cannabidiol-type cannabinoid compounds

Abstract

The present invention relates to cannabinoid compounds of the cannabidiol (CBD) type for use as pharmaceuticals. The CBD-type cannabinoid, 6-hydroxycannabidiol (6-0 H CBD), is a metabolite of CBD. Cannabinoids can be produced by synthetic means, and methods for producing 6-0 H CBD are described herein. Additionally, published herein are data demonstrating the effects of 6-0 H CBD in disease models.

Description

[Technical Field]

[0001] The present invention relates to cannabinoid compounds of the cannabidiol (CBD) type for use as medicines.

[0002] The CBD-type cannabinoid 6-hydroxy cannabidiol (6-OH CBD) is a metabolite of CBD.

[0003] Cannabinoids can be produced by synthetic means.

[0004] Presented herein are data demonstrating the effects of 6-OH CBD in disease models. Additionally, methods for producing 6-OH CBD are described. [Background technology]

[0005] Cannabinoids are natural and synthetic compounds structurally or pharmacologically related to components of the cannabis plant or endogenous agonists (endocannabinoids) of the cannabinoid receptors CB1 or CB2. The only way these compounds are produced in nature is by the cannabis plant. Cannabis belongs to the flowering plants in the Cannabaceae family and includes the species Cannabis sativa, Cannabis indica, and Cannabis ruderalis (sometimes considered part of Cannabis sativa).

[0006] The cannabis plant contains a highly complex mixture of compounds. At least 568 unique molecules have been identified. These compounds include cannabinoids, terpenoids, sugars, fatty acids, flavonoids, other hydrocarbons, nitrogenous compounds, and amino acids.

[0007] Cannabinoids exert their physiological effects through various receptors, including, but not limited to, adrenergic receptors, cannabinoid receptors (CB1 and CB2), GPR55, GPR3, and GPR5. The primary cannabinoids present in the cannabis plant are the cannabinoid acids Δ9-tetrahydrocannabinolic acid (Δ9-THCA) and cannabidiolic acid (CBDA), along with minor amounts of each of the neutral (decarboxylated) cannabinoids. In addition, cannabis may contain lower levels of other minor cannabinoids. According to Lewis, MM et al., ACS Omega, 2, 6091-6103 (2017), "The chemical composition, pharmacological profile, and full physiological effects of these medicinal plants, and more importantly, extracts from cannabis, are still not fully understood."

[0008] Crude extracts from the cannabis plant containing CBD have been used by patients suffering from diseases and disorders. However, such crude products are unsuitable for use in pharmaceutical formulations. Those seeking to produce more consistent CBD preparations for use in treating diseases or disorders have made concerted efforts to synthetically produce CBD or to attempt to remove all compounds other than CBD, particularly psychoactive compounds such as THC, from plant-derived cannabinoids. See, for example, U.S. Patent No. 2014 / 0298511.

[0009] The present invention encompasses the surprising discovery that a metabolite of CBD has therapeutic effects. This compound, 6-hydroxycannabidiol (6-OH CBD), can be produced synthetically and used in purified form.

[0010] Cannabinoids are a class of compounds, many of which are naturally derived from the cannabis plant or can be produced synthetically through chemical synthesis.

[0011] Over 100 different cannabinoids produced by cannabis have been identified. These cannabinoids include: Phytocannabinoids; endocannabinoids and synthetic cannabinoids (which are novel cannabinoids or synthetically produced versions of phytocannabinoids or endocannabinoids) can be divided into different groups.

[0012] Phytocannabinoids are naturally occurring cannabinoids found in cannabis plants. Phytocannabinoids can be isolated from plants to produce highly purified extracts. Phytocannabinoids can be obtained as neutral (decarboxylated) or carboxylic acid forms, depending on the method used to extract cannabinoids from plant materials. For example, heating the carboxylic acid form will decarboxylate most of the carboxylic acid form to a neutral form. While phytocannabinoids are only produced from plants, versions of phytocannabinoids can be synthetically produced through chemical synthesis.

[0013] Endocannabinoids are endogenous, lipid-based retrograde neurotransmitters that bind to cannabinoid receptors and cannabinoid receptor proteins expressed in the mammalian central nervous system (including the brain) and peripheral nervous system. The endocannabinoid system is involved in regulating numerous physiological and cognitive processes, including reproduction, pregnancy, pre- and postnatal development, appetite, pain sensation, mood, and memory, as well as mediating the pharmacological effects of cannabis.

[0014] Synthetic cannabinoids are compounds that have cannabinoid-like structures and are produced using chemical means rather than from plants.

[0015] Specific cannabinoids are described in more detail below.

[0016] Cannabidiol (CBD) is the major cannabinoid component of cannabis species, such as hemp plants (Cannabis sativa). Unlike other cannabinoids, such as THC, cannabidiol does not bind to CB1 or CB2 receptors, meaning that binding to the receptors is negligible with respect to inducing pharmacological effects. Therefore, cannabidiol does not cause central or peripheral nervous system effects mediated by CB1 or CB2 receptors. CBD has little or no psychotropic (cannabis-like) activity, and its molecular structure and properties are substantially different from those of other cannabinoids.

[0017] The administration of cannabidiol is the subject of research in an attempt to provide alternative treatments for a variety of diseases and disorders that may be amenable to treatment.

[0018] Numerous studies have been conducted in animals to determine the metabolism of CBD. The pharmacokinetics of CBD are complex, primarily due to a substantial first-pass effect. This in turn contributes to the poor oral bioavailability of CBD in humans and other species.

[0019] The most abundant metabolite of CBD is the hydroxylated 7-carboxy derivative of CBD, which: 2"-OH-7-COOOH,3",4",5"-trinor CBD; CBD-glucuronide; 4"-OH-7-COOH CBD; 2"-OH-7-COOH CBD; 10-OH-7-COOH CBD; 3"-OH-7-COOH CBD; 7-OH-3"-COOH,4",5"-dinor CBD; 7-COOH-8,9-dihydro-8,9-diOH CBD; 1"-OH-7-COOH CBD; 6-OH-42-COOH,5"-nor CBD; 6-OH-3"-COOH,4",5"-dinor CBD; 7-COOH CBD; 7-OH-4"-COOH,5"-nor CBD; 4"-COOH,5"-nor CBD; 7-OH CBD; 8,9-dihydro-7,8,9-triOH CBD; Cannabinol; 3"-COOH,4",5"-dinor CBD; 2"-COOH,3",4",5"-trinor CBD; 2",6-diOH,3",4",5"-trinor CBD; 6,7-diOH CBD; 7-OH-1"-COOH,2",3",4",5"-tetranor CBD; 6-OH CBD; 7-OH-5"-COOH CBD; 1"-COOH,2",3",4",5"-tetranor CBD; 6-OH-1"-COOH,2",3",4",5"-tetranor CBD and 6-OH-5"-COOH CBD (Ujvary and Hanus, 2016) Includes:

[0020] U.S. Patent No. 6,630,507 describes numerous analogs of cannabidiol. The compound 6-OH CBD has been extensively described in the literature, but no data has been presented to provide evidence that this compound can have any therapeutic effect.

[0021] Tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. THC is a partial agonist of the CB1 and CB2 receptors. Synthetic THC, or dronabinol, is approved for the treatment of anorexia in AIDS patients and nausea and vomiting caused by cancer chemotherapy.

[0022] Of the over 100 naturally occurring cannabinoids identified in Cannabis sativa, seven have been classified as CBD-type compounds, and these cannabinoids have the same absolute structure as CBD. These are: CBD, Cannabidiolic acid (CBDA), Cannabidivarin (CBDV), Cannabidivarin acid (CBDVA), Cannabidiol-C1 (CBD-C1), Cannabidiol-C4 (CBD-C4), Cannabidiol-C6 (CBD-C6), and Cannabidiol monomethyl ether (CBDM) is.

[0023] Cannabidiolic acid (CBDA) is the primary form in which CBD exists in the cannabis plant, and it is converted to CBD after decarboxylation.

[0024] Cannabidivarin (CBDV), a CBD homologue with a shortened side chain by two methylene bridges, is a non-psychoactive cannabinoid that has been shown to have anticonvulsant activity in mouse models of epilepsy.

[0025] Cannabidiol-C1 (CBD-C1), also known as cannabidiorcol, is a CBD homologue with a shortened side chain by four methylene bridges. CBD-C1 occurs naturally in plants that produce CBD, but has been shown to have no therapeutic effect.

[0026] Cannabidiol-C4 (CBD-C4), known as nor-cannabidiol, is a homolog of CBD with a side chain shortened by one methylene bridge. CBD-C4 occurs naturally in plants that produce CBD and, prior to the present invention, has been shown to have no therapeutic effect.

[0027] Cannabidiol-C6 (CBD-C6) is a homolog of CBD with an augmented side chain by one methylene bridge. CBD-C6 can occur naturally in plants that produce CBD and, prior to the present invention, has been shown to have no therapeutic effect.

[0028] The present invention demonstrates the first data showing that the compound 6-hydroxy cannabidiol can have therapeutic efficacy. [Prior art documents] [Patent documents]

[0029] [Patent Document 1] U.S. Patent No. 2014 / 0298511 [Patent Document 2] U.S. Patent No. 6,630,507 Summary of the Invention [Means for solving the problem]

[0030] According to a first aspect of the present invention, there is provided 6-hydroxy cannabidiol (6-OH CBD) for use as a medicine.

[0031] Preferably, the 6-OH CBD is present as a synthetic compound. Alternatively, the 6-OH CBD is present as a pure and isolated compound.

[0032] Preferably, the dose of 6-OH CBD is greater than 100 mg / kg / day. More preferably, the dose of 6-OH CBD is greater than 250 mg / kg / day. More preferably, the dose of 6-OH CBD is greater than 500 mg / kg / day. More preferably, the dose of 6-OH CBD is greater than 750 mg / kg / day. More preferably, the dose of 6-OH CBD is greater than 1000 mg / kg / day. More preferably, the dose of 6-OH CBD is greater than 1500 mg / kg / day.

[0033] Alternatively, the dose of 6-OH CBD is less than 100 mg / kg / day. More preferably, the dose of 6-OH CBD is less than 50 mg / kg / day. More preferably, the dose of 6-OH CBD is less than 20 mg / kg / day. More preferably, the dose of 6-OH CBD is less than 10 mg / kg / day. More preferably, the dose of 6-OH CBD is less than 5 mg / kg / day. More preferably, the dose of 6-OH CBD is less than 1 mg / kg / day. More preferably, the dose of 6-OH CBD is less than 0.5 mg / kg / day.

[0034] According to a second aspect of the present invention, there is provided a composition for use as a medicine comprising 6-hydroxy cannabidiol (6-OH CBD) and one or more pharmaceutically acceptable excipients.

[0035] According to a third aspect of the present invention, there is provided 6-hydroxycannabidiol (6-OH CBD) for use in the treatment of epilepsy. Preferably, the epilepsy is treated in a mammal. More preferably, the mammal is a human. Alternatively, the mammal is a dog.

[0036] According to a fourth aspect of the present invention, there is provided a method for producing 6-hydroxy cannabidiol.

[0037] Embodiments of the present invention are further described below with reference to the accompanying drawings. [Brief explanation of the drawings]

[0038] [Figure 1] Figure 1 shows the effect of 6-OH CBD in the MEST test in mice. [Figure 2] FIG. 2 shows the pharmacokinetics of 6-OH CBD in mouse plasma and brain following a single intravenous or intraperitoneal administration. DETAILED DESCRIPTION OF THE INVENTION

[0039] The cannabinoids described in this application are listed below with their standard abbreviations. [ka] [Example]

[0040] Example 1: Synthetic Production Method for α 6-Hydroxy Cannabidiol (6-OH CBD)

[0041] The compound 6-OH CBD is a known metabolite of cannabidiol.

[0042] The synthetic pathways described below detail methods that can be used to produce the cannabinoid α 6-OH CBD.

[0043] In the scheme, R=C5H 11

[0044] To cannabidiol (5.00 g, 15.8 mmol) in anhydrous pyridine (20 mL) was added acetic anhydride (5.13 g, 4.75 mL, 50.2 mmol) and the solution was stirred for 4 h. Dichloromethane (300 mL) was added and the solution was washed with water (200 mL), 1 M hydrochloric acid (200 mL), saturated aqueous sodium bicarbonate (200 mL), dried (MgSO), and concentrated to give cannabidiol diacetate (5.72 g, quantitative) as a straw-yellow oil which was used without further purification.

[0045] To cannabidiol diacetate (6.18 g, 15.5 mmol) in glacial acetic acid (14 mL) and acetic anhydride (7.12 g, 6.59 mL, 69.8 mmol) was added sodium dichromate (4.87 g, 18.6 mmol), and the mixture was stirred at room temperature for 4 days. The resulting solution was diluted with water (200 mL) and extracted with diethyl ether (200 mL, followed by 150 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2 × 100 mL), dried (MgSO), and concentrated to yield a yellow oil. It was purified using a Biotage Isolera automated chromatography system under normal phase conditions (silica column, 5 → 32% gradient of ethyl acetate in petrol) with detection at 254 nm to yield 6-oxo-cannabidiol diacetate (2.03 g, 33%) as a colorless oil.

[0046] Rf = 0.45 (ethyl acetate - petrol, 1:4 v / v)

[0047] To lithium aluminum hydride (355 mg, 9.37 mmol) in diethyl ether (36 mL) at 0 °C was added 6-oxo-cannabidiol diacetate (0.92 g, 2.23 mmol) in diethyl ether (8 mL), and the mixture was stirred at room temperature for 4 h. The resulting mixture was cooled in an ice bath and quenched by the careful dropwise addition of water (10 mL). 1 M hydrochloric acid (60 mL) was added, and the mixture was extracted with diethyl ether (100 mL). The organic layer was washed with saturated brine (80 mL), dried (MgSO), and concentrated to give a pale yellow oil. It was purified using a Biotage Isolera automated chromatography system under normal phase conditions (silica column, 7 → 47% gradient of ethyl acetate in petrol) with detection at 254 nm to give 6-oxo-cannabidiol (0.51 g, 69%) as a white glassy solid.

[0048] Rf = 0.34 (ethyl acetate - petrol, 3:7 v / v)

[0049] [ka]

[0050] The resulting substance was identified as α 6-hydroxy-cannabidiol (6-OH CBD). The compound has the chemical formula C 21 H 30 It is a yellow glassy semi-solid substance with O3 and a molecular weight of 330.5 g / mol.

[0051] The purity of the compound was tested by HPLC and shown to yield 95.6% pure material.

[0052] 6-OH CBD was stored at -20°C and protected from light until required for testing.

[0053] Example 2: Evaluation of 6-hydroxycannabidiol (6-OH CBD) for anticonvulsant activity using the maximal electroshock seizure (MES) test in mice.

[0054] The effects of 6-OH CBD were tested in the maximal electroshock seizure (MES) test, a seizure model in mice.

[0055] The maximal electroshock seizure (MES) test is widely used preclinically to evaluate the anticonvulsant properties of molecules and standard antiepileptic drugs (Loscher et al., 1991).

[0056] The MES test is a highly convincing model in which mice are subjected to a predetermined, sufficiently intense level of electrical stimulation, reliably inducing toxic hindlimb extensor seizures in 100% of control animals. Thus, the MES test is a rigorous assessment of anticonvulsant activity (Swinyard, 1985).

[0057] [method] Naive mice were acclimated to the procedure room in their home cages with food and water available ad libitum.

[0058] Animals were dosed intraperitoneally (ip) according to treatment group.

[0059] The vehicle (10 ml / kg ip, 60 min pretreatment time) was a 1:1:18 mixture of 5% ethanol, 5% kolliphor EL, and 90% saline.

[0060] The test compound, α 6-OH CBD, was prepared according to the method described in Example 1.

[0061] The test compound, 6-OH CBD, was administered at doses of 3, 30, 100, and 200 mg / kg, 10 ml / kg ip with a 60 min pretreatment period.

[0062] Additionally, a dose of 100 mg / kg CBD was given at 10 ml / kg ip with a 120 min pretreatment period to assess the drug's effects over a longer time course.

[0063] Valproate, the positive control, was used at 250 mg / kg (10 ml / kg ip, 30 min pretreatment time).

[0064] Following a predetermined high-level (30 mA: 50 Hz) electric shock (0.2 s duration) delivered to the cornea, of sufficient intensity to reliably induce toxic hindlimb extensor seizures in 100% of control animals, mice were individually assessed for the occurrence of toxic hindlimb extensor seizures.

[0065] Seizure induction was measured as an all-or-nothing effect scored as either present (+) or absent (0) for each animal.

[0066] Data were collected by an observer blinded to the treatment for each animal and expressed as the number of +'s or 0's for each treatment group.

[0067] The percent inhibition of the relevant vehicle-treated group (protection relative to vehicle-treated controls) was then determined.

[0068] Significant differences between individual treatment groups and the vehicle-treated group were assessed using a 2-tailed Fisher's Exact Probability test (p<0.05 considered significant).

[0069] [result] Table 1 below demonstrates the data presented in this experiment.

[0070] In the positive control group treated with valproate (250 mg / kg), administered i.p. 30 min before testing, all animals were scored as seizure-free, a result that was statistically significant (p<0.001) compared with vehicle control.

[0071] In the 6-OH CBD-treated group, 3 mg / kg of 6-OH CBD administered i.p. 120 minutes before the test had no effect. However, 30, 100, and 200 mg / kg of 6-OH CBD enabled all mice in the group to tolerate the seizures, demonstrating a statistically significant difference compared to the vehicle (p<0.001).

[0072] In addition, administration of 6-OH CBD (100 mg / kg) given at 120 minutes also demonstrated a statistically significant reduction in seizures compared to vehicle control.

[0073] [Table 1]

[0074] [Conclusion] These data demonstrate for the first time a therapeutic effect for the compound 6-OH CBD.

[0075] Data showing that 6-OH CBD given 2 hours (120 minutes) before mice received an electric shock demonstrates that the compound was able to have long-lasting effects.

[0076] These data are important because they provide previously unknown evidence that these cannabinoids have potential therapeutic value.

[0077] Example 3: Evaluation of 6-hydroxycannabidiol (6-OH CBD) for anticonvulsant activity using the mouse maximal electroshock seizure threshold (MEST) test.

[0078] The effects of 6-OH CBD were tested in the maximal electroshock seizure threshold (MEST) test, a mouse model of generalized seizures.

[0079] The maximal electroshock seizure threshold (MEST) test is widely used preclinically to assess the proconvulsant or anticonvulsant properties of test compounds (Loscher et al., 1991).

[0080] In the MEST test, the ability of a drug to alter the seizure threshold current required to induce toxic extensor muscle spasms of the hind limbs is measured according to the "up and down" shock titration method (Kimball et al., 1957). An increase in the seizure threshold indicates an effective anticonvulsant effect. All antiepileptic drugs with clinically proven efficacy against generalized tonic-clonic seizures, including sodium channel inhibitors (e.g., lamotrigine), exhibit anticonvulsant properties in this test in mice.

[0081] Conversely, a decrease in the seizure threshold indicates a proconvulsant effect such as that observed with known convulsants, such as picrotoxin.

[0082] The ability of test compounds to alter the strength of the stimulus (expressed as current (mA)) required to induce the presence of a toxic hind limb extensor muscle spasm is assessed in the MEST. The current (CC) that produces a toxic hind limb extension in 50% of the animals in the treatment group is determined. 50 The seizure threshold for the treatment group was determined by the presence (+) or absence (0) of toxic hindlimb extensor spasms, as determined by the CC of the vehicle control group. 50 It is compared to.

[0083] [method] Research details: Naive mice were allowed to acclimate to the procedure room in their home cages for up to 7 days, with food and water available ad libitum.

[0084] All animals were weighed at the beginning of the study and randomly assigned to treatment groups based on the average distribution of body weights among groups. All animals were dosed via intraperitoneal (ip) injection at 10 mL / kg with either vehicle, 3, 10, or 30 mg / kg test compound, or 2.5 mg / kg diazepam.

[0085] Animals were individually evaluated for the occurrence of toxic hindlimb extensor convulsions resulting from a single electric shock 30 min after vehicle administration, 30, 15, and 60 min after administration of 3, 10, and 30 mg / kg 6-OH CBD, respectively, and 30 min after administration of diazepam.

[0086] The first animal in the treatment group had an expected or estimated CC 50 For subsequent animals, the current was either lowered or increased depending on the outcome of the previous animal's seizure.

[0087] Data from each treatment group were calculated based on the CC of the treatment group. 50 was used to calculate ± SEM values.

[0088] Test Compound: Vehicle: (5% ethanol, 5% solutol, 90% saline) was prepared as follows: 2 mL of ethanol, 2 mL of solutol were warmed to 60°C in 36 mL of saline (1:1:18).

[0089] Positive control: Diazepam was used at 2.5 mg / kg.

[0090] The test compound, α 6-OH CBD, was prepared according to the method described in Example 1. 6-OH CBD was administered at 3, 10, and 30 mg / kg (ip) in a 1:1:18 ethanol:solutol:0.9% saline formulation.

[0091] Sample Collection: Each animal was immediately humanely killed after confirming the onset of convulsions due to brain destruction from the blow to the skull, followed by permanent cessation of circulation by decapitation under The Humane Killing of Animals under Schedule 1 to the Animals (Scientific Procedures) Act 1986. Terminal blood and brain collection was performed following decapitation.

[0092] Blood was collected into lithium-heparin tubes and centrifuged at 1500 x g for 10 minutes at 4°C. The resulting plasma was removed (>100 μL) and divided into two aliquots of 0.5 mL Eppendorf tubes containing 100 μL of ascorbic acid (100 mg / mL) for stabilization. Brains were removed, washed with saline, and bisected. Each half was placed into a separate 2 mL screw-cap cryovial, weighed, and frozen on dry ice.

[0093] [Statistical analysis] Data for each treatment group were recorded as the number of +s and 0s at each current level employed, and this information was then used to calculate CC 50 was used to calculate the value (the current value required to show a seizure response in 50% of the animals) ± standard error.

[0094] The effect of 6-OH CBD was also significantly different from the CC group from the vehicle control group. 50 was calculated as the percentage change in Significant differences between drug-treated animals and controls were assessed according to Litchfield and Wilcoxon (1949).

[0095] [result] Table 2 below demonstrates the data obtained in this experiment and Figure 1 illustrates these results.

[0096] In the vehicle group, CC 50 The value was calculated to be 24.0 mA.

[0097] In the group treated with the positive control diazepam (2.5 mg / kg), CC was significantly increased when administered i.p. 30 min before the test. 50 The value was 48.8 mA, which was statistically significant (p<0.001) compared to the vehicle control.

[0098] In the 6-OH CBD treatment group, 6-OH CBD at doses of 3, 10, and 30 mg / kg, when administered i.p. 30, 15, and 60 minutes before testing, induced statistically significant CC1 reductions compared to vehicle at all three doses of the compound. 50 values ​​were obtained.

[0099] The above data demonstrate that this compound has therapeutic efficacy. [Table 2]

[0100] [result] 6-OH CBD produced a dose-related increase in MEST, providing evidence that the compound exhibits anticonvulsant properties. Significant effects were observed at 3, 10, and 30 mg / kg compared to vehicle.

[0101] These data are important because they provide previously unknown evidence that the cannabinoids may have therapeutic value.

[0102] Example 4: Pharmacokinetics of 6-hydroxycannabidiol (6-OH CBD)

[0103] The objectives of this study were to determine the brain and plasma pharmacokinetic parameters of 6-OH CBD following a single intravenous or intraperitoneal administration of 6-OH CBD to mice; and to determine the brain:plasma concentration ratio of 6-OH-CBD.

[0104] [method] Each of the 99 male mice received a single intravenous or intraperitoneal dose of 6-OH CBD, as detailed in Table 3 below. [Table 3]

[0105] For each formulation, 6-OH CBD was formulated at the required concentration in ethanol:Corifol EL (Cremophor EL):0.9% (w / v) saline (1:1:18, v / v / v).

[0106] Each animal received a single intravenous dose via the tail vein at a nominal dose volume of 2 mL / kg or a single intraperitoneal dose at a nominal dose volume of 5 mL / kg.

[0107] Following dosing, a sample of terminal blood was collected from each animal via cardiac puncture and the brain was removed at each of the following time points: Intravenous group: 7, 15 and 30 minutes, 1, 2, 4, 8, 12 and 24 hours; Intraperitoneal group: 15 and 30 minutes, 1, 2, 4, 8, 12 and 24 hours

[0108] Blood was collected into tubes containing lithium heparin anticoagulant and centrifuged to prepare plasma. Brain samples were frozen on dry ice, then weighed and flash-frozen before bioanalysis. The remaining sample was discarded. Plasma was stabilized with an equal volume of ascorbic acid solution and then flash-frozen before bioanalysis.

[0109] Stabilized plasma samples were analyzed to determine the concentration of 6-OH CBD using a suitable LC-MSMS method, and the results of these analyses were evaluated to determine non-compartmental pharmacokinetic parameters.

[0110] [result] Tables 4 and 5 demonstrate the results obtained in this study, and Figure 2 illustrates the results. The following parameters were determined:

[0111] The following parameters were determined: C max Maximum observed concentration. T max The time at which the maximum concentration was observed. AUC 0-t Area under the concentration-time curve from time 0 to the last quantifiable concentration, predicted by the linear trapezoidal method. AUC 0-24 Area under the concentration-time curve from 0 to 24 h predicted using the linear trapezoidal method. t 1 / 2 Elimination half-life, determined as ln(2) / λz. Cl Dose / AUC 0-inf Clearance was calculated as (intravenous dose only). V ss Volume of distribution calculated as Cl / λz (intravenous doses only) based on the terminal elimination phase. F abs Absolute bioavailability of intraperitoneal doses.

[0112] [Table 4]

[0113] [Table 5]

[0114] As can be seen from Table 4, after intravenous (IV) administration of 6-OH CBD at the dose level of 1 mg / kg, T max was observed 0.117 hours (7 minutes) after administration. max After reaching 6-OH CBD, the concentration decreased with a half-life (t 1 / 2 The overall plasma clearance was 48.7 mL / min / kg, and the volume of distribution was 1.90 L / kg.

[0115] Following intraperitoneal (IP) administration at 3, 10, or 30 mg / kg, 6-OH CBD exhibited a T of 0.250 hours (15 minutes) at each dose level. max value, absorbed. C max After reaching 0.05, plasma concentrations increased with a half-life (t 1 / 2 ) values ​​were similar across each dose level evaluated.

[0116] After IP administration, plasma 6-OH CBD exposure (C max and AUC 0-24 The observed increase in exposure was more than proportional to dose, with a C value of 0.01 for a 10-fold increase in dose level. max 16.7 times and AUC 0-24 This was a 33.2-fold increase.

[0117] After IP administration, the absolute bioavailability of 6-OH CBD was 52.1%, 75.8%, and 173% at 3, 10, and 30 mg / kg, respectively.

[0118] After systemic administration, 6-OH CBD had a T of 0.117 hours after IV administration. max values ​​and ranged from 0.250 to 1. max After reaching 6-OH CBD, the concentration decreases and the half-life (t 1 / 2 ) values ​​were 0.312 hours after IV administration and ranged between 0.569 and 0.919 hours after IP administration, with a trend toward increasing values ​​with increasing dose levels.

[0119] As can be seen from Table 5, after IP administration, the exposure of 6-OH CBD in the brain (C max and AUC 0-24The observed increase in exposure was more than proportional to dose, with a C value of 0.01 for a 10-fold increase in dose level. max 15.8 times and AUC 0-24 This was a 32.6-fold increase.

[0120] 6-OH C of CBD max and AUC 0-24 The brain:plasma ratio for max ranged from 1.23 to 2.03, and AUC 0-24 ranged from 1.41 to 2.01. After IP administration, the ratios for both parameters were similar across each dose level evaluated. However, the ratios for both parameters were higher after IV compared to IP administration.

[0121] [result] Following intraperitoneal administration, 6-OH CBD exhibited a 15-minute T max values ​​and was absorbed in 7 minutes for 1 mg / kg IV.

[0122] The results of this study provide evidence of excellent pharmacokinetic parameters (bioavailability, clearance, etc.) for the compound 6-OH CBD.

Claims

1. A composition for use in the treatment of epilepsy, comprising 6-hydroxy cannabidiol (6-OH CBD).

2. 10. The composition of claim 1, wherein the 6-OH CBD is in the form of a synthetic compound.

3. 10. The composition of claim 1, wherein the 6-OH CBD is in the form of a pure or isolated compound.

4. 4. The composition of claim 1, wherein the dose of 6-OH CBD is greater than 100 mg / kg / day.

5. 4. The composition of claim 1, wherein the dose of 6-OH CBD is less than 100 mg / kg / day.

6. A composition for use in the treatment of epilepsy, comprising 6-hydroxy cannabidiol (6-OH CBD) and one or more pharmaceutically acceptable excipients.

7. 10. The composition of claim 1, wherein the epilepsy to be treated is epilepsy in a mammal.

8. The composition of claim 7, wherein the mammal is a human.

9. The composition of claim 7, wherein the mammal is a dog.

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