WO2021252957A1

WO2021252957A1 - Cannabinoid complexes and methods of making and using them

Info

Publication number: WO2021252957A1
Application number: PCT/US2021/037093
Authority: WO
Inventors: Raimundo GARCIA; Neale DAVIS; David BURCHAM
Original assignee: Test Kitchens, Inc.
Priority date: 2020-06-11
Filing date: 2021-06-11
Publication date: 2021-12-16

Abstract

Cannabinoid complexes, compositions and formulations comprising those complexes, and methods of making and using them are provided.

Description

CANNABINOID COMPLEXES AND METHODS OF MAKING AND USING THEM

Claim of Priority under 35 U.S.C. §119

[0001] The present Application for Patent claims priority to Provisional Application No. 63/038,009 entitled “Cannabinoid Complexes and Methods of Making and Using Them” filed June 11, 2020, which is hereby expressly fully incorporated by reference herein.

BACKGROUND

Field

[0002] The invention relates to cannabinoid complexes, compositions and formulations comprising those complexes, and methods of making and using them.

Background

[0003] Cannabis, also known as hemp or marijuana, evolved about 28 million years ago on the eastern Tibetan Plateau. A close relative of the common hop found in beer, the plant still grows wild across Central Asia.

[0004] Hemp and cannabis have a 10,000 year old history of use and cultivation. The earliest recorded use of hemp cord in pottery was identified at a Taiwanese village approximately 8000 BC, Cannabis seeds and oil were used by the Chinese as food as early as 6000 BCE. Chinese farmers began to grow it for oil and for fiber to make rope, clothing, and paper more than 4000 years ago; the Scythians also cultivated it and used it to weave fine hemp cloth.

[0005] An early use of Cannabis as an intoxicant was established by clear physical evidence that mourners burned cannabis for its intoxicating fumes on a remote mountain plateau in Central Asia some 2500 years ago. (Jiang HE, Li X, Zhao YX, Ferguson DK, Hueber F, Bera S, Wang YF, Zhao LC, Liu CJ, Li CS (2006) A new insight into Cannabis sativa (Cannabaceae) utilization from 2500- year-old Yanghai Tombs, Xinjiang, China. J Ethnopharmacol 108:414. Ancient artwork and textual references from Syria to China hint at even earlier cannabis drug use. In India, “Bhang” (dried cannabis leaves, seeds and stems) was described in the Atharvaveda (“Science of Charms,” a Hindu sacred text from 2000-800BCE) as “Sacred Grass,” one of the five sacred plants of India. It is still used today, medicinally and ritually as an offering to Shiva. The Zoroastrian Zendavesta, an ancient Persian religious text of several hundred volumes refers to bhang as the "good narcotic” around 700-600 BCE.

[0006] The first recorded use of cannabis as medicine, by Emperor Shen Neng of China, was in 2737, while the earliest physical evidence of medicinal use (the presence of D6- tetrahydrocannabinol [Dό-THC] in ashes) dates to around 400AD. More recently, cannabis was described in the United States Pharmacopoeia for the first time in 1850, and subsequently was widely utilized as a patent medicine during the 19th and early 20th centuries.

[0007] Federal restriction of cannabis use and sale first occurred in 1937 with the passage of the Marihuana Tax Act. The Act was struck down in 1969 for violating the 5th Amendment prohibition against self-incrimination, only to be replaced by passage of The Controlled Substances Act (“CSA”) in 1970. The CSA classified cannabis as a Schedule I drug, prohibiting its use for any purpose based on its then lack of accepted medical use and presumed high potential for abuse. It remains illegal at the federal level, however legalization at the state level is accelerating, and federal legalization appears imminent.

[0008] See Medicinal Cannabis: History, Pharmacology, And Implications for the Acute Care Setting Bridgeman MB, Abazia DT. Medicinal Cannabis: History, Pharmacology, And Implications for the Acute Care Setting. P T. 2017;42(3):180- 188.Mary Bama Bridgeman.

Early Cannabinoid Research and the Discovery of the Endocannabinoid System

[0009] Research beginning in the last decades of the nineteenth century led to the isolation of cannabinol and cannabidiol (CBD) and the tentative isolation of a tetrahydrocannabinol by the end of the 1940s (see e.g. Todd AR. 1946. Hashish. Experientia 2:55-60). Starting in the 1960s, 9-tetrahydrocannabinol (THC) and numerous other plant cannabinoids were isolated, their structures were determined, most were also synthesized, and research into their biology began. (Paton WDM, Pertwee RG. 1973. The actions of cannabis in man. In Marijuana, ed. R Mechoulam, pp. 287- 333. New York: Academic 3. Mechoulam R. 1970. Marihuana chemistry. Science 168:1159-66). Advances in plant cannabinoid chemistry and the upsurge of cannabis use in the Western world led to extensive pharmacological and physiological research, particularly on THC and somewhat less on CBD, which continues to accelerate. Some clinical studies were also reported during this time. By the mid-1980s, a fairly detailed picture of the pharmacology of plant cannabinoids had emerged, but the mechanism of these effects remained unknown.

[0010] The CB1 and CB2 cannabinoid receptors were discovered in 1988 and 1993, respectively (Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC. 1988. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34:605-13; Munro S, Thomas KL, Abushaar M. 1993 Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61-65). Both receptors are activated by THC, As receptors are presumably formed in the living body to be activated not by plant constituents but rather by endogenous molecules, a search for such molecules led to the identification of arachidonoyl ethanolamide (anandamide) (10) and 2-arachidonoyl glycerol (2- AG) as endogenous agonists of these receptors. The enzymes involved in the synthesis and hydrolysis of these agonists were also identified, as well as proteins which act as chaperones that ferry the lipophilic ligands from the postsynaptic membranes in the brain where they are synthesized on demand and through the cytosol to reach their intracellular targets.

The Endocannabinoid System and its role in physiological processes and pathological disease states

[0011] Observation of cannabis’s psychoactive effects prompted research that led to the discovery of the endocannabinoid system. Components of that system include the CB 1 and CB2 receptors, endogenous cannabinoids and related compounds, binding and transport proteins and biosynthetic enzymes and metabolic enzymes.

Cannabinoid Receptors

[0012] CB1 and CB2 are both G protein coupled cannabinoid receptors. CB1 is found primarily in the central nervous system (CNS), and its activation leads to typical cannabis psychoactivity. CB2 is predominantly expressed in various immune cells. Activation of CB2 does not mediate psychoactivity, but instead is generally involved in protective biological actions. [0013] Endocannabinoids may also activate, albeit at higher concentrations, transient receptor potential cation channel subfamily V member 1 (TRPV1) channels (29) and numerous other receptors (30-34), including GPR18, GPR55, GPR92, GPR119, and peroxisome proliferator-activated receptor a (PPARa) (for a recent review, see 35). The pharmacology of GPR18 and GPR55 is related to that of CB1 and CB2, while that of GPR92 and GPR119 differs considerably.

Endogenous Ligands

[0014] Endogenous endocannabinoid receptor ligands, generally unsaturated fatty-acid ethanolamides, glycerols or glycerol ethers), include anandamide, primarily a CB1 ligand, and 2-arachidonoylglyceral (2-AG, a CB2 ligand. In addition to anandamide and 2-AG, other endogenous compounds are known to bind to the CB 1 and CB2 receptors and other receptors implicated in the endocannabinoid system include (1) N-homo-y- linolenoylethanolamine and (2) Ndocosatetr-aenoylethanolamine isolated from porcine brain and shown to bind to the cannabinoid CB1 receptor with high affinity, (3) 2- eicosa-5',8',H',14'- tetraenylglycerol, a metabolically stable ether-linked analogue of 2- arachidonoylglycerol (2-AG) present in human and murine blood; (4) Narachidonoyl dopamine (NADA) an endogenous “capsaicin-like” substance in mammalian nervous tissues that also activates cannabinoid CB1 receptors, but not dopamine D1 and D2 receptors, and (5) Virodhamine, an arachidonic acid and ethanolamine joined by an ester linkage and shown to have antagonist properties at the CB 1 cannabinoid receptor; (6) NAAA (N-acyl amino acids, which are longchain fatty acid amides with amino acids and NAE (long-chain fatty acid amides with ethanol amine), including PEA, (7) Endogenous peptides having CB 1 agonist or inverse agonist activity, including among them (8) “Pepcans” (e.g., Pepcan-12), for which no physiological role is yet known (Bauer M, et al. 2012. Identification and quantification of a new family of peptide endocannabinoids (pepcans) showing negative allosteric modulation at CB1 receptors. J. Biol. Chem. 287:36944-67) - endogenous peptides found to cause negative allosteric modulation of CB 1.

[0015] Notably, the pharmacology of the endocannabinoid system is further complicated by the fact that different compounds binding the same receptor can activate different biochemical pathways, likely explained by biased agonism. (52,53). Proteins effecting intracellular transport, re-uptake and release

[0016] Cytosolic binding proteins chaperone endocannabinoid receptor ligands to intracellular targets; may also be involved in uptake and transport to the presynaptic membranes.

Role of the endocannabinoid system in physiological processes and disease pathology

[0017] Today, the endocannabinoid system is known to be involved in a long list of physiological processes/functions and pathological disease states. See e.g., Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease- successes and failures. FEBS J. 2013;280(9):1918-1943. doi:10.1111/febs.12260.

Cannabis Chemistry and Plant “Chemovars”

[0018] The chemistry of C. sativa is known to be extraordinarily complex. Over 560 chemical compounds, including 104 phytocannabinoids, have been identified today. In addition to phytocannabinoids (C21 terpenophenolic compounds (C22 for the carboxylated forms) exerting physiological and often psychotogenic effect and possessing monoterpene and alkylresorcinol moieties in their molecules [4,5,6]), they include alkanes, sugars, nitrogenous compounds (such as spermidine alkaloids or muscarine), flavonoids, non-cannabinoid phenols, phenylpropanoids, steroids, fatty acids, approximately 140 different terpenes that are predominantly monoterpenes such as b-myrcene, a- and b-pinene, aterpinolene, but also sesquiterpenes including b- caryophyllene, di- and tri terpenes, as well as various other common compounds.

[0019] ( See ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A. Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod. 2017; 103:1-36 and Gonsalves J, Rosado T, Soares S, et al. Cannabis and Its Secondary Metabolites: Their Use as Therapeutic Drugs, Toxicological Aspects, and Analytical Determination. Medicines (Basel). 2019;6(1):31. Published 2019 Feb 23. doi:10.3390/medicines6010031.)

[0020] The main types of natural cannabinoids belong to the families of the cannabigerol-type, cannabichromene-type, cannabidiol-type, cannabinodiol-type, tetrahydrocannabinol-type, cannabinol-type, cannabitriol-type, cannabielsoin-type, isocannabinoids, cannabicyclol-type, cannabicitran-type, and cannabichromanone-type. They are generally categorized as varinic, acidic, or “minor” cannabinoids ( ._<?., that are not present in high quantities in common varieties of Cannabis sativa L). [0021] Out of over 100 cannabinoids identified so far, the most potent in terms of psychoactive activity is trans-D-9-tetrahydrocannabinol (THC). Four stereoisomers of THC exist, but only the (-)-trans isomer occurs naturally. Two structurally related substances (D9-tetrahydrocannabinol-2-oic acid and D9- tetrahydrocannabinol-4-oic acid - THCA) are usually also present, sometimes in large amounts. The heat of combustion during smoking converts partly THCA to THC. One isomer which is also active (D8-THC) occurs in much smaller amounts. Other related compounds include cannabidiol (CBD) and cannabinol (CBN), the latter particularly in aged samples, and presenting pharmacological effects different than those attributed to THC. All these compounds are collectively known as cannabinoids and, unlike many other psychoactive substances, are not nitrogenous bases.

[0022] Breeding efforts have produced an enormous variety of cannabis “chemovars” (plant varieties characterized in terms of their phytochemical profiles vs. the use of morphological taxonomic criteria traditionally used) that are enriched in single components, especially THC and CBD. Recently, cannabis breeders have begun breeding chemovars that are rich in the varinic-, minor- and acidic cannabinoids.

Cannabinoid Pharmacology and Therapeutic Use of Cannabinoids

[0023] The fact that THC and CBD bind CB1 and CB2 receptors are found in the human CNS and on the surface of human immune cells initially sparked the now rapidly accelerating interest in identifying potential therapeutic uses for cannabinoids and developing them as pharmaceuticals. However, owing to federal illegality of cannabis and cannabis-derived materials and resulting limitations on cultivation and possession, clinical research for most applications is still at a very early stage and relatively little is known about the pharmacology and pharmacokinetics of cannabinoid action or clinical applications.

Mechanism of Action and Therapeutic Uses of CBD and THC

[0024] Both old and new data on THC and CBD, as well as data on the lesser known cannabinoids, point to multiple signaling possibilities for cannabinoids. As discussed above, the CB1 and CB2 receptors are members of the rhodopsin-like class A GPCR superfamily; as such, they exhibit complex pharmacology. CB1 and CB2 can form heteroreceptor complexes with each other and with other GPCR receptors, which can display properties and activities distinct from those displayed by the individual receptors. Further complicating the picture is that the signaling elicited by a single compound via a particular receptor complex can vary widely depending on the conformation of the receptor complex at the time of binding. This complexity creates enormous challenges for pharmaceutical development of cannabinoids, but also provides the key to discovering new therapeutic uses for CBD and THC, and for identifying therapeutic uses for the lesser studies cannabinoids.

[0025] THC appears to behave as an agonist/partial agonist at CB1, decreasing levels of cytosolic cAMP, and as a partial agonist of CB2. In contrast, there is some evidence that CBD may indirectly affect CBIR-mediated signaling by ultimately inhibiting degradative enzymes, thereby increasing the levels of endogenous cannabinoids that are able to activate cannabinoid receptors [16]. More recent data demonstrates that CBD may have a bimodal dose-dependent mechanism of action with respect to CB 1 and CB2. In low doses, CBD acts as a negative allosteric modulator of both CB1 and CB2, while fairly high concentrations are required for CBD to act as a (partial) agonist upon binding to the orthosteric center.

[0026] The mechanisms of action for the lesser-known cannabinoids are still being investigated.

[0027] Even through research into pharmaceutical uses for cannabinoids and other cannabis-derived phytochemicals is still at an early stage, there is substantial evidence obtained from controlled research and clinical studies and published in peer-reviewed scientific publications, that demonstrate the value of using THC, CBD, cannabis plant material and plant extracts for a number of disease indications as well as to prevent or ameliorate associated symptoms. A recent comprehensive, in-depth review of existing evidence regarding the health effects of using cannabis and/or its constituents by an ad hoc committee of the National Academies of Sciences, Engineering and Medicine provides an excellent overview. Notably, the data reviewed by the NAACS committee were primarily studies of CBD, THC, whole cannabis, and whole-plant extracts.

[0028] See National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. https://doi.org/10.17226/24625. The committee’s findings are tabulated below. Table 1: Therapeutic Uses of Cannabinoid Compounds

_

[0029] To date, only three cannabinoid pharmaceuticals, all of them containing THC and/or CBD, have received regulatory approval. THC and its synthetic analog nabilone are FDA-approved only for the treatment of chemotherapy-induced nausea and vomiting and to stimulate appetite in cachexia associated with AIDS or terminal tumors. The oral mucosal spray Sativex (nabiximols in the United States), which contains 2.7 mg THC and 2.5 mg CBD per dose), is approved in over 30 countries for the management of pain primarily associated with multiple sclerosis (MS). Epidiolex, an orally administered preparation of pure CBD, approved by the FDA in 2018 for treatment of refractory childhood epilepsy syndromes (Dravet syndrome and Lennox- Gastaut syndrome).

[0030] Recent work provides evidence that CBD activity via receptors other than the canonical endocannabinoid receptors accounts for its efficacy with respect to treating Dravet syndrome. Cannabidiol increased survival and delayed worsening of neonatal welfare in Scnla+/- mice, reduced premature mortality, improved social behavior and memory function, and reduced anxiety-like and depressive-like behaviors, but did not show adverse effects on motor function or gait even with chronic administration. Patra PH et ah, Cannabidiol improves survival and behavioral co-morbidities of Dravet syndrome in mice. Br J Pharmacol. 2020;177(12):2779-2792. doi: 10.1111/bph.15003.

[0031] In addition to its therapeutic efficacy for refractory epilepsy syndromes, CBD’s potential anti-depressant activity and the underlying mechanisms were studied using the olfactory bulbectomy mouse model of depression (OBX). Behavioral tests (open field and sucrose preference tests) and neurochemical studies (microdialysis and autoradiography of 5-HT1A receptor functionality) were performed following treatment with CBD, and pharmacological antagonism of those effects of CBD were assayed to dissect out the mechanism of action. The data showed that CBD exerts fast and maintained antidepressant-like effects as evidenced by the reversal of the OBX-induced hyperactivity and anhedonia. In vivo microdialysis revealed that the administration of CBD significantly enhanced serotonin and glutamate levels in vmPFCx in a different manner depending on the emotional state and the duration of the treatment. The potentiating effect upon neurotransmitters levels occurring immediately after the first injection of CBD might underlie the fast antidepressant-like actions in OBX mice. Both antidepressant-like effect and enhanced cortical 5-HT/glutamate neurotransmission induced by CBD were prevented by 5-HT1A receptor blockade. Moreover, adaptive changes in pre- and post-synaptic 5-HT1A receptor functionality were also found after chronic CBD use. These results suggest that CBD could represent a novel fast antidepressant drug, via enhancing both serotonergic and glutamate cortical signaling through a 5-HT1A receptor-dependent mechanism. Linge R, et al. Cannabidiol induces rapid-acting antidepressant- like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuropharmacology. 2016;103:16- 26. doi: 10.1016/j .neuropharm.2015.12.017

Mechanisms of Action and Therapeutic Uses for the Lesser Known Cannabinoids

[0032] CBD and THC are the most well-studied of the cannabinoid compounds, but there is growing evidence for the therapeutic use of the lesser known cannabinoids. A recent review article summarizing the scientific literature regarding mechanisms of action and in vitro and in vivo disease models provides strong support for the considerable potential these molecules hold as pharmaceuticals for a for a broad scope of diseases. See Franco R et al. Biological potential of varinic-, minor-, and acidic phytocannabinoids [published online ahead of print, 2020 May 13]. Pharmacol Res. 2020; 104801. doi: 10.1016/j .phrs.2020.104801.

Additive, Synergistic and Entourage Effects of Phytocannabinoids

[0033] As discussed above, endocannabinoid ligand activity can be modified by lipids and other non-cannabinoid compounds, a phenomenon known as the “entourage effect” and first discovered in 1998. (Ben-Shabat, S., Fride, E., Sheskin, T., Tamiri, T., Rhee, M. H., Vogel, Z., et al. (1998) An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol. 353, 23-31. doi:10.1016/S0014- 2999(98)00392-6). Somewhat analogously, synergistic and additive interactions of cannabinoids can also play a role in mediating the pharmacological and physiological activities of cannabinoids. Without being bound by theory, it has been postulated that these types of effects help explain how botanical drugs are often more efficacious than their isolated components, a hypothesis that is entirely consistent with and plausible given the complex nature of cannabinoid signaling, (Mechoulam, R., and Ben-Shabat, S. (1999). From gan-zi-gun- nu to anandamide and 2-arachidonoylglycerol: the ongoing story of cannabis. Nat. Prod. Rep. 16, 131-143. doi: 10.1039/a703973e). Understanding the mechanisms underlying these effects and whether and how they might be leveraged for medicinal use of phytocannabinoids is an active area of research.

[0034] There is already existing data demonstrating that administration of plant extracts provide benefits not seen when comparable amounts of isolated compounds are administered as single agents. See e.g., Feldman et al., Potential combinations of endocannabinoid/endocannabinoid-like compounds and antibiotics against methicillin- resistant Staphylococcus aureus. PLoS One. 2020;15(4):e0231583. Published 2020 Apr 15. doi:10.1371/journal.pone.0231583; De Petrocellis et al.,. 2002. Effect on cancer cell proliferation of palmitoylethanolamide, a fatty acid amide interacting with both the cannabinoid and vanilloid signaling systems. Fundam. Clin. Pharmacol. 16:297-302); and Gouaze- Anders son et al., Inhibition of acid ceramidase by a 2- substituted aminoethanol amide synergistically sensitizes prostate cancer cells to N-(4- hydroxyphenyl) retinamide. Prostate. 2011;71(10):1064-1073. doi:10.1002/pros.21321. Additionally, there is evidence of whole plant extracts providing the same benefits but at significantly lower dosages than required when isolated cannabinoids are used, and with significantly reduced or no adverse side effects.

[0035] For example, anecdotal information from clinicians utilizing high-CBD Cannabis extracts to treat severe epilepsy, such as Dravet and Lennox- Gastaut syndromes, showed that their patients demonstrated notable improvement in seizure frequency (Goldstein, 2016; Russo, 2017; Sulak et al., 2017) with doses far lower than those reported in formal clinical trials of Epidiolex, a 97% pure CBD preparation with THC removed (Devinsky et al., 2016, 2017, 2018; Thiele et al., 2018). This observation was recently subjected to meta-analysis of 11 studies with 670 patients in aggregate (Pamplona et al., 2018). Those results showed that 71% of patients improved with CBD-predominant Cannabis extracts vs. 36% on purified CBD (p < 0.0001). The response rate at 50% improvement in seizure frequency was not statistically different in the two groups and both groups achieved seizure-free status in about 10% of patients. However, the mean daily doses were markedly divergent in the groups: 27.1 mg/kg/d for purified CBD vs. only 6.1 mg/kg/d. for CBD-rich Cannabis extracts, a dose only 22.5% of that for CBD alone. Furthermore, the incidence of mild and severe adverse events was demonstrably higher in purified CBD vs. high-CBD extract patients (p < 0.0001), a result that the authors attributed to the lower dose utilized, which was achieved in their opinion by the synergistic contributions of other entourage compounds. Such observations support the hypothesis of greater efficacy for Cannabis extracts combining multiple anticonvulsant components, such as CBD, THC, THCA, THCV, CBDV, linalool, and even caryophyllene (Lewis et al., 2018).

[0036] These studies and others provide a firm foundation for cannabis synergy, and support for botanical drug development vs. that of single components (BonnMiller et al., 2018), or production via fermentation methods in yeast or other micro-organisms. An example of the power of conventional selective breeding is illustrated in the form of a Cannabis chemovar named CARYODIOL (TM) for its enhanced caryophyllene content (0.83%) as a CB2 agonist, along with highly favorable Type III THC:CBD ratio of 1:39.4. Such a preparation portends to be applicable to treatment of numerous clinical conditions including: pain, inflammation, fibrotic disorders, addiction, anxiety, depression, autoimmune diseases, dermatological conditions and cancer. Pacher and Mechoulam, 2011; Russo, 2011; Xi et al., 2011; Russo and Marcu, 2017; Lewis et al., 2018. Producing such a combination from microbial sources might require combinations of cannabinoids from multiple yeast species and, as a result, it would represent a combination product subject to a difficult regulatory path compared to Cannabis preparations from extracts of a single species (e.g., nabiximols) that has been accepted as a unitary formulation in 30 countries across the globe (Food and Drug Administration, 2015).

[0037] Russo EB. The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No "Strain," No Gain. Front Plant Sci. 2019;9:1969. Published 2019 Jan 9. doi:10.3389/fpls .2018.01969” Recreational use and cannabis chemovars

[0038] D Like alcohol, cannabis is marketed for recreational use in the rapidly increasing number of states which have legalized it for that purpose. Cannabis breeders targeting the recreational market have produced an enormous variety of cannabis chemovars that vary widely in their phytochemical profiles, and recreational cannabis consumers often seek out specific individual chemovars (often referred to as “strains” or “varieties”) because of the particular subjective experience they provide to the user. However, current recreational products are inherently problematic. Inhalation of combustible material has obvious health risks, while edibles prepared with extracted oils or pure THC generally do not provide minor cannabinoids in concentrations high enough to provide full benefits or the characteristic subjective experience obtained by smoking owing to low concentration in plantae, first pass metabolism, and poor bioavailability due to both poor solubility in aqueous solutions and poor ability to cross cell membranes.

Technical problems addressed

[0039] A significant disadvantage of existing cannabinoid formulations is that because they are prepared from single, highly purified cannabinoid compounds, they cannot provide the advantages of the additive, synergistic or entourage effects provided by cannabinoid complexes.

[0040] Further, producing cannabinoid complex formulations using purified cannabinoids is untenable owing to the high cost of using purified individual components. De novo biochemical synthesis of cannabinoids has been shown to be non cost effective (Carvalho et ah, 2017). Moreover, a necessary prerequisite of reproducing the cannabinoid profile of a particular plant chemovar in order to reproduce that profile in a formulation necessarily requires costly and time-consuming analytical chemistry laboratory services.

[0041] While producing cannabinoids in microbial hosts such as yeast, and in genetically modified plants are potentially more economical, especially in cases where one or more of the components are present in relatively small quantities in plantae , this approach has significant drawbacks. The regulatory approval pathway for the use of microorganisms with multiple genetic alterations is long and costly. Moreover, the cost of preparing full-spectrum formulations using purified cannabinoids becomes progressively more expensive as the number of cannabinoids increases, even in microorganisms, as it requires multiple genetic modifications. Additionally, depending on the physical characteristics of each component, production of multi-cannabinoid formulations themselves can be a many- step process.

[0042] Existing broad- spectrum formulations do not offer nearly the same bioavailability to make micro-amounts of the minor cannabinoids beneficial to the human body. Other formulation procedures also degrade or lose the micro terpenes and cannabinoids that have lower flash points than the more frequently sought-after THC & CBD which have high flash points.

[0043] Hence there is a need for cannabinoid complex suitable for research, therapeutic, dietary, cosmetic and/or recreational use that

• are inexpensive, fast and efficient to produce,

• provide phytochemical profiles that are identical to or closely approximate the phytochemical profiles provided by specific cannabis chemovars,

• contain one or more of the minor cannabinoids, including cannabinoid complexes which are enriched in the minor cannabinoids, depleted of CBD, which can cause adverse effects when consumed in large amounts, and/or provide elevated levels of THC demanded by consumers of recreational cannabis products

[0044] There is a further need for cannabinoid complex formulations suitable for research, therapeutic, dietary and/or recreational use that provide elevated amounts of the minor cannabinoids and further provide improved bioavailability of those and other lipophilic bioactive phytochemicals which can also be present, including but not limited to THC.

[0045] There is further a need for compositions comprising such formulations, including but not limited to foods, beverages, dietary supplements, pharmaceuticals, and cosmetics.

[0046] There is further a need for methods of manufacturing cannabis complexes that are enriched in the minor cannabinoids, contain elevated amounts of THC and/or contain reduced amounts of CBD, as well as formulations containing those complexes.

SUMMARY

[0047] The cannabinoid complexes of the present invention meet these needs. [0048] Some embodiments of the invention relate to a multi-cannabinoid complex prepared from raffinate derived from cannabis plant biomass. In some embodiments, the raffinate can be a product of a purification of a cannabis plant distillate. In some embodiments, the raffinate can be depleted for a predominant cannabinoid present in the cannabis plant distillate by at least 33%. In some embodiments, the multicannabinoid complex can include two or more cannabinoid compounds selected from: cannabigerolic acid (CBG-A), cannabigerol (CBG), Cannabidiolic acid (CBD-A), Cannabidiol (CBD), D9 tetrahydrocannabinolic acid (THC-A), A9-tetrahydrocannabinol (THC), cannabichromenic acid (CBC-A)cannabichromene (CBC), Cannabigerovarinic (CBGV-A), Cannabidivarinic acid (CBDV-A), Cannabidivarin (CBDV), Tetrahydrocanabivarinic acid (THCV-A), tetrahydrocannabivarin (THCV), Cannabichromevarinic acid (CBCV-A), cannabinol (CBN), cannabicyclol (CBL) and/or cannabinodiolic acid (CBND-A). In some embodiments, none of the two or more cannabinoid compounds present in the complex constitutes greater than 59.9% of the total cannabinoids in the complex. In some embodiments, all cannabinoids in the complex except the predominant cannabinoid can exist in ratios that substantially correspond to ratios of the same cannabinoids in the cannabis plant biomass.

[0049] In some embodiments, the two or more cannabinoids can be selected from: cannabigerolic acid (CBG-A), cannabigerol (CBG), Cannabidiolic acid (CBD-A), Cannabidiol (CBD), cannabichromene (CBC), Cannabidivarin (CBDV) and/or cannabinol (CBN).

[0050] In some embodiments, the CBC, when present, can be present in a concentration range of from about 0% to about 10% w/v.

[0051] In some embodiments, CBG, when present, can be present in a concentration range of from about 0% to 59.9% w/v.

[0052] In some embodiments, CBD-A, when present, can be present in a concentration range of from about 0% to 10%.

[0053] In some embodiments, CBD, when present, can be present in a concentration range of from about 0% to about 59.9%.

[0054] In some embodiments, CBD-V, when present, can be present in a concentration range of from about 0% to about 10%.

[0055] In some embodiments, CBN when present, can be present in a concentration range of from about 0% to about 10%. [0056] In some embodiments, THC, when present, can be present in a concentration range from about 0% to about 59.9%.

[0057] In some embodiments, the predominant cannabinoid can be selected from THC, CBD, and CBG.

[0058] Some embodiments of the invention relate to a cannabinoid formulation including the multi-cannabinoid complex disclosed herein. In some embodiments, the formulation can be in a form selected from: an oil-based formulation, an aqueous formulation, a solid formulation, a powder formulation, an emulsion, a pre-spray emulsion and/or a pre-spray powder.

[0059] In some embodiments, the formulation can further include an emulsifier. In some embodiments, the emulsifier can be TPGS and/or Tween 80.

[0060] Some embodiments of the invention relate to a method of making a multi- cannabinoid complex. The method can include one or more of: a. providing raw cannabis biomass; b. extracting the raw plant material to produce first product, wherein the first product can be a crude cannabis oil or a cannabis distillate; c. removing the undesirable lipids, waxes, starches and/or esters from the first product to produce a de waxed cannabis oil; d. decarboxylating some or all of the cannabinoic acids present in the de- waxed cannabis oil by heating to a temperature of at least about 105 C to about 140 C for a period of at least about 20 minutes to about 120 minutes to produce a de waxed cannabis oil containing a cannabinoid complex including two or more neutral cannabinoid compounds, and wherein none of the two or more neutral cannabinoid compounds present in the complex constitutes greater than 59.9% of the total cannabinoids in the complex; and e. concentrating the cannabinoid complex by distillation of the decarboxylated cannabis oil to produce a distilled cannabis oil containing the cannabinoid complex including two or more cannabinoids selected from: cannabigerolic acid (CBG-A), cannabigerol (CBG), Cannabidiolic acid (CBD-A), Cannabidiol (CBD), D9 tetrahydrocannabinolic acid (THC-A), A9-tetrahydrocannabinol (THC), cannabichromenic acid (CBC-A)cannabichromene (CBC), Cannabigerovarinic (CBGV-A), Cannabidivarinic acid (CBDV-A), Cannabidivarin (CBDV), Tetrahydrocanabivarinic acid (THCV-A), tetrahydrocannabivarin (THCV), Cannabichromevarinic acid (CBCV-A), cannabinol (CBN), cannabicyclol (CBL) and/or cannabinodiolic acid (CBND-A). In some embodiments, one or more of the cannabinoid compounds can be a neutral cannabinoid. [0061] In some embodiments, the method can further include the step of: f. remediating the de-waxed cannabis oil to produce a refined cannabis oil enriched in the minor cannabinoids and depleted in CBD or THC.

[0062] In some embodiments, the raw cannabis biomass can include two or more varieties of cannabis selected to be combined in specified ratios to permit the distilled cannabis oil to possess a desired cannabinoid profile.

[0063] Provided herein are cannabinoid complexes having two or more cannabinoids, formulations, compositions and methods of making and using those cannabinoid complexes, formulations and compositions.

[0064] According to one aspect of the invention, the specification provides a cannabinoid complex having two or more cannabinoid compounds selected from the group consisting of cannabigerolic acid (CBG-A), cannabigerol (CBG), Cannabidiolic acid (CBD-A), Cannabidiol (CBD), A9-tetrahydrocannabinolic acid (THC-A), D9- tetrahydrocannabinol (THC), cannabichromenic acid (CBCA)cannabichromene (CBC), Cannabigerovarinic (CBGV-A), Cannabidivarinic acid (CBDV-A), Cannabidivarin (CBDV), Tetrahydrocanabivarinic acid (THCV-A), tetrahydrocannabivarin (THCV)Cannabichromevarinic acid (CBCV-A), cannabinol (CBN), cannabicyclol (CBL) and cannabinodiolic acid (CBND-A).

[0065] In one embodiment of this aspect of the invention, the cannabinoid profile is identical to or closely approximates the cannabinoid profile of the plant biomass from which the cannabinoid complexes were prepared. In another embodiment, the cannabinoid complex is enriched and/or depleted in one or more cannabinoid compounds. In various exemplary embodiments, the cannabinoid complex includes two or more cannabinoids selected from the group consisting of cannabigerolic acid (CBG- A), cannabigerol (CBG), Cannabidiolic acid (CBD-A), Cannabidiol (CBD), cannabichromene (CBC), Cannabidivarin (CBDV) and cannabinol (CBN). In alternate preferred embodiments, the cannabinoid complex is enriched in one or more minor cannabinoid compound, In preferred embodiments, the cannabinoid complex is enriched in one or both of CBN or CBG.

[0066] In various exemplary embodiments, the cannabinoid complex can contain one or more cannabinoid compounds selected from the group consisting of CBG, when present, in a concentration range of from about 0% to about 10% w/w; CBG, when present, in a concentration range of from about 0% to 59.9% w/w; CBD-A, when present, in a concentration range of from about 0% to 10%; CBD, when present, is present in a concentration range of from about 0% to about 59.9%; CBC, when present, in a concentration range of from about 0% to about 10%,w/w; CBD-V, when present, in a concentration range of from about 0% to about 10%, and CBN, when present, in a concentration range of from about 0% to about 10%.

[0067] In one exemplary embodiment, the cannabinoid complex is provided in an extracted cannabis oil. In a further exemplary embodiment, the cannabis oil containing the cannabinoid complex can optionally further contain one or more non-cannabinoid phytochemicals such as one or more terpenes, sesquiterpenes, phenolic compounds including volatile organic compounds (VOCs) or flavonoids.

[0068] In further alternative embodiments, the cannabinoid complex is provided as a formulation selected from the group consisting of an oil-based formulation, an aqueous formulation, a solid formulation, a powder formulation, an emulsion, a pre-spray emulsion and a pre- spray powder.

[0069] Another aspect of the invention provides a method of making a multicannabinoid complex. In one embodiment, the method includes the steps of (a) providing raw cannabis biomass, (b) extracting the raw plant material to produce a crude cannabis oil, (c) removing the undesirable lipids, fats and waxes from the crude cannabis oil to produce a de-waxed cannabis oil, (d) decarboxylating some or all of the cannabinoic acids present in the de-waxed cannabis oil by heating to a temperature of at least about 105 C to about 140 C for a period of at least about 20 minutes to about 120 minutes to produce a de-waxed cannabis oil containing a cannabinoid complex comprising two or more neutral cannabinoid compounds, and (e) concentrating the cannabinoid complex by distillation of the decarboxylated cannabis oil to produce a distilled cannabis oil containing the cannabinoid complex consisting of two or more cannabinoids selected from the group consisting of cannabigerolic acid (CBG-A), cannabigerol (CBG), Cannabidiolic acid (CBD-A), Cannabidiol (CBD), D9- tetrahydrocannabinolic acid (THC-A), A9-tetrahydrocannabinol (THC), cannabichromenic acid (CBCA)cannabichromene (CBC), Cannabigerovarinic (CBGV- A), Cannabidivarinic acid (CBDV-A), Cannabidivarin (CBDV), Tetrahydrocanabivarinic acid (THCV-A), tetrahydrocannabivarin

(THCV)Cannabichromevarinic acid (CBCV-A), cannabinol (CBN), cannabicyclol (CBL) and cannabinodiolic acid (CBND-A), wherein one or more of the cannabinoid compounds is a neutral cannabinoid.

[0070] In another embodiment, the method includes the further step of (e) remediating the distilled cannabis oil produced for CBD to produce a refined cannabis oil enriched in the minor cannabinoids and depleted in CBD.

[0071] Also provided are formulations comprising any of the cannabinoid complexes described above. Such formulations can be provided in the form of a liquid, such as an oil or aqueous solution, solid, powder, pre-spray emulsion or spray powder. These cannabinoid formulations can optionally contain one or more non-cannabinoid phytochemicals as above.

[0072] Also provided are compositions containing a cannabinoid complex as described above, including but not limited to foods, beverages, food additives, pharmaceuticals, cosmetics, and recreational products such as tinctures, sprays, nebulizers and topicals. In addition to the cannabinoid complex, such compositions can optionally contain non- cannabinoid phytochemicals as above and/or one or more additives such as one or more medicinal herbs, dietary supplements and/or VOCs.

[0073] Also provided herein are methods of making cannabinoid complexes from cannabis or hemp biomass that are less costly and require fewer steps and less time to manufacture than existing methods, and that can be customized to produce cannabinoid complexes having specific cannabinoid profiles. Also provided are methods of making cannabis oils which further contain one or more non-cannabinoid phytochemicals.

[0074] The cannabinoid complexes described and claimed herein, and the refined cannabis oils, formulations and products which contain them, provide a number of advantages over the prior art.

[0075] First, as will be described below, they are substantially cheaper, easier and less time-consuming to produce than cannabinoid complexes prepared using purified cannabinoids, chemically synthesized cannabinoids or cannabinoids produced using microorganisms or other bio-manufacturing processes.

[0076] Further the cannabinoid complexes described herein provide additive, synergistic and entourage effects that single isolated cannabinoids cannot provide.

[0077] Cannabinoid complexes that are enriched in the minor cannabinoids represent an improvement over existing full-spectrum cannabis oils known in the art because such oils are generally prepared using methods that maximize CBD and/or THC, and therefore do not provide a cannabinoid profile that is identical to or closely approximates the original plant material in terms of the relative concentrations of cannabinoids. Further, most of the minor cannabinoids are present in plantae in extremely small amounts, such that full spectrum oils produced by standard methods contain only negligible amounts of those minor cannabinoids, if any, and therefore those oils cannot provide the additive, synergistic and entourage effects provided by cannabinoid complexes according to aspects of the present invention.

[0078] Finally, the methods described and claimed herein make it is possible to quickly, easily and economically produce cannabinoid complexes with customized cannabinoid profiles, including profiles which reproduce or closely approximate the cannabinoid profile of specific cannabis plant chemovars, by either selecting one or more particular cannabis chemovars as the starting material or by modifying the manufacturing process to either enrich or deplete particular cannabinoids.

DETAILED DESCRIPTION

DEFINITIONS

[0079] The term “cannabis” as used herein refers collectively to plants of the Cannabaceae Cannabis genus/species, without regard to the particular subspecies, varietal designation, or relative THC content, and is intended to include plants commonly referred to as “hemp.”

[0080] The terms “crude extracted oil” refers to cannabis oil as it is originally extracted from plant biomass and that has not undergone any further processing, remediation or purification steps. “Semi-refined oil” refers to cannabis oil that has undergone at least one processing, remediation or purification step. “Refined oil” refers to cannabis oil that is the final product of the manufacturing process. “Remediated oil” refers to cannabis oil that has undergone a remediation step to remove one or more unwanted compounds, for example lipids, waxes, unwanted phytochemicals or contaminants.

[0081] The complex chemistry of cannabis and hemp includes over 560 compounds, collectively termed “phytochemicals,” including terpenes, sesquiterpenes, carbohydrates, fatty acids and their esters, amides, amines, phytosterols, phenolic compounds, volatile organic compounds (VOCs) and cannabinoids.

[0082] As used herein, the terms “phytocannabinoid,” “cannabinoid” and “cannabinoid compound” refers to both neutral cannabinoid compounds and cannabinoid acids, including but are not limited to cannabigerolic acid (CBG-A), cannabigerol (CBG), cannabidiolic acid (CBD-A), cannabidiol (CBD), D9 tetrahydrocannabinolic acid (THC- A), A9-tetrahydrocannabinol (THC), cannabichromenic acid (CBC-A), cannabichromene (CBC), cannabigerovarinic (CBGV-A), cannabigerovarin (CBGV), cannabidivarinic acid (CBDV-A), cannabidivarin (CBDV), tetrahydrocanabivarinic acid (THCV-A), tetrahydrocannabivarin (THCV), cannabichromevarinic acid (CBCV-A), cannabichromevarin (CBCV), cannabinol (CBN), cannabicyclol (CBL), cannabinodiolic acid (CBND-A) and cannabinodiol (CBND).

[0083] Cannabinoids can be divided into CBD, THC, neutral, varinic, acidic, and “minor” (i.e., cannabinoids that are not present in high quantities in common varieties of Cannabis sativa L).

[0084] As used herein, the term “cannabinoid profile” refers to the overall cannabinoid composition present in, for example, a plant, cannabinoid complex, composition or formulation, and can be described in terms of the particular cannabinoids present. A cannabinoid profile can also be described by further specifying the relative concentrations of each of the cannabinoid compounds present in terms of each cannabinoid compound’s relative concentration, expressed as % w/w relative to the total cannabinoid content.

[0085] As used herein, the term “substantially correspond” means that quantitative measures of properties in two compared compositions are proportionally the same, allowing for minor variations and normal errors in measurement. For example, if the ratio of THCV to CBDV is an original cannabinoid complex is 1:2, a substantially corresponding ratio in a raffinate would also be roughly 1:2 such as, for example 0.9:2, 1.1:2, 1:1.8, 1:1.9, 1:2.1, or 1:2.2.

[0086] As used herein, the term “enriched” refers to a cannabinoid that is present in a higher proportional concentration than was present in the plant material or crude cannabis oil from which it was prepared. Conversely the term “depleted” refers to cannabinoids that have a lower proportionate concentration as compared to its relative concentration in the plant material or crude cannabis oil from which it was prepared.

[0087] The term “cannabinoid complex” refers to a combination of two or more cannabinoid compounds that is prepared by a bulk process, the compounds being selected from the group consisting of CBG-A, CBG, CBD-A, CBD, THC-A, THC, CBC-A. CBC, CBGV-A, CBGV, CBDV-A, CBDV, THCV-A, THCV, CBCVA, CBCV, CBN, CBL, CBND-A, and CBND. In various preferred embodiments, the cannabinoid complex contains two or more cannabinoid compounds selected from the group consisting of CBG-A, CBG, CBD-A, CBD, CBC, CBDV and CBN. In various more preferred embodiments, the cannabinoid complex is enriched in CBD, THC and/or CBG.

[0088] The term “raffinate” refers to a post-extraction product from which a given desired component has been fully or partially extracted, isolated, and/or recovered. For example, in solvent extraction, the raffinate is the liquid stream which remains after solutes from the original liquid are removed through contact with an immiscible liquid. In practice, a crude oil prepared from cannabis biomass can be extracted by various means to obtain a purified “target component” such as, for example, CBD or THC. Extraction protocols focused on purity of the target component, rather than on maximal recovery of the target component, will typically leave some of the target component in the raffinate. Depending upon the extraction protocol, the other components that were present in the initial pre-extraction material will essentially all remain present in the raffinate, while the target component will also be present at some level in the raffinate, but will be quantitatively depleted in the raffinate in comparison with its original abundance in the pre-extraction material.

[0089] As used herein, the term “TPGS” or “Vitamin E TPGS” means D-a-tocopheryl polyethylene glycol succinate, a water-soluble derivative of natural Vitamin E.

METHODS OF MANUFACTURING CANNABINOID COMPLEXES

[0090] In accordance with one aspect of the invention, the specification provides a bulk process for manufacturing a cannabis oil containing a cannabinoid complex comprising two or more cannabinoids selected from the group consisting of CBG-A, CBG, CBD-A, CBD, THC-A, THC, CBC-A. CBC, CBGV-A, CBGV, CBDV-A, CBDV, THCV-A, THCV, CBCV-A, CBCV, CBN, CBL, CBND-A, and CBND. Embodiments of this aspect include processes that produce cannabinoid complexes having cannabinoid profiles that are identical to or closely approximate the cannabinoid profile of the plant material from there were prepared. In various exemplary embodiments, the process produces a cannabinoid complex containing the same cannabinoids as the plant biomass from which it is derived. In various other exemplary embodiments, the process produces a cannabinoid complex with a cannabinoid profile that is identical to or closely approximates the cannabinoid profile of the starting plant biomass and/or the crude cannabis oil initially extracted from the plant biomass, wherein further each of the cannabinoid compounds are present in a relative concentration that is the same as or closely approximates their relative concentration in the plant material or crude cannabis oil extract.

[0091] In various alternative embodiments, the process produces a cannabinoid complex that is enriched or depleted in one or more cannabinoid compounds selected from the group consisting of CBG-A, CBG, CBD-A, CBD, THC-A, THC, CBC-A. CBC, CBGV-A, CBGV, CBDV-A, CBDV, THCV-A, THCV, CBCV-A, CBCV, CBN, CBL, CBND-A, and CBND. Exemplary embodiments include processes which produce cannabinoid complexes that are enriched in one, two or all of THC, CBD, or CBG. In various alternative embodiments, the process produces a cannabinoid complex that is enriched in one or more of the minor cannabinoids, preferably CBG. In various other embodiments, the process produces cannabinoid complexes that are depleted in one or more cannabinoids, preferably CBD. In one exemplary embodiment, described in Example 1 below, the process produces a cannabinoid complex containing CBG-A, CBG, CBD-A, CBD, CBC, CBDV and CBN that is depleted in CBD and enriched in the remaining cannabinoids. In preferred embodiments, some or all of the neutral cannabinoid compounds are decarboxylated.

[0092] In various alternative embodiments, the process produces a cannabis oil containing a cannabinoid complex such as are described above, and that further contains one or more non-cannabinoid phytochemicals such as terpenes, sesquiterpenes, phenolic compounds including volatile organic compounds (VOCs) and flavonoids. In preferred embodiments of this aspect of the invention, a single bulk process is used.

[0093] In accordance with one aspect of the invention, the specification provides a process of producing a cannabinoid complex that includes the steps of

• Providing cannabis plant biomass and

• Extracting the biomass to produce a crude cannabis oil containing a cannabinoid complex having a cannabinoid profile that is the same as or closely approximates the cannabinoid profile of the cannabis plant biomass.

[0094] In various other embodiments, the crude cannabis oil undergoes further a processing step to remove undesirable or unwanted lipids, waxes, starches and/or esters. In one exemplary embodiment, the process includes the steps of • Providing cannabis plant biomass

• Extracting the cannabis plant biomass to produce a crude cannabis oil extract containing a cannabinoid complex having a cannabinoid profile that is the same as or closely approximates the cannabinoid profile of the cannabis plant biomass,

• Further processing the crude cannabis oil to remove undesirable lipids, fats, starches and/or esters to produce a semi-refined cannabis oil.

[0095] Optionally, the process can further include a decarboxylation step, preferably following removal of lipids, waxes, starches and esters, to convert some or all of the cannabinoic acids present in the semi-refined cannabis oil into their neutral forms. In one exemplary embodiment, the process includes the steps of

• Providing cannabis plant biomass,

• Further processing the crude cannabis oil to remove undesirable lipids, fats, starches and/or esters to produce a winterized cannabis oil free of unwanted lipids, waxes, starches and/or esters, and

• Decarboxylating some or all of the cannabinoid acids present in the winterized cannabis oil by heating to produce a decarboxylated cannabis oil containing neutral cannabinoid compounds.

[0096] Optionally, the process can include a further step of concentrating the cannabinoid complex. In one exemplary embodiment, the process includes the steps of

• Providing cannabis plant biomass,

• Further processing the crude cannabis oil to remove undesirable lipids, fats, starches and/or esters to produce a winterized cannabis oil free of unwanted lipids, waxes, starches and/or esters, and • Concentrating the cannabinoid oil to produce a concentrated cannabinoid complex.

[0097] In an alternate embodiment, the concentration step can follow decarboxylation. In one exemplary embodiment, the process includes the steps of

• Providing cannabis plant biomass,

• Further processing the crude cannabis oil to remove undesirable lipids, fats, starches and/or esters to produce a winterized cannabis oil free of unwanted lipids, waxes, starches and/or esters,

• Decarboxylating some or all of the cannabinoid acids present in the winterized cannabis oil by heating to produce a decarboxylated cannabis oil containing neutral cannabinoid compounds, and

• Concentrating the cannabinoid oil to produce a cannabis oil distillate containing a concentrated cannabinoid complex.

[0098] In still other alternative embodiments, the process can include one or more remediation steps to remove undesirable VOC's, hydrocarbons such as terpenes, polymeric terpenes, aldehydes, heavy metals, microbes such as yeast or molds, and microbial toxins, or to deplete selected cannabinoid compounds. In one exemplary embodiment, the process includes the steps of

• Providing cannabis plant biomass,

• Further processing the crude cannabis oil to remove undesirable waxes, lipids starches and/or esters to produce a semi-refined cannabis oil free of unwanted lipids, waxes, starches and/or esters,

• Concentrating the semi-refined cannabis oil to produce a cannabis oil distillate containing a concentrated cannabinoid complex, and • Remediating the semi-refined cannabis oil to remove selected cannabinoids to produce an oil depleted in the cannabinoids being removed and enriched in the remaining cannabinoid compounds.

[0099] In preferred embodiments, the process additionally includes a decarboxylation step, preferably following removal of undesirable waxes, lipids, starches and/or esters, for example:

• Providing cannabis plant biomass,

• Decarboxylating some or all of the cannabinoic acids present in the semirefined cannabis oil to convert them to their neutral forms, and

• Concentrating the semi-refined cannabis oil to produce a cannabis oil distillate containing a concentrated cannabinoid complex, and

• Remediating the semi-refined cannabis oil to remove selected cannabinoids to produce an oil depleted in the cannabinoids being removed and enriched in the remaining cannabinoid compounds.

[00100] Cannabis plant biomass is selected according to criteria that can include but is not limited to price and/or the desired phytochemical profile or cannabinoid profile of the final cannabinoid complex obtained, especially with respect to the minor cannabinoids.

[00101] In preferred embodiments the method uses cannabis biomass from a single cannabis chemovar chosen on the basis of its cannabinoid profile to produce a crude cannabis oil containing a cannabinoid complex having a cannabinoid profile that is identical to or closely approximates the cannabinoid profile of the plant chemovar. In alternative embodiments, two or more cannabis chemovars are selected to give a final cannabinoid complex having a particular cannabinoid profile. This approach offers the advantages of eliminating the need for additional remediation steps in the manufacturing process and/or the need to add purified components, both of which add expense and increase the time needed to produce the cannabinoid complex.

[00102] With respect to the extraction of raw cannabis plant biomass to produce a crude cannabis oil extract containing a cannabinoid complex, a number of extraction techniques are known in the art, including but not limited to organic solvent extraction using organic solvents such as ethanol, butane, propane or a combination thereof, carbon dioxide supercritical fluid extraction, and carbon dioxide subcritical fluid extraction. With respect to organic solvent extraction, the choice of solvent is in part determined by the relative scale of the extraction. In preferred embodiments, the method employs organic solvent extraction, propane or butane/propane as a solvent at a 70:30 to a 95:5 ratio, preferably 70:30. In a more preferred embodiment, butane is employed because it produces a crude cannabis oil extract that is relatively pure and typically requires fewer postprocessing purification steps than oils produced using other solvent systems, but having the distinct disadvantage of positing significant safety hazard when used in large amounts for large-scale extraction.

[00103] Optionally, the crude oil resulting from cannabis biomass extraction can be remediated to remove undesirable or unwanted compounds such as lipids, waxes, starches and/or esters. A number of methods for removing lipids and waxes are known in the art, the choice of method being determined in part by the initial extraction method employed. In one exemplary embodiment, “in-line dewaxing” is employed. In one exemplary embodiment, the plant biomass is first extracted using butane, and the resulting crude cannabis oil/butane mix is then transferred to a second chamber, where it is chilled to a temperature sufficient to precipitate undesirable and unwanted lipids and waxes, which are then removed via passing the chilled butane/oil mixture through qualitative filters held at the bottom of the chamber where the mixture is being chilled to precipitate undesirables. The mixture is pushed through the filters and into a collection vessel where the butane is evaporated and recovered, leaving a de-waxed cannabis oil containing a cannabinoid complex. In another exemplary embodiment of in-line de-waxing, butane extraction is followed by chilling the butane/cannabis oil extract mixture, then passing it under pressure through gradually reducing filter membranes to remove solidified material, leaving a dewaxed semi-refined crude oil.

[00104] In one exemplary embodiment, initial extraction of the crude cannabis oil and removal of unwanted lipids and waxes are accomplished in a single step. For example, the cannabis plant material is extracted using ethanol chilled to below 0C, preferably to 30C, and the solidified waxes are allowed to precipitate. The ethanol is recovered using a film evaporation system, leaving a de-waxed cannabis oil containing a cannabinoid complex.

[00105] In a preferred exemplary embodiment, unwanted lipids and waxes are removed following extraction of the crude cannabis oil by employing a winterization step. In various exemplary embodiments, the crude cannabis oil extract is dissolved in an organic solvent such as acetone, methanol, hexane, pentane or ethanol, or a mixture of two or more solvents. In general, the crude cannabis oil is dissolved in the solvent or solvent mixture at a ratio of 1:5 up to 1:20 oil to solvent, then chilled to precipitate the unwanted lipids and waxes, which are removed via a Buchner funnel filtration that employs a medium flow qualitative filter stacked under a quantitative filter, either under pressure or using vacuum-assisted flow. The remaining solvent is remediated, for example via a rotary evaporator or a falling film evaporator.

[00106] Decarboxylation of cannabinoic acids can be accomplished by gradually heating the crude oil extract or dewaxed oil, preferably in a resin reaction vessel at a minimum temperature of at least about 105 for at least about 20 minutes, preferably at 140 C for 2 hours. Optionally, a vacuum oven or convection oven can be employed.

[00107] Concentration of the cannabinoid complex can be accomplished, by a number of methods known in the art. The step is preferably performed after dewaxing of the crude oil, optionally after decarboxylation of some or all of the cannabinoic acids. In one embodiment, the cannabinoid complex is concentrated by distillation of the decarboxylated oil, for example by using a rolled film molecular distiller, a table-top short path distillation apparatus. In general, distillation methodology and apparatus are widely known in the art.

[00108] The concentrated oil can optionally be further remediated for CBD, THC or other cannabinoids and/or other unwanted or undesirable contents such as undesirable VOCs, hydrocarbons such as terpenes, polymerized terpenoids, long chain hydrocarbons, aldehydes, ketones and/or ketones, heavy metals, microbes such as yeasts or molds, microbial toxins such as mycotoxins, and others, by methods commonly known in the art. In one exemplary embodiment, decarboxylated distillate is subjected to a crash out recrystallization step in order to remove excess CBD. Alternately, remediation steps can be omitted, for example for embodiments where a final product high in CBD or which contains non-cannabinoid phytochemicals is desired.

[00109] In a preferred embodiment a pentane crash-out step is used to remove excess

CBD. In one exemplary embodiment, de-waxed cannabis oil is concentrated by distillation. The distillate is then weighed and combined with pentane at a 2:1 ratio with heating until the distillate is completely dissolved in the pentane; alternatively, 1:1 oihethanol is used. The resulting solution is placed into a food-safe container, then slowly cooled at a rate of at least 4 C per 10 minutes in a -10 C freezer until the CBD crystallizes and precipitates from solution, whereupon the crystalized CBD is removed and either discarded or saved for use for other purposes. The remaining solution is then relieved of pentane, for example by falling film evaporation followed by heating in a vacuum oven for 12 hours, or evaporative methods such as wiped film evaporation.

[00110] The resulting remediated oil contains a cannabinoid complex depleted in CBD and enriched in the minor cannabinoids. It can be used in a number of ways, for example as a stand-alone product, or to prepare cannabinoid complex formulations such as liquids, emulsions, solids, powders, pre-spray emulsions and/or spray powders, which are also enriched in minor cannabinoids.

[00111] In alternate embodiments, the process includes a remediation step to remove

THC, for example using a process includes the steps of

• Providing cannabis plant biomass,

• Further processing the crude cannabis oil by an in-line dewaxing process to remove undesirable waxes, lipids starches and/or esters to produce a semirefined cannabis oil free of unwanted lipids, waxes, starches and/or esters,

• Remediating the semi-refined cannabis oil to remove some or all of the THC to produce an oil depleted in THC and enriched in the remaining cannabinoid compounds, and

• Concentrating the semi-refined cannabis oil to produce a refined cannabis oil having a cannabinoid complex depleted of THC and enriched in the remaining cannabinoid compounds. [00112] In alternate exemplary embodiment, the process includes the steps of

• Providing cannabis plant biomass,

• Extracting the plant biomass by hydrocarbon extraction using to produce a slurry of butane mixed with crude cannabis oil containing a cannabinoid complex,

• Removing unwanted lipids, waxes, starches and esters from the slurry by inline dewaxing to produce a de-waxed cannabis oil containing the cannabinoid complex,

• Relieving the slurry of butane by apply heat to the collection vessel to achieve a butane-cannabis oil slurry containing between 10-30% butane, preferably 20% butane,

• Transferring the slurry to a pressure vessel and pressurizing the vessel to between about 50-100 psi, preferably lOOpsi, using an inert gas while simultaneously heating the slurry to a temperature of from about 90 F to 95 F,

• Periodically releasing volatilized butane and inert gas when the internal vessel pressure exceeds 100 psi until THC crystals are observed to form at the base of the vessel, and continuing to release volatilized butane until crystal formation is complete to produce a remediated cannabis oi mixed with THC crystals,

• Withdrawing heat from the vessel,

• Recovering the remediated cannabis oil by adding chilled pentane to the vessel, then separating the crystals from the pentane:cannabis oil slurry, and

• Relieving the slurry of pentane by evaporation using a rolling or falling film evaporation apparatus to produce a remediated cannabis oil depleted of THC.

[00113] In alternative embodiments, the extraction step can substitute pentane or a 70:30 butane:propane mix butane.

[00114] In alternative embodiments, the distillate is remediated for CBD, THC and other compounds using chromatographic methods, such as reverse or normal phase chromatography, centrifugal partition chromatography (CPC), high performance liquid chromatography (HPFC), and flash chromatography. [00115] Optionally, in cases where a cannabinoid complex high in CBD-A but low in

THC is desirable, the de-waxed cannabis oil is remediated for THC prior to decarboxylation.

[00116] The methods described and claimed herein offer a number of advantages over the prior art:

[00117] the processes require only a small number of steps, and are therefore faster, less expensive and more efficient,

[00118] the process can be used to manufacture multi-cannabinoid formulations that are enriched in minor cannabinoids more cheaply, quickly, and efficiently as compared to methods which employ individual purified cannabinoid compounds as their starting material,

[00119] the process can produce a cannabinoid complex having a total cannabinoid profile or alternatively a minor cannabinoid profile that is identical to or closely approximates the total or minor cannabinoid profile of the plant chemovar it was prepared from,

[00120] the process can be used to manufacture multi-cannabinoid formulations which have minor cannabinoid profiles that are identical to or closely approximate the cannabinoid profile of the plant chemovar from which the oil was isolated, without the need to first perform expensive chemical analysis to determine the cannabinoid profile, thus facilitating high-throughput production of cannabinoid complexes form multiple chemovars.

[00121] The process can be used to manufacture cannabinoid complexes having a specific cannabinoid profile by using a combination of plant chemovars as the starting material, thereby reducing or eliminating the need for downstream remediation or addition of purified cannabinoid compounds.

[00122] Cannabinoid complexes prepared according to the methods described herein are more marketable to consumers who consider isolated cannabinoids to be adulterated and therefore inferior.

CANNABINOID COMPLEXES

[00123] In accordance with another aspect of the invention, the specification provides cannabinoid complexes that contain two or more cannabinoid compounds selected from the group consisting of cannabigerolic acid (CBG-A), cannabigerol (CBG), cannabidiolic acid (CBD-A), cannabidiol (CBD), D9 tetrahydrocannabinolic acid (THC- A), A9-tetrahydrocannabinol (THC), cannabichromenic acid (CBC-A), cannabichromene (CBC), cannabigerovarinic (CBGV-A), cannabigerovarin (CBGV), cannabidivarinic acid (CBDV-A), cannabidivarin (CBDV), tetrahydrocanabivarinic acid (THCV-A), tetrahydrocannabivarin (THCV), cannabichromevarinic acid (CBCV-A), cannabichromevarin (CBCV), cannabinol (CBN), cannabicyclol (CBL), cannabinodiolic acid (CBND-A) and cannabinodiol (CBND).

[00124] Cannabinoid complexes can be characterized in terms of their cannabinoid profiles with respect to the individual cannabinoid compounds present and further with respect to the proportion each cannabinoid represents relative to the total cannabinoid content of a composition on a %w/w basis.

[00125] In one embodiment of this aspect, the cannabinoid compound contains the full profile of cannabinoid compounds present in the plant biomass from which it was prepared. In one exemplary embodiment, the cannabinoid complex contains the same cannabinoid profile as the starting plant material, and wherein the relative proportion of each individual cannabinoid is identical to or closely approximates the relative proportion on a % w/w basis of cannabinoids present in the original plant biomass. In alternative exemplary embodiments, a subset of cannabinoids maintains the same relative concentration with respect to a reference cannabinoid.

[00126] In alternative embodiments of this aspect, the specification provides cannabinoid complexes enriched or depleted in one or more cannabinoid compounds. In various preferred embodiments, the cannabinoid complex is enriched in one or more cannabinoids selected from CBG-A, CBG, CBD-A, CBD, THC-A, THC, CBC-A. CBC, CBGV-A, CBGV, CBDV-A, CBDV, THCV-A, THCV, CBCV-A, CBCV, CBN, CBL, CBND-A, and CBND.. In various preferred embodiments, the cannabinoid complex contains two or more cannabinoid compounds selected from the group consisting of CBG-A, CBG, CBD-A, CBD, CBC, CBDV and CBN. In various other preferred embodiments, the cannabinoid complex is enriched in CBD, THC and/or CBG. In various other preferred embodiments, the enriched cannabinoids are selected from CBN, CBD-A, CBDV, CBG-A, CBG, CBC and CBD. Exemplary embodiments include cannabinoid complexes that are enriched in THC, CBD or both THC and CBD. [00127] In still other, more preferred embodiments, the cannabinoid complex is enriched in one or more of the minor cannabinoids. In preferred exemplary embodiments, the cannabinoid complex is enriched in CBG or CBN, more preferably CBG.

[00128] In still other embodiments, the cannabinoid complex is depleted in THC.

[00129] The proportional concentration of a cannabinoid present in the cannabinoid complexes made in accordance with the present invention can vary. For example, in various exemplary embodiments, the cannabinoid complex comprises two or more of the following:

[00130] CBN present in a concentration range of from about 0% to about 10%, such as from about 0%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%;

[00131] CBD-A present in a concentration range of from about 0 to 10%, such as from about 0%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%;

[00132] CBD-V present in a concentration range of from about 0% to about 10%, such as from about 0%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%;

[00133] CBG present in a concentration range of from about 0% to about 59.9%, such as from 0% to about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, to about 55.9%;

[00134] CBG- A present in a concentration range from about 0% to about 10%, such as from about 0% to about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%; [00135] CBC present in a concentration range of from about 0% to about 10%, such as from about 0%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%;

[00136] CBD present in a concentration range of from about 0% to about 59.9%, such as from 0% to about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 55.9%, and/or

[00137] THC present in a concentration range of from about 0% to about 59.9%, such as from 0% to about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 55.9%.

[00138] The cannabinoid complexes described and claimed herein can be provided as a cannabis oil, which can optionally further contain one or more non-cannabinoid phytochemicals such as one or more terpenes, sesquiterpenes, phenolic compounds including volatile organic compounds (VOCs) and flavonoids.

[00139] Example 1 infra describes the preparation of a cannabis oil containing a cannabinoid complex enriches in CBG, CBC and delta-9 THC and depleted in CBD.

CANNABINOID COMPLEXES - EXEMPLARY USES

[00140] The cannabinoid complexes described herein, including refined cannabis oils that contain cannabinoid complexes alone or in combination with additional phytochemicals, are useful as stand-alone products or as ingredients useful for manufacturing products including but not limited to prescription and nonprescription pharmaceuticals, foods and beverages, dietary supplements, food additives, cosmetics, and recreational products, as will now be described.

[00141] A number of therapeutic uses for CBD, THC and CBG are known. Further, research into the mechanisms of action, pharmacology and pharmacokinetics of the less studied cannabinoids is highly active, as is research into the additive, synergistic and entourage effects obtained when two or more cannabinoids or whole plant extracts are co-administered. Cannabinoid complexes according to the present invention are therefore valuable research tools useful for further elucidation of the basis of cannabinoid bioactivity alone or in combination and for developing cannabinoid combinations as pharmaceuticals.

[00142] Further, there is high consumer demand for recreational products that contain full spectrum cannabinoids but are free of the health risks associated with smoking plant material. Specific cannabis chemovars are sought after because of the unique subjective experience they provide as a result of their phytocannabinoid profile. Hence recreational products that contain cannabinoid complexes of the present invention represent useful improvements over the existing art with respect to recreational products owing to their phytocannabinoid profiles and the fact that they can be administered orally or topically instead of by smoking.

CANNABINOID COMPLEX FORMULATIONS

[00143] In yet another aspect of the invention, the specification provides formulations of the cannabis complexes described herein, including formulations comprising a cannabinoid complex and which can optionally further contain one or more non- cannabinoid phytochemicals such as one or more terpenes, sesquiterpenes, phenolic compounds including volatile organic compounds (VOCs) and flavonoids.

[00144] The cannabinoid complexes provided herein can be provided in a number of different forms, including but not limited to liquid forms such as oils or aqueous solutions, emulsions or pre-spray emulsions, and solids such as powders or spray powders.

AQUEOUS FORMULATIONS

[00145] In yet another alternative embodiment, the specification further provides aqueous formulations of the cannabinoid complexes described above, and further provides methods of preparing them.

[00146] Cannabinoids administered orally generally exhibit poor bioavailability. Not only are the neutral cannabinoid compounds poorly soluble in water, “first pass effects” i.e., poor gut absorption due to poor cut wall permeability and deactivation by liver enzymes greatly reduce the amount of cannabinoids that reach the systemic circulation, resulting in low blood plasma concentrations. While a number of means of solubilizing lipophilic ingredients are known in the art, such as sonication or cavitation (electrostatic), general emulsifiers for hydrophobic, or hydrogen bonding interactions between the bioactive compounds and an encapsulating material, such methods generally cannot circumvent first pass effects.

[00147] In a preferred embodiment, the solubilizing means is a TPGS derivative of

Vitamin E. The use of TPGS offers a number of significant advantages. Its amphiphilic structure makes it a multifunctional drug delivery powerhouse that serves simultaneously as a solubilizer, absorption and permeation enhancer, emulsifier and surface stabilizer. Yang C et ak. Recent Advances in the Application of Vitamin E TPGS for Drug Delivery. Theranostics. 2018;8(2):464- 485. Published 2018 Jan 1. doi:10.7150/thno.22711. TPGS has also been shown to strongly enhance the secretion of chylomicrons at low concentration and enhance intestinal lymphatic transport Fan Z, et ak, A new function of Vitamin E-TPGS in the intestinal lymphatic transport of lipophilic drugs: enhancing the secretion of chylomicrons. Int J Pharm. 2013 Mar 10; 445(1- 2):141-7.

[00148] While the use of TPGS in cannabinoid compositions are known (e.g., US Pat.

No. 10,568, 865), such compositions have so far been limited to those containing purified CBD and THC. The present invention is therefore novel, as the cannabinoid complex used to prepare the formulations and compositions described and claimed herein are not purified cannabinoids, but instead contain two or more cannabinoid complexes having two or more cannabinoids prepared by a bulk process. They can therefore provide additive, synergistic and entourage effects not provided by single cannabinoid formulations or compositions. Moreover, formulations enriched in one or more minor cannabinoids can in addition provide therapeutic and recreational effects and benefits that are not provided by full- spectrum oils currently known in the art, since those oils generally contain negligible amounts of minor cannabinoids, if any owing to the lower flash points of the minor cannabinoids as compared to THC and CBD.

[00149] Cannabinoid complexes formulated as TPGS emulsions provide a number of important advantages. Without being bound by theory, TPGS greatly improves cannabinoid bioavailability, resulting in increased blood plasma concentration, and thereby improves efficacy, especially for cannabinoids present in low relative concentrations. In the alternative, it allows for the use of lower cannabinoid concentrations in the formulation without a loss of efficacy. TPGS offers the further advantages of high biocompatibility, enhanced drug solubility, improved drug permeation and selective antitumor activity. Notably, TPGS can inhibit the activity of ATP dependent P-glycoprotein and act as a potent excipient for overcoming multi-drug resistance (MDR) in tumor.

[00150] Optionally, surfactants and/or detergents such as for example polysorbate 80

(Tween 80) can be added as a co-surfactant to aid in dispersion and stability of the emulsion created by TPGS. In the alternative, polysorbate 80 can be used as an alternative to TPGS to create a water-soluble microemulsion containing the cannabinoid complex.

Preparation of aqueous cannabinoid formulations

[00151] Generally, such aqueous cannabinoid complex formulations can be prepared using the steps of

• Providing a cannabis oil containing a multi-cannabinoid complex

• Combining the cannabis oil containing the multi-cannabinoid complex with a solubilizing means and water to produce an aqueous solution containing the multi-cannabinoid complex.

[00152] In one exemplary embodiment of this aspect, the method includes the steps of

• Determining the desired amount of final product having a target payload of a reference cannabinoid,

• Selecting a final TPGS concentration between 92-95% TPGS w/w.

• Calculating the amount of TPGS

• Providing a cannabis oil containing a cannabinoid complex enriched in the minor cannabinoids

• Melting 92-95% TPGS per gram of oil in a jacketed reactor and heating to 60 C.

• Adding the cannabis oil to the TPGS with agitation to produce a uniform liquid containing polymeric micelles

• Slowly adding distilled water pre-heated to 60C titrating to produce a clear liquid crystal gel

• Slowly cooling the gel while continuously agitating it to liquify the gel and achieve a pseudo-emulsion wherein the cannabinoids are encapsulated by TPGS. [00153] In various other exemplary embodiments, the formulation can optionally be further modified by adding other ingredients, for example, flavor agents such as bitter blocker, preservatives such as for example polysorbate or sodium benzoate, or pH buffers and/or acidifiers such as for example citric acid depending on whether the formulation is used as a stand-alone product vs. as an additive for manufacturing foods, beverages and the like. The use of citric acid in particular provides the additional benefits of functioning as a preservative, a flavoring, a chelator. Moreover, the favor of citric acid is compatible with the cannabinoid payload, similar to terpenes such as limonene terpene.

[00154] An exemplary embodiment is described in Example 2 herein.

[00155] Aqueous formulations of the cannabinoid complex of the present invention are useful for a wide variety of purposes. Including as additives for foods, beverages, dietary supplements, pharmaceuticals, cosmetics and/or recreational products such as edibles such as foods and beverages, sprays and tinctures, They are especially useful for purposes of investigative research to more fully characterize the pharmacology, pharmacokinetics and physiological activity cannabinoid compounds, especially those associated with minor cannabinoids as well as additive, synergistic and entourage effects mediated by multiple cannabinoids. These effects can be investigated, for example by comparing the physiological effects of formulations which provide the same cannabinoid profile but vary with respect to the concentration of particular cannabinoids.

SOLIDS and POWDERS

[00156] In another embodiment, multi-cannabinoid complexes can be provided in the form of powders and solids.

EMULSIONS

[00157] In another embodiment, multi-cannabinoid complexes can be provided in the form of emulsions.

PRE-SPRAY EMULSIONS AND SPRAY POWDERS

[00158] In another embodiment, multi-cannabinoid complexes can be provided in the form of pre-spray emulsions and spray powders [00159] In another embodiment, multi-cannabinoid complexes can be provided in the form of recreational edibles, sprays, tinctures and/or oils.

COMPOSITIONS

[00160] In yet another aspect of the invention, the specification provides compositions such as prescription and non-prescription pharmaceuticals, foods, beverages, dietary supplements, food additives, cosmetics and recreational products such as tinctures, sprays, nebulizers and topical products. Such products can contain a wide variety of additives depending on their intended use.

[00161] For example, compositions of cannabinoid complexes in accordance with the present invention can contain one or more non-cannabinoid phytochemicals, including but not limited to one or alkanes, sugars, nitrogenous compounds, including but not limited to spermidine alkaloids or muscarine, flavonoids, noncannabinoid phenols, phenylpropanoids, steroids, fatty acids monoterpenes, including but not limited to b- myrcene, a- and b-pinene, a-terpinolene, and sesquiterpenes including but not limited to b-caryophyllene, di- and triterpenes.

[00162] Such compositions can contain, in addition or in the alternative, one or more medicinal herbs or homeopathic formulations including but not limited to one or more of aconite, apis, arnica, arsenicum, belladonna, calendula, hepar sulph, nux vomica, rhus tox and sulphur;

[00163] Such compositions can contain, in addition or in the alternative, one or more dietary supplements including but not limited to one or more vitamins, minerals, co enzymes, anti-oxidants, essential fatty acids and VOCs.

[00164] Such compositions can contain, in addition or in the alternative, one or more carriers including but not limited to one or more of medium-chain triglyceride (MCT) oil , coconut oil, avocado oil, vegetable cooking oil such as canola, olive, com, walnut, grapeseed, peanut and the like, butter, gelatin, chocolate, cocoa butter and flour and the like.

[00165] Such compositions can contain, in addition or in the alternative, one or more natural and/or artificial sweeteners, including but not limited to one or more of cane sugar, beet sugar, high fructose com syrup, stevia, glucose, sucrose, dextrose, sorbitol, xylitol, saccharine, sucralose aspartame, acesulfame potassium, neotame and the like. [00166] Such compositions can contain, in addition or in the alternative, one or more animal or vegetable milks including but not limited to one or more of cow’s milk, goat’s milk, sheep’s milk, coconut milk, almond milk, soy milk, or milk proteins such as casein and, whey proteins.

PHARMACEUTICAL FORMULATIONS & DOSAGE FORMS [00167] In another embodiment, multi-cannabinoid complexes can be provided as an active pharmaceutical ingredient (API) in pharmaceutical formulations and dosage forms.

RECREATIONAL PRODUCTS: EDIBLES, TINCTURES, SPRAYS, NEBULIZERS AND TOPICALS

[00168] In accordance with another aspect of the invention, the specification provides cannabinoid complexes containing two or more cannabinoid compounds selected from CBD-A, CBD, CBCA, CBC, CBGVA, CBG, THCVA, CBD-V, CBDVA, CBCVA, CBL, CBNDA, THCVA, THCV, CBN. In one embodiment, the cannabinoid complex is produced using any of the methods described above.

ADVANTAGES PROVIDED BY MULTI-CANNABINOID COMPLEXES and MULTIC ANNAB INOID COMPLEXES ENRICHED IN MINOR C ANN AB IN OIDS [00169] While single cannabinoid compositions and full spectrum cannabis oils are known in the art, cannabis oils, formulations and products containing cannabinoid complexes having cannabinoid profiles that are either identical to or that closely approximate the cannabinoid profile of the original plant material or that are enriched in one or more of the minor cannabinoids are new and previously unknown. Such compositions offer a number of advantages over single ingredient cannabinoid formulations, multi-cannabinoid compositions prepared form purified individual components and full spectrum oils. Without being bound by theory, the formulations described and claimed herein provide the following advantages:

[00170] they can be produced relatively cheaply using raw plant biomass as the starting material instead of requiring the use of expensive purified cannabinoid compounds [00171] single cannabinoid formulations cannot provide the additive, synergistic or entourage effects provided by the cannabinoid complexes described herein. [00172] Existing full spectrum formulations do not provide the same therapeutic benefits as are provided by cannabinoid formulations of the present invention owing to the fact that such oils contain very low concentrations of the minor cannabinoids, or lack those cannabinoids entirely, having been lost through the use of manufacturing processes that degrade or lose micro-terpenes and cannabinoids that have lower flash points than CBD and THC

[00173] a cannabinoid complex with a cannabinoid profile that is identical to or closely approximates the cannabinoid profile of a particular plant chemovar can provide the same therapeutic effects and subjective experience provided by smoking the combusted plant material but without the health risks associated with inhaling combusted materials; and

[00174] a cannabinoid complex having a cannabinoid profile that is identical to or closely approximates the minor cannabinoid profile of a particular plant chemovar provides a means to investigate and compare the therapeutic benefits and recreational effects of specific cannabis chemovars, as well provide the ability to tease out the contextual contribution of individual cannabinoids.

[00175] Finally, formulations comprising a cannabinoid complex and further comprising

TPGS are especially advantageous due to the increased bioavailability that TPGS imparts. Cannabinoids can therefore be administered in significantly lower amounts while still providing the same beneficial effects. Further, the biological effects of the minor cannabinoids, normally present in vanishingly low amounts or else entirely absent from prior art full spectrum formulations, are manifest in formulations according to the present invention owing to their enhanced concentration in formulations of the present invention, and are further increased by the increased bioavailability provided by TPGS in formulations which contain it.

EXAMPFES

[00176] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. EXAMPLE 1: PREPARATION OF A CANNABINOID COMPLEX ENRICHED

IN MINOR CANNABINOIDS.

[00177] Refined cannabis oil containing a cannabinoid complex enriched in minor cannabinoids was prepared as follows.

[00178] First, raw hemp biomass was processed into crude oil using hydrocarbon/co2/ethanol extraction. The crude oil was further processed to remove undesirable lipids/fats/waxes by dissolving the crude oil in ethanol in a 2:1 ratio, then cold precipitating and removing the lipids and waxes to produce a de-waxed cannabis oil.

[00179] Next, the cannabinoid acids were decarboxylated by placing the semirefined crude oil in a resin reaction vessel and heating it at 140 degrees Celsius for 2 hours. The decarboxylated crude was then distilled using a rolled film molecular distiller.

[00180] The distillate was remediated for excess CBD. After collection, the distillate was weighed and combined with pentane at a 2:1 ratio under heat to dissolve distillate in the reagent. The solution was then transferred into a food grade bucket and placed in a freezer at -10 degrees Celsius. CBD crystal precipitate is removed by filtration.

[00181] The pentane/cannabinoid solution was relieved of pentane by falling film evaporation leaving a semi-refined cannabis oil consisting of all minor cannabinoids as well as CBD. The semi-refined oil was then poured in a borosilicate pan approximately 2.5 inches thick and placed in a vacuum oven for 12 hours to remediate any residual pentane. After pentane was remediated to acceptable levels, the oil was collected for use in preparing a water soluble formulation consisting of (TPGS) and water.

[00182] The cannabinoid profile of the refined oil was determined and reported as % by dry weight.

[00183] Results: Total THC = 9.211%; Total CBD = 41.8; Total cannabinoids =

62.914% Potential active Delta-9 THC - 9.183% Results below 0.07% are reported as “trace.” Standard detection limit is +/- 0.02%; results below that limit were not reported. Individual cannabinoid compounds are tabulated below. Table 2: Cannabinoid profile of refined cannabis oil containing cannabinoid complex enriched in minor cannabinoids

EXAMPLE 2: PREPARATION OF AN AQUEOUS FORMULATION CONTAINING CANNABINOID COMPLEX ENRICHED IN CBG, CBC and

CBD-V

[00184] An aqueous formulation, containing cannabinoid complex prepared in Example

1, was prepared using TPGS as a solubilizer.

[00185] First, input parameters (target formulation volume, mg/ml CBD payload, concentrate potency were entered into a formulation spreadsheet designed to calculate reagent quantities based on target formulation parameters (specifically, target formulation volume (L), desired CBD payload (mg/ml), concentrate potency (%w/w), and %TPGS (%w/v between 93%-98%)) and cannabinoid oil parameters (specifically, relative concentration of a reference cannabinoid).

[00186] Calculations of reagent amounts were performed as follows:

CBD needed (gm) = target CBD payload (mg/ml) * (target formulation vol (L)/1,000)

Total TPGS needed (g) = (Total CBD concentrate (g) * Total parts TPGS) - CBD needed (g)

Sodium benzoate (g) = (0.1%*target formulation vol (L)) * 1000

Bitter Blocker (ml) = (0.3% * target formulation vol (L)) * 1000 Citric Acid (g) = (0.25% * target formulation vol (L)) * 1000

Total distilled water needed (g) = [1.016 * (Target vol (L) *1000)] - total ingredients sans water (g) target density = 1.016 ingredients sans water = CBD cone + TPGS + Sodium Benzoate + Bitter Blocker + Citric Acid

[00187] TPGS was then melted by placing it in a jacketed reactor set to 60C and

300rmps. After melting was complete, refined cannabis oil prepared in Example 1 was added and stirred until the mixture was fully homogenized.

[00188] Next, distilled water pre -heated to 60C was added to the TPGS/Cannabinoid complex mixture slowly until a clear liquid crystal gel was achieved, after which the rest of the water was added.

[00189] The temperature of the jacketed reactor was then cooled to approximately 20C over a 20 minute period with continued stirring to obtain a mixture free of large crystal gel particles. Stirring continued until the mixture was fully liquified, at which point bitter blocker was added, followed by citric acid, and then sodium benzoate.

[00190] The mixture was then filtered using a Buchner style filter funnel fitted with a 5 micron sintered disk filter under vacuum by slowly pouring the formulation into the funnel. When filtration was complete, the resulting formulation was transferred into a storage container and placed in a dark, cool area.

[00191] Since modifications will be apparent to those of skill in the art, it is intended that this invention be limited only by the scope of the appended claims.

[00192] The various methods and techniques described above provide a number of ways to carry out the application. Of course, it is to be understood that not necessarily all objectives or advantages described are achieved in accordance with any particular embodiment described herein. Thus, for example, those skilled in the art will recognize that the methods can be performed in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objectives or advantages as taught or suggested herein. A variety of alternatives are mentioned herein. It is to be understood that some embodiments specifically include one, another, or several features, while others specifically exclude one, another, or several features, while still others mitigate a particular feature by including one, another, or several other features.

[00193] Furthermore, the skilled artisan will recognize the applicability of various features from different embodiments. Similarly, the various elements, features and steps discussed above, as well as other known equivalents for each such element, feature or step, can be employed in various combinations by one of ordinary skill in this art to perform methods in accordance with the principles described herein. Among the various elements, features, and steps some will be specifically included and others specifically excluded in diverse embodiments.

[00194] Although the application has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the embodiments of the application extend beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and modifications and equivalents thereof.

[00195] In some embodiments, any numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the disclosure are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and any included claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the application are approximations, the numerical values set forth in the specific examples are usually reported as precisely as practicable.

[00196] In some embodiments, the terms “a” and “an” and “the” and similar references used in the context of describing a particular embodiment of the application (especially in the context of certain claims) are construed to cover both the singular and the plural. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (for example, “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the application and does not pose a limitation on the scope of the application otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application.

[00197] Variations on preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. It is contemplated that skilled artisans can employ such variations as appropriate, and the application can be practiced otherwise than specifically described herein. Accordingly, many embodiments of this application include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the application unless otherwise indicated herein or otherwise clearly contradicted by context.

[00198] All patents, patent applications, publications of patent applications, and other material, such as articles, books, specifications, publications, documents, things, and/or the like, referenced herein are hereby incorporated herein by this reference in their entirety for all purposes, excepting any prosecution file history associated with same, any of same that is inconsistent with or in conflict with the present document, or any of same that may have a limiting effect as to the broadest scope of the claims now or later associated with the present document. By way of example, should there be any inconsistency or conflict between the description, definition, and/or the use of a term associated with any of the incorporated material and that associated with the present document, the description, definition, and/or the use of the term in the present document shall prevail.

[00199] In closing, it is to be understood that the embodiments of the application disclosed herein are illustrative of the principles of the embodiments of the application. Other modifications that can be employed can be within the scope of the application. Thus, by way of example, but not of limitation, alternative configurations of the embodiments of the application can be utilized in accordance with the teachings herein. Accordingly, embodiments of the present application are not limited to that precisely as shown and described.

Claims

WHAT IS CLAIMED IS:

1. A multi-cannabinoid complex prepared from raffinate derived from cannabis plant biomass, wherein said raffinate is a product of a purification of a cannabis plant distillate, and wherein said raffinate is depleted for a predominant cannabinoid present in the cannabis plant distillate by at least 33%, wherein said multicannabinoid complex comprises two or more cannabinoid compounds selected from the group consisting of cannabigerolic acid (CBG-A), cannabigerol (CBG), Cannabidiolic acid (CBD-A), Cannabidiol (CBD), D9 tetrahydrocannabinolic acid (THC-A), A9-tetrahydrocannabinol (THC), cannabichromenic acid (CBC-A)cannabichromene (CBC), Cannabigerovarinic (CBGV-A), Cannabidivarinic acid (CBDV-A), Cannabidivarin (CBDV), Tetrahydrocanabivarinic acid (THCV-A), tetrahydrocannabivarin

(THCV)Cannabichromevarinic acid (CBCV-A), cannabinol (CBN), cannabicyclol (CBL) and cannabinodiolic acid (CBND-A), and wherein none of the two or more cannabinoid compounds present in the complex constitutes greater than 59.9% of the total cannabinoids in the complex, and wherein all cannabinoids in the complex except the predominant cannabinoid exist in ratios that substantially correspond to ratios of the same cannabinoids in the cannabis plant biomass.

2. The multi-cannabinoid complex of claim 1, wherein said two or more cannabinoids are selected from the group consisting of cannabigerolic acid (CBG-A), cannabigerol (CBG), Cannabidiolic acid (CBD-A), Cannabidiol (CBD), cannabichromene (CBC), Cannabidivarin (CBDV) and cannabinol (CBN).

3. The multi-cannabinoid complex of claim 2, wherein a. CBC, when present, is present in a concentration range of from about 0% to about 10% w/v, b. CBG, when present, is present in a concentration range of from about 0% to

59.9% w/v, c. CBD-A, when present, is present in a concentration range of from about 0% to 10%, d. CBD, when present, is present in a concentration range of from about 0% to about 59.9%, e. CBD-V, when present, is present in a concentration range of from about 0% to about 10%, f. CBN when present, is present in a concentration range of from about 0% to about 10%, and g. THC, when present, is present in a concentration range from about 0% to about 59.9%.

4. The multi-cannabinoid complex of claim 1, wherein the predominant cannabinoid is selected from THC, CBD, and CBG.

5. A cannabinoid formulation comprising the multi-cannabinoid complex of any of claims 1-4, wherein the formulation is in a form selected from the group consisting of an oil-based formulation, an aqueous formulation, a solid formulation, a powder formulation, an emulsion, a pre-spray emulsion and a pre-spray powder.

6. The cannabinoid formulation of claim 5, further comprising an emulsifier.

7. The cannabinoid formulation of claim 6, wherein the emulsifier is selected from TPGS and Tween 80.

8. A method of making a multi-cannabinoid complex comprising the steps of a. Providing raw cannabis biomass, b. Extracting the raw plant material to produce first product, wherein the first product is a crude cannabis oil or a cannabis distillate, c. Removing the undesirable lipids, waxes, starches and/or esters from the first product to produce a de-waxed cannabis oil, d. Decarboxylating some or all of the cannabinoic acids present in the de waxed cannabis oil by heating to a temperature of at least about 105 C to about 140 C for a period of at least about 20 minutes to about 120 minutes to produce a de-waxed cannabis oil containing a cannabinoid complex comprising two or more neutral cannabinoid compounds, and wherein none of the two or more neutral cannabinoid compounds present in the complex constitutes greater than 59.9% of the total cannabinoids in the complex e. Concentrating the cannabinoid complex by distillation of the decarboxylated cannabis oil to produce a distilled cannabis oil containing the cannabinoid complex comprising two or more cannabinoids selected from the group consisting of cannabigerolic acid (CBG-A), cannabigerol (CBG), Cannabidiolic acid (CBD-A), Cannabidiol (CBD), D9 tetrahydrocannabinolic acid (THC-A), A9-tetrahydrocannabinol (THC), cannabichromenic acid (CBC-A)cannabichromene (CBC), Cannabigerovarinic (CBGV-A), Cannabidivarinic acid (CBDV-A), Cannabidivarin (CBDV), Tetrahydrocanabivarinic acid (THCV-A), tetrahydrocannabivarin (THCV), Cannabichromevarinic acid (CBCV-A), cannabinol (CBN), cannabicyclol (CBL) and cannabinodiolic acid (CBND- A), wherein one or more of the cannabinoid compounds is a neutral cannabinoid.

9. The method of claim 8, further comprising the step of f. Remediating the de-waxed cannabis oil to produce a refined cannabis oil enriched in the minor cannabinoids and depleted in CBD or THC.

10. The method of claim 8, wherein the raw cannabis biomass comprises two or more varieties of cannabis selected to be combined in specified ratios to permit the distilled cannabis oil to possess a desired cannabinoid profile.