Cannabinoid-based preparations

Abstract

The present invention relates to cannabinoid-based formulations, and more particularly to methods for preparing cannabinoid-based formulations, the formulations themselves, and their use in therapy. The present invention particularly relates to cannabidiol (CBD)-based formulations, their manufacture, and their use for the treatment of pain, inflammation, autoimmune diseases, neurological disorders, neoplasms, nausea, hypertension, hypertrophic cardiomyopathy, or fibrosis.

Description

Technical Field

[0001] The present invention relates to cannabinoid-based formulations, and particularly to methods for preparing cannabinoid-based formulations, the formulations themselves, and their use in therapy, but are not limited thereto. The present invention particularly relates to cannabidiol (CBD)-based formulations for treating pain, inflammation, autoimmune diseases, neurological diseases, neoplasms, nausea, hypertension, hypertrophic cardiomyopathy, or fibrosis, their manufacture and use.

Background Art

[0002] Cannabinoids are several structural classes of compounds mainly contained in the cannabis plant. The most well-studied cannabinoids include cannabidiol (CBD), tetrahydrocannabinol (THC), and cannabinol (CBN). CBD is the most widely studied phytocannabinoid (i.e., cannabinoid derived from plants) because it has therapeutic activity and no psychoactive effects. Furthermore, this compound exhibits various pharmacological effects such as anti-inflammatory, analgesic, and anxiolytic effects, and has been used alone for multiple health conditions over the years.

[0003] In addition to the pharmacological activity of cannabinoids such as CBD, recent evidence suggests that terpenes (which are responsible for the aroma and flavor of many plants) are also pharmacologically active, as they are found in various amounts and types in Cannabis sativa plants and other plants. Terpenes can not only bind to the same receptors as cannabinoids in some cases, but they also have distinct beneficial effects of their own, modulating cannabinoids to create an entourage effect and potentially yielding better results than either chemical alone. The possible synergistic mechanisms of cannabinoids and terpenes involve the promotion of the active form of cannabinoid receptors, the regulation of endocannabinoid synthesis and degradation, and subsequent activation of these receptors by endocannabinoids. Furthermore, terpenes have been shown to enhance drug penetration through various mechanisms, which are described in detail elsewhere.

[0004] Unfortunately, CBD, used to treat various health conditions, is typically extracted directly from the cannabis plant. Standardizing CBD extracts is extremely difficult, if not impossible, due to various factors affecting the biochemical composition of the cannabis plant, including geographical location where the plant is cultivated, fluctuating growth conditions (i.e., soil and weather conditions), the timing of CBD extraction, and differences in extraction methods. This significant variability in cannabis plants and extraction parameters means that currently available CBD preparations suffer from the problem of inconsistent reproducibility, and therefore the amount of CBD stated on the label is not always accurate (Non-Patent Literature 1).

[0005] Furthermore, as mentioned earlier, cannabis plants can vary significantly in the levels and composition of terpenes, which are thought to contribute to a wide range of beneficial effects due to the entourage effect produced by the modulation of cannabinoids. However, current extraction methods do not allow for the reproducible and consistent extraction of terpenes from cannabis plants. Therefore, similar to CBD, this lack of reproducibility and batch-to-batch terpene variation means that customers cannot be confident that they are ingesting the exact same CBD / terpene mixture to treat their condition. Because the composition of CBD preparations differs from batch to batch, differences in therapeutic activity occur between batches of preparations. Moreover, there have been cases where switching from one preparation to another has had extremely harmful effects on a patient's health (Non-Patent Literature 2).

[0006] Another challenge with currently available CBD preparations is that direct extraction of CBD from natural cannabis plants frequently results in varying levels of tetrahydrocannabinol (THC) contamination. THC is a controlled substance with undesirable addictive and psychoactive effects that are not necessary for the beneficial effects of CBD in treating the various diseases listed above. Therefore, there are strict legal limits on the amount of THC that can be included in CBD preparations. However, THC poses safety concerns, and current extraction methods cannot completely remove THC when extracting CBD and terpenes from cannabis plants; in other words, CBD products often contain THC (Non-Patent Literature 1).

[0007] Preparations containing cannabinoids and terpenes are called cannabis-based products for medical use (CBPMs). CBPMs are being added to the treatment paradigm for many patients suffering from acute and chronic inflammatory diseases, pain, and negative emotional symptoms such as anxiety and depression, for which conventional therapies have limited or no effect. For this reason, the National Institute for Health and Care Excellence (NICE) and the International Association for the Study of Pain (IASP) are particularly calling for human studies using CBPMs. However, the need for treatment of multiple treatment-resistant diseases such as autoimmune diseases, fibromyalgia, chemotherapy-induced peripheral neuropathy (CIPN), and endometriosis remains unmet, as these are characterized by pain, inflammation, and other adverse effects that negatively impact the quality of life for patients suffering from these diseases. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Liebling et al., 2022, An Analysis of Over-the-Counter Cannabidiol Products in the United Kingdom, Cannabis and Cannabinoid Research, 7, 2, 207-213 [Non-Patent Document 2] Booth and Bohlmann, 2019, Terpenes in Cannabis sativa -From plant genome to humans, 284, July, 67-72 [Overview of the project] [Problems that the invention aims to solve]

[0009] Because there is currently no universal cure for the aforementioned diseases, most patients require multiple alternative treatments, which are often inconvenient and cause numerous side effects. Furthermore, while many CBD preparations are now available as food supplements and tout numerous health benefits, there is little evaluation of whether they are administered in appropriate formulations to achieve the blood concentrations required to support these claims. A recent study analyzing various CBD-containing products in the UK found that there was considerable variation in the actual levels of CBD present in these products, as well as varying levels of THC contamination (Non-Patent Literature 1). However, currently, there are no available CBD-containing products that comply with GMP standards.

[0010] Therefore, there is a need for new medical CBPM formulations for the treatment of various diseases such as pain, inflammation, autoimmune diseases, neurological disorders, neoplasms, nausea, hypertension, hypertrophic cardiomyopathy, and fibrosis. These formulations are manufactured in accordance with established pharmaceutical standards and GMP guidelines for use in medical research and clinical practice, as well as in food products, thereby facilitating access to pharmaceutical-grade CBPMs, supply for clinical trials, and contributions to patient benefit. Furthermore, to treat these diseases, there is a need to manufacture standardized cannabinoid (e.g., CBD)-based formulations that contain little to no THC and reproducible, consistent levels of the desired cannabinoids (which may be multiple) and associated terpenes. This standardization means that the composition and biological activity of CBD formulations are identical from batch to batch, thereby giving patients significantly greater confidence in CBPM products and their therapeutic effects for treating pain, inflammation, autoimmune diseases, neurological disorders, neoplasms, nausea, hypertension, hypertrophic cardiomyopathy, and fibrosis. [Means for solving the problem]

[0011] As described in the examples and shown in Figures 1 and 2, the inventors have devised an innovative method for producing embodiments of highly standardized CBD-based formulations for the treatment of pain, inflammation, autoimmune diseases, neurological disorders, neoplasms, nausea, hypertension, hypertrophic cardiomyopathy, and fibrosis, as shown in Tables 3, 7, and 8. The formulation initially consists of a mixture of cannabinoids, CBD, and highly specific terpenes, using a CBD isolate of known purity and a mixture of highly defined terpenes, allowing for the preparation of formulations in standardized amounts of each component while minimizing THC contamination.

[0012] Therefore, according to a first aspect of the present invention, a cannabinoid-based formulation, (i) One or more cannabinoids, (ii) A plurality of terpenes selected from the group of terpenes consisting of myrcene, caryophyllene, ocimene, pinene, limonene, humulene, and linalool, Includes, The formulations provided are cannabinoid-based formulations that are substantially THC-free.

[0013] In a second embodiment, a method is provided for producing a cannabinoid-based formulation according to the first embodiment, comprising (i) combining one or more cannabinoids with (ii) a plurality of terpenes selected from the group of terpenes consisting of myrcene, caryophyllene, ocimene, pinene, limonene, humulene, and linalool, wherein the formulation is substantially THC-free.

[0014] In a third embodiment, a cannabinoid-based formulation obtained or obtainable by the method of the second embodiment is provided.

[0015] In a fourth embodiment, a therapeutic cannabinoid-based formulation of the first or third embodiment is provided.

[0016] In a fifth aspect, a cannabinoid-based formulation according to the first or third aspect is provided for the treatment, improvement, or prevention of pain, inflammation, autoimmune diseases, neurological diseases, neoplasms, nausea, hypertension, hypertrophic cardiomyopathy, or fibrosis.

[0017] A sixth embodiment provides a method for treating, preventing or improving a subject suffering from pain, inflammation, autoimmune disease, neurological disease, neoplasm, nausea, hypertension, hypertrophic cardiomyopathy, or fibrosis, the method comprising administering or keeping to a subject in need of such treatment a therapeutically effective dose of a cannabinoid-based formulation according to the first or third embodiment.

[0018] Advantageously and preferably, the method of the second embodiment combines one or more cannabinoids of known purity with a plurality of terpenes, also of known purity, to produce a formulation of the first or third embodiment in which the concentration and purity of each component are fully standardized and fully reproducible with no variation between different batches. The cannabinoid-based formulation of the present invention will be understood herein to be referred to as MRX1. One embodiment of the formulation (i.e., "MRX1") is shown in Table 3. Thus, using the method of the second embodiment, a certificate of analysis can be issued for each batch of the formulation of the present invention, showing its stability data and evidence that there is substantially no THC contamination, thereby giving the patient complete confidence in the composition of the formulation and, consequently, its therapeutic effect.

[0019] THC can be detected using any standard analytical chemistry approach, such as liquid chromatography with ultraviolet (UV) or mass spectrometry (MS or MS / MS) detection (e.g., Lukas Vaclavik et al., (2019) 'Quantitation of Cannabinoids in Cannabis Dried Plant Materials, Concentrates, and Oils Using Liquid Chromatography-Diode Array Detection Technique with Optional Mass Spectrometric Detection: Single-Laboratory Validation Study, First Action 2018.11' Journal of AOAC INTERNATIONAL, Volume 102, Issue 6, 1 November 2019, Pages 1822-1833).

[0020] The concentration of THC in the formulation of the first or third embodiment is preferably less than 1000 μg per finished product, for example, in the case of 30 ml, this corresponds to 0.0033% (weight / volume). Therefore, the concentration of THC in the formulation is preferably less than 0.01% (weight / volume), more preferably less than 0.005% (weight / volume), and even more preferably less than 0.001% (weight / volume). Preferably, the concentration of THC in the formulation is less than 0.0005% (weight / volume), even more preferably less than 0.0002% (weight / volume), and most preferably less than 0.0001% (weight / volume). However, preferably, this formulation does not contain THC that can be detected using reasonable and validated analytical means.

[0021] The term "cannabinoid" may refer to any lipophilic ligand capable of interacting with receptors involved in the endocannabinoid system (ECS). Cannabinoids can include phytocannabinoids (i.e., plant-derived cannabinoids), endocannabinoids (i.e., endogenous cannabinoids), or synthetic cannabinoids (i.e., artificial). Conventionally, cannabinoids have been thought to selectively bind to cannabinoid receptors (CB) 1 and 2. However, further research in ECS pharmacology has led to the discovery of various molecular targets for cannabinoids independent of CBR1 and CBR2, such as transient receptor potential (TRP) channels and two orphan G protein-coupled receptors (GPR55 / 18). Chemically, cannabinoids are meroterpenoids (C 21~22 terpenophenol compounds) obtained by alkylation of alkylresorcinol and monoterpene units. These are mainly synthesized and stored within glandular trichomes and are most abundant in the female inflorescences of the cannabis plant.

[0022] One or more cannabinoids may be selected from the group of cannabinoids consisting of cannabidiol (CBD), cannabinol (CBC), cannabigerol (CBG), and cannabigerol monomethyl ether (CBGM). One or more cannabinoids may include two or more cannabinoids selected from the group consisting of cannabidiol (CBD), cannabinol (CBC), cannabigerol (CBG), and cannabigerol monomethyl ether (CBGM). One or more cannabinoids may include three or more cannabinoids selected from the group consisting of cannabidiol (CBD), cannabinol (CBC), cannabigerol (CBG), and cannabigerol monomethyl ether (CBGM). One or more cannabinoids may include four or more cannabinoids selected from the group consisting of cannabidiol (CBD), cannabinol (CBC), cannabigerol (CBG), and cannabigerol monomethyl ether (CBGM).

[0023] However, preferably, one or more cannabinoids include CBD. The one or more cannabinoids may include an isolate of CBD. Preferably, the formulation does not include CBC. Preferably, the formulation does not include CBG. Preferably, the formulation does not include CBGM.

[0024] Preferably, the chemical structure of CBD, a phytocannabinoid used in the method of the present invention, is of formula [I]:

Chemical formula

[0025] Referring to FIG. 1, in one embodiment, one or more cannabinoids can be prepared using solvent (e.g., alcohol or alkane) extraction from plant material (e.g., the inflorescence and / or leaves of Cannabis sativa), a slurry is generated, and then this slurry can be filtered to generate a crude liquid extract. The crude extract is then cooled (at less than -20 °C or less than -40 °C for at least 12 hours, preferably at -80 °C for 24 hours) to precipitate fats and waxes, and then this can be filtered to generate a "winterised" extract. The solvent can then be removed under reduced pressure, and the remaining crude product is preferably "decarboxylated" to convert acidic compounds to a neutral form, which is typically carried out at a temperature above 100 °C for at least 20 minutes, more preferably at 120 °C for at least 30 minutes. The obtained decarboxylated extract can then be further purified by distillation to remove residual exogenous non-cannabinoid materials. The distillation step can be carried out at 100 °C to 200 °C, preferably 130 °C to 180 °C, and may be a short-path distillation. After dissolving the obtained material in a solvent (e.g., alcohol) to near the saturation point of the solution, an anti-solvent (e.g., alkane) can be added (slowly) to induce crystallization. After the first crystallization (cannabinoids with a purity of about 95%, preferably CBD) is complete, the solid material can be filtered and redissolved in alcohol, and a second crystallization can be carried out to produce the isolated cannabinoids (preferably CBD) of the required specifications.

[0026] Referring to Figure 2, in a preferred embodiment, one or more cannabinoids may be prepared using enzymatic digestion of plant material (e.g., inflorescences and / or leaves of Cannabis sativa). The plant material may contain a water content of at least 20%, preferably at least 30%, and more preferably at least 40%. Preferably, the plant material is brought into contact with the enzyme solution. The enzyme solution preferably contains one or more enzymes selected from the group of enzymes consisting of cellulase, beta-glucosidase, hemicellulase, xylanase, glucanase, beta-glucanase, pectinase, amylase, alpha-amylase, phospholipase, beta-mannanase, arabinanase, phytase, and protease. Preferably, the pH of the enzyme solution is adjusted to at least about pH 4, more preferably at least about pH 5, and even more preferably about pH 5.6. pH adjustment may be achieved using citric acid. A weight ratio of 1:20 of aqueous enzyme solution to plant material may be used. Preferably, about 1% to 10% (by weight) of plant material is used per 99% to 10% (by weight) enzyme solution. The plant material is preferably macerated before, during, and / or after contact with the enzyme solution.

[0027] Preferably, the plant material is contacted with lipids to extract the plant compound of interest (i.e., cannabinoid). For example, the lipid may be vegetable oil, MCT oil, seed oil, or olive oil. The weight ratio of lipid to plant material is about 2:1, preferably 1:1, more preferably 1:1.5. The plant material is preferably macerated before, during, and / or after contact with lipids. The mixture is preferably stirred and macerated. The mixture is preferably stirred at a temperature of about 5°C to 80°C, more preferably 8°C to 65°C, most preferably 10°C to 50°C for at least 30, 40, or 60 minutes. Once the plant material is completely decomposed and dissolved, it is preferable to separate the oil phase and aqueous phase by gravity, centrifugation, filtration, or a combination thereof. The oil layer is preferably transferred to another container with a stirring function. Preferably, the oil layer is contacted with an aqueous base. The base may preferably be an aqueous solution of 0.1 M NaOH or KOH with a pH of 12 or higher. The weight of the basic aqueous solution may be 1:3, preferably 1:4, more preferably 1:5, relative to the cannabinoid-containing oil. This mixture is stirred for at least 10 to 20 minutes at a temperature preferably about 20°C to 100°C, more preferably 30°C to 90°C, and most preferably 40°C to 80°C. Once the previous step is complete, the mixture is brought into contact with preferably a combination of (i) sodium chloride and / or calcium carbonate and (ii) glucose and / or fructose. Preferably, this mixture is stirred for a further 10, 15, or 20 minutes.

[0028] Once complete, the layers may be separated, preferably by gravity or centrifugation, and then the aqueous layer may be separated. Preferably, the pH of the separated aqueous layer is reduced to less than 3, 2, or 1. This can be achieved by contacting the aqueous layer with an acid, more preferably phosphoric acid (e.g., 85% orthophosphoric acid). Preferably, the solution is stirred for a further 10, 15, or 20 minutes to produce a precipitate of cannabinoid salts. Preferably, this liquid is filtered to obtain a cannabinoid-rich solid precipitate with a total cannabinoid content of 65% to 90%. The cannabinoid-rich precipitate may then be heated at at least 90°C, 100°C, or 120°C for at least 30, 45, or 60 minutes, or until complete decarboxylation is achieved. The obtained material may be dissolved in a solvent (e.g., alcohol) to near the saturation point of the solution, and then crystallization may be induced by (slowly) adding a reverse solvent (e.g., alkane). Next, optionally, the solid material may be filtered and redissolved in a solvent (e.g., alcohol) to perform a second crystallization to produce isolated cannabinoids (preferably CBD) of the required specifications.

[0029] The purity of one or more cannabinoids (preferably CBD) may be at least 97%, at least 98%, or at least 99%, or about 98% to 100%, when measured by an HPLC-UV assay at a detection wavelength of 220 nm. As shown in Figure 3, the inventors possess a Certificate of Analysis (COA) for the CBD isolate. This standard is set to comply with the ICH Q3A guidance on impurities in novel drug substance ingredients, namely, to demonstrate that organic impurities (trace cannabinoids, solvents, etc.), inorganic impurities (e.g., heavy metals), and microbial contamination are well controlled. Of particular relevance is the decision to set the standard for d9-tetrahydrocannabinol at 0.02%, which is lower than the requirement that any single known organic impurity be 0.15% or less.

[0030] The concentration of one or more cannabinoids (preferably CBD) in a cannabinoid-based formulation may be at least 2% (weight / volume), at least 3% (weight / volume), or at least 4% (weight / volume). The concentration of one or more cannabinoids (preferably CBD) in a cannabinoid-based formulation may be at least 5% (weight / volume), at least 6% (weight / volume), or at least 7% (weight / volume). Preferably, the concentration of one or more cannabinoids (preferably CBD) in a cannabinoid-based formulation may be at least 8% (weight / volume), at least 9% (weight / volume), or at least 10% (weight / volume). Preferably, the concentration of one or more cannabinoids (preferably CBD) in a cannabinoid-based formulation may be at least 11% (weight / volume), or at least 12% (weight / volume).

[0031] The concentration of one or more cannabinoids (preferably CBD) in a cannabinoid-based formulation may be less than 20% (weight / volume), less than 19% (weight / volume), or less than 18% (weight / volume). The concentration of one or more cannabinoids (preferably CBD) in a cannabinoid-based formulation may be less than 17% (weight / volume), less than 16% (weight / volume), or less than 15% (weight / volume). Preferably, the concentration of one or more cannabinoids (preferably CBD) in a cannabinoid-based formulation may be less than 14% (weight / volume), less than 13% (weight / volume), or less than 12% (weight / volume). Preferably, the concentration of one or more cannabinoids (preferably CBD) in a cannabinoid-based formulation may be less than 11% (weight / volume), less than 10% (weight / volume), or less than 9% (weight / volume).

[0032] The concentration of one or more cannabinoids (preferably CBD) in a cannabinoid-based formulation may be 1% to 25% (weight / volume), 3% to 20% (weight / volume), or 5% to 17% (weight / volume). Preferably, the concentration of one or more cannabinoids (preferably CBD) in a cannabinoid-based formulation is 7% to 13% (weight / volume), 8% to 12% (weight / volume), or 9% to 11% (weight / volume). Preferably, the concentration of one or more cannabinoids (preferably CBD) in a cannabinoid-based formulation is about 10% (weight / volume). It will be understood that any of the lower limits of the concentration of one or more cannabinoids described herein can be combined with any of the upper limits of the concentration of one or more cannabinoids.

[0033] Multiple terpenes are selected from the group of terpenes consisting of myrcene, caryophyllene, ocimene, pinene, limonene, humulene, and linalool. Terpenes are lipids (complex compounds of fatty acids) and belong to the terpenoid family. Chemically, terpenes exhibit a distinctive carbon skeleton composed of basic 5-carbon isoprene units (C5H8, 2-methyl-1,3-butadiene) most commonly linked in a head-to-tail orientation. However, they can be constructed in other configurations with varying degrees of oxidation, unsaturation, functional groups, and cyclization, resulting in a highly diverse range of structural classes. However, terpenes can be categorized according to the number (n) of isoprene units in the molecule. Isoprenes are gaseous hydrocarbons released from several plants as natural byproducts of plant metabolism. However, some larger and more complex terpenes, such as squalene and lanosterol, are also found in animals.

[0034] As shown in Figures 1 and 2, multiple terpenes can be prepared by first steam distillation of suitable plant species to produce essential oils. The resulting essential oils can then be purified by chromatography (preferably flash chromatography) to separate the individual terpene components to the desired purity.

[0035] The purity of multiple terpenes, when measured by GC-MS, can be at least 90%, preferably at least 92%, and more preferably at least 95% of the total terpenes.

[0036] Multiple terpenes can be selected from the group of terpenes shown in Table 1.

[0037] TIFF2026517935000003.tif45170

[0038] Therefore, multiple terpenes can be selected from the group of terpenes consisting of monoterpenes, sesquiterpenes, diterpenes, sesterpenes, triterpenes, tetraterpenes, and polyterpenes.

[0039] Preferably, the monoterpene is selected from the group of monoterpenes consisting of alpha-pinene, limonene, cis-ocimene, beta-myrcene, and linalool.

[0040] Preferably, the sesquiterpene is selected from the group of sesquiterpenes consisting of beta-caryophyllene and alpha-humulene.

[0041] The chemical structures of terpenes that may be present in a pharmaceutical formulation are shown below. Terpenes are classified according to the number of carbon atoms. Monoterpenes [ka]

[0042] Sesquiterpenes [ka]

[0043] As described in the examples, the inventors have synthesized preferred embodiments of the cannabinoid-based formulations of the present invention having specific terpene compositions. These embodiments also include cannabinoids (i.e., CBD) and excipients or carriers (e.g., MCT oil). In one embodiment, the composition is a formulation summarized in Table 3, and its terpene mixture is described below.

[0044] Preferably, the plurality of terpenes comprises at least three terpenes selected from the group of terpenes consisting of myrcene, caryophyllene, ocimene, pinene, limonene, humulene, and linalool.

[0045] Preferably, the plurality of terpenes comprises at least four terpenes selected from the group of terpenes consisting of myrcene, caryophyllene, ocimene, pinene, limonene, humulene, and linalool.

[0046] Preferably, the plurality of terpenes comprises at least five terpenes selected from the group of terpenes consisting of myrcene, caryophyllene, ocimene, pinene, limonene, humulene, and linalool.

[0047] Preferably, the plurality of terpenes comprises at least six terpenes selected from the group of terpenes consisting of myrcene, caryophyllene, ocimene, pinene, limonene, humulene, and linalool.

[0048] Preferably, the plurality of terpenes comprises at least seven terpenes selected from the group of terpenes consisting of myrcene, caryophyllene, ocimene, pinene, limonene, humulene, and linalool.

[0049] Therefore, in preferred embodiments of the cannabinoid-based formulations of the present invention, the plurality of terpenes include pinene, and more preferably include α-pinene.

[0050] The concentration of α-pinene in a cannabinoid-based formulation may be at least 0.0001% (weight / volume), or at least 0.001% (weight / volume). Preferably, the concentration of α-pinene in a cannabinoid-based formulation may be at least 0.005% (weight / volume), at least 0.01% (weight / volume), or at least 0.02% (weight / volume). The concentration of α-pinene in a cannabinoid-based formulation may be less than 0.75% (weight / volume), less than 0.5% (weight / volume), or less than 0.3% (weight / volume). The concentration of α-pinene in a cannabinoid-based formulation may be less than 0.2% (weight / volume), less than 0.15% (weight / volume), or less than 0.1% (weight / volume). The concentration of α-pinene in the cannabinoid-based formulation may be 0.0001% to 0.5% (weight / volume), 0.01% to 0.3% (weight / volume), or 0.01% to 0.2% (weight / volume). The concentration of α-pinene in the cannabinoid-based formulation may be 0.01% to 0.05% (weight / volume), 0.01% to 0.04% (weight / volume), or 0.01% to 0.03% (weight / volume). Preferably, the concentration of α-pinene in the cannabinoid-based formulation is about 0.02% (weight / volume). Preferably, the concentration of α-pinene in the cannabinoid-based formulation is about 0.0225% (weight / volume). Preferably, the concentration of α-pinene in the cannabinoid-based formulation is about 0.0230% (weight / volume). More preferably, the concentration of α-pinene in the cannabinoid-based formulation is approximately 0.0329% (weight / volume). It will be understood that any lower limit of α-pinene concentration described herein can be combined with any upper limit of α-pinene concentration.

[0051] In a preferred embodiment, the terpenes include limonene.

[0052] The concentration of limonene in a cannabinoid-based formulation may be at least 0.0001% (weight / volume), or at least 0.001% (weight / volume). Preferably, the concentration of limonene in a cannabinoid-based formulation may be at least 0.005% (weight / volume), at least 0.01% (weight / volume), or at least 0.02% (weight / volume). The concentration of limonene in a cannabinoid-based formulation may be less than 0.75% (weight / volume), less than 0.5% (weight / volume), or less than 0.3% (weight / volume). The concentration of limonene in a cannabinoid-based formulation may be less than 0.2% (weight / volume), less than 0.15% (weight / volume), or less than 0.1% (weight / volume). The concentration of limonene in the cannabinoid-based formulation may be 0.0001% to 0.5% (weight / volume), 0.01% to 0.3% (weight / volume), or 0.01% to 0.2% (weight / volume). The concentration of limonene in the cannabinoid-based formulation may be 0.01% to 0.05% (weight / volume), 0.01% to 0.04% (weight / volume), or 0.01% to 0.03% (weight / volume). The concentration of limonene in the cannabinoid-based formulation may be 0.03% to 0.09% (weight / volume), 0.03% to 0.08% (weight / volume), or 0.03% to 0.07% (weight / volume). Preferably, the concentration of limonene in the cannabinoid-based formulation is about 0.02% (weight / volume). Preferably, the concentration of limonene in the cannabinoid-based formulation is about 0.0225% (weight / volume). Preferably, the concentration of limonene in the cannabinoid-based formulation is about 0.060%. More preferably, the concentration of limonene in the cannabinoid-based formulation is about 0.0329%. It will be understood that any of the lower limits of limonene concentration described herein can be combined with any of the upper limits of limonene concentration.

[0053] In preferred embodiments, the plurality of terpenes include ocimene, and more preferably β-ocimene.

[0054] The concentration of β-ocimene in a cannabinoid-based formulation may be at least 0.0001% (weight / volume), or at least 0.001% (weight / volume). Preferably, the concentration of β-ocimene in a cannabinoid-based formulation may be at least 0.005% (weight / volume), at least 0.01% (weight / volume), at least 0.02% (weight / volume), or at least 0.03% (weight / volume). The concentration of β-ocimene in a cannabinoid-based formulation may be less than 0.75% (weight / volume), less than 0.5% (weight / volume), or less than 0.3% (weight / volume). The concentration of β-ocimene in a cannabinoid-based formulation may be less than 0.2% (weight / volume), less than 0.15% (weight / volume), or less than 0.1% (weight / volume). The concentration of β-ocimene in a cannabinoid-based preparation may be 0.0001% to 0.5% (weight / volume), 0.01% to 0.3% (weight / volume), or 0.01% to 0.2% (weight / volume). The concentration of β-ocimene in a cannabinoid-based preparation may be 0.01% to 0.07% (weight / volume), 0.01% to 0.06% (weight / volume), 0.01% to 0.05% (weight / volume), or 0.01% to 0.04% (weight / volume). The concentration of β-ocimene in a cannabinoid-based preparation may be 0.001% to 0.05% (weight / volume), 0.001% to 0.04% (weight / volume), 0.001% to 0.02% (weight / volume), or 0.001% to 0.01% (weight / volume). Preferably, the concentration of β-ocimene in the cannabinoid-based formulation is about 0.03% (weight / volume). Preferably, the concentration of β-ocimene in the cannabinoid-based formulation is about 0.0302% (weight / volume). More preferably, the concentration of β-ocimene in the cannabinoid-based formulation is about 0.01% (weight / volume). More preferably, the concentration of β-ocimene in the cannabinoid-based formulation is about 0.008% (weight / volume). It will be understood that any of the lower limits of β-ocimene concentration described herein can be combined with any of the upper limits of β-ocimene concentration.

[0055] In preferred embodiments, the terpenes include caryophyllene, preferably β-caryophyllene.

[0056] The concentration of β-caryophyllene in a cannabinoid-based formulation may be at least 0.0001% (weight / volume), or at least 0.001% (weight / volume). Preferably, the concentration of β-caryophyllene in a cannabinoid-based formulation may be at least 0.005% (weight / volume), at least 0.01% (weight / volume), at least 0.02% (weight / volume), at least 0.03% (weight / volume), or at least 0.04% (weight / volume). The concentration of β-caryophyllene in a cannabinoid-based formulation may be less than 0.75% (weight / volume), less than 0.5% (weight / volume), or less than 0.3% (weight / volume). The concentration of β-caryophyllene in a cannabinoid-based formulation may be less than 0.2% (weight / volume), less than 0.15% (weight / volume), or less than 0.1% (weight / volume). The concentration of β-caryophyllene in cannabinoid-based preparations may be 0.0001% to 0.5% (weight / volume), 0.01% to 0.3% (weight / volume), or 0.01% to 0.2% (weight / volume). The concentration of β-caryophyllene in cannabinoid-based preparations may be 0.01% to 0.08% (weight / volume), 0.01% to 0.07% (weight / volume), 0.01% to 0.06% (weight / volume), or 0.01% to 0.05% (weight / volume). The concentration of β-caryophyllene in cannabinoid-based preparations may be 0.01% to 0.1% (weight / volume), 0.01% to 0.09% (weight / volume), 0.01% to 0.08% (weight / volume), or 0.03% to 0.08% (weight / volume). Preferably, the concentration of β-caryophyllene in the cannabinoid-based formulation is about 0.05% (weight / volume). Preferably, the concentration of β-caryophyllene in the cannabinoid-based formulation is about 0.0459% (weight / volume). Preferably, the concentration of β-caryophyllene in the cannabinoid-based formulation is about 0.07% (weight / volume). Preferably, the concentration of β-caryophyllene in the cannabinoid-based formulation is about 0.071% (weight / volume). More preferably, the concentration of β-caryophyllene in the cannabinoid-based formulation is about 0.0671% (weight / volume).It will be understood that any of the lower limits of β-caryophyllene concentrations described herein can be combined with any of the upper limits of β-caryophyllene concentrations.

[0057] In a preferred embodiment, the terpenes include humulenes, preferably alpha-humulenes.

[0058] The concentration of alpha-humulene in a cannabinoid-based formulation may be at least 0.0001% (weight / volume), or at least 0.001% (weight / volume). Preferably, the concentration of alpha-humulene in a cannabinoid-based formulation may be at least 0.005% (weight / volume), at least 0.01% (weight / volume), or at least 0.02% (weight / volume). The concentration of alpha-humulene in a cannabinoid-based formulation may be less than 0.75% (weight / volume), less than 0.5% (weight / volume), or less than 0.3% (weight / volume). The concentration of alpha-humulene in a cannabinoid-based formulation may be less than 0.2% (weight / volume), less than 0.15% (weight / volume), or less than 0.1% (weight / volume). The concentration of alpha-humulene in a cannabinoid-based preparation may be 0.0001% to 0.5% (weight / volume), 0.01% to 0.3% (weight / volume), or 0.01% to 0.2% (weight / volume). The concentration of alpha-humulene in a cannabinoid-based preparation may be 0.001% to 0.04% (weight / volume), 0.001% to 0.03% (weight / volume), or 0.001% to 0.02% (weight / volume). The concentration of alpha-humulene in a cannabinoid-based preparation may be 0.01% to 0.04% (weight / volume), 0.01% to 0.03% (weight / volume), or 0.01% to 0.02% (weight / volume). The concentration of alpha-humulene in the cannabinoid-based formulation may be 0.005% to 0.04% (weight / volume), 0.005% to 0.03% (weight / volume), or 0.005% to 0.02% (weight / volume). Preferably, the concentration of alpha-humulene in the cannabinoid-based formulation is about 0.02% (weight / volume). Preferably, the concentration of alpha-humulene in the cannabinoid-based formulation is about 0.0151% (weight / volume). Preferably, the concentration of alpha-humulene in the cannabinoid-based formulation is about 0.01% (weight / volume). More preferably, the concentration of alpha-humulene in the cannabinoid-based formulation is about 0.008% (weight / volume).It will be understood that any of the lower limits of alpha-humulene concentrations described herein can be combined with any of the upper limits of alpha-humulene concentrations.

[0059] In the first preferred embodiment, the plurality of terpenes include myrcene, preferably β-myrcene.

[0060] The concentration of β-myrcene in a cannabinoid-based formulation may be at least 0.0001% (weight / volume), or at least 0.001% (weight / volume). Preferably, the concentration of β-myrcene in a cannabinoid-based formulation may be at least 0.005% (weight / volume), at least 0.01% (weight / volume), at least 0.02% (weight / volume), at least 0.03% (weight / volume), at least 0.04% (weight / volume), or at least 0.05% (weight / volume). The concentration of β-myrcene in a cannabinoid-based formulation may be less than 0.75% (weight / volume), less than 0.5% (weight / volume), or less than 0.3% (weight / volume). The concentration of β-myrcene in a cannabinoid-based formulation may be less than 0.2% (weight / volume), less than 0.15% (weight / volume), or less than 0.1% (weight / volume). The concentration of β-myrcene in a cannabinoid-based formulation may be 0.0001% to 0.5% (weight / volume), 0.01% to 0.3% (weight / volume), or 0.01% to 0.2% (weight / volume). The concentration of β-myrcene in a cannabinoid-based formulation may be 0.01% to 0.1% (weight / volume), 0.01% to 0.08% (weight / volume), 0.01% to 0.07% (weight / volume), or 0.01% to 0.06% (weight / volume). Preferably, the concentration of β-myrcene in a cannabinoid-based formulation is about 0.05% (weight / volume). Preferably, the concentration of β-myrcene in a cannabinoid-based formulation is about 0.061% (weight / volume). More preferably, the concentration of β-myrcene in a cannabinoid-based formulation is about 0.0731% (weight / volume). It will be understood that any of the lower limits of β-myrcene concentrations described herein can be combined with any of the upper limits of β-myrcene concentrations.

[0061] In a first preferred embodiment, the terpenes include linalool.

[0062] The concentration of linalool in a cannabinoid-based formulation may be at least 0.0001% (weight / volume) or at least 0.001% (weight / volume). Preferably, the concentration of linalool in a cannabinoid-based formulation may be at least 0.005% (weight / volume) or at least 0.01% (weight / volume). The concentration of linalool in a cannabinoid-based formulation may be less than 0.75% (weight / volume), less than 0.5% (weight / volume), or less than 0.3% (weight / volume). The concentration of linalool in a cannabinoid-based formulation may be less than 0.2% (weight / volume), less than 0.15% (weight / volume), or less than 0.1% (weight / volume). The concentration of linalool in a cannabinoid-based formulation may be 0.0001% to 0.5% (weight / volume), 0.01% to 0.3% (weight / volume), or 0.01% to 0.2% (weight / volume). The concentration of linalool in a cannabinoid-based formulation may be 0.01% to 0.05% (weight / volume), 0.01% to 0.04% (weight / volume), 0.01% to 0.03% (weight / volume), or 0.01% to 0.02% (weight / volume). Preferably, the concentration of linalool in a cannabinoid-based formulation is about 0.01% (weight / volume). Preferably, the concentration of linalool in a cannabinoid-based formulation is about 0.0125% (weight / volume). Preferably, the concentration of linalool in a cannabinoid-based formulation is about 0.0120% (weight / volume). More preferably, the concentration of linalool in the cannabinoid-based formulation is about 0.0183% (weight / volume). It will be understood that any lower limit of linalool concentration described herein can be combined with any upper limit of linalool concentration.

[0063] Preferably, the method involves combining a cannabinoid and a plurality of terpenes with a pharmaceutically acceptable excipient or carrier. Thus, in a preferred embodiment, the cannabinoid-based formulation further comprises a pharmaceutically acceptable excipient or carrier.

[0064] Preferably, the method involves contacting a cannabinoid with a pharmaceutically acceptable excipient or carrier at a temperature of about 10°C to 70°C, preferably about 15°C to 60°C, more preferably about 20°C to 50°C, to form a mixture of the cannabinoid and the excipient or carrier. Preferably, the mixture of the cannabinoid and the excipient or carrier is stirred.

[0065] Preferably, a mixture of cannabinoids and an excipient or carrier is brought into contact with a plurality of terpenes at a temperature of about 10°C to 70°C, preferably about 15°C to 60°C, more preferably about 20°C to 50°C to produce the formulation of the present invention.

[0066] As used herein, “pharmaceutically acceptable vehicle” means any known compound or combination of known compounds that is useful to those skilled in the art for formulating a pharmaceutical composition.

[0067] In one embodiment, the pharmaceutically acceptable vehicle may be a liquid, and the pharmaceutical composition may be in the form of a suspension in solution. Liquid vehicles are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs, and pressurized compositions. Cannabinoids and terpenes may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, alcohol, ion buffer solution, organic solvent, mixtures thereof, or pharmaceutically acceptable oil or fat. The liquid vehicle may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers, or osmotic pressure modifiers. Suitable examples of liquid vehicles for oral administration include water (partially containing the above-mentioned additives, e.g., cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (monohydric and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionally distilled coconut oil and arachis oil).

[0068] Pharmaceutically acceptable carriers, excipients, and diluents are relatively inert or pharmaceutically effective substances that facilitate administration and may be supplied as liquid solutions or suspensions, emulsions, or solids suitable for dissolving or suspending in a liquid before use. For example, excipients may provide a suitable viscosity or act as diluents. Suitable excipients include, but are not limited to, stabilizers, wetting agents and emulsifiers, salts for altering osmotic pressure, encapsulating agents, pH buffers, and buffers. Such excipients include any pharmaceutical product suitable for direct delivery to the subject (e.g., sublingually) that can be administered without excessive toxicity. Pharmaceutically acceptable excipients include, but are not limited to, sorbitol, any of the various TWEEN compounds, and liquids such as water, saline, glycerol, and ethanol. Pharmaceutically acceptable salts may include, for example, mineral salts such as hydrochloride, hydrobromide, phosphate, and sulfate, and organic salts such as acetate, propionate, malonate, or benzoate.

[0069] In some embodiments, pharmaceutically acceptable excipients may include pharmaceutically acceptable carriers. Such pharmaceutically acceptable carriers may be sterile liquids such as water and oil, and may include petroleum, animal, plant, or synthetic sources such as peanut oil, soybean oil, or mineral oil. Saline solutions and aqueous dextrose, polyethylene glycol (PEG), and glycerol solutions may also be used as liquid carriers, particularly for sublingual solutions. Additional components, such as preservatives, buffers, isotonic agents, antioxidants and stabilizers, nonionic wetting or clarifying agents, or viscosity enhancers, may also be used. A detailed description of pharmaceutically acceptable excipients and carriers is found in Remington's Pharmaceutical Sciences (Ed Remington JP and Gennaro AR; Mack Pub. Co. Easton, Pa 1990).

[0070] However, most preferably, the pharmaceutically acceptable excipient or carrier comprises a medium-chain triglyceride (MCT), preferably an MCT oil. Therefore, in preferred embodiments, the cannabinoid-based formulation further comprises a medium-chain triglyceride (MCT), preferably an MCT oil. Suitable MCTs may be selected from the group consisting of triglycerol linkers having three fatty acid residues with a carbon chain length in the range of 1 to 14. The chemical formulas of each of these MCTs are as follows: [ka] This is shown in the equation (where X = 1 to 14).

[0071] MCT oil is preferably obtained from fractionally distilled coconut oil. Preferred triglycerides have carbon chain lengths of C6, C8, C10, or C12. Preferably, the triglycerides are almost entirely C8 and highly purified.

[0072] The concentration of MCT oil in a cannabinoid-based formulation may be at least 80% (weight / volume), at least 82% (weight / volume), or at least 84% (weight / volume). Preferably, the concentration of MCT oil in a cannabinoid-based formulation may be at least 86% (weight / volume), or at least 88% (weight / volume). The concentration of MCT oil in a cannabinoid-based formulation may be less than 96% (weight / volume), less than 95% (weight / volume), or less than 94% (weight / volume). The concentration of MCT oil in a cannabinoid-based formulation may be less than 92% (weight / volume), or less than 90% (weight / volume). The concentration of MCT oil in a cannabinoid-based formulation may be 85% to 93% (weight / volume), 86% to 92% (weight / volume), 87% to 91% (weight / volume), or 88% to 90% (weight / volume). Preferably, the concentration of MCT oil in the cannabinoid-based formulation is about 89.8% (weight / volume). Preferably, the concentration of MCT oil in the cannabinoid-based formulation is about 89.8013% (weight / volume). More preferably, the concentration of MCT oil in the cannabinoid-based formulation is about 89.7597% (weight / volume). It will be understood that any of the lower limits of MCT oil concentration described herein can be combined with any of the upper limits of MCT oil concentration.

[0073] The cannabinoid-based formulations of the present invention are preferably in liquid form. The formulations may include tinctures.

[0074] Preferably, the formulation can be administered by sublabial, buccal, sublingual, or oropharyngeal delivery. By preparing liquid formulations for sublabial, buccal, oropharyngeal (oral) delivery, it is possible to introduce the active substances (i.e., cannabinoids and terpenes) into the systemic circulation via the mucous membrane, thereby increasing the bioavailability of the drug by avoiding first-pass metabolism, and thus enhancing activity and efficacy. Advantageously, while oral administration of cannabinoids is considered the most prevalent method in the drug delivery market today, given their lipophilicity and low bioavailability for gastrointestinal absorption, the formulations of the present invention remarkably enable administration via this route. Liquid formulations can also be prepared for inhalation or spray delivery to the respiratory tract, as well as for topical application to skin and mucous membrane surfaces.

[0075] The formulation may be administered at least once a day, at least once a week, or at least once a month. The formulation may be administered two or three times a day, two or three times a week, or two or three times a month.

[0076] The formulation may be administered to a "subject" in need of treatment, which may be a vertebrate, mammal, or domestic animal. Therefore, the formulation according to the present invention may be used to treat any mammal, such as livestock (e.g., horses), domestic pets, or for other veterinary purposes. However, most preferably, the subject is human.

[0077] The "therapeutic dose" of a formulation is any amount necessary to treat the target medical disease when administered to a subject.

[0078] Preferably, pain, inflammation, autoimmune diseases, neurological diseases, neoplasms, nausea, hypertension, hypertrophic cardiomyopathy, or fibrosis is selected from the group of diseases consisting of chemotherapy-induced peripheral neuropathy (CIPN), endometriosis, osteoarthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, fibromyalgia, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease (COPD), gout, scleroderma, lupus, Ehlers-Danlos syndrome, pericarditis, myocarditis, myocardial infarction, chemotherapy-induced nausea, anxiety, type 1 diabetes mellitus, cardiovascular diseases, primary hypertension, secondary hypertension, resistant hypertension, isolated systolic hypertension, malignant hypertension, obstructive hypertrophic cardiomyopathy, non-obstructive hypertrophic cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, renal fibrosis, mediastinal fibrosis, retroperitoneal fibrosis, myelofibrosis, cutaneous fibrosis, and scleroderma.

[0079] All features and / or steps of any method or process described herein (including the attached claims, abstract, and drawings) may be combined in any combination with any of the above embodiments, except for at least some combinations in which such features and / or steps are mutually exclusive.

[0080] For a better understanding of the present invention and to illustrate how embodiments of the present invention can be carried out, refer to the accompanying drawings as examples. [Brief explanation of the drawing]

[0081] [Figure 1] This is a flowchart illustrating a first embodiment of a method for producing a CBD formulation of the present invention, comprising a CBD isolate, a terpene isolate, and MCT oil as an excipient. [Figure 2] This flowchart shows a second embodiment of a method for producing a CBD formulation of the present invention, comprising a CBD isolate, a terpene isolate, and MCT oil as an excipient. [Figure 3] This figure shows a Certificate of Analysis (COA) for one embodiment of a CBD raw material. [Figure 4]This figure shows a Certificate of Analysis (COA) indicating that the cannabinoid-based formulation of the present invention (referred to as MRX1) substantially does not contain 13 non-CBD cannabinoid analyzers. [Figure 5] This figure shows the cumulative concentration of CBD that has permeated the porcine mucosal tissue membrane over time. [Figure 6] This figure shows the experimental design for a pilot study on the effects of the present invention's cannabinoid-based formulation (MRX1) in a mouse model of heart failure with preserved ejection fraction (HFpEF). [Figure 7] This figure shows the water intake, calorie intake, and weight gain from baseline of mice in a pilot study on the effects of the cannabinoid-based formulation of the present invention in a mouse model of heart failure with preserved left ventricular ejection fraction (HFpEF). [Figure 8] This figure shows the changes in blood glucose levels, heart weight, and white adipose tissue content (all adjusted for body length / weight) in mice from a pilot study on the effects of the cannabinoid-based formulation of the present invention in a mouse model of heart failure with preserved left ventricular ejection fraction (HFpEF). *P<0.05, **P<0.01. [Figure 9] This figure shows the effects of the cannabinoid-based formulation of the present invention on HFD / LNAME and cardiovascular variables in a pilot study on the effects of the cannabinoid-based formulation of the present invention on a mouse model of heart failure with preserved left ventricular ejection fraction (HFpEF). *P<0.05, **P<0.01. [Figure 10] This figure shows the protein expression of anti-inflammatory cytokines in mouse cardiac tissue from a pilot study on the effects of the present invention's cannabinoid-based formulation (MRX1) in a mouse model of heart failure with preserved left ventricular ejection fraction (HFpEF). *P<0.05. [Figure 11]This figure shows the water intake, calorie intake, and body weight gain from baseline in a mouse model of heart failure with preserved left ventricular ejection fraction (HfpEF) for normally fed mice and HFD / L-NAME mice, with or without the cannabinoid-based formulation (MRX1) of the present invention. [Figure 12] This figure shows the plasma levels of CBD and its metabolites in a mouse model of heart failure with preserved left ventricular ejection fraction (HfpEF). [Figure 13] This figure shows the blood glucose levels and tissue weights of mice in a mouse model of heart failure with preserved left ventricular ejection fraction (HfpEF). *P<0.05, **P<0.01. [Figure 14] This figure shows the changes in blood pressure and heart rate (top panel), systolic function (middle panel), and diastolic function (bottom panel) in mice with or without the cannabinoid-based formulation of the present invention (MRX1) or RGU MRX1 in a mouse model of heart failure with preserved left ventricular ejection fraction (HfpEF). *P<0.05, **P<0.01, ***P<0.001. [Figure 15] This figure shows the expression of markers for heart failure, fibrosis, and inflammation in the cardiac tissue of HFpeF mice treated with a vehicle or the cannabinoid-based formulation of the present invention (MRX1) in a mouse model of heart failure with preserved left ventricular ejection fraction (HfpEF). *P<0.05, **P<0.01, ***P<0.001. [Figure 16] This figure shows the expression of IL1ra, JE, and TIMP1 in adipose tissue of HfpeF mice treated with a vehicle or the cannabinoid-based formulation of the present invention (MRX1) in a mouse model of heart failure with preserved left ventricular ejection fraction (HfpeF). *P<0.05, **P<0.01, ***P<0.001. [Figure 17] This figure shows the design of a Phase II placebo-controlled, double-blind, crossover trial of the cannabinoid-based formulation of the present invention for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). [Modes for carrying out the invention] [Examples]

[0082] background The inventors have devised a novel method for consistently and reproducibly producing, from scratch, highly standardized formulations containing a mixture of cannabinoids (e.g., CBD) and specific terpenes for use in the treatment of pain, inflammation, autoimmune diseases, neurological disorders, neoplasms, nausea, hypertension, hypertrophic cardiomyopathy, and fibrosis. This method allows for the synthesis of formulations with precisely standardized amounts of each component by combining a CBD isolate of known purity, a highly defined mixture of terpenes of known purity, and medium-chain triglyceride (MCT) oil of known purity, while simultaneously minimizing THC contamination.

[0083] Example 1 - Method for producing a CBD preparation Referring to Figures 1 and 2, the inventors have designed a novel method for producing a highly uniform and reproducible CBD-based formulation (referred to here as MRX1). This method involves the following steps: 1. The process of extracting CBD from the Cannabis sativa plant to produce a CBD extract; 2. The process of purifying the CBD isolate from the CBD extract (to a specified purity); 3. The process of extracting terpenes from suitable plant species to produce terpene extracts (i.e., essential oils); 4. The process of purifying terpenes (to a specified purity) from terpene extracts, and then blending some of them to create a terpene blend; 5. The process of preparing MCT oil (to the specified purity); 6. A step of mixing CBD isolate, terpene blend, and MCT oil to produce the CBD preparation of the present invention.

[0084] Each of these processes will be described in detail.

[0085] Example 2 - Preparation of CBD isolate The inventors used two different embodiments of a method for extracting a pure CBD isolate: solvent extraction (shown in Figure 1) and enzymatic extraction (shown in Figure 2).

[0086] Solvent extraction (Figure 1) Referring to Figure 1 (left), in the first embodiment, a CBD isolate is prepared from suitable plant material (Cannabis sativa inflorescence and / or leaves) by solvent extraction (e.g., using either alcohol or alkane) to produce a slurry, which is then filtered to produce a crude liquid extract. The crude extract is cooled to preferably -80°C for 24 hours in a process called "winterisation" to precipitate fats and waxes, and these fats and waxes are then filtered to produce a so-called "wintered" extract.

[0087] Next, the solvent (i.e., alcohol or alkane) is removed under reduced pressure, and the remaining crude oil is "decarboxylated" to convert the acidic compounds into a neutral form, which is typically carried out at 120°C for at least 30 minutes, ideally at least 1 hour. The resulting decarboxylated extract is further purified by short-path distillation at 130°C–180°C to remove any remaining exogenous non-cannabinoid material. The resulting material is dissolved in alcohol (i.e., solvent) to near the saturation point of the solution, and then alkane (acting as a reverse solvent) is slowly added to induce crystallization. Once the first crystallization (CBD with a purity of approximately 95%) is complete, the solid material is filtered and redissolved in alcohol, and then a second crystallization is carried out to produce isolated CBD of the required specifications.

[0088] Enzyme extraction (Figure 2) Referring to Figure 2, in the second embodiment, one or more cannabinoids are prepared using enzymatic digestion of plant material (e.g., inflorescences and / or leaves of Cannabis sativa). The plant material may contain about 40% water. The plant material is brought into contact with an enzyme solution containing one or more combinations of the enzymes cellulase, beta-glucosidase, hemicellulase, xylanase, glucanase, beta-glucanase, pectinase, amylase, alpha-amylase, phospholipase, beta-mannanase, arabinanase, phytase, and protease. The pH of the enzyme solution is adjusted to about pH 5.6 using citric acid. Plant material is used in a weight ratio of 1% to 10% (by weight) in a 99% to 10% (by weight) enzyme solution. The plant material is macerated before, during, and / or after contact with the enzyme solution. In addition to the enzyme solution, the plant material is also brought into contact with lipids for extracting cannabinoids (i.e., CBD). For example, the lipids may be vegetable oil, MCT oil, seed oil, or olive oil. The weight ratio of lipids to plant material is approximately 1:1.5. The plant material is macerated before, during, and / or after contact with the lipids.

[0089] Next, the mixture of plant material, enzyme, and lipids is stirred and macerated at 10°C to 50°C for about 1 hour. Once the plant material has completely decomposed and dissolved, it is separated into an oil phase and an aqueous phase by gravity, centrifugation, filtration, or a combination thereof. The oil layer is transferred to another container with a stirring function. The oil layer is brought into contact with an aqueous base such as 0.1 M NaOH or KOH with a pH of 12 or higher. The weight ratio of the aqueous base solution to the cannabinoid-containing oil is 1:5. This mixture is stirred at a temperature of 40°C to 80°C for at least 20 minutes.

[0090] Once the previous step is complete, the mixture is brought into contact with (i) sodium chloride and / or calcium carbonate and (ii) glucose and / or fructose, and then stirred for a further 20 minutes. Upon completion, the layers are separated by gravity or centrifugation, and the aqueous layer may be separated thereafter. The pH of the aqueous layer is reduced to approximately 1 by contacting the separated aqueous layer with 85% orthophosphoric acid. The solution is stirred for a further 20 minutes, and the cannabinoid salt precipitates. This liquid is filtered to obtain a cannabinoid-rich solid precipitate with a total cannabinoid content of 65% to 90%. The cannabinoid-rich precipitate is heated at at least 120°C for 60 minutes, or until complete decarboxylation is achieved. The obtained material is dissolved in a solvent (e.g., alcohol) to near the saturation point of the solution, and then the reverse solvent (e.g., alkane) is added (slowly) to induce crystallization. Optionally, the solid material may be filtered and redissolved in a solvent (e.g., alcohol), and a second crystallization may be performed to produce isolated cannabinoids (preferably CBD) of the required specifications.

[0091] Certificate of Analysis (COA) Referring to Figure 3, a Certificate of Analysis (COA) for one embodiment of a CBD raw material is shown. As can be seen, various parameters have been measured and are well within acceptable limits. In particular, the inventors note that the d9-tetrahydrocannabinol (THC) standard can be set at 0.02%, which is significantly lower than the pharmaceutical requirement of 0.15% or less for any known organic impurities.

[0092] Example 3 - Preparation of terpene blend Referring to Figures 1 and 2 (right), terpenes are prepared by steam distillation to produce essential oils from suitable plant species such as lavender. The resulting essential oils are purified to their individual components by flash chromatography using silica. The following example concerns the purification of linalool from lavender, but it will be understood that other essential oils containing one or more terpenes can be prepared from other plant species.

[0093] A steam distillation apparatus is a sealed system in which macerated lavender is placed in a boiling vessel, and then enough water is added to fluidize the plant material. Steam is introduced into the bottom of the vessel through a dip tube extending from the top of the vessel. The mixture is heated to a boiling point, and the steam moves through a manifold located at the top of the boiling vessel to a water-cooled condenser. The condensate is collected and separated, and the essential oil layer at the top is collected.

[0094] The essential oil is dissolved in 90:10 heptane:ethyl acetate at an appropriate concentration and introduced into a flash chromatography system. Separation is performed using a silica-packed column and a 90:10 heptane:ethyl acetate mobile phase. Linalool with a purity of over 95% is obtained from the subsequent fraction.

[0095] The inventors used isolated terpenes after the purification process as raw materials for the manufacture of CBD formulations. The purity standard for the raw material terpenes is 95% or higher (GC measurement). Impurities are mainly other terpenes, and all impurities exceeding 0.2% are identified in order to include them as part of the formulation and to ensure the highest consistency.

[0096] Next, terpenes are combined by weight to produce a highly reproducible terpene mixture or blend. As shown in Figures 1 and 2, the resulting essential oils each contain terpenes with a purity of 95% or more, and these are mixed together to form terpene blends with a purity of 95% or more (i.e., terpene X, terpene Y, and / or terpene Z, etc.). Table 2 shows one exemplary embodiment of a terpene mixture.

[0097] TIFF2026517935000007.tif72170

[0098] Example 4 - Preparation of MCT oil Referring to Figures 1 and 2 (left), commercially available pharmaceutical-grade MCT oil is obtained from H Plus Limited (L2 3YL, Exchange Flags, Walker House, Liverpool, UK). For example, MCT is obtained from fractionally distilled coconut oil and has carbon chain lengths of C6, C8, C10, or C12, but a highly refined C8 chain length is preferred.

[0099] Example 5 - CBD preparation This method involves producing a cannabinoid-based formulation of the present invention by combining the CBD isolate from Example 2, the terpene isolate from Example 3, and the MCT oil from Example 4. This is achieved by first mixing the CBD isolate and MCT oil with stirring at approximately 20°C to 50°C. Then, the CBD / MCT solution is mixed with a mixture of terpenes with stirring at approximately 20°C to 50°C to produce a CBD / MCT / terpene formulation.

[0100] The inventors designed embodiments of a CBD-based formulation having the composition shown in Table 3.

[0101] TIFF2026517935000008.tif93170

[0102] The inventors have designed another embodiment of a CBD-based formulation having the composition shown in Table 7.

[0103] TIFF2026517935000009.tif93170

[0104] The inventors have designed another preferred embodiment of a CBD-based formulation having the composition shown in Table 8.

[0105] TIFF2026517935000010.tif93170

[0106] Example 6 - Formulation containing only CBD (MRX1) In this specification, the analysis of the cannabinoid-based formulation of the present invention, designated as MRX1, was carried out by Phytovista Laboratories, a specialized ISO-accredited laboratory for testing CBD and hemp products. Phytovista Laboratories used HPLC-DAD and UV spectrophotometry to test MRX1 for the presence of 13 non-CBD cannabinoid analytes, namely cannabidiolic acid (CBDA), cannabidiovaleric acid (CBDVA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromene (CBC), cannabichromenic acid (CBCA), cannabinocyclol (CBL), tetrahydrocannabivarinic acid (THCVA), tetrahydrocannabivarin (THCV), cannabinol (CBN), Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC), and Δ9-tetrahydrocannabinolic acid A (Δ9-THCA-A).

[0107] As shown in Figure 4, Phytovista Laboratories issued an analytical certificate confirming that MRX1 contains all 13 analytes below the limit of quantification (<LOQ) (LOQ is 0.0025).

[0108] Example 7 - Bioavailability of MRX1 In this specification, a mucosal and cutaneous permeation study by Franz cell analysis of the cannabinoid-based formulation of the present invention, designated as MRX1, was carried out at Nottingham Trent University.

[0109] Objective The objective of this study was to determine systemic exposure to MRX1 over time in a porcine (pig) mucosal tissue permeability test using an in vitro model (Franz cell apparatus) that utilizes a proprietary transdermal formulation containing the cannabinoid isolate cannabidiol (CBD) in a lipid matrix (including the following combinations: medium-chain triglycerides (MCT), propylene glycol, ethanol, and terpenes (β-myrcene, β-caryophyllene, β-ocimene, α-pinene, limonene, α-humulene, and linalool)), i.e., one embodiment of the cannabinoid-based formulation of the present invention.

[0110] Materials and measuring instruments MRX1, cannabidiol (CBD) isolate, Kollisolv MCT70, propylene glycol, and anhydrous ethanol were supplied to the aforementioned university. The cannabidiol reference standard was used as received from the supplier (Restek, #34011). All other solvents were used as supplied (analytical grade or LCMS grade, Fisher Scientific and Sigma) without further purification. The instruments used included a DixonScience Franz cell spectrometer (#XFCDR01) and an Agilent 7890A series gas chromatograph combined with an Agilent 5975C MDS equipped with ALS 7693, which is supported by NIST library searches.

[0111] method Franz Cell Protocol Franz cell experiments were performed in three consecutive sets for five separate formulations (i.e., BCMS_032_020, BCMS_032_021, BCMS_032_022, BCMS_032_023, and BCMS_032_024) using a single MRX1 formulation (0.5 mL sample containing 10%–20% CBD by weight / volume). Each Franz cell was performed over 5 hours using porcine mucosal tissue membrane, with specific sampling time points at 0, 30, 60, 90, 120, 150, 180, 240, and 300 minutes.

[0112] In summary, the following actions were taken: Tissue from the mucous membrane of pigs was collected from fresh (less than 4 hours) euthanized pigs (approximately 6 months old) before starting the procedure, and excess tissue was carefully removed from the skin samples. All samples were washed and dried before loading into the Franz cell apparatus. The receptor packing volume was approximately 2.0 mL and the effective diffusion area was 1.33 cm². 2 A Franz cell apparatus was used.

[0113] The receptor compartment of the Franz cell was filled with deaerated phosphate-buffered saline (PBS - sodium chloride 8.0 g / L, potassium chloride 0.2 g / L, disodium hydrogen phosphate 1.15 g / L, potassium dihydrogen phosphate 0.2 g / L) at pH 7.4 (±0.1) containing bovine serum albumin (4% vol / vol), and was maintained at 37°C (±1°C).

[0114] The prepared tissue was placed in the Franz cell apparatus and secured in place to ensure a tight seal. One hour before starting the analysis, the skin was saturated in situ by placing a small amount (approximately 0.5 mL) of buffer medium on top of the skin / donor chamber. After confirming that the sample was saturated and there was no leakage into the system, the buffer medium was removed from the donor chamber.

[0115] The Franz cell apparatus was continuously monitored to ensure there were no air bubbles beneath the skin film. If air bubbles were present, the sample chamber was carefully angled to remove them. The system temperature was maintained at 37°C (±1°C) with 5% CO2, and constant stirring was maintained using a magnetic stirrer bar to ensure uniform mixing of the receptor solution throughout the analysis.

[0116] The five formulations provided for the study were individually applied to receptor reservoirs in direct contact with the surface of the tissue membrane (0.5 mL, stored at room temperature).

[0117] Using a pre-weighed sterile Pasteur pipette, the sample was slowly applied to the skin surface, ensuring complete coverage. The pipette was then weighed again, and the weight of the residue removed from the Franz cell apparatus was measured. The timer was then started at 0 minutes. At each specified time point (0, 30, 60, 90, 120, 150, 180, 240, and 300 minutes), the entire buffer phase (2 mL) was removed from the receptor chamber using a sterile syringe and needle. The sample aliquots were then rapidly frozen (using liquid nitrogen) and placed in a freezer (-20°C) in preparation for chromatographic analysis. The receptor chamber was immediately refilled with fresh buffer (2 mL equilibrated at 37°C), ensuring that the chamber was completely filled and free of air bubbles.

[0118] After the final sampling time (5 hours), the agitator was stopped and the Franz cell apparatus was carefully disassembled. The removed skin tissue samples were placed in a clean, dry beaker, and the donor chamber was placed in a separate beaker.

[0119] Buffer solution (10 mL) was added to each beaker, and the skin and donor chamber surfaces were thoroughly rinsed. The washing solutions were then rapidly frozen with liquid nitrogen and placed in a freezer (-20°C) in preparation for chromatographic analysis.

[0120] Frozen skin samples were freeze-dried, ground into a fine powder, and weighed in a state prepared for chromatographic analysis.

[0121] GC / MS protocol An Agilent 7890A gas chromatograph was used in combination with an Agilent 5975C MDS mass spectrometer and a DB-5ms GC column (nominal 30.0m × 250μm × 0.25μm) Ultra Inert size, in split mode (10:1) with a constant flow rate of helium gas (1 mL / min) for all experiments.

[0122] All aliquot samples at each time point were allowed to return to room temperature, and the CDB was extracted with chloroform (2.0 mL) and dried with magnesium sulfate (approximately 0.2 g). The aqueous layer was discarded using a suction station (Gilson, UK), and the organic layer (1 mL) was transferred to an amber-colored GC / MS sample vial ready for analysis.

[0123] The sample (10 mL) collected from the washed Franz cell apparatus was extracted in chloroform (4.0 mL) and dried with magnesium sulfate (approximately 0.4 g). The aqueous layer was discarded using a suction station (Gilson, UK), and the organic layer (1 mL) was transferred to an amber-colored GC / MS sample vial ready for analysis.

[0124] A sample (10 mL) collected from washed skin was extracted in chloroform (2.0 mL), dried with magnesium sulfate (approximately 0.2 g), filtered, and then transferred to an amber-colored GC / MS sample vial (1 mL) ready for analysis.

[0125] The powdered, lyophilized skin sample was dispersed in chloroform (3 × 1.0 mL), filtered, dried with magnesium sulfate (approximately 0.2 g), and transferred to an amber-colored GC / MS sample vial (1 mL) ready for analysis.

[0126] The sample was loaded into the GM / MS automated sampler. The GM / MS instrument was programmed to heat from the initial temperature (130°C) to 300°C using a 10°C / min ramp, and hold for 2 minutes. The total run time per sample was 24 minutes. The mass spectrometer was operated in full scan mode with a scan range of 40 amu to 450 amu and an ionization energy of 70 eV.

[0127] result Analysis of Franz cells permeable to CDB across porcine mucosal tissue 1. Study on CBD permeation over time

[0128] TIFF2026517935000011.tif65170

[0129] TIFF2026517935000012.tif65170

[0130] Referring to FIG. 5, Franz cell analysis of CBD permeation across ex vivo porcine mucosal tissue membranes showed that sample BCMS_032_020, which is one embodiment of the cannabinoid-based formulation of the present invention containing 10% CBD, 0.250% terpene, and 100% MCT, exhibited a higher CBD permeation rate across porcine mucosa, followed by sample BCMS_032_021, which is another embodiment of the cannabinoid-based formulation of the present invention containing 10% CBD, 0.250% terpene, and 100% MCT. This confirms that the presence of terpene increases the permeation rate of CBD across the skin membrane. CBD permeation from formulations based on ethanol:propylene glycol (50:50), namely samples BCMS_032_022 and BCMS_032_023, was significantly lower compared to the MCT formulation. Furthermore, it was demonstrated that CBD permeation also decreased in sample BCMS_032_024 consisting of EtOH:propylene glycol (50:50) together with terpene, compared to the MCT formulation.

[0131] Example 8 - The MRX1 formulation substantially does not contain THC Analysis of embodiments of the cannabinoid-based formulation of the present invention was conducted by BCM Analytical Services, a contract testing business of the Fareva group, which provides full-spectrum pharmaceutical analysis and testing. BCM Analytical Services used HPLC to test embodiments of the cannabinoid-based formulation of the present invention for impurities including d9-THC and d8-THC.

[0132] As shown in Table 6 below, from the results of the HPLC analysis of the formulation, both d9-THC and d8-THC were below the detection limit (<LOD), and thus it was confirmed that the formulation of the present invention substantially does not contain THC.

[0133] TIFF2026517935000013.tif65170

[0134] Example 9 - Anti-inflammatory effect of MRX1 The efficacy of an embodiment of the cannabinoid-based formulation of the present invention, referred to herein as MRX1, in a mouse model of heart failure with preserved left ventricular ejection fraction (HfpEF) was studied by Dr. Nadine Godsman and Dr. Sarah Walsh at the Centre for Cardiometabolic Health Research in Aberdeen, UK, and Robert Gordon University.

[0135] background Heart failure with preserved left ventricular ejection fraction (HfpEF) is a form of heart failure in which the ejection fraction (the percentage of blood ejected from the left ventricle during systolic contraction) is normal, but diastolic dysfunction occurs due to increased left ventricular sclerosis. This reduces left ventricular relaxation during diastole, resulting in increased pressure and / or impaired filling. HfpEF is characterized by thickening of the ventricular wall (concentric hypertrophy), which causes an increase in left ventricular mass, typically accompanied by normal or slightly reduced end-diastolic filling volume.

[0136] Left ventricular hypertrophy in HfpEF occurs as a result of changes in the extracellular matrix surrounding cardiomyocytes, with the accumulation of additional collagen material through the fibrotic process, contributing to wall hardening. While many factors are involved in activating the fibrotic process, the activation of an inflammatory response that attracts collagen-producing fibroblasts to cardiac tissue plays a crucial role. Although various factors contribute to the development of HfpEF, hypertension, obesity, metabolic syndrome, and a sedentary lifestyle have been identified as important risk factors.

[0137] There is strong evidence that cannabidiol (CBD) acts as an anti-inflammatory agent and also helps prevent cardiac damage caused by ischemia / reperfusion injury. The aim of this study is to determine whether MRX1, an oil-based CBD preparation containing 10% CBD, has the ability to slow or prevent the progression of cardiac structural and functional changes in a preclinical mouse model of HfpEF, which mimics risk factors for both hypertension and obesity through administration of the nitric oxide (NO) synthase inhibitor L-NAME and intake of a high-fat diet, respectively.

[0138] Pilot dose selection study To ensure that sufficient high doses of MRX1 were used in drug intervention studies, preliminary dose studies were conducted. Male C57BL / 6J mice (8-10 weeks old) were fed a high-fat diet with L-NAME (0.5 g / L) added to drinking water or a corresponding control diet for 7 weeks. In HFD / L-NAME mice, the vehicle and MRX1 (35 mg / kg or 90 mg / kg, equivalent to 3.5 mg / kg and 9 mg / kg CBD, respectively) were administered in drinking water at weeks 6 and 7 of the dietary intervention period. Cremophor was used to achieve mixing of MRX1 oil and water. The animals had free access to food and water. Daily water intake was measured to determine food intake and calculate actual CBD intake (mg / kg).

[0139] At the end of the intervention period, mice were anesthetized, and blood pressure was measured via carotid artery cannula. After euthanasia by anesthetic overdose, tissue and blood samples were collected to assess various variables. The experimental design for the pilot study is shown in Figure 6.

[0140] result Referring to Figure 7, in response to the HFD / L-NAME intervention, while water intake did not change, calorie intake and body weight increased compared to mice fed a normal diet. MRX1 intervention did not alter water intake or food intake, but high doses of MRX1 slowed body weight gain compared to the vehicle.

[0141] Referring to Figure 8, when mice fed a vehicle were given an HFD / L-NAME diet, there was no change in blood glucose levels or cardiac weight (corrected for tibial length), but the ratio of white adipose tissue (WAT) to body weight significantly increased. Neither dose of MRX1 affected blood glucose levels or the HW:TL ratio. However, the increase in the WAT:BW ratio was prevented in mice supplemented with high doses of MRX1, but not in mice supplemented with low doses of MRX1.

[0142] Referring to Figure 9, in vehicle-treated mice, the HFD / LNAME diet resulted in elevated systolic and diastolic blood pressure compared to mice fed a normal diet, indicating hypertension in the mice. MRX1 dose-dependently prevented the elevation of both systolic and diastolic blood pressure caused by this diet. Heart rate was unaffected by diet alone or by low-dose MRX1 intake. High-dose MRX1 appeared to slightly decrease heart rate, but this was not statistically significant.

[0143] To determine whether MRX1 has any effect on the expression of inflammatory markers, cytokine arrays were performed on cardiac tissue samples. As shown in Figure 10, HFD / LNAME treatment suppressed two anti-inflammatory cytokines (IL-1ra and IL-4) in the heart, which was not observed in mice administered high doses of MRX1.

[0144] Overview of Dose Selection Studies Mice treated with high concentrations of MRX1 (90 mg / kg) showed reduced white adipose tissue (WAT) accumulation. However, since these mice had already reduced calorie intake before MRX1 administration, this effect is unlikely to be related to MRX1 treatment. Both doses of MRX1 (35 mg / kg and 90 mg / kg) exhibited antihypertensive effects, lowering both systolic and diastolic blood pressure in mice. Furthermore, high doses of MRX1 (90 mg / kg) restored the protein expression of cardiac anti-inflammatory cytokines that had been reduced by dietary therapy. Based on these findings, a target dose of 100 mg / kg of MRX1 was selected as the dose for the intervention study.

[0145] Intervention study to determine the effect of MRX1 on HfpEF Dose-selection studies have shown that a dose of 9 mg / kg of MRX1 exhibits both antihypertensive effects and elevated levels of anti-inflammatory cytokines in the heart. Therefore, the objective of the intervention study was to determine whether MRX1 could improve both the functional and structural changes in the heart observed in HfpEF. Furthermore, since certain terpenes have been shown to possess independent cardioprotective properties, we investigated whether increasing terpene levels in the preparation of MRX1 formulations could provide additional benefits.

[0146] Similar to the dose-selection study, male C57BL / 6J mice (8-10 weeks old, 12 mice per experimental group) were fed a high-fat diet containing L-NAME (0.5 g / L) in drinking water or a corresponding control diet for 7 weeks. HFD / L-NAME mice were administered either a vehicle, MRX1 (1 mg / ml in drinking water, target intake 100 mg / kg), or MRX1 with additional terpenes (additional 0.05% BCP, 0.01% beta-pinene, and 0.001% farnesol, referred to as RGU MRX1) in drinking water at weeks 6 and 7 of the dietary intervention period. Water intake was measured daily to calculate the actual intake of the formulation.

[0147] result Referring to Figure 11, water intake remained constant throughout the dietary intervention period in both normally fed mice and vehicle-treated HFD / L-NAME mice. However, water intake decreased slightly in both the MRX1 and RGU MRX1 groups, so the accurate dose consumed was recalculated as 60 mg / kg (CBD 6 mg / kg). In a dose-selection study using a terpene-free MRX1 formulation, the decrease in water intake was not affected, and similarly, the vehicle (Cremophor) did not affect water intake, suggesting that the presence of terpenes in both formulations made them unpalatable to the mice. Calorie intake and weight gain were similar in all three HFD / L-NAME intervention groups.

[0148] To confirm that sufficient plasma levels of CBD were achieved, plasma samples were collected at the end of the experimental period and sent for quantitative analysis of CBD and its metabolites, 7-OH-CBD (7-hydroxycannabidiol) and 7-COOH-CBD (7-carboxycannabidiol). Analysis was performed on pooled samples collected from 5 mice in each group, and 5 independent pooled samples were tested. Referring to Figure 12, both MRX1 and RGU MRX1 administered at a calculated dose of 60 mg / kg achieved similar plasma CBD levels of 2.6 μM and 2.8 μM, respectively. Both major metabolites of CBD were detected in similar amounts.

[0149] Referring to Figure 13, HFD / L-NAME resulted in elevated blood glucose levels, but this effect was not observed in any of the MRX1 treatment groups. Regarding tissue weight, liver weight did not change with HFD / L-NAME in any group, but as shown in Figure 13 (upper panel), the WAT:BW ratio increased significantly in all three groups. Cardiac weight in the vehicle-treated HFD / L-NAME group was significantly increased compared to normally fed mice, which is consistent with the development of cardiac hypertrophy. MRX1 significantly suppressed this increase in cardiac weight, and RGU MRX1 resulted in a smaller increase in cardiac weight, but this was not statistically significant. Similarly, lung weight also increased with HFD / L-NAME, but this effect was not observed in mice treated with either MRX1 or RGU MRX1. As shown in Figure 13 (lower panel), the ratio of wet to dry lung weight was similar in all four groups, indicating that the increase in lung weight in the vehicle-treated mice was not due to pulmonary edema but rather suggested pulmonary fibrosis.

[0150] As seen in dose-selection studies, both MRX1 and RGU MRX1 exhibited significant antihypertensive effects, demonstrating reductions in both systolic and diastolic blood pressure, as shown in Figure 14 (upper panel). Since these effects occurred without any impact on heart rate, it is likely that the antihypertensive effect is achieved through a reduction in peripheral resistance rather than an effect on cardiac output. This was confirmed by pressure-volume loop analysis performed in closed-chest animals under terminal anesthesia to determine both systolic and diastolic function, and as shown in Figure 14 (middle panel), there was no difference in cardiac output in either group.

[0151] Because this is a model of diastolic dysfunction, changes in systolic function were not significant, and there were no differences in ejection fraction (EF) and cardiac contractility (dP / dtmax) between normally fed mice and any of the three HFD / L-NAME groups. However, as shown in Figure 14 (middle panel), HFD / L-NAME intervention increased end-systolic pressure in the vehicle-treated group.

[0152] Regarding diastolic function, no changes were observed in either ventricular relaxation (dP / dtmin) or left ventricular end-diastolic volume (EDV). However, while HFD / L-NAME mice treated with the vehicle tended to show increased left ventricular end-diastolic pressure, suggesting ventricular wall hardening, this trend was not observed in the MRX1 treatment group, although, as shown in Figure 14 (lower panel), this was not statistically significant.

[0153] qPCR was used to assess changes in the expression of various markers of heart failure, cardiac fibrosis, and inflammation in cardiac tissue. Referring to Figure 15, mRNA expression of brain natriuretic peptide (BNP), a hormone secreted by cardiomyocytes in response to stretching caused by increased ventricular blood volume and a clinical marker of heart failure, was significantly increased in response to HFD / L-NAME. This increase was not observed at all in the hearts of mice treated with MRX1, but was decreased in mice treated with RGU MRX1. Collagen 1 (Col1) and collagen 3 (Col3) are extracellular matrix proteins, and elevated levels of these indicate the presence of cardiac sclerosis / fibrosis. Both Col1 and Col3 mRNA levels were significantly elevated in the vehicle-treated HFpEF model, but as shown in Figure 15, this effect was almost completely suppressed by MRX1, and the protective effect of RGU MRX1 was small. Regarding the inflammatory response, the HFpEF model did not show an increase in Nrf2 (a master regulator of inflammation) expression, but COX-2 expression was slightly (not statistically significant) increased, and neither MRX1 nor RGU MRX1 altered the expression of either of these two inflammatory markers.

[0154] Summary of an intervention study to assess the effects of MRX1 on HfpEF In mice treated with oral administration of both types of MRX1 at a dose of 60 mk / kg (equivalent to 6 mg / kg of CBD) for two weeks, cannabidiol (CBD), 7-hydroxycannabidiol (7-OH-CBD), and 7-carboxycannabidiol (7-COOH-CBD) were all detected in their plasma. The achieved plasma CBD concentrations were similar for both formulations (2.6 μM to 2.8 μM). At this dose, MRX1 reduced the increase in systolic blood pressure, increase in cardiac and lung weight, and BNP expression observed in this HFpeF model. RGU MRX1 also reduced the increase in systolic blood pressure and lung weight.

[0155] In this study, the model did not show significant diastolic dysfunction, but EDP tended to decrease in response to MRX1, which may indicate a reduction in myocardial stiffness. This appears to be related to an antifibrotic effect, as seen in the decreased expression of Col1 and Col3 in cardiac tissue. Overall, MRX1 exerts antihypertensive, antihypertrophic, and antifibrotic effects.

[0156] In preliminary drug-treated mice, cytokine analysis of WAT was also performed, yielding some interesting results that are perhaps worth noting. For example, as shown in Figure 16, in the HFpeF model, adipose tissue expression of IL1ra was significantly increased, and this was dose-dependently decreased by MRX1. IL1ra is an anti-inflammatory cytokine, but it is also a biomarker of adipocyte dysfunction and is known to increase in obesity and metabolic syndrome. Furthermore, both JE, an early response gene encoding the monocyte-specific cytokine MCP-1, and TIMP1, an inhibitory molecule that regulates matrix metalloproteinases and plays a major role in the composition of the extracellular matrix, were highly expressed in the WAT of vehicle-treated mice but not in MRX1-treated mice.

[0157] Example 10 - Treatment of chemotherapy-induced peripheral neuropathy (CIPN) One embodiment of the cannabinoid-based formulation of the present invention (which may be referred to herein as MRX1) will be used to treat chemotherapy-induced peripheral neuropathy (CIPN) in an upcoming Phase II placebo-controlled, double-blind, crossover trial. The Phase II clinical trial will commence in 2024 and will be conducted by the University of Edinburgh. The study will be led by Professor Marie Fallon, Head of Palliative Care at St. Columba Hospice in Edinburgh, Scotland, and Honorary Consultant for Palliative Care at Western General Hospital. Professor Fallon is a world-leading researcher and has previously conducted clinical trials using CBD.

[0158] The applicant of this application entered into a drug supply agreement with the University of Edinburgh and the Lothian Health Board on November 7, 2023.

[0159] This Phase II trial will assess the effective analgesic effects of MRX1 in 92 patients with CIPN, as well as various secondary outcomes including motor function, quality of life, anxiety and depression, and sleep volume and efficiency. The trial design is shown in Figure 17.

[0160] This trial demonstrates that the inventors can demonstrate that the cannabinoid-based formulations of the present invention, including embodiments such as MRX1, are effective in treating CIPN over a 5-week period and also improve various secondary outcomes.

[0161] MRX1 was administered using an appropriate dosing regimen and titration schedule based on available nonclinical and clinical evidence, as well as data to be collected from a Phase I pharmacokinetic study to be conducted for MRX1 in 2024, which will be further discussed in Example 13.

[0162] We will collect data on inflammatory markers to investigate the mechanism of action of CBD in the prevention and treatment of CIPN, and to investigate dose-response pharmacodynamics using specific and potentially novel biomarkers for the severity of CIPN pathology, thereby supporting the evaluation of efficacy and effective doses.

[0163] Inflammation of the central nervous system is also investigated using brain connectome and fMRI, which provides specific and potentially novel biomarkers for the pathogenesis and severity of CIPN, supporting the evaluation of efficacy and effective doses.

[0164] Following the completion of this Phase II trial, the inventors plan to advance MRX1 to a Phase III trial to demonstrate its efficacy in treating CIPN in a larger population. The inventors will also work with the Medicines and Healthcare Products Regulatory Agency (MHRA) and the National Institute for Health and Care Excellence (NICE) in the UK to explore marketing authorization for MRX1 for the treatment of CIPN, and will proceed with evaluation by NICE and marketing as an approved drug in the UK through the NHS.

[0165] Example 11 - Treatment of pain associated with endometriosis One embodiment of the cannabinoid-based formulation of the present invention (which may be referred to herein as MRX1) is planned for use in an upcoming Phase II double-blind, placebo-controlled trial for the treatment of pain associated with endometriosis. The Phase II clinical trial is scheduled to begin in 2024 and will be conducted by the University of Edinburgh. This research will be led by Dr. Lucy Whitaker, Senior Clinical Research Fellow at the Centre for Reproductive Health, University of Edinburgh.

[0166] The applicant of this application entered into a drug supply agreement with the University of Edinburgh and the Russian Health Service on February 22, 2024.

[0167] This Phase II trial will evaluate the efficacy of MRX1 in treating pain associated with endometriosis in 100 patients with confirmed endometriosis via laparoscopy or imaging (performed within the past 5 years) and chronic pelvic pain lasting more than 6 months. The trial will investigate the feasibility of adoption and maintenance of MRX1. It will also assess the impact on other symptoms, including fatigue, as well as on quality of life and the frequency of healthcare visits.

[0168] The trial design is a 12-week, double-blind, placebo-controlled trial without crossovers. It will be conducted at two sites: NHS Lothian and NHS Grampian.

[0169] This trial will allow the inventors to demonstrate that MRX1 is effective in treating pain associated with endometriosis over a 12-week period and also improves the various secondary outcomes outlined above. Furthermore, patient opioid use will be recorded before and during treatment to collect data on MRX1's ability to reduce opioid use.

[0170] MRX1 was administered using an appropriate dosing regimen and titration schedule based on available nonclinical and clinical evidence, as well as data to be collected from a Phase I pharmacokinetic study to be conducted for MRX1 in 2024, which will be discussed in more detail in Example 13.

[0171] To investigate the mechanism of action of CBD in the prevention and treatment of pain associated with endometriosis, blood samples will be collected for testing of inflammatory markers.

[0172] Following the completion of this Phase II trial, the inventors plan to advance MRX1 to a Phase III trial to demonstrate its efficacy in treating pain associated with endometriosis in a larger population. The inventors will also work with the Medicines and Healthcare Regulatory Agency (MHRA) and the National Institute for Health and Care Excellence (NICE) in the UK to explore marketing authorization for MRX1 for the treatment of endometriosis, and will proceed with evaluation by NICE and marketing as an approved drug in the UK through the NHS.

[0173] Example 12 - Elucidation of the pathogenicity of fibroblasts and mesenchymal stromal cells in endometriosis Fibroblasts play a crucial role in endometriosis, contributing to its complex pathogenesis. In short, fibroblasts are known to influence extracellular matrix (ECM) remodeling, contribute to inflammatory processes, regulate angiogenesis, and have immunomodulatory effects. All of these processes are related to endometriosis, and there is evidence that fibroblasts are involved in all of them.

[0174] Using one embodiment of the cannabinoid-based formulation of the present invention (which may be referred to herein as MRX1), a co-funded doctoral student at the University of Reading, under the guidance of Professor Darius Widela, will conduct and investigate the following:

[0175] 1) Inflammation is simulated by exposing fibroblasts / mesenchymal stem / stromal cells (MSCs) to tumor necrosis factor-α, IL-1β, and IL-6 individually or in combination with MRX1, followed by immunocytochemical staining for the NF-κB subunit p65. Imaging and analysis of NF-κB translocations are performed using the Revvity Operetta high-content imaging system (with machine learning capabilities). 2) Assess the secretion of pro-angiogenic and pro-inflammatory factors by ELISA (e.g., FGF-2, IL-6, IL-1β, VEGF). 3) Collect secretomes from fibroblasts / MSCs treated as described in 2) and use them in an in vitro angiogenesis model of HUVEC. 4) The secretome generated as described above is used in the human monocyte polarization assay. 5) Fibroblasts and MSCs are treated as described in 1), and the composition of the deposited ECM (collagen, proteoglycans, and glycoproteins (e.g., fibronectin, laminin), matrix metalloproteinases (MMPs), integrins, and basement membrane components) is studied using immunocytochemistry and high-content imaging (see 1 above).

[0176] The inventors hypothesize that MRX1 can reduce inflammatory signaling, the production of pro-angiogenic factors, and ECM remodeling by fibroblasts and MSCs, thereby regulating immune cells toward a regulatory M2 phenotype.

[0177] Example 13 - Phase I Pharmacokinetic (PK) Study Embodiments of the cannabinoid-based formulation of the present invention (which may be referred to herein as MRX1) are administered to healthy volunteers to determine the safety and PK profile of the MRX1 formulation. MRX1 is administered to 20 to 30 participants using dosing regimens and titration schedules aligned with nonclinical and clinical evidence, as well as the MRX1 formulations that the inventors expect to be used in clinical practice to treat various chronic inflammatory pain disorders.

[0178] Phase I PK studies are scheduled to be conducted by the Galeno Research Division in Brazil in 2024. MRX1 will be administered to participants over a period of 1 to 3 weeks. Blood samples will be taken periodically and tested for analytes including: cannabidiol (CBD), 7-carboxycannabidiol (7-COOH-CBD), 7-hydroxycannabidiol (7-OH-CBD), delta-9 tetrahydrocannabinol (THC), 11-carboxy-Δ9-THC (11-OH-THC), and 11-hydroxy-Δ9-THC (11-COOH-THC).

[0179] In line with the novel and innovative features of the cannabinoid-based formulation of the present invention and the fact that the formulation is substantially THC-free, the inventors anticipate that the levels of delta-9 tetrahydrocannabinol (THC) and its metabolites detected in participant blood samples will be low or zero. This will provide further evidence of the novelty of the cannabinoid-based formulation of the present invention when administered to humans.

[0180] As discussed in Example 7, based on our research and the results of previous permeability studies conducted with respect to the cannabinoid-based formulations of the present invention, we also anticipate that the cannabinoid-based formulations of the present invention, such as MRX1, will achieve superior CBD bioavailability compared to other CBD formulations in oil formulations. The presence of the unique terpene blend in the cannabinoid-based formulations of the present invention is expected to increase the permeability, and therefore the bioavailability, of CBD in the bloodstream.

[0181] Following the completion of this Phase I trial, the inventors will be able to utilize these demonstrated novel properties and the resulting bioavailability data to better target the dosing regimens and titration schedules used for the cannabinoid-based formulations of the present invention in additional clinical trials, including two Phase II clinical trials conducted by the University of Edinburgh using the cannabinoid-based formulations of the present invention to treat chemotherapy-induced peripheral neuropathy and pain associated with endometriosis, respectively, as discussed in Examples 10 and 11.

[0182] conclusion The resulting CBD preparations are referred to as cannabis-based products (CBPMs) for medicinal use in humans or animals. Specifically, CBPMs are preparations containing cannabidiol (CBD) isolate, terpenes, and medium-chain triglyceride (MCT) oil in liquid form, and are delivered via sublabial, buccal, sublingual, or oropharyngeal administration. The use of these preparations is primarily focused on diseases associated with pain, inflammation, autoimmune diseases, neurological disorders, neoplasms, nausea, hypertension, hypertrophic cardiomyopathy, and fibrosis.

[0183] The formulation (or CBPM) is a broad-spectrum CBD mixture consisting of a specific combination of CBD and terpenes, manufactured to pharmaceutical standards in accordance with Good Manufacturing Practice (GMP) guidelines, and designed to produce precise physical effects. To date, no GMP-compliant products are available in the UK; therefore, the pharmaceutical formulation of the present invention bridges this gap and facilitates the availability and provision of pharmaceutical-grade CBPM for use in clinical trials and patient treatment.

[0184] When these liquid formulations are prepared for sublabial, buccal, or sublingual delivery, the drug can be introduced into the systemic circulation via the mucous membrane, thereby improving activity and efficacy by avoiding first-pass metabolism and increasing the drug's bioavailability. Advantageously, while oral administration of cannabinoids is considered the most prevalent method of drug delivery on the market today, given their lipophilic nature and low bioavailability due to gastrointestinal absorption, the formulations of the present invention remarkably enable administration via this route.

[0185] The active pharmaceutical ingredients in CBPM preparations are CBD and terpenes. MCT oil is not considered an active ingredient because it acts as a pharmaceutically acceptable carrier, excipient, or diluent. The active ingredients are thought to interact with the endocannabinoid system (ECS) and modulate various physiological responses. The ECS is a complex lipid cell signaling system composed of cannabinoid receptors (CBRs) 1 and 2, endogenous cannabinoids (endocannabinoids), anandamide (N-arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG), anandamide transporter protein (TP), and enzymes responsible for the synthesis and degradation of endocannabinoids (fatty acid amide hydrolase, FAAH, and monoacylglycerol lipase, MAGL). However, further research into the pharmacology of the endocannabinoid system has led to the discovery of various molecular targets of cannabinoids and terpenes independent of CBR1 and CBR2, including transient receptor potential (TRP) channels, two orphan G protein-coupled receptors (GPR55 and GPCR18), and peroxisome proliferator-activated receptors (PPARs). The endocannabinoid system (ECS) regulates homeostasis of various physiological processes, including inflammation, pain, appetite, metabolism, and memory.

[0186] The ECS modulates a "retrograde negative feedback mechanism" in the CNS. During neuronal depolarization, AEA and 2-AG are synthesized at the postsynaptic terminals of dendritic spines and somatic dendritic compartments. AEA and 2-AG are then released into the interneuronal cleft, suppressing the secretion of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in GABAergic afferent neurons and the secretion of the excitatory neurotransmitter glutamate in glutamatergic neurons. Furthermore, eCB signaling in non-neuronal tissues controls several physiological processes, including spermatogenesis, pain, and immune system regulation. Because the ECS modulates multiple cellular functions that play crucial roles in pain, neuromodulation, mood, immunity, and other physiological processes, therapeutic agents targeting this system, such as CBPM described herein, hold potential as novel approaches to treating a variety of diseases, including pain, inflammation, autoimmune diseases, neurological disorders, neoplasms, nausea, hypertension, hypertrophic cardiomyopathy, and fibrosis.

[0187] CBPM is being added to the treatment paradigm for many patients suffering from acute and chronic inflammatory diseases, pain, and negative emotional symptoms such as anxiety and depression, for which conventional therapies have had limited or no effect. For this reason, the National Institute for Health and Care Excellence (NICE) and the International Association for the Study of Pain (IASP) are particularly calling for human studies using CBPM.

[0188] Therefore, there is currently an unmet need for the treatment of several treatment-resistant diseases, including pain, inflammation, autoimmune diseases, neurological disorders, neoplasms, nausea, hypertension, hypertrophic cardiomyopathy, and fibrosis. Since there is no one-size-fits-all treatment, most patients require multiple alternative treatment approaches. Furthermore, while numerous CBD preparations are now available as food supplements and claim many health benefits, there is little evaluation of whether they are administered in appropriate formulations to achieve the blood concentrations required to support these claims. The method of the present invention addresses this need and produces medical-grade CBPM in accordance with pharmaceutical standards and GMP guidelines for use in medical research and clinical practice.

Claims

1. Cannabinoid-based formulations, (i) One or more cannabinoids, (ii) Multiple terpenes selected from the group of terpenes consisting of myrcene, caryophyllene, ocimene, pinene, limonene, humulene, and linalool, Includes, The aforementioned formulation is a cannabinoid-based formulation that is substantially free of THC.

2. The cannabinoid-based formulation according to claim 1, wherein the concentration of THC in the formulation is less than 0.01% (weight / volume), less than 0.005% (weight / volume), or less than 0.001% (weight / volume).

3. The cannabinoid-based formulation according to claim 1 or 2, wherein the concentration of THC in the formulation is less than 0.0005% (weight / volume), less than 0.0002% (weight / volume), or less than 0.0001% (weight / volume).

4. The cannabinoid-based formulation according to any one of claims 1 to 3, wherein the formulation does not contain THC detectable by reasonable analytical means.

5. The cannabinoid-based formulation according to any one of claims 1 to 4, wherein the one or more cannabinoids are selected from the group of cannabinoids consisting of cannabidiol (CBD), cannabichromene (CBC), cannabigerol (CBG), and cannabigerol monomethyl ether (CBGM).

6. The cannabinoid-based formulation according to any one of claims 1 to 5, wherein the one or more cannabinoids comprises CBD.

7. The cannabinoid-based formulation according to any one of claims 1 to 6, wherein the one or more cannabinoids comprises an isolate of cannabidiol (CBD).

8. The cannabinoid-based formulation according to any one of claims 1 to 7, wherein the formulation does not contain CBC, CBG, or CBGM.

9. The cannabinoid-based formulation according to any one of claims 1 to 8, wherein the purity of the one or more cannabinoids is at least 97%, at least 98%, or at least 99%, or about 98% to 100%.

10. The cannabinoid-based formulation according to any one of claims 1 to 9, wherein the concentration of one or more cannabinoids, preferably CBD, in the cannabinoid-based formulation is at least 2% (weight / volume), at least 3% (weight / volume), or at least 4% (weight / volume).

11. The cannabinoid-based formulation according to any one of claims 1 to 10, wherein the concentration of one or more cannabinoids, preferably CBD, in the cannabinoid-based formulation is at least 5% (weight / volume), at least 6% (weight / volume), or at least 7% (weight / volume).

12. The cannabinoid-based formulation according to any one of claims 1 to 11, wherein the concentration of one or more cannabinoids, preferably CBD, in the cannabinoid-based formulation is at least 8% (weight / volume), at least 9% (weight / volume), or at least 10% (weight / volume).

13. The cannabinoid-based formulation according to any one of claims 1 to 12, wherein the concentration of one or more cannabinoids, preferably CBD, in the cannabinoid-based formulation is 7% to 13% (weight / volume) or 8% to 12% (weight / volume).

14. The cannabinoid-based formulation according to any one of claims 1 to 13, wherein the concentration of one or more cannabinoids, preferably CBD, in the cannabinoid-based formulation is 9% to 11% (weight / volume).

15. The cannabinoid-based formulation according to any one of claims 1 to 14, wherein the purity of the plurality of terpenes may be at least 90%, at least 92%, or at least 95% of the total terpenes.

16. The cannabinoid-based formulation according to any one of claims 1 to 15, wherein the plurality of terpenes comprises at least three, at least four, or at least five terpenes selected from the group of terpenes consisting of myrcene, caryophyllene, ocimene, pinene, limonene, humulene, and linalool.

17. The cannabinoid-based formulation according to any one of claims 1 to 16, wherein the plurality of terpenes comprises at least six or at least seven terpenes selected from the group of terpenes consisting of myrcene, caryophyllene, ocimene, pinene, limonene, humulene, and linalool.

18. (i) The pinene is α-pinene, and optionally the concentration of α-pinene in the cannabinoid-based formulation is at least 0.0001% (weight / volume), at least 0.001% (weight / volume), at least 0.01% (weight / volume), less than 0.75% (weight / volume), less than 0.5% (weight / volume), less than 0.3% (weight / volume), 0.0001% to 0.5% (weight / volume), 0.01% to 0.3% (weight / volume), 0.01% to 0.2% (weight / volume), 0.01% to 0.05% (weight / volume), 0.01% to 0.04% (weight / volume), or 0.01% to 0.03% (weight / volume); (ii) The concentration of limonene in the cannabinoid-based formulation is at least 0.0001% (weight / volume), at least 0.001% (weight / volume), at least 0.01% (weight / volume), less than 0.75% (weight / volume), less than 0.5% (weight / volume), less than 0.3% (weight / volume), 0.0001% to 0.5% (weight / volume), 0.01% to 0.3% (weight / volume), 0.01% to 0.2% (weight / volume), 0.01% to 0.05% (weight / volume), 0.01% to 0.04% (weight / volume), 0.01% to 0.03% (weight / volume), 0.03% to 0.09% (weight / volume), 0.03% to 0.08% (weight / volume), or 0.03% to 0.07% (weight / volume); (iii) The ocimene is β-ocimene, and optionally the concentration of β-ocimene in the cannabinoid-based formulation is at least 0.0001% (weight / volume), at least 0.001% (weight / volume), at least 0.01% (weight / volume), less than 0.75% (weight / volume), less than 0.5% (weight / volume), less than 0.3% (weight / volume), 0.0001% to 0.5% (weight / volume), 0.01% to 0.3% (weight / volume) The amounts are 0.01% to 0.2% (weight / volume), 0.01% to 0.07% (weight / volume), 0.01% to 0.06% (weight / volume), 0.01% to 0.05% (weight / volume), 0.01% to 0.04% (weight / volume), 0.001% to 0.05% (weight / volume), 0.001% to 0.04% (weight / volume), 0.001% to 0.02% (weight / volume), or 0.001% to 0.01% (weight / volume); (iv) The caryophyllene is β-caryophyllene, and optionally the concentration of β-caryophyllene in the cannabinoid-based preparation is at least 0.0001% (weight / volume), at least 0.001% (weight / volume), at least 0.01% (weight / volume), less than 0.75% (weight / volume), less than 0.5% (weight / volume), less than 0.3% (weight / volume), 0.0001% to 0.5% (weight / volume), 0.01% to The percentages are 0.3% (weight / volume), 0.01%–0.2% (weight / volume), 0.01%–0.08% (weight / volume), 0.01%–0.07% (weight / volume), 0.01%–0.06% (weight / volume), 0.01%–0.05% (weight / volume), 0.01%–0.1% (weight / volume), 0.01%–0.09% (weight / volume), 0.01%–0.08% (weight / volume), or 0.03%–0.08% (weight / volume); (v) The humulene is alpha-humulene, and optionally the concentration of alpha-humulene in the cannabinoid-based formulation is at least 0.0001% (weight / volume), at least 0.001% (weight / volume), at least 0.01% (weight / volume), less than 0.75% (weight / volume), less than 0.5% (weight / volume), less than 0.3% (weight / volume), 0.0001% to 0.5% The values ​​are % (weight / volume), 0.01% to 0.3% (weight / volume), 0.01% to 0.2% (weight / volume), 0.01% to 0.04% (weight / volume), 0.01% to 0.03% (weight / volume), 0.01% to 0.02% (weight / volume), 0.005% to 0.04% (weight / volume), 0.005% to 0.03% (weight / volume), or 0.005% to 0.02% (weight / volume); (vi) The myrcene is β-myrcene, and optionally the concentration of β-myrcene in the cannabinoid-based preparation is at least 0.0001% (weight / volume), at least 0.001% (weight / volume), at least 0.01% (weight / volume), less than 0.75% (weight / volume), less than 0.5% (weight / volume), less than 0.3% (weight / volume), 0.0001% to 0.5% (weight / volume), 0.01% to 0.3% (weight / volume), 0.01% to 0.2% (weight / volume), 0.01% to 0.1% (weight / volume), 0.01% to 0.08% (weight / volume), 0.01% to 0.07% (weight / volume), or 0.01% to 0.06% (weight / volume); and / or (vii) The concentration of linalool in the cannabinoid-based formulation is at least 0.0001% (weight / volume), at least 0.001% (weight / volume), at least 0.01% (weight / volume), less than 0.75% (weight / volume), less than 0.5% (weight / volume), less than 0.3% (weight / volume), 0.0001% to 0.5% (weight / volume), 0.01% to 0.3% (weight / volume), 0.01% to 0.2% (weight / volume), 0.01% to 0.05% (weight / volume), 0.01% to 0.04% (weight / volume), 0.01% to 0.03% (weight / volume), or 0.01% to 0.02% (weight / volume). A cannabinoid-based formulation according to any one of claims 1 to 17.

19. The cannabinoid-based formulation according to any one of claims 1 to 18, wherein the cannabinoid-based formulation further comprises a pharmaceutically acceptable excipient or carrier.

20. The cannabinoid-based formulation according to claim 19, wherein the pharmaceutically acceptable excipient or carrier comprises a medium-chain triglyceride (MCT), preferably MCT oil.

21. The chemical formula for the aforementioned MCT is as follows: 【Chemistry 1】 A cannabinoid-based formulation according to claim 20, wherein X = 1 to 14 in the formula.

22. The cannabinoid-based formulation according to claim 20 or 21, wherein the concentration of MCT oil in the cannabinoid-based formulation is at least 80% (weight / volume), at least 82% (weight / volume), at least 84% (weight / volume), at least 86% (weight / volume), at least 88% (weight / volume), less than 96% (weight / volume), less than 95% (weight / volume), less than 94% (weight / volume), less than 92% (weight / volume), less than 90% (weight / volume), 85% to 93% (weight / volume), 86% to 92% (weight / volume), 87% to 91% (weight / volume), or 88% to 90% (weight / volume).

23. The cannabinoid-based preparation according to any one of claims 1 to 22, wherein the cannabinoid-based preparation is in liquid form and optionally includes a tincture.

24. The cannabinoid-based formulation according to any one of claims 1 to 23, wherein the formulation can be administered by sublabial, buccal, sublingual, or oropharyngeal delivery.

25. A method for producing a cannabinoid-based formulation according to any one of claims 1 to 24, comprising: (i) combining one or more cannabinoids and (ii) a plurality of terpenes selected from the group consisting of myrcene, caryophyllene, ocimene, pinene, limonene, humulene, and linalool to produce a cannabinoid-based formulation, wherein the formulation is substantially THC-free.

26. A cannabinoid-based formulation obtained or obtainable by the method of claim 25.

27. A cannabinoid-based preparation for therapeutic use according to any one of claims 1 to 24 or 26.

28. A cannabinoid-based preparation according to any one of claims 1 to 24 or 26, for the treatment, improvement or prevention of pain, inflammation, autoimmune diseases, neurological disorders, neoplasms, nausea, hypertension, hypertrophic cardiomyopathy, or fibrosis.

29. A cannabinoid-based formulation for use in the application described in claim 28, wherein the pain, inflammation, autoimmune disease, neurological disease, neoplasm, nausea, hypertension, hypertrophic cardiomyopathy, or fibrosis is selected from the group of diseases consisting of chemotherapy-induced peripheral neuropathy (CIPN), endometriosis, osteoarthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, fibromyalgia, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease (COPD), gout, scleroderma, lupus, Ehlers-Danlos syndrome, pericarditis, myocarditis, myocardial infarction, chemotherapy-induced nausea, anxiety, type 1 diabetes mellitus, cardiovascular disease, primary hypertension, secondary hypertension, resistant hypertension, isolated systolic hypertension, malignant hypertension, obstructive hypertrophic cardiomyopathy, non-obstructive hypertrophic cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, renal fibrosis, mediastinal fibrosis, retroperitoneal fibrosis, myelofibrosis, cutaneous fibrosis, and scleroderma.

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