide at ratios from 3:4 to 9:4 (w/w); CBDA + myrcene at ratios from 1:4 to 9:4 (w/w); and CBDA + eudesmol at ratios from 1:4 to 9:4 (w/w).
Example 4 - IL-6 assay
[0154] Like TNF-a, IL-6 is considered a pro-inflammatory cytokine. IL-6 is secreted by T cells and macrophages which stimulates an immune response. IL-6 is responsible for increased production of neutrophils in bone marrow. It supports the growth of B cells and is antagonistic to differentiation of T cells into regulatory T cells. It is capable of crossing the blood-brain barrier and initiating synthesis of PGE2 in the hypothalamus, thereby changing the body's temperature set point.
[0155] The cannabinoids and terpene mixtures were assayed to determine if the blends showed synergistic inhibition on the inflammatory cytokine IL-6. The dose dependent effects of the individual cannabinoids and terpenes are shown in Figure 20.
[0156] The cannabinoids and terpenes tested inhibited IL-6 release in a dose dependent manner (Figure 22). The most active compound for IL-6 inhibition was CBD (Table 12). The cannabinoids were significantly more potent inhibitors of IL-6 compared to the terpenes.
[0157] To investigate if there is a synergistic relationship between the cannabinoids and terpenes they were tested as mixtures. The cannabinoids were combined with terpenes at ratios defined by their activity (Table 4). The dose response results for the combinations are shown in Figures 23-30 and Table 13. Some combinations showed synergistic interactions. The 'best' combinations show synergy and/or high potency. These combinations have been highlighted in bold in Table 13 and the increase in potency of CBD or CBDA in the combinations have been presented by reference to their w/w ratios in Table 14.
[0158] The combination of CBD and caryophyllene oxide at a CBD : caryophyllene oxide ratio of 3:4 (w/w) was the most potent combination (Table 14). It produced an IC5 o of 2.6 g/mL which is only slightly more active (not significantly) than CBD alone. However, in this combination the concentration of the CBD at the IC5 0 was 1.1 g/ml. Accordingly, the CBD is nearly double the potency in this optimal combination.
[0159] The combination of CBDA and myrcene at a CBDA: myrcene ratio of 3:4 (w/w) was the most potent combination (Table 14). In this optimal combination, the potency was more than doubled as compared to CBDA alone.
Summary
[0160] CBD and CBDA each showed a synergistic anti-inflammatory effect on the release of IL-6 from LPS stimulated RAW264.7 cells when combined with terpenes at multiple ratios.
[0161] For CBD, terpene combinations which resulted in a CI less than 1 were: CBD +
caryophyllene oxide at a ratio of 3:4 (w/w); CBD + myrcene at ratios from 1:36 to 3:4 (w/w); and CBD + eudesmol at ratios from 1:36 to 3:4 (w/w).
[0162] For CBDA, a CI less than 0.5 (i.e., statistically significant synergism) was observed for the CBDA + myrcene combination at a ratio of 3:4 (w/w) at IC 7 5 and IC 90 .
Example 5 - Prostaglandin assay
[0163] The prostaglandin assay was conducted on select samples and combinations based on the NO, IL-6, TNF-a results. The combinations tested in the prostaglandin assay are shown in Table 18.
[0164] Prostaglandin E2 (PGE2) is a major indicator of inflammation and the enzymes that produce it, cyclooxygenases (COX), are the major target for NSAIDs (e.g., aspirin and diclofenac). PGE2 increases blood flow to sites of inflammation by augmenting arterial dilation and increased microvascular permeability. Pain also results from PGE2 action on sensory neurons and central sites within the spinal cord and brain (Funk, 2001, Science, 294(5548):1871-1875).
[0165] Cannabinoids, terpenes and blended mixtures (Table 17) were assayed to determine if the blends exhibited equivalent activity in the inhibition of PGE2 as compared to the pure compounds. The cannabinoids and terpenes tested inhibited PGE2 release in a dose dependent manner. The most active compound for PGE2 inhibition was CBD (Table 18). The cannabinoids were significantly more potent inhibitors of PGE2 compared to the terpenes.
[0166] To investigate if there is a synergistic relationship between the cannabinoids and terpenes they were tested in select mixtures. The dose response results for the combinations are shown in Figures 31-35 and Table 19.
[0167] The combination of CBD and eudesmol at a CBD : eudesmol ratio of 2:1 (w/w) was the most potent combination (Table 19). It produced an IC5 0 of 1.2 g/mL which is only slightly more active (not significantly) than CBD alone. However, in this combination the concentration of the CBD at the IC5 0 was 0.8 tg/ml.
[0168] The combination of CBD, caryophyllene oxide, eudesmol and myrcene at a CBD : caryophyllene oxide: eudesmol : myrcene ratio of 9:3:3:3 (w/w) had an IC5o of 4.5 g/mL. This was higher than CBD alone, however at higher levels of inhibition (90%) showed a synergistic interaction with a CI value of 0.69. The IC9o for CBD alone was calculated to be 9.4 tg/mL. The IC9o of the combination of CBD, caryophyllene oxide, eudesmol and myrcene was 13.5 tg/mL, the IC 90 for CBD alone in the combination was 6.26 g/mL. In this optimal combination, the potency of CBD was increased 33% as compared to CBD alone.
Summary
[0169] The combination of CBD, eudesmol, myrcene and caryophyllene oxide produced more potent inhibitory effects in combination as compared to CBD alone.
Discussion
[0170] Collectively, these data demonstrate that combinations of CBD or CBDA with one or more or all of the terpenes -caryophyllene, caryophyllene oxide, myrcene, and eudesmol synergize to significantly inhibit inflammatory molecules in vitro. The methods described herein have been reduced to practice in methods for modulating an inflammatory response and methods for the treatment of an inflammatory condition, such as sepsis, traumatic injury, ischemia, asthma, burns, irritable bowel syndrome, Alzheimer's disease, cancer, major depression, arthritis, multiple sclerosis and pain. In this context, the combination of CBD or CBDA with one or more or all of the terpenes -caryophyllene, caryophyllene oxide, myrcene, and eudesmol can be used to modulate inflammatory mediators, such as NO, TNF-a, IL-6 and PGE2, which are known to be elevated in chronic inflammatory conditions. Further, pharmaceutical compositions comprising CBD or CBDA with one or more or all of the terpenes -caryophyllene, caryophyllene oxide, myrcene, and eudesmol synergize to the extent that it makes it possible to reduce the dose of CBD or CBDA to a level that may improve the safety profile of the pharmaceutical compositions, particularly for long-term use, while still eliciting a therapeutic effect.
Table 3. Anti-inflammatory assays and positive controls
Assay Plating Stimulation Incubation Kit Positive Control time time supplier NO 48h LPS 18h Griess 1400W (Cayman) (50ng/ml) Reagent TNFa 48h LPS 18h Peprotech Dexamethasone (50ng/ml) (USA) (Sigma) IL-6 48h LPS 18h Peprotech Dexamethasone (50ng/ml) (USA) (Sigma) Prostaglandins 48h LPS 18h Cayman Aspirin (Cayman), (50ng/ml) (USA) Diclofenac (Cayman)
Table 4. Activity ratios converted to weight-by-weight (w/w) ratios for each cannabinoid / terpene combination
Cannabinoid Terpene weight (mg) Activity (C) weight p.w/w Caryophyllene Myrcene Eudesmol ratio (mg) (CBD caryophyllene ratio ()oxide (0) (M) (E) or CBDA)orCD) (B) CB 1:9 0.25 18 1:72 CB 1:3 0.625 15 1:24 CB 1:1 1.25 10 1:8 CB 3:1 1.875 5 3:8 CB 9:1 2.25 2 9:8 CO 1:9 0.25 9 1:36 CO 1:3 0.625 7.5 1:12 CO 1:1 1.25 5 1:4 CO 3:1 1.875 2.5 3:4 CO 9:1 2.25 1 9:4 CM 1:9 0.25 9 1:36 CM 1:3 0.625 7.5 1:12 CM 1:1 1.25 5 1:4 CM 3:1 1.875 2.5 3:4 CM 9:1 2.25 1 9:4 CE 1:9 0.25 9 1:36 CE 1:3 0.625 7.5 1:12 CE 1:1 1.25 5 1:4 CE 3:1 1.875 2.5 3:4 CE 9:1 2.25 1 9:4
Table 5. IC50 for NO inhibition of cannabinoids and terpenes
p- Cayophylene1400 CBD CBDA CaryophylleneMyrcene Eudesmol caryophyllene oxide W IC50 1.3 8.9 -42 35 -145 76 25 (pg/mL) 95% CI 1.1 - 6.9 - ND - 120 30-44 56 - 49-180 21 IC50 1.5 12 1525 32 (pg/mL)
Table 6. NO Assay IC5o and CI results
GraphPad Compusyn IC50 95% CI IC50 CI (ICo) CI (IC7s) CI (IC90) (pg/mL) (pg/mL) CBD 1.3 1.1-1.5 1.47 - - CBDA 8.9 6.9-12 8.85 - -
P- 42 NA-120 68 - - caryophyllene Caryophyllene 35 30-44 65 - - oxide Myrcene 145 56-1525 57 - - Eudesmol 76 49-180 75.65 - -
CB 1:72 427 Wide 419 9.94 55.06 315.92 CB 1:24 38 22-106 38 1.57 5.87 22.90 CB 1:8 10 9.5-11 10 0.89 0.82 0.78 CB 3:8 4.1 3.7-4.5 3.9 0.76 0.64 0.55 CB 9:8 1.8 1.4-2.1 1.75 0.64 0.67 0.71 CO 1:36 20 12-52 20 0.66 1.41 3.03 CO 1:12 8.4 7.3-10 8.5 0.56 0.58 0.60 CO 1:4 4.5 4.1-5.1 4.3 0.63 0.53 0.44 CO 3:4 1.9 1.5-2.3 1.9 0.55 0.72 0.94 CO 9:4 1.4 1.2-1.6 1.4 0.66 0.79 0.95 CM 1:36 50 15-27313 50 1.78 4.10 9.51 CM 1:12 11 NA-16 50 3.44 8.23 19.80 CM 1:4 6.6 5.8-8.0 6.4 0.96 0.93 0.91 CM 3:4 2.4 1.9-3.2 2.4 0.73 0.80 0.88 CM 9:4 1.7 1.4-1.9 1.7 0.79 0.79 0.80 CE 1:36 411 36-NA 410 12.78 352.37 10355.60 CE 1:12 9.4 8.0-12 9.2 0.59 0.55 0.52 CE 1:4 3.8 3.3-4.4 4.5 0.65 0.63 0.63
CE 3:4 1.8 2.4-2.3 1.8 0.53 1.15 2.47 CE 9:4 1.8 1.6-2.1 1.8 0.86 1.02 1.21 AB 1:72 21 Wide NA - - AB 1:24 23 18-44 22.9 0.42 0.53 0.73 AB 1:8 14 NA-21 38.7 0.99 0.95 1.08 AB 3:8 11 8.2-22 11 0.46 0.39 0.40 AB 9:8 6 4.4-20 6 0.40 0.30 0.26 AO 1:36 14 NA-54 20 0.36 0.25 0.18 AO 1:12 16 11-37 15 0.35 0.33 0.31 AO 1:4 8.6 6.9-14 8 0.28 0.17 0.11 AO 3:4 6.2 4.9-9.4 6 0.35 0.25 0.19 AO 9:4 3.7 3.0-5.5 3.7 0.30 0.19 0.12 AM 1:36 21 NA-571 27 0.53 0.40 0.31 AM 1:12 12 9.2-20 12 0.29 0.23 0.18 AM 1:4 7.1 NA-9.1 15 0.54 0.32 0.20 AM 3:4 6.6 5.0-13 7 0.40 0.27 0.19 AM 9:4 3.4 2.7-4.9 3.5 0.29 0.18 0.11 AE 1:36 15 NA-38 14 0.23 0.12 0.06 AE 1:12 12 9.0-21 12 0.25 0.14 0.08 AE 1:4 7.3 5.8-11 7.2 0.24 0.15 0.10 AE 3:4 5.2 4.2-8.4 5.3 0.30 0.17 0.10 AE 9:4 5.1 3.6-10 5.1 0.42 0.36 0.31 A - CBDA, B - -caryophylkene; C - CBD; E - Eudesmol; M - Myrcene; G - Caryophyllene oxide; italics indicates a synergistic combination; bold indicates high potency and synergy.
Table 7. The most active and synergistic combinations relative to NO inhibition
Concentration % increase in Compusyn of Concentration Compound/ CI potency of ICso cannabinoid of terpene at Mixture (ICso) cannabinoid in (pg/mi) atIC5 0 ICso(Pgmi) combination (9g/ml) CBD 1.5 - - - CBDA 8.9 - - - -Caryophyllene 68 - - -
Caryophyllene 66 - - -
oxide Myrcene 57 - - -
Eudesmol 76 - - -
CB 9:8 1.8 0.64 0.93 0.82 59% CO 3:4 1.9 0.55 0.80 1.06 85% CO 9:4 1.4 0.66 0.96 0.43 53% CM 9:4 1.7 0.79 1.15 0.51 28% CE 3:4 1.8 0.53 0.77 1.02 92% CE 9:4 1.8 0.86 1.26 0.56 16% AB 9:8 6.0 0.4 3.20 2.84 177% AO 9:4 3.7 0.3 2.55 1.13 248% AM 9:4 3.5 0.29 2.40 1.07 269% AE 3:4 5.3 0.3 2.29 3.05 287% A - CBDA, B - -cryophyllene; C - CBD; E - Eudesmol; M - Myrcene; 0 - Caryophyllene oxide.
Table 8. 95% Confidence Interval (CI) range calculations at IC50 (pg/mL)
Lower Upper Cannabinoid Terpene Cannabinoid Terpene end end at lower end at lower at higher at higher end end end CBD 1.112 1.484 1.112 - 1.484 CB 9:8 1.441 2.092 0.763 0.678 1.108* 0.984 CO 3:4 1.502 2.302 0.644 0.858 0.987* 1.315 CO 9:4 1.195 1.627 0.824 0.371 1.123 0.504 CM 9:4 1.437 1.902 0.995 0.442 1.317 0.585 CE 3:4 1.44 2.289 0.617 0.823 0.981* 1.308 CE 9:4 1.61 2.079 1.115 0.495 1.439 0.640 AB 9:8 6.906 11.73 6.906 - 11.73 AO 9:4 4.425 20.14 2.343 2.082 10.662 9.478 AM 9:4 2.961 5.519 2.050 0.911 3.821* 1.698 AE 3:4 2.729 4.907 1.889 0.840 3.397* 1.510 CB 9:8 4.218 8.41 1.808 2.410 3.604* 4.806
Table 9. IC50 for TNF-a inhibition of cannabinoids and terpenes
CBD CBDA P- Caryophyllene Myrcene Eudesmol caryophyllene oxide
4.7 20 Not active 19 21 53 (pg/L 95% confidence 3.2 5.1 to interval to 30 14 to 25 15 to 30 wide IC5 0 9.7 (tg/mL)
Table 10. TNF-a Assay IC5o and CI results
GraphPad Compusyn IC50 95% CI IC50 CI (ICo) CI (ICs) CI (IC90) (pg/mL) (pg/mL) CBD 4.7 3.2-9.7 5.3 - - CBDA 20 5.1-30 19.8 - - P- - Infinit - -
caryophyllene Caryophyllene 19 14-25 Infinit - - oxide Myrcene 21 15-30 18.8 - - Eudesmol 53 wide 20.6 - - CB 1:72 - 52.4 NaN NaN NaN CB 1:24 - Infinit NaN NaN NaN
CB 1:8 - Infinit NaN NaN NaN CB 3:8 - Infinit NaN NaN NaN CB 9:8 4.5 3.9-6.6 6.6 NaN 0.29 0.13 CO 1:36 14 wide 12.2 0.69 0.48 0.34 CO 1:12 12 8.3-100 11.1 0.71 0.49 0.34 CO 1:4 8.6 wide-31 8.4 0.68 0.40 0.24 CO 3:4 6.6 3.8-55 6.6 0.74 0.84 0.99 CO 9:4 3.4 wide-13 4.9 0.72 0.34 0.16 CM 1:36 - 0.0 0.00 0.00 0.00 CM 1:12 8.8 wide 35.3 2.10 1.47 1.05 CM 1:4 11 wide- 10.6 0.81 0.47 0.29 797 CM 3:4 - wide 192.0 20.97 15.46 11.74 CM 9:4 - wide 107.8 15.79 10.76 7.45 CE 1:36 wide - - - CE 1:12 wide - - -
CE 1:4 wide - -
CE 3:4 28 5.7- wide 27.8 2.57 3.60 5.21 CE 9:4 - - Infinit NaN Infinit Infinit AB 1:72 - Infinit NaN NaN NaN AB 1:24 - Infinit NaN NaN NaN AB 1:8 - 0.0 NaN 0.00 0.00 AB 3:8 - Infinit NaN NaN NaN AB 9:8 7.6 wide 15.9 NaN 0.05 0.01 AO 1:36 11 8.9-23 14.4 0.77 0.50 0.33 AO 1:12 11 wide 45.3 2.40 2.99 3.92 AO 1:4 wide 139.2 7.34 5.86 5.38 AO 3:4 12 wide 12.1 0.63 0.45 0.45 AO 9:4 5.8 3.1- 5.8 0.30 0.13 0.11 wide AM 1:36 16 wide- 15.5 0.75 0.51 0.35 372 AM 1:12 - Infinit Infinit Infinit Infinit AM 1:4 15 wide 21.6 1.06 0.63 0.44 AM 3:4 10 wide- 9.9 0.49 0.32 0.30 537 AM 9:4 9.4 4.4-132 9.4 0.47 0.29 0.32 AE 1:36 wide - - - AE 1:12 wide 940.2 20.21 6.74 2.33 AE 1:4 10 6.3- wide 10.0 0.25 0.06 0.01 AE 3:4 6.7 3.8-33 6.7 0.22 0.08 0.03 AE 9:4 6.7 wide 7.1 0.29 0.04 0.01 A - CBDA, B - -caryophyllee; C - CBD; E - Eudesmol; M - Myrcene; G - Caryophyllene oxide; italics indicates a synergistic combination; bold indicates high potency and synergy.
Table 11. The most active and synergistic combinations relative to TNF-a inhibition
% increase in Compusyn Concentration Concentration Compound/ IC5 0 of cannabinoid of terpene at potencyof Mixture (IC5 0 ) cannabinoid in (pg/mI) atICso (9g/m) ICso(Pgmi) combination
CBD 5.3 - - - CBDA 19.8 - - - P- Infinit - - -
Caryophyllene Caryophyllene 18.8 - - -
oxide Myrcene 20.6 - - -
Eudesmol 52.4 - - -
C:B 9:8 6.6 NaN 3.5 3.1 50% C:0 9:4 4.9 0.7 3.4 1.5 57% A:B 9:8 15.9 NaN 8.4 7.5 136% A:O 9:4 5.8 0.3 4.0 1.8 392% A:E 3:4 6.7 0.2 2.9 3.8 588% A:E 9:4 7.1 0.3 4.9 2.2 306% A - CBDA, B - b-caryophyllene; C - CBD; E - Eudesmol; M - Myrcene; 0 - Caryophyllene oxide.
Table 12. IC50 for IL-6 inhibition of cannabinoids and terpenes
CBD CBDA P-Caryophyllene Caryophyllene Myrcene Eudesmol oxide IC50 1.8 11 79 11 23 23 (tg/mL 95% confidence 1.6 7.6 to interval to 1t Wide 8.7 to 13 19 to 31 19 to 28 IC50 2.0 (tg/mL)
Table 13. IL-6 Assay IC5o and CI results
GraphPad Compusyn CI CI CI IC5o 95% CI IC5o (IC5o) (IC75) (IC90) (pg/mL) (pg/mL) CBD 1.8 1.6-2.0 1.9 - - CBDA 11 7.6-19 10.7 - -
P- 79 wide 90.9 - - caryophyllene Caryophyllen 11 8.7-13 10.4 - - e oxide Myrcene 23 19-31 23.5 - - Eudesmol 23 19-28 21.8 - - CB 1:72 29 wide 400.8 7.30 9.20 11.86 CB 1:24 26 wide -166 24.6 0.79 0.82 0.87 CB 1:8 13 11-19 15.4 1.07 1.14 1.22 CB 3:8 6 5.1-nd 9.8 1.51 1.59 1.69 CB 9:8 3.2 2.8-3.6 4.7 1.37 1.43 1.51 CO 1:36 11 8.5-16 9.7 1.05 0.76 0.58 CO 1:12 9.7 7.7-17 9.4 1.23 0.93 0.77 CO 1:4 6.1 5.0-8.7 5.8 1.07 1.00 1.01 CO 3:4 2.7 2.2-3.2 2.6 0.76 0.72 0.72 CO 9:4 2.3 wide 4.2 1.70 1.76 1.85 CM 1:36 13 9.2-42 13.3 0.74 0.70 0.72 CM 1:12 7.8 6.6-11 7.3 0.59 0.52 0.49 CM 1:4 5.6 4.9-6.4 7.8 1.11 1.07 1.08 CM 3:4 4.5 3.8-6.2 6.7 1.70 1.80 1.94 CM 9:4 3 2.6-3.4 5.3 2.03 2.27 2.54 CE 1:36 8 5.2-39 7.9 0.47 0.58 0.74 CE 1:12 11 8.3-21 10.0 0.84 0.89 0.97 CE 1:4 6.3 4.7-11 6.3 0.91 1.85 3.78
CE 3:4 3.1 2.3-4.7 3.1 0.79 1.22 1.88 CE 9:4 2.7 2.2-3.4 2.8 1.07 1.30 1.59 AB 1:72 95 wide 113.7 1.38 1.75 2.28 AB 1:24 - 64381.7 921.03 5983.74 40956.20 AB 1:8 - - Infinit NaN Infinit Infinit
AB 3:8 25 wide -955 27.6 0.93 0.67 0.53 AB 9:8 13 6.8-52 14.9 0.82 0.53 0.37 AO 1:36 60 18-7046 60.4 5.83 13.45 31.10 AO 1:12 26 16-72 26.4 2.55 2.54 2.55 AO 1:4 16 10-41 16.2 1.56 1.33 1.16 AO 3:4 - - Infinit NaN Infinit Infinit
AO 9:4 14 5.6-208 14.0 1.32 1.41 1.52 AM 1:36 57 nd- 67.9 2.98 2.94 2.93 1902065606 4 AM 1:12 - wide Infinit Infinit Infinit Infinit AM 1:4 - wide Infinit Infinit Infinit Infinit AM 3:4 9.8 wide -31 11.0 0.71 0.40 0.23 AM 9:4 102 10- wide 96.9 7.55 14.12 27.03 AE 1:36 155 26- wide 156.5 7.39 19.07 49.79 AE 1:12 38 14-3427 39.3 1.95 3.61 6.90 AE 1:4 38 9.1-83024 39.1 2.17 3.06 4.63 AE 3:4 - - Infinit NaN Infinit Infinit
AE 9:4 - - Infinit NaN Infinit Infinit
A - CBDA, B - -caryophyllee; C - CBD; E - Eudesmol; M - Myrcene; G - Caryophyllene oxide; italics indicates a synergistic combination; bold indicates high potency and synergy.
Table 14. The most active and synergistic combinations relative to IL-6 inhibition
% increase in Compusyn Concentration Concentration Compound/ IC5 0 of cannabinoid of terpene at potencyof Mixture (IC5 0 ) cannabinoid in (Ag/ml) atICso ( g/m) ICso(Pgmi) combination
CBD 1.9 - - - CBDA 10.7 - - - -Caryophyllene 90.9 - - -
Caryophyllene 10.4 - - -
oxide Myrcene 23.5 - - -
Eudesmol 21.8 - - -
C:B 9:8 4.7 11.37 2.5 2.2 -24% C:0 3:4 2.6 0.76 1.1 1.5 67% C:0 9:4 4.2 1.7 2.9 1.3 -35% C:M 9:4 5.3 2.03 3.6 1. -48% C:E 3:4 3.1 0.79 1.3 1.8 43% C:E 9:4 2.8 1.07 1.9 0.9 -1% A:M 3:4 11 0.71 4.7 6.3 127% A - CBDA, B - -caryophyllene; C - CBD; E - Eudesmol; M - Myrcene; 0 - Caryophyllene oxide.
Table 15. Summary of systematic ratio testing IC50in NO, TNF-a and IL-6 assays
GraphPad IC5o GraphPad IC5o GraphPad IC5o (pg/mL) (pg/mL) (pg/mL) Assay NO TNF-a IL-6 CBD 1.3 4.7 1.8 CBDA 8.9 20 11 3-caryophyllene 42 Not active 79 Caryophyllene oxide 35 19 11 Myrcene 145 21 23 Eudesmol 76 53 23
CB 1:72 427 Not active 29 CB 1:24 38 Not active 26 CB 1:8 10 Not active 13
CB 3:8 4.1 Not active 6 CB 9:8 1.8* 4.5* 3.2* CO 1:36 20 14 11 CO 1:12 8.4 12 9.7 CO 1:4 4.5 8.6 6.1 CO 3:4 1.9* 6.6 2.7* CO 9:4 1.4* 3.4* 2.3* CM 1:36 50 Not active 13 CM 1:12 11 8.8 7.8 CM 1:4 6.6 11 5.6 CM 3:4 2.4 - 4.5 CM 9:4 1.7* - 3* CE 1:36 411 - 8 CE 1:12 9.4 - 11 CE 1:4 3.8 - 6.3 CE 3:4 1.8* 28 3.1* CE 9:4 1.8* - 2.7*
AB 1:72 21 Not active 95 AB 1:24 23 Not active AB 1:8 14 Not active AB 3:8 11 Not active 25 AB 9:8 6* 7.6* 13 AO 1:36 14 11 60 AO 1:12 16 11 26 AO 1:4 8.6 - 16 AO 3:4 6.2 12 AO 9:4 3.7* 5.8* 14 AM 1:36 21 16 57 AM 1:12 12 - AM 1:4 7.1 15 AM 3:4 6.6 10 9.8* AM 9:4 3.4* 9.4 102 AE 1:36 15 - 155 AE 1:12 12 - 38 AE 1:4 7.3 10 38 AE 3:4 5.2* 6.7* AE 9:4 5.1* 6.7* A - CBDA, B - f-caryophyllene; C - CBD; E - Eudesmol; M - Myrcene; G - Caryophyllene oxide.
Table 16. Selected cannabinoid / terpene combinations based on systematic testing
Ratio NO TNF-a IL-6 (w/w) IC50 CI IC50 CI IC50 CI (pg/mL) (pg/mL) (pg/mL) C:B 9:8 1.8 0.64 6.6 - 4.7 1.37
C:0 3:4 1.9 0.55 4.9 7.2 2.6 0.76
C:0 9:4 1.4 0.66 4.9 0.7 4.2 1.7
C:M 9:4 1.7 0.79 Not active - 5.3 2.03
C:E 3:4 1.8 0.53 Not active - 3.1 0.79
C:E 9:4 1.8 0.86 Not active - 2.8 1.07
A:B 9:8 6 0.4 15.9 - 14.9 0.82
A:O 9:4 3.7 0.3 5.8 0.3 14 1.3
A:M 3:4 - - 9.9 0.49 11 0.71
A:M 3:4 3.5 0.29 9.4 4.7 97 7
A:E 3:4 5.3 0.3 6.7 0.2 Not active
A:E 9:4 - - 7.1 0.3 Not active
A - CBDA, B - -caryophyllene; C - CBD; E - Eudesmol; M - Myrcene; 0 - Caryophyllene oxide.
Table 17. Cannabinoid / terpene combinations selected for testing in prostaglandin assay
Ratio CBD Caryophyllene Myrcene Eudesmol p-caryophyllene (w/w) (mg) oxide (mg) (mg) (mg) (mg) CO 3:4 1 1 CM 9:4 2 1 CE 9:4 2 1 CBD: 10 3 3 3 terpene mixture 10:9 CB 9:8 1 1 B - -caryophyllene; C - CBD; E - Eudesmol; M - Myrcene; 0 - Caryophyllene oxide.
Table 18. IC50 of terpenes, cannabinoids and NSAIDs in prostaglandin assay
C 0 M E B Diclofenac Aspirin IC50 0.91 230 970 Not Not 0.0022 12 (tg/mL) active active 95% CI 0.76-1.1 Wide 214- - - 0.00028- 0.91-1.6 IC50 1325542 0.0028 (tg/mL) B - P-caryophyllene; C - CBD; E - Eudesmol; M - Myrcene; 0 - Caryophyllene oxide.
Table 19. IC5o and CI of terpenes and cannabinoids in prostaglandin assay
GraphPad Compusyn IC50 95% CI IC50 CI (ICo) CI (ICs) CI (IC90) (pg/mL) (pg/mL) 3- na - - -
caryophyllene Eudesmol na - - -
Myrcene 970 - 949 -
Diclofenac 0.0022 0.0002- - - - 0.0028 Aspirin 1.2 0.91-1.6 - - - Caryophyllene 230 wide 448 - - oxide CBD 0.91 0.76-1.1 0.91 - - CE 2:1 1.2 0.98-1.4 1.5 n 0.96 1 CB 1:1 5 4.0-6.3 5 n 1.4 0.75* CEMO 4.5 3.6-5.5 4.5 2.3 1.3 0.69* 9:3:3:3 CO 1:1 4.2 3.5-5.1 4.2 1.8 1.2 0.61* CM 2:1 2.5 1.9-3.3 2.5 4.6 1.5 1.2 B - -caryophyllene; C - CBD; E - Eudesmol; M - Myrcene; 0 - Caryophyllene oxide; na - not active.
Table 20. Summary of results for NO, IL-6, TNF-a and PGE2 assays
Assay/ IC50 (pg/mL) NO TNF-a IL-6 PGE2 CBD 1.3 4.7 1.8 0.91 CBDA 8.9 20 11 3-caryophyllene 42 na 79 na Caryophyllene oxide 35 19 11 230 Myrcene 145 21 23 971 Eudesmol 76 53 23 na CB 1:72 427 na 29 CB 1:3 38 na 26 CB 1:8 10 na 13 CB 3:8 4.1 na 6 CB 9:8 1.8* 4.5* 3.2* 5 CO 1:36 20 14 11 CO 1:12 8.4 12 9.7 CO 1:4 4.5 8.6 6.1 CO 3:4 1.9* 6.6 2.7* 4.2 CO 9:4 1.4* 3.4* 2.3* CM 1:36 50 na 13 CM 1:12 11 8.8 7.8 CM 1:4 6.6 11 5.6 CM 3:4 2.4 na 4.5 CM 9:4 1.7* na 3* 2.5 CE 1:36 411 na 8 CE 1: 12 9.4 na 11 CE 1:4 3.8 na 6.3 CE 3:4 1.8* 28 3.1*
CE 9:4 1.8 na 2.7* 1.2 CEMO - -- 4.5 B - 3-caryophyllene; C- CBD; E- Eudesmol; M- Myrcene; 0- Caryophyllene oxide; na - not active.
Claims (5)
1. A pharmaceutical composition comprising a cannabinoid and a terpene, wherein: a. the cannabinoid is selected from cannabidiol (CBD) or a pharmaceutically acceptable salt or functional derivative thereof, and cannabidiolic acid (CBDA) or a pharmaceutically acceptable salt or functional derivative thereof; and b. wherein the terpene is enriched for eudesmol or a pharmaceutically acceptable salt or functional derivative thereof.
2. The pharmaceutical composition of claim 1, comprising a cannabinoid :eudesmol ratio of from about 1:100 to about 10:1 (w/w).
3. The pharmaceutical composition of claim 2, comprising a cannabinoid :eudesmol ratio of from about 1:36 to about 9:4 (w/w).
4. The pharmaceutical composition of claim 3, comprising a cannabinoid :eudesmol ratio of about 2:1 (w/w).
5. A method for the treatment or prevention of an inflammatory condition, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 4 to a subject in need thereof.
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