Cannabinoid oral preparations

Abstract

The present invention relates to a cannabinoid-containing oral solution. Preferably, the cannabinoid is cannabidiol (CBD), cannabidivarin (CBDV), or cannabidiol-C4 (CBD-C4). More preferably, the CBD, CBDV, or CBD-C4 is present at a concentration between 25 mg / mL and 75 mg / mL. More preferably still, the CBD, CBDV, or CBD-C4 is present at a concentration of 50 mg / mL. In a further embodiment, the oral solution is formulated with one or more edible oils. Preferably, the edible oil is sesame oil. In a preferred embodiment of the present invention, the oral formulation comprises a low concentration of ethanol.

Description

[Technical Field]

[0001] The present invention relates to an oral solution containing a cannabinoid. Preferably, the cannabinoid is cannabidiol (CBD), cannabidivarin (CBDV), or cannabidiol-C4 (CBD-C4). More preferably, CBD, CBDV, or CBD-C4 is present at a concentration between 25 mg / mL and 75 mg / mL. More preferably, CBD, CBDV, or CBD-C4 is still present at a concentration of 50 mg / mL.

[0002] In further embodiments, the oral solution is formulated with one or more edible oils. Preferably, the edible oil is sesame oil. A preferred embodiment of the present invention is that the oral formulation contains a low concentration of ethanol. [Background technology]

[0003] The use of cannabinoids in pharmaceuticals has required the discovery of more effective methods of drug delivery. This is partly due to factors such as poor aqueous solubility, limited bioavailability, and instability of cannabinoids, but also because the use of cannabinoids at relatively high doses (up to 2000 mg per day) and / or in burdensome parent groups, such as young children, and / or under certain prescriptions may create further burdens.

[0004] Currently, there are four types of commercially available cannabinoid preparations on the market.

[0005] Dronabinol (Marinol®) is a synthetic tetrahydrocannabinol (THC) derived from sesame oil and delivered orally as a capsule.

[0006] Navilon (Cesamet®) is a synthetic cannabinoid and THC analog that is delivered orally in capsules along with povidone and corn starch.

[0007] Nabiximol (Sativex®) is a natural cannabinoid extract containing specified amounts of THC and cannabidiol (CBD), delivered as a liquid by means of an oral mucosal spray.

[0008] Epidiolex® or Epidyolex® is an oral solution containing 100 mg / mL of CBD approved for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome. The CBD is formulated in sesame seed oil and further contains the sweetener sucralose, strawberry flavoring, and up to 10 v / v% ethanol.

[0009] While there are no clear FDA guidelines regarding the maximum permissible ethanol concentration in prescription drugs, the paper "Ethanol in Liquid Preparations Intended for Children, Paediatrics: Official Journal of The American Academy of Paediatrics, 1984: 73:405" recommends that blood alcohol concentration (BAC) should not exceed 0.25 g / L (250 mg / L) following a single dose of alcohol-containing medication.

[0010] WO2015 / 184127 (Insys) discloses a number of different oral formulations, including alcohol-free formulations, alcohol-containing formulations, and lipid-containing formulations, in which cannabinoids are formulated optionally with water in a mixture of polyethylene glycol and propylene glycol. In each of the disclosed formulations, the cannabinoid is synthetically produced cannabidiol (as opposed to naturally extracted). CBD is present in formulations at concentrations ranging from 1% to 35%.

[0011] According to the draft guideline of the European Medicines Agency (EMA / CHMP / 507988 / 2013), for children aged 2 to 6 years, the theoretical limit of blood alcohol concentration (BAC) following a single administration of an alcohol-containing formulation is 0.01 g / L (10 mg / L) or less, and ethanol intake should be 6 mg / kg / day or less.

[0012] For pediatric products intended for younger children, it is desirable to have formulations with low or no ethanol, preferably distributed as syrups, because younger children are found to have difficulty swallowing capsules. They also prefer sweetened and flavored products, especially where the taste of cannabinoids requires masking.

[0013] Pharmaceutically acceptable sweeteners and flavoring agents are generally polar in nature; therefore, unlike cannabinoids which are highly lipophilic, they require polar solvents to dissolve them.

[0014] Oral delivery of cannabinoids generally results in poor bioavailability. For example, Epidiolex® which is provided as an oral solution of 100 mg / mL in sesame oil has an average C max of and an average AUC 0-t of 189 ng / mL and 995 ng·h / mL, respectively. Since young children cannot swallow solid dosage forms, they require oral formulations, but due to the poor bioavailability of formulations such as Epidiolex®, administration of a large volume of the drug is required. This presents challenges resulting from gastrointestinal problems associated with the large intake of edible oils such as sesame oil.

Prior Art Literature

Patent Documents

[0015]

Patent Document 1

Non-Patent Documents

[0016] [Non-Patent Document 1] "Ethanol in Liquid Preparations Intended for Children, Paediatrics: Official Journal of The American Academy of Paediatrics, 1984: 73:405" [Non-Patent Document 2] European Medicines Agency Draft Guideline (EMA / CHMP / 507988 / 2013) [Summary of the Invention] [Problem to be Solved by the Invention]

[0017] An object of the present invention is to develop a lipid-based oral preparation that can impart high bioavailability. [Means for Solving the Problem]

[0018] Surprisingly, the applicant has found that reducing the concentration of cannabinoid in the oral preparation results in an increase in bioavailability. This leads to unexpected and beneficial effects.

[0019] According to a first aspect of the present invention, there is provided a cannabinoid-containing oral solution comprising a cannabinoid and a lipid solvent, wherein the cannabinoid is present at a concentration of 25 to 75 mg / mL.

[0020] In one embodiment, C produced in a human max is more than 250 ng / mL.

[0021] In a further embodiment, AUC produced in a human 0-t is more than 1250 ng·h / mL.

[0022] Preferably, the cannabinoid is selected from the following: cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), tetrahydrocannabivaric acid (THCVA), cannabidiol-C1 (CBD-C1), cannabidiol-C4 (CBD-C4), and cannabidiol-C6 (CBD-C6).

[0023] More preferably, the cannabinoid is cannabidiol (CBD).

[0024] In further embodiments, cannabinoids are present at a concentration of approximately 50 mg / mL.

[0025] Preferably, the lipid solvent is an edible oil. More preferably, the edible oil is selected from the following: coconut oil, corn oil, cottonseed oil, hemp seed oil, olive oil, palm oil, peanut oil, rapeseed / canola oil, safflower oil, sesame oil, soybean oil, short-chain triglycerides, medium-chain triglycerides, long-chain triglycerides, and sunflower oil.

[0026] Preferably, the cannabinoid is cannabidiol (CBD) and the edible oil is sesame oil.

[0027] Preferably, the cannabinoid is cannabidiol (CBD), and the edible oil is soybean oil.

[0028] Preferably, the cannabinoid is cannabidiol (CBD), and the edible oil is olive oil.

[0029] Preferably, the cannabinoid is cannabidiol (CBD), and the edible oil is a medium-chain triglyceride.

[0030] Preferably, the cannabinoid is cannabidivarin (CBDV), and the edible oil is sesame oil.

[0031] Preferably, the cannabinoid is cannabidiol-C4 (CBD-C4), and the edible oil is sesame oil.

[0032] Preferably, the cannabinoid is cannabidiol-C4 (CBD-C4), and the edible oil is soybean oil.

[0033] Preferably, the cannabinoid is cannabidiol-C4 (CBD-C4), and the edible oil is olive oil.

[0034] Preferably, the cannabinoid is cannabidiol-C4 (CBD-C4), and the edible oil is a medium-chain triglyceride.

[0035] Preferably, the formulation further contains ethanol. Preferably, the ethanol is present in a concentration of less than 10 w / v%. More preferably, the ethanol is present in a concentration of less than 1 w / v%.

[0036] Preferably, cannabinoid-containing oral solutions are for use in the treatment of diseases or injuries selected from the group consisting of: epilepsy and associated syndromes, Dravet syndrome, Lennox-Gastaut syndrome, myoclonic seizures, juvenile myoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile convulsions, West syndrome, infantile spasms, refractory infantile spasms, tuberous sclerosis, brain tumors, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety disorders, early psychosis, Alzheimer's disease, and autism.

[0037] Embodiments of the present invention will be further described herein with reference to the accompanying drawings. [Brief explanation of the drawing]

[0038] [Figure 1] This shows the PK profiles of CBD after testing with four different formulations. [Figure 2] The PK profiles of 7-OH CBD after testing with four different formulations are shown. [Figure 3] The PK profiles of 7-COOH CBD after testing with four different formulations are shown. [Figure 4] This study demonstrates the effects of various dosage concentrations of CBD formulated in different oils. [Figure 5] This study demonstrates the effects of various CBDV dosage concentrations. [Figure 6] This study demonstrates the effects of various dosage concentrations of CBD-C4 formulated in different oils. [Modes for carrying out the invention]

[0039] Oral delivery of cannabinoids generally results in poor bioavailability; for example, Epidiolex®, which is offered as an oral solution of 100 mg / mL in sesame oil, has a C content of 189 ng / mL. max , and AUC of 995 ng.h / mL 0-t This is a concern. Young children require oral formulations because they cannot swallow solid dosage forms, but due to the poor bioavailability of formulations such as Epidiolex®, there is a demand for large volumes of the medicine. This presents a challenge stemming from gastrointestinal problems associated with the large-scale intake of edible oils such as sesame oil.

[0040] The objective of this invention is to develop a lipid-based oral formulation that can confer high bioavailability.

[0041] Surprisingly, the applicant found that reducing the concentration of cannabinoids in the oral formulation resulted in increased bioavailability. This was unexpected and led to beneficial effects.

[0042] The following examples illustrate the development of a claimed formulation that provides increased bioavailability.

[0043] [Table 1] [Examples]

[0044] Pharmacokinetic studies of pharmaceutical formulations The pharmacokinetic properties of various oral formulations containing cannabidiol (CBD) were tested.

[0045] The compositions of these formulations are listed in Table 1 (Table 2) below.

[0046] [Table 2]

[0047] The formulation further contained sweeteners and fragrances.

[0048] These formulations were tested in healthy volunteers according to the following protocol.

[0049] Protocol details Participants were randomized to one of four treatment series, where they received a single oral dose of each CBD formulation over treatment periods 1–4:

[0050] Test procedure 1: Oral single dose of 750 mg of CBD (100 mg / mL CBD), under fasting conditions, in a total volume of 7.5 mL.

[0051] Test procedure 2: Oral single dose of 750 mg CBD-reduced ethanol preparation (50 mg / mL CBD), under fasting conditions, total volume 15 mL.

[0052] Test procedure 3: Oral single dose of 750 mg CBD-reduced ethanol preparation (100 mg / mL CBD), under fasting conditions, in a total volume of 7.5 mL.

[0053] Test procedure 4: Oral single dose of 750 mg CBD-reduced ethanol preparation (150 mg / mL CBD), under fasting conditions, total volume 5 mL.

[0054] Pharmacokinetic properties were tested via blood sampling at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 hours after administration.

[0055] result Figures 1-3 detail the PK profiles of CBD and its two main metabolites, 7-OH CBD and 7-COOH CBD, for the four different formulations tested.

[0056] As shown in Figure 1, formulation 2 resulted in a dramatic increase in plasma CBD concentration compared to the other formulations. This increase was unexpected, as it was a lower concentration of CBD at 50 mg / mL.

[0057] As expected, formulation 2 also resulted in increased concentrations of two metabolites, 7-OH CBD and 7-COOH CBD, compared to the other formulations.

[0058] Tables 2 (Table 3) to 4 (Table 5) below summarize this data. In the tables, OS is formulation 1, 50 mg / mL is formulation 2, 100 mg / mL is formulation 3, and 150 mg / mL is formulation 4.

[0059] [Table 3]

[0060] [Table 4]

[0061] [Table 5]

[0062] As shown in Table 5 (Table 6) below, the ratio of the test formulation to the reference formulation (Formulation 1) was much higher for Formulation 2 (50 mg / mL). Both Formulation 3 and Formulation 4 yielded a ratio of approximately 1, which means they were effectively bioequivalent to the reference formulation.

[0063] [Table 6]

[0064] Table 6 (Table 7) details the ratio of CBD metabolites to the parent compound CBD for four different formulations.

[0065] [Table 7]

[0066] These data indicate a twofold increase in the bioavailability of CBD for formulation 2 (50 mg / mL CBD). Furthermore, there was a difference in the metabolite-to-parent ratio for this formulation. The ratio of CBD metabolites to the parent compound CBD was lower in formulation 2 compared to the other formulations.

[0067] Conclusion: The data presented in this example clearly demonstrate that supplying lower concentrations of CBD in oral formulations resulted in better bioavailability. Furthermore, these data showed that formulations with lower concentrations of CBD yielded a more beneficial ratio of metabolites to their parent.

[0068] These data are important because they suggest that the 7-COOH CBD metabolite is inactive, and that reducing the amount of this metabolite formed in this way leads to an increase in the activity of the parent compound.

[0069] A further advantage of lower-concentration CBD formulations lies in the undesirable hepatotoxicity associated with CBD. Clinical trials have shown that Epidiolex® (highly purified plant-derived CBD) can cause elevated hepatic transaminases (alanine aminotransferase - ALT and / or aspartate aminotransferase - AST), particularly when used in combination with other antiepileptic drugs, such as clobazam and valproate.

[0070] In the controlled trial, the incidence of ALT elevation exceeding three times the upper limit of normal was 13% in patients treated with Epidiolex®, compared to 1% in patients with placebo, and less than 1% of patients treated with Epidiolex® had ALT or AST levels exceeding 20 times the upper limit of normal. [Examples]

[0071] Pharmacokinetic studies of CBD formulations in rats The pharmacokinetic properties of various oral formulations containing cannabidiol (CBD) were tested in rats.

[0072] The compositions of these formulations are listed in Table 7 (Table 8) below.

[0073] [Table 8]

[0074] Protocol details The animals were acclimatized for a minimum period of 5 days. Rats were kept in a room where the temperature was maintained between 19 and 25°C and the relative humidity between 40% and 70% under thermostat control, and were exposed to fluorescence each day (12 hours baseline).

[0075] To achieve the required final concentration, an appropriate amount of the required test substance was transferred to a suitable formulation container and an appropriate volume of the required oil vehicle was added, as detailed in Annex 4.

[0076] Each animal received a single oral dose administered by gavage at a nominal dose level of 50 mg / kg and at a nominal dose volume between 0.25 mL / kg and 1 mL / kg. The amount of the administered formulation dosed to each animal was determined from the difference in mass of the dosing equipment before and after dosing, together with the concentration of the dose formulation (based on the test item mass and total formulation mass).

[0077] Three animals were tested for each formulation.

[0078] Following dosing, the animals were returned to their holding cages. Blood samples (approximately 150 μL) were collected by venipuncture from the jugular vein at each of the following time points:

[0079] 0.5, 1, 2, 4, 8, 16 and 24 hours after dosing.

[0080] Samples were collected into tubes containing K2EDTA anticoagulant and centrifuged (2300 g, 10 minutes, 4° C) within 30 minutes to yield plasma. Blood cells were discarded. Samples were processed within 1 hour of sample collection and frozen at <-50° C.

[0081] Following the final blood sampling occasion, animals were euthanized via overdose of sodium pentobarbitone (death was confirmed by cervical dislocation or exsanguination).

[0082] Results Figure 4 shows the exposure assessed by two pharmacokinetic parameters AUC last and C max for the different formulations tested. Table 8 (Table 9) to Table 10 (Table 11) summarize the mean pharmacokinetic parameters.

[0083] Formulation 1 and Formulation 2 (sesame oil) As can be seen in Figure 4 and Table 8 (Table 9), Formulation 1 has a higher AUC when compared to another formulation in sesame oil (Formulation 2) lastValue and C max This yielded a value that was consistent with the results of Example 1, and here again, this was unexpected because it was a lower concentration of CBD at 50 mg / mL.

[0084] As expected, formulation 1 also resulted in increased concentrations of two metabolites, 7-OH CBD and 7-COOH CBD, compared to formulation 2. This is demonstrated in Tables 9 (Table 10) and 10 (Table 11).

[0085] Formulation 3, Formulation 4, and Formulation 5 (olive oil) Similar to formulations 1 and 2, formulation 3 has a higher AUC compared to formulation 4, which has a higher CBD content. last Value and C max This yielded the following values ​​(see Figure 4). At the highest CBD concentration of 200 mg / mL (formulation 5), C max Surprisingly, it was still lower than 100 mg / mL. This, too, provides data indicating increased bioavailability of formulations with lower CBD concentrations.

[0086] Formulation 6, Formulation 7, and Formulation 8 (Soybean Oil) Formulation 6, as shown in Figure 4, had the highest C among all the formulations tested. max It had a value. Compared to formulations 7 and 8, which had higher CBD concentrations, formulation 6 had higher bioavailability of CBD.

[0087] Tables 9 (Table 10) and 10 (Table 11) show that formulation 6 also resulted in increased concentrations of two metabolites, 7-OH CBD and 7-COOH CBD, compared to formulations 7 and 8.

[0088] Formulation 9, Formulation 10, and Formulation 11 (MCT oil) Despite having the lowest CBD concentration at 50 mg / mL compared to both formulations 10 and 11, formulation 9 has a higher AUC. last Value and C maxIt had a value (see Figure 4 and Table 8 (Table 9)).

[0089] As expected, formulation 9 also resulted in increased concentrations of two metabolites, 7-OH CBD and 7-COOH CBD, compared to formulations 10 and 11, as evidenced by Tables 9 and 11.

[0090] Formulation 12, Formulation 13, and Formulation 14 (hemp seed oil) Formulation 13 has a higher AUC than formulations 12 and 14. last Value and C max It brought value.

[0091] [Table 9]

[0092] [Table 10A] [Table 10B]

[0093] [Table 11A] [Table 11B]

[0094] Tables 11.1 (Table 12) to 11.5 (Table 16) below detail the ratios of CBD metabolites to the parent compound CBD for different formulations.

[0095] [Table 12]

[0096] These data indicate a difference in the metabolite-to-parent ratio between these two formulations. The ratio of metabolites to parent was lower in formulation 1 compared to formulation 2.

[0097] [Table 13]

[0098] These data show differences in the metabolite-to-parent ratio among these three formulations. The 7-OH CBD:CBD ratio was lower in formulation 3 compared to formulation 5.

[0099] [Table 14]

[0100] The ratio of metabolites to the parent was considerably lower in formulation 6 compared to formulations 7 and 8.

[0101] [Table 15]

[0102] The ratio of 7-OH CBD to CBD was lower in formulation 9 compared to formulations 10 and 11.

[0103] [Table 16]

[0104] Both the 7-OH CBD:CBD and 7-COOH CBD:CBD ratios were lower in formulation 12 compared to formulation 14.

[0105] Conclusion: CBD and its metabolite C maxExposure levels, as assessed by values ​​and AUC values, were generally observed to be higher at a 50 mg / mL dose concentration compared to 100 mg / mL and 200 mg / mL for different vehicles.

[0106] The data presented in this example further demonstrate that supplying lower concentrations of CBD resulted in better bioavailability in the different oil formulations tested, including sesame, olive, soybean, MCT, and hemp oils. This is consistent with the results of the low-CBD concentration formulation in sesame oil in Example 1 and reaffirms this conclusion.

[0107] Furthermore, these data showed that lower concentrations of CBD formulations resulted in a more beneficial ratio of metabolites to their parent.

[0108] As mentioned earlier, these data are important because they suggest that the 7-COOH CBD metabolite is inactive, and that reducing the amount of this metabolite formed in this way leads to an increase in the activity of the parent compound. [Examples]

[0109] Pharmacokinetic studies of CBDV formulations in rats The pharmacokinetic properties of various oral formulations, including cannabidivarin (CBDV), were tested in rats.

[0110] The composition of these formulations is described in Table 12 (Table 17) below.

[0111] [Table 17]

[0112] Protocol details These formulations were tested in rats according to the protocol described in Example 2.

[0113] result Figure 5 shows the AUC of two pharmacokinetic parameters for the different formulations tested. last and C max Tables 13 (Table 18) to 15 (Table 20) summarize the mean pharmacokinetic parameters.

[0114] As shown in Figure 5, formulation 1 has the highest AUC among the three formulations. last This yielded a value, while formulation 2 had the highest C max This resulted in a lower value. Therefore, the highest concentration of CBDV in 75 mg / mL (Formulation 3) did not yield the expected highest value. This finding is consistent with the results of Examples 1 and 2, in which formulations with lower cannabinoid concentrations resulted in better bioavailability.

[0115] As expected, formulations 1 and 2 also resulted in increased concentrations of the two metabolites 7-OH CBD and 7-COOH CBDV compared to formulation 3. This is demonstrated in Tables 14 (Table 19) and 15 (Table 20).

[0116] [Table 18]

[0117] [Table 19]

[0118] [Table 20]

[0119] Conclusion: CBDV and its metabolite C max The exposure levels, as assessed by the values ​​and AUC values, increased as the administered concentration decreased from 75 mg / mL to 25 mg / mL for the formulation in sesame oil.

[0120] The data presented in this example clearly demonstrate that supplying lower concentrations of CBDV resulted in better bioavailability in different formulations. This provides further evidence that formulations with lower cannabinoid concentrations can lead to unexpected beneficial effects and is consistent with the results of Examples 1 and 2. [Examples]

[0121] Pharmacokinetic study of CBD-C4 formulations in rats The pharmacokinetic properties of various oral formulations containing cannabidiol-C4 (CBD-C4) were tested.

[0122] The compositions of these formulations are listed in Table 16 (Table 21) below.

[0123] [Table 21]

[0124] Protocol details These formulations were tested in rats according to the protocol described in Example 2.

[0125] result Figure 6 shows the AUC of two pharmacokinetic parameters for the different formulations tested. last and C max This is shown. Tables 17 (Table 22) to 19 (Table 24) summarize the mean pharmacokinetic parameters.

[0126] Formulation 1, Formulation 2, and Formulation 3 (sesame oil) As shown in Figure 6, Formulation 1 has a higher AUC compared to the other two formulations in sesame oil (Formulation 2 and Formulation 3). last Value and C max This yielded a value consistent with the results of Examples 1, 2, and 3, which showed that formulations with lower cannabinoid concentrations demonstrated better bioavailability.

[0127] Formulation 4, Formulation 5, and Formulation 6 (olive oil) Similar to formulation 1, formulation 3, with its lower concentration, yielded better bioavailability results compared to formulations 4 and 5, which contained higher concentrations of CBD-C4 (see Figure 6).

[0128] Formulation 7, Formulation 8, and Formulation 9 (Soybean Oil) Of the three formulations, formulation 9, a 200 mg / mL CBD-C4 formulation in soybean oil, had the lowest AUC. last Value and C max It presented a similar pattern that yielded the desired values. Compared to formulations 7 and 8 at higher CBD concentrations, formulation 6 exhibited higher bioavailability of CBD.

[0129] Tables 18 (Table 23) and 19 (Table 24) show that formulation 7 also resulted in increased concentrations of two metabolites, 7-OH CBD and 7-COOH CBD, compared to formulations 8 and 9.

[0130] Formulation 10, Formulation 11, and Formulation 12 (MCT oil) Formulation 11, which is of moderate dose, has a lower AUC compared to formulations 10 and 12. last Value and C max This yielded a value (see Figure 6).

[0131] Formulation 13, Formulation 14, and Formulation 15 (hemp seed oil) Formulation 15 has a higher AUC compared to formulations 13 and 14. last Value and C max It brought value.

[0132] [Table 22A] [Table 22B]

[0133] [Table 23A] [Table 23B]

[0134] [Table 24A] [Table 24B]

[0135] Tables 20.1 (Table 25) and 20.2 (Table 26) below detail the ratios of CBD-C4 metabolites to the parent compound CBD-C4 for different formulations.

[0136] [Table 25]

[0137] These data indicate differences in the metabolite-to-parent ratio among these three formulations. The ratio of metabolites to parent was lower in formulation 1 compared to formulations 2 and 3.

[0138] [Table 26]

[0139] The ratio of metabolites to the parent was lower in formulation 4 compared to formulations 5 and 6.

[0140] Conclusion: CBD-C4 and its metabolite C max The exposure levels, as assessed by the values ​​and AUC values, increased for different vehicles as the administered concentration decreased from 200 mg / mL to 50 mg / mL.

[0141] The data presented in this example clearly demonstrate that lower concentrations of CBD-C4 resulted in better bioavailability in the different oil formulations tested.

[0142] Furthermore, these data showed that lower concentrations of CBD-C4 formulations resulted in a more beneficial ratio of metabolites to their parent.

[0143] Thus, the data further supports the results of the previous examples, which showed that supplying lower concentrations of cannabinoids in oral formulations leads to a surprising and unexpected effect of increased bioavailability.

Claims

1. An oral cannabinoid-containing solution comprising a cannabinoid, a lipid solvent, and ethanol, wherein the cannabinoid is present at a concentration of 50 mg / mL, the ethanol is present at less than 1 w / v%, the cannabinoid is selected from cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidiol-C1 (CBD-C1), cannabidiol-C4 (CBD-C4), and cannabidiol-C6 (CBD-C6), and the lipid solvent is selected from hemp seed oil, olive oil, sesame oil, soybean oil, and short-chain triglycerides.

2. C produced in humans max The cannabinoid-containing oral solution according to claim 1, characterized in that the concentration is greater than 250 ng / mL.

3. AUC generated in humans 0-t The cannabinoid-containing oral solution according to claim 1, wherein the concentration is greater than 1250 ng.h / mL.

4. The cannabinoid-containing oral solution according to claim 1, wherein the cannabinoid is cannabidiol (CBD).

5. The cannabinoid-containing oral solution according to claim 1, wherein the cannabinoid is cannabidiol (CBD) and the lipid solvent is sesame oil.

6. The cannabinoid-containing oral solution according to claim 1, wherein the cannabinoid is cannabidiol (CBD) and the lipid solvent is soybean oil.

7. The cannabinoid-containing oral solution according to claim 1, wherein the cannabinoid is cannabidiol (CBD) and the lipid solvent is olive oil.

8. The cannabinoid-containing oral solution according to claim 1, wherein the cannabinoid is cannabidiol (CBD) and the lipid solvent is a medium-chain triglyceride.

9. The cannabinoid-containing oral solution according to claim 1, wherein the cannabinoid is cannabidivarin (CBDV) and the lipid solvent is sesame oil.

10. The cannabinoid-containing oral solution according to claim 1, wherein the cannabinoid is cannabidiol-C4 (CBD-C4) and the lipid solvent is sesame oil.

11. The cannabinoid-containing oral solution according to claim 1, wherein the cannabinoid is cannabidiol-C4 (CBD-C4) and the lipid solvent is soybean oil.

12. The cannabinoid-containing oral solution according to claim 1, wherein the cannabinoid is cannabidiol-C4 (CBD-C4) and the lipid solvent is olive oil.

13. The cannabinoid-containing oral solution according to claim 1, wherein the cannabinoid is cannabidiol-C4 (CBD-C4) and the lipid solvent is a medium-chain triglyceride.

14. An oral cannabinoid-containing solution according to any one of claims 1 to 13, for use in the treatment of a disease or disorder selected from the group consisting of epilepsy and associated syndromes, Dravet syndrome, Lennox-Gastaut syndrome, myoclonic seizures, juvenile myoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile seizures, West syndrome, infantile spasms, refractory infantile spasms, tuberous sclerosis, brain tumors, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety disorders, early psychosis, Alzheimer's disease, and autism.

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