Oral formulations of cannabinoid

Abstract

The present disclosure provides formulations of cannabinoids having advantages such as high drug loading and stability, as well as related methods of making and using these formulations.

Description

Cross-citation of applications related to oral cannabinoid formulations

[0001] This application claims priority to U.S. Provisional Application No. 63 / 530,613, filed August 3, 2023, and U.S. Provisional Application No. 63 / 648,085, filed May 15, 2024, each of which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0002] This invention relates to cannabinoid preparations and methods of using them. Background Technology

[0003] It is well known that oral medication administration is generally preferred because it provides patients with the most convenient and often the cheapest route, thereby improving adherence. These benefits translate into high demand, reflected in the number of drugs approved for oral administration. Despite the advantages of oral delivery, drug suitability via this route remains a growing challenge. It has been noted that an increasing number of compounds in the drug development pipeline exhibit poor solubility and / or permeability. Without sufficient formulations of these compounds, their conversion potential is diminished due to their poor and variable oral bioavailability.

[0004] Many cannabinoids (natural and synthetic compounds that are structurally or pharmacologically associated with components of the cannabis plant or endogenous agonists of cannabinoid receptors CB1 or CB2) face such formulation challenges. Cannabinoids present in the cannabis plant include over 100 natural cannabinoids, including tetrahydrocannabinol (THCA) and cannabidiol (CBDA), as well as cannabidiol-like compounds such as cannabidiol (CBDA), cannabidiol (CBDV), cannabidiol (CBDVA), cannabidiol-C1 (CBD-C1), cannabidiol-C4 (CBD-C4), and cannabidiol monomethyl ether (CBDM). Cannabidiol (CBD) is one of the major cannabinoids derived from plants of the genus *Cannabis*, representing one such compound. As a highly lipophilic drug with low water solubility (estimated <13 µg / mL) and undergoing adequate first-pass metabolism (logP≈6), CBD has an oral bioavailability of approximately 6%. Formally, CBD is classified as a Class II compound in the Biopharmaceutics Classification System (BCS) due to its low water solubility and high intestinal permeability. Therefore, strategies to improve the dissolution or dispersion rate of CBD will increase its bioavailability. Given the physicochemical properties of CBD, lipid formulations have experienced the most remarkable success.

[0005] To date, the only FDA-approved CBD formulation is Epidiolex. ®Epidiolex is a sesame oil-based solution designed for the treatment of rare childhood epilepsy and tuberous sclerosis. However, sesame oil formulations are limited by varying absorption, patient allergies, limited drug loading, and poor stability. Furthermore, Epidiolex... ® This includes ethanol, which has drawbacks when used in certain patient groups. Epidiolex ® Once opened, it must be used completely within 12 weeks; this limited lifespan increases the cost of approved treatments. Therefore, there is a need for formulations that can improve CBD absorption without relying on sesame oil as an excipient (which has its associated drawbacks). Summary of the Invention

[0006] This disclosure provides compositions for formulating therapeutic agents. These compositions are effective at dissolving therapeutic agents, especially those that are difficult to dissolve.

[0007] In some embodiments, this disclosure provides a cannabinoid formulation comprising: cannabinoid; one or more fatty acid glycerides; and one or more polyethylene glycol-containing fatty acid esters.

[0008] In some implementations, cannabinoids are cannabidiols.

[0009] In some embodiments, cannabinoids are present in the formulation at an amount greater than about 5% by weight. In some embodiments, cannabinoids are present in the formulation at an amount from about 10% by weight to about 50% by weight. In some embodiments, cannabinoids are present in the formulation at about 20% by weight. In some embodiments, cannabinoids are present in the formulation at about 40% by weight.

[0010] In some embodiments, the ratio of one or more fatty acid glycerides to one or more polyethylene glycol-containing fatty acid esters is in the range of about 30:70 to about 70:30. In some embodiments, the one or more fatty acid glycerides include glyceryl oleate (Peceol). In some embodiments, the one or more polyethylene glycol-containing fatty acid esters include one or more of the following: lauroyl polyoxyglyceride (Gelucire 44 / 14), GELUCIRE ® 48 / 16, GELUCIRE ® 50 / 13, GELUCIRE ® 59 / 14 and Labrasol ALF.

[0011] In some embodiments, the fatty acid glyceride and the polyethylene glycol-containing fatty acid ester are each present in the formulation at an amount of about 30% to about 60% by weight. In some embodiments, the fatty acid glyceride and the polyethylene glycol-containing fatty acid ester are each present in the formulation at an amount of about 39% to about 41% by weight. In some embodiments, the fatty acid glyceride and the polyethylene glycol-containing fatty acid ester are each present in the formulation at about 40% by weight. In some embodiments, the fatty acid glyceride and the polyethylene glycol-containing fatty acid ester are each present in the formulation at about 36.4% by weight, and wherein ethanol is present in the formulation at about 7.2% by weight.

[0012] In some embodiments, D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) is present in the formulation at an amount of about 3% to about 4% by weight. In some embodiments, fatty acid glycerides and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 38% by weight, and TPGS is present in the formulation at about 4% by weight. In some embodiments, fatty acid glycerides and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 34.58% by weight, and TPGS is present in the formulation at about 3.64% by weight, and ethanol is present in the formulation at about 7.2% by weight.

[0013] In some implementations, the polyethylene glycol-containing fatty acid esters include lauroyl polyoxyglyceride (Gelucire44 / 14).

[0014] In some embodiments, the formulation comprises one or more antioxidants. In some embodiments, one or more antioxidants include butylated hydroxytoluene (BHT).

[0015] In some embodiments, a single dose of the formulation contains at least 50 mg of cannabinoids. In some embodiments, a single dose of the formulation contains cannabinoids in the range of about 50 mg to about 2,000 mg. In some embodiments, a single dose contains about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1250 mg, or about 1500 mg of cannabinoids. In some embodiments, a single dose contains about 100 mg of cannabinoids. In some embodiments, a single dose contains about 300 mg of cannabinoids. In some embodiments, a single dose contains about 600 mg of cannabinoids. In some embodiments, a single dose contains about 1,000 mg of cannabinoids.

[0016] In some embodiments of the method of administering the formulation in treating a subject's illness or injury, the formulation is administered in an amount of cannabinoid, such as an amount of about 50 mg to about 3,000 mg daily. In some embodiments of the method of administering the formulation in treating a subject's illness or injury, the formulation is administered in an amount of cannabinoid, such as an amount of about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,250 mg, about 1,500 mg, about 2,000 mg, about 2,500 mg, or about 3,000 mg daily. In some embodiments of the method of administering the formulation in treating a subject's illness or injury, the formulation is administered in an amount of cannabinoid, such as an amount of about 100 mg daily. In some embodiments of the method of administering the formulation in treating a subject's illness or injury, the formulation is administered in an amount of cannabinoid, such as an amount of about 300 mg daily. In some embodiments of the method of administering the formulation in treating a subject's disease or injury, the formulation is administered in an amount such as about 600 mg of cannabinoids per day. In some embodiments of the method of administering the formulation in treating a subject's disease or injury, the formulation is administered in an amount such as about 1,000 mg of cannabinoids per day.

[0017] In some embodiments, the formulation is prepared for oral administration. In some embodiments, the formulation is a self-emulsifying drug delivery system. In some embodiments, the formulation does not contain sesame oil or ethanol.

[0018] In some embodiments, after storage at room temperature for up to three months, the cannabinoid concentration remains at approximately 80% above the initial concentration. In some embodiments, the Cmax of the cannabinoid after oral administration is at least approximately equal to the Cmax after oral administration of the cannabinoid sesame oil formulation. In some embodiments, the systemic exposure (AUC) of the cannabinoid after oral administration is... ∞ It is at least approximately equal to the systemic exposure following oral administration of cannabinoid sesame oil preparations.

[0019] In some embodiments, the Cmax of cannabinoids after oral administration of the formulation for at least about 2 hours, 4 hours, 6 hours, 8 hours, or 10 hours after food ingestion, and for at least 2 hours before food ingestion, is at least about 50% of the Cmax after oral administration of the formulation approximately simultaneously with food. In some embodiments, the systemic exposure (AUC) of cannabinoids after oral administration of the formulation for at least 2 hours, 4 hours, 6 hours, 8 hours, or 10 hours after food ingestion, and for at least 2 hours before food ingestion is... 0-∞() is at least about 50% of the systemic exposure following oral administration of the formulation at approximately the same time as food.

[0020] In some embodiments, this disclosure provides a formulation comprising more than about 5% by weight of cannabinoids. In some embodiments, the formulation comprises about 10% by weight to about 50% by weight of cannabinoids. In some embodiments, the formulation comprises about 20% by weight of cannabinoids. In some embodiments, the formulation comprises about 40% by weight of cannabinoids.

[0021] In some embodiments, this disclosure provides a capsule comprising any formulation disclosed herein. In some embodiments, the capsule is a soft gel capsule.

[0022] In some embodiments, this disclosure provides a method for administering cannabinoids to a subject, the method comprising administering any formulation disclosed herein or any capsule disclosed herein.

[0023] In some embodiments, this disclosure provides a method of treating a disease or injury in a subject in need, the method comprising administering any of the formulations disclosed herein or any of the capsules disclosed herein.

[0024] In some embodiments, the disease or injury is selected from the group including: high clinical risk of psychosis, insomnia, first-episode psychosis, psychosis in Parkinson's disease, schizophrenia, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, Alzheimer's disease, postpartum psychosis, phobia of strange environments, acute stress disorder, and schizoaffective disorder. In some embodiments, the disease or injury is high clinical risk of psychosis. In some embodiments where the disease or injury is high clinical risk of psychosis, the method includes administering a preparation comprising: cannabinoids; one or more fatty acid glycerides; one or more polyethylene glycol-containing fatty acid esters; wherein the fatty acid glycerides and polyethylene glycol-containing fatty acid esters are each present in the preparation at about 40% by weight. In some embodiments, the disease or injury is insomnia. In some embodiments where the disease or injury is insomnia, the method includes administering a preparation comprising: cannabinoids; one or more fatty acid glycerides; one or more polyethylene glycol-containing fatty acid esters; wherein the fatty acid glycerides and polyethylene glycol-containing fatty acid esters are each present in the preparation at about 40% by weight. Attached Figure Description

[0025] Figure 1. Schematic diagram of the preparation of the cannabidiol (CBD) self-emulsifying drug delivery system (SEDDS).

[0026] Figure 2. Bar graph of droplet diameter (mean ± SD) for SEDDS formulations with different CBD concentrations. All formulations were dispersed in phosphate-buffered saline (0.5% w / v) and the resulting droplet size was measured after stirring at 100 rpm and 37°C for 2 h. The average polydispersity index values ​​for all formulations were <0.5.

[0027] Figures 3A and 3B. Drug solubilization of SEDDS formulations with different CBD contents after dispersion (0.5% w / v) in phosphate-buffered saline at 37°C for 1 h for a series of pre-filtered dispersions (Figure 3A) and a selected unfiltered dispersion (Figure 3B). When loaded with 20% w / w CBD, formulations 1 and 3 correspond to CBD SEDDS A and C, respectively. No dispersion showed significant drug precipitation. Filtering of dispersions was found to increase the variability of drug solubilization measurements, but the average solubilization was consistent with that of the unfiltered dispersions.

[0028] Figure 4. Dispersion curves (mean ± SD) of CBD SEDDS A, B, C, and D after storage at room temperature (i.e., 20°C–25°C) and under light-free refrigeration conditions for 0, 14, or 30 days. The pre-concentrate (n=3) was dispersed in PBS at 0.5% w / v daily.

[0029] Figure 5. Dispersion curves (mean ± SD) of CBD SEDDS A, B, C, and D after three months of storage at room temperature (i.e., 20°C–25°C) and in the absence of light. The pre-concentrate (n=3) was dispersed in PBS at 0.5% w / v daily.

[0030] Figure 6. CBD drug content (mean ± SD) in CBDSEDDS A, B, C, and D preconcentrates (n=3) stored at room temperature (i.e., 20°C–25°C) and in the absence of light for three months. Values ​​are scaled to the CBD content at the initial time point. For each time point, the bars from left to right correspond to the legend from top to bottom.

[0031] Figure 7. CBD drug content (mean ± SD, n=3) in CBDSO, CBD SEDDS C, and CBD SEDDS D preconcentrates during one month of storage at room temperature (i.e., 20°C–25°C) and in the absence of light. Values ​​are scaled to the CBD content at the initial time point. For each time point, the bars from left to right correspond to the legend from top to bottom.

[0032] Figure 8. Dispersion curves (mean ± SD) of CBD SEDDS A, B, C, and D in fasting-state simulated gastric juice (FaSSGF), fasting-state simulated intestinal juice (FaSSIF), feeding-state simulated intestinal juice (FeSSIF), and phosphate-buffered saline (PBS). The pre-concentrates (n=3) were dispersed daily at 0.5% w / v in each corresponding medium. For each formulation, the circles from top to bottom at the 60-minute time point correlate with FASSIF, PBS, FaSSGF, and FeSSIF.

[0033] Figures 9A and 9B. Dispersion curves of each CBD SEDDS formulation (i.e., A, B, C, D) in various media (i.e., FaSSGF, FaSSIF, FeSSIF, PBS), heatmaps of Fraser distance values ​​(Figure 9A) and bar graphs of scaled areas under the curve (AUC) values ​​(mean ± SD) (Figure 9B). Statistical analysis was performed using aligned-rank transform two-way ANOVA and Tukey post-hoc comparison test. Statistical difference compared to CBD SEDDS C dispersed in FaSSIF; * p < 0.05; *** p < 0.001. Statistical difference compared to CBD SEDDS A dispersed in FaSSIF; * p < 0.05.

[0034] Figure 10. Drug treatment of selected CBD SEDDS in various sample fractions before and after in vitro digestion after centrifugation (mean ± SD, n ≥ 3). Statistical differences between the two formulations in each fraction at a given time; ** p < 0.01; *** p < 0.001

[0035] Figure 11. Schematic diagram of the pharmacokinetic study. CBD formulations were administered orally at a dose of 20 mg / kg via gavage on day 0, followed by blood samples collected from the saphenous vein at designated time points. n = 5–10 animals / group. The formulations tested were: CBD medium-chain triglyceride oil (MCT), CBD SO, CBD SEDDS C, and CBD SEDDS D.

[0036] Figure 12. Plasma concentration-time curves of CBD after oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D are shown in Figure 11. Data are presented as mean ± SEM, n ≥ 5. The inset depicts plasma concentration-time plots with a semi-logarithmic axis. At the two-hour time point, the lines from top to bottom correspond to: CBD SEDDS C, CBD SO, CBD SEDDS D, and CBD MCT.

[0037] Figures 13A to 13D. A visual summary of the pharmacokinetic parameters obtained after oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D is shown in Figure 11. Box plots of time to reach maximum observed plasma concentration (Tmax), with individual observations indicated by crosses (Figure 13A); box plots of maximum observed CBD plasma concentration (Cmax) (Figure 13B); bar plots of area under the plasma concentration-time curve from 0h to 8h (mean ± SEM, n≥5) (Figure 13C); bar plots of extrapolated area under the plasma concentration-time curve (mean ± SEM, n≥5) (Figure 13D).

[0038] Figure 14. Box plot representation of CBD plasma concentration-time curves after oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D, as shown in Figure 11. n≥5. Empty points represent average values.

[0039] Figure 15. Individual plasma concentration-time curves of CBD after oral administration of CBD MCT, CBD SO, CBD SEDDS C and CBD SEDDS D are shown in Figure 11.

[0040] Figure 16. CBD concentrations in tissues 4 h after oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D are shown in Figure 11. Data are presented as mean ± SEM, n=5. Statistical difference compared to CBD SO; * p < 0.05. For each tissue, the bars from left to right correspond to the legend from top to bottom.

[0041] Figure 17. Plasma concentration-time curves of CBD after oral administration of 20 mg / kg CBD SEDDS C to fasted and non-fasted rats. Data are presented as mean ± SEM, n ≥ 5. At time = 2 h, the top line represents no fasting, and the bottom line represents fasting.

[0042] Figure 18. Box plot representation of plasma concentration-time curves of CBD after oral administration of 20 mg / kg CBD SEDDS C to fasted and non-fasted rats. n≥5. Empty points represent mean values. For each time point, the bars from left to right correspond to non-fasted and fasted rats, respectively.

[0043] Figure 19. Summary of pharmacokinetic studies of different CBD formulations administered orally to rats.

[0044] Figure 20. Mean values ​​of key PK parameters in rats treated with different CBD formulations

[0045] Figure 21. Box plot of Cmax (ng / mL) of CBD in fed or fasted rats treated with different CBD formulations. For each formulation, the left bar represents fed rats and the right bar represents fasted rats.

[0046] Figure 22. Box plots showing the Tmax (h) of CBD in fed or fasted rats treated with different CBD formulations. For each formulation, the left bar represents fed rats and the right bar represents fasted rats.

[0047] Figure 23. Box plots showing the T1 / 2 (h) of CBD in fed or fasted rats treated with different CBD formulations. For each formulation, the left bar represents fed rats and the right bar represents fasted rats.

[0048] Figure 24. AUC of CBD in fed or fasted rats treated with different CBD formulations 0-last The box plot is shown in (ng.h / mL). For each formulation, the left bar represents food intake, and the right bar represents fasting.

[0049] Figure 25. AUC of CBD in fed or fasted rats treated with different CBD formulations 0-inf The box plot is shown in (ng.h / mL). For each formulation, the left bar represents food intake, and the right bar represents fasting. Detailed Implementation

[0050] This disclosure provides compositions for formulating therapeutic agents. These compositions effectively dissolve therapeutic agents, particularly those that are difficult to dissolve. These compositions advantageously enhance the bioavailability of the therapeutic agents while also providing high concentrations of the therapeutic agents. This disclosure also provides therapeutic agent formulations based on these compositions that effectively deliver therapeutic agents, particularly those for oral administration. This disclosure provides cannabinoid formulations based on these compositions, including CBD formulations. The disclosed formulations effectively dissolve cannabinoids (including CBD), thereby providing formulations with increased cannabinoid concentrations and simultaneously providing enhanced bioavailability of cannabinoids (including CBD).

[0051] Self-emulsifying drug delivery systems (SEDDS) are an example of advanced lipid formulations that can be used to enhance the absorption of cannabinoids, including CBD. Simply put, SEDDS are isotropic mixtures of oils, surfactants, and / or co-solvents that spontaneously assemble into colloidal dispersions or emulsions when mixed with aqueous media, such as in the gastrointestinal environment. SEDDS offer the potential to address the formulation needs of cannabinoids, including CBD, by increasing their apparent solubility and also delivering high therapeutic doses.

[0052] definition :

[0053] While the following terms are considered to be well understood by one of ordinary skill in the art, the following definitions are set forth in order to facilitate the interpretation of the subject matter currently disclosed.

[0054] The term "a / kind" refers to one / kind or more / kinds of the entity, that is, it can refer to a plural referent. Similarly, the terms "a / kind," "one / kind or more / kinds," and "at least one / kind" are used interchangeably in this document. Furthermore, the reference to "one element" by the indefinite article "a" does not preclude the possibility of more than one element among the elements, unless the context explicitly requires the existence of one and only one element.

[0055] As used herein in the specification and claims, the phrase “and / or” should be understood to mean “any one or both” of the elements so combined, that is, elements that coexist in some cases and exist separately in others. Multiple elements listed with “and / or” should be interpreted in the same way, that is, “one or more” of the elements so combined. In addition to the elements specifically identified by the “and / or” clause, other elements may optionally exist, whether related to or unrelated to those specifically identified. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “comprising / including / containing,” a reference to “A and / or B” may refer only to A in one embodiment (optionally including elements other than B); in another embodiment only to B (optionally including elements other than A); in yet another embodiment both A and B (optionally including other elements); and so on.

[0056] As used herein in the specification and claims, the phrase “at least one” when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list, but not necessarily including every single element specifically listed in the list and at least one of each element, and does not exclude any combination of elements in the list. This definition also allows for the optional presence of elements other than those specifically indicated in the list referred to by the phrase “at least one,” whether related to or unrelated to those specifically indicated elements. Thus, as a non-limiting example, “at least one of A and B” (or equivalently, “at least one of A or B”, or equivalently, “at least one of A and / or B”) in one embodiment may refer to at least one, optionally including more than one A, without B (and optionally including elements other than B); in another embodiment may refer to at least one, optionally including more than one B, without A (and optionally including elements other than A); in yet another embodiment may refer to at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0057] Throughout this application, the term "about" is used to indicate that a value includes inherent error variations in the equipment or method used to determine that value, or variations present in the sample being measured. In some embodiments, the term "about" means within 5% of the reported value. When used in conjunction with a range or series of values, the term "about" applies to the endpoints of the range or each value listed in the series, unless otherwise stated.

[0058] As used herein, the verb "comprising" and its variations are used in a non-limiting sense to mean that items following the word are included, but not that items not specifically mentioned are excluded.

[0059] It should also be noted that the claims may be drafted to exclude any optional elements. Therefore, this statement is intended to serve as a preliminary basis for using exclusive terms such as “solely,” “only,” “consisting of,” or “negative” in conjunction with the listed claim elements.

[0060] "Subject" is a live animal, particularly a mammal, that can be treated with the pharmaceutical compositions described herein. In some embodiments, the subject is a human. In some embodiments, the human subject is a human child, human adolescent, or human adult. In some embodiments, the subject or patient is a non-human animal, including research animals such as mice, rats, pigs, dogs, rabbits, monkeys, or other non-human primates or goats.

[0061] As used herein, “formulation” encompasses the term “composition.” Therefore, a formulation can refer to a composition containing one or more cannabinoids. Additionally or alternatively, a formulation can refer to a composition containing one or more cannabinoids and one or more pharmaceutically acceptable excipients.

[0062] As used herein, “active agent” refers to a pharmaceutical substance (e.g., cannabinoids, optionally CBD) that produces the desired biological effect. It should be understood that CBD is an illustrative embodiment of a cannabinoid, and CBD formulations are illustrative embodiments of cannabinoid formulations, as used herein. The term “cannabidiol” and the abbreviation “CBD” are used interchangeably herein and refer to molecules according to the following structure. Furthermore, in addition to biologically derived and synthetically derived CBD, the active agents of the formulations described herein also include prodrugs and derivatives of CBD.

[0063]

[0064] Unless otherwise stated, all weight percentages (i.e., “weight %”, “wt. %”, and “% w / w”) mentioned herein are measured relative to the total weight of the formulation or particles, depending on the context.

[0065] As used herein, “major” should be understood to mean a weight percentage greater than any other weight percentage. For example, the major form of a fatty acid glyceride (e.g., monoglyceride) is a fatty acid glyceride present in a greater amount than any other single form of said fatty acid glyceride.

[0066] As used herein, “dosage” refers to the amount of a preparation administered to a patient and containing a therapeutically effective amount of one or more cannabinoids. For example, a dosage may be a tablet or a capsule containing a preparation disclosed herein.

[0067] As used herein, “treatment” refers to a reduction in the severity and / or frequency of symptoms, the elimination of symptoms and / or underlying causes, a reduction in the likelihood of symptoms and / or underlying causes occurring, and the improvement or repair of damage. Therefore, “treating” a patient with the active agents described herein includes suppressing specific symptoms, diseases, or disorders in susceptible individuals and treating individuals with clinical symptoms.

[0068] As used herein, "effective dose" refers to a dose that encompasses both therapeutic and preventative effective doses. As used herein, "therapeutic effective dose" refers to the dose that effectively achieves the desired therapeutic outcome. The therapeutic effective dose of a given active agent will typically vary depending on the type and severity of the disorder or disease being treated, as well as factors such as the patient's age, sex, and weight.

[0069] SEDDS formulations

[0070] This disclosure provides formulations containing cannabinoids (including CBD). In some embodiments, the formulation is a SEDDS formulation. As used herein, the terms "cannabinoid SEDDS formulation" and "cannabinoid SEDDS" are used interchangeably and refer to a cannabinoid-containing SEDDS formulation as disclosed herein. As used herein, "CBD SEDDS formulation" and "CBD SEDDS" are used interchangeably and refer to a CBD-containing SEDDS formulation as disclosed herein. SEDDS are isotropic mixtures of oils, surfactants, solvents, and co-solvents / surfactants. SEDDS can be used in formulation design to improve the absorption of highly lipophilic drug compounds, such as cannabinoids, after oral administration. When mixed with an aqueous medium, such as in a gastrointestinal environment, SEDDS spontaneously assemble into colloidal dispersions or emulsions. Furthermore, when the SEDDS composition is released into the intestinal lumen, the composition disperses to form coarse, fine, or microemulsions, allowing the drug to remain in solution in the intestine, thereby avoiding frequent dissolution steps that limit the rate of absorption of hydrophobic drugs from their crystalline state. The use of SEDDS typically results in improved bioavailability and / or a more consistent time profile for absorption from the gut. A description of the composition of SEDDS can be found in CW Pouton, Advanced Drug Delivery Reviews 25: 47-58 (1997).

[0071] In the context of cannabinoids (including CBD), SEDDS have been shown to improve systemic exposure relative to MCT oil or lipid-free solutions (Cherniakov et al. Eur. J. Pharm. Sci. 2017, 109, 21-30; Knaub et al. Molecules. 2019, 24 (16), 2967; Nakano et al. Med. Cannabis Cannabinoids. 2019, 2(1), 35-42; Kok et al. Eur. J. Pharm. Sci. 2022, 168, 106058; De Prá et al. Int. J. Pharm. 2021, 609, 121159). SEDDS formulations containing sesame oil have also been reported to produce more predictable plasma concentration-time profiles compared to sesame oil as the sole medium, although no relative improvement in absorption has been observed (Izgelov et al., Eur. J. Pharm. Biopharm. 2020, 154, 108-115). This disclosure provides SEDDS formulations that provide improved gastrointestinal absorption and systemic exposure of cannabinoids (including CBD) after oral administration. In some embodiments, these formulations do not contain sesame oil. In some embodiments, these formulations do not contain ethanol.

[0072] In some embodiments, this disclosure provides cannabinoid preparations comprising:

[0073] Cannabinoids, CBD, optional;

[0074] One or more fatty acid glycerides; and

[0075] One or more fatty acid esters containing polyethylene glycol.

[0076] In some embodiments, the formulation contains a cannabinoid, such as CBD, in an amount greater than or equal to about 1% by weight. In some embodiments, the formulation contains a cannabinoid in an amount greater than or equal to about 5% by weight, greater than or equal to about 10% by weight, greater than or equal to about 15% by weight, greater than or equal to about 20% by weight, greater than or equal to about 25% by weight, greater than or equal to about 30% by weight, greater than or equal to about 35% by weight, greater than or equal to about 40% by weight, greater than or equal to about 45% by weight, greater than or equal to about 50% by weight, or greater than or equal to about 55% by weight. In some embodiments, the formulation contains a cannabinoid in an amount from about 1% to about 60% by weight. In some embodiments, the formulation comprises about 10% by weight to about 50% by weight of cannabinoids. In some embodiments, the formulation comprises about 20% by weight to about 40% by weight, about 10% by weight to about 60% by weight, about 20% by weight to about 60% by weight, or about 30% by weight to about 60% by weight of cannabinoids. In some embodiments, the formulation comprises about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight of cannabinoids. In some embodiments, the formulation comprises about 20% by weight of a cannabinoid, such as CBD. In some embodiments, the formulation comprises about 30% by weight of a cannabinoid, such as CBD. In some embodiments, the formulation comprises about 40% by weight of a cannabinoid, such as CBD. In some embodiments, the formulation comprises a range of cannabinoids, such as CBD, formed from any two of the disclosed weight percentages. For example, about 15% by weight to about 40% by weight.

[0077] In some embodiments, the formulation contains greater than or equal to about 1% by weight of CBD. In some embodiments, the formulation contains greater than or equal to about 5% by weight, greater than or equal to about 10% by weight, greater than or equal to about 15% by weight, greater than or equal to about 20% by weight, greater than or equal to about 25% by weight, greater than or equal to about 30% by weight, greater than or equal to about 35% by weight, greater than or equal to about 40% by weight, greater than or equal to about 45% by weight, greater than or equal to about 50% by weight, or greater than or equal to about 55% by weight of CBD. In some embodiments, the formulation contains less than or equal to about 70% by weight, less than or equal to about 65% by weight, less than or equal to about 60% by weight, less than or equal to about 55% by weight, less than or equal to about 50% by weight, less than or equal to about 45% by weight, less than or equal to about 40% by weight, less than or equal to about 35% by weight, less than or equal to about 35% by weight, less than or equal to about 30% by weight, or less than or equal to about 25% by weight of CBD. In some embodiments, the formulation contains from about 1% to about 60% by weight of CBD. In some embodiments, the formulation comprises about 10% by weight to about 50% by weight of CBD. In some embodiments, the formulation comprises about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight of CBD. In some embodiments, the formulation comprises about 20% by weight of CBD. In some embodiments, the formulation comprises about 30% by weight of CBD. In some embodiments, the formulation comprises about 40% by weight of CBD. In some embodiments, the formulation comprises CBD within the range of weight percentages formed by any two of the disclosed weight percentages. For example, about 15% by weight to about 40% by weight.

[0078] This disclosure provides cannabinoid SEDDS formulations comprising one or more fatty acid glycerides and one or more polyethylene glycol (PEG)-containing fatty acid esters. In some embodiments, the formulation comprises one or more fatty acid glycerides and one or more PEG-containing fatty acid esters in a ratio ranging from about 30:70 wt% to about 70:30 wt%. In some embodiments, the formulation comprises one or more fatty acid glycerides and one or more PEG-containing fatty acid esters in a ratio ranging from about 40:60 wt% to about 60:40 wt%. In some embodiments, the formulation comprises one or more fatty acid glycerides and one or more polyethylene oxide-containing fatty acid esters in a ratio of about 50:50 wt%. In some embodiments, the one or more fatty acid glycerides include oleic acid glycerides (e.g., Peceol). ®), and one or more PEG-containing fatty acid esters include PEG-containing fatty acid esters derived from fatty acids, including saturated and unsaturated fatty acids having eight (8) to twenty-two (22) carbon atoms (e.g., Gelucire 44 / 14). ® ).

[0079] SEDDS formulations contain fatty acid glycerides

[0080] The disclosed cannabinoid SEDDS formulations contain one or more fatty acid glycerides. As used herein, the term "fatty acid glyceride" refers to an ester formed between glycerol and one or more fatty acids comprising monoesters, diesters, and triesters (i.e., glycerides). Suitable fatty acids include saturated and unsaturated fatty acids having eight (8) to twenty-two (22) carbon atoms (i.e., C8-C22 fatty acids). In some embodiments, suitable fatty acids include C8-C18 fatty acids.

[0081] Fatty acid glycerides that can be used in formulations can be supplied from commercially available sources. A representative source of fatty acid glycerides is PECEOL. ® (Gattefosse, Saint Priest Cedex, France) A commercially available mixture of mono-, di-, and tri-esters (commonly referred to as "glyceryl oleate" or "glyceryl monooleate").

[0082] PECEOL ® Its functions include solubilizing lipophilic compounds and acting as a bioavailability enhancer. In some embodiments, PECEOL ® It contains long-chain fatty acids (C 18:1 The medium is used in the Lipid Formulation Classification System (LFCS) Type I (Oily), Type II (SEDDS), and Type III (SMEDDS) for applications related to lymphatic absorption. In some embodiments, PECEOL ® It is an oily carrier used in oral or topical formulations. In some implementations, PECEOL ® It has a viscosity of 220 mPa·s (20°C) and an HLB of 1. Safety is inferred from its Generally Recognized As Safe (GRAS) status and priority for use in approved pharmaceutical products.

[0083] In some implementations, when PECEOL ® When used as a source of fatty acid glycerides in a formulation, the fatty acid glycerides comprise about 32% to about 52% by weight of fatty acid monoglycerides, about 30% to about 50% by weight of fatty acid diglycerides, and about 5% to about 20% by weight of fatty acid triglycerides. In some embodiments, PECEOL ®It contains oleic acid (C18:1) and consists of monoglycerides, diglycerides, and triglycerides, with the monoglyceride fraction being dominant.

[0084] In some embodiments, the formulations disclosed herein may contain less than about 10% by weight of glycerol.

[0085] SEDDS formulations contain polyethylene glycol-containing fatty acid esters.

[0086] As mentioned above, CBD formulations contain one or more polyethylene glycol (PEG) modified lipids, such as PEG-containing phospholipids or one or more PEG-containing fatty acid esters, and are typically mixtures of PEG-containing phospholipids or mixtures of PEG-containing fatty acid esters.

[0087] Therefore, in one embodiment, the CBD formulation of this disclosure comprises: (a) cannabinoids, optionally cannabidiol; (b) one or more fatty acid glycerides; and (c) one or more PEG-containing fatty acid esters.

[0088] As used herein, the term "polyethylene glycol-containing fatty acid ester" refers to a fatty acid ester containing a polyethylene glycol group (i.e., a PEG group) covalently coupled to a fatty acid via an ester bond. As used herein, the terms "polyethylene glycol," "polyethylene oxide," and "PEG" are used interchangeably. PEG-containing fatty acid esters include mono- and di-fatty acid esters of PEG. Suitable PEG-containing fatty acid esters are derived from fatty acids, including saturated and unsaturated fatty acids having eight (8) to twenty-two (22) carbon atoms (i.e., PEG esters of C8-C22 fatty acids). In some embodiments, suitable PEG-containing fatty acid esters are derived from fatty acids, including saturated and unsaturated fatty acids having eight (8) to eighteen (18) carbon atoms (i.e., PEG esters of C8-C18 fatty acids). In some embodiments, suitable PEG-containing fatty acid esters include saturated C8-C18 fatty acids.

[0089] The molecular weight of the PEG group in a PEG-containing fatty acid ester can be altered to optimize the solubility of the therapeutic agent (e.g., cannabinoids, optionally CBD) in the formulation. A representative average molecular weight of the PEG group can be from about 350 g / mol to about 7000 g / mol. In one embodiment, the average molecular weight of the PEG group is about 1500. In another embodiment, the average molecular weight of the PEG group is about 6000. In yet another embodiment, the average molecular weight of the PEG group is about 400.

[0090] In this embodiment, the cannabinoid preparation contains one or more PEG-containing fatty acid esters, and is typically a mixture of PEG-containing fatty acid esters (mono- and di-fatty acid esters of PEG).

[0091] PEG-containing fatty acid esters that can be used in formulations are available from commercially available sources. A representative PEG-containing fatty acid ester (a mixture of monoesters and diesters) may be named GELUCIRE. ® Available commercially from Gattefosse, Saint Priest, Cedex, France. An illustrative example of a suitable PEG-containing fatty acid ester includes GELUCIRE. ® 44 / 14, GELUCIRE ® 48 / 16, GELUCIRE ® 50 / 13, GELUCIRE ® 59 / 14 and Labrasol ALF. These GELUCIRE ® The numbers in the name refer to the material's melting point and hydrophilic / lipophilic balance (HLB), respectively.

[0092] In some implementations, GELUCIRE ® 44 / 14, GELUCIRE ® 50 / 13, GELUCIRE ® 59 / 14 or Labrasol ALF PEG-containing fatty acid esters comprise (a) monoesters, diesters, and triesters of glycerol (glyceryl esters) and (b) monoesters and diesters of polyethylene glycol (polyethylene glycol). In some embodiments, GELUCIRE ® 44 / 14, GELUCIRE ® 50 / 13, GELUCIRE ® 59 / 14 or Labrasol ALF containing PEG fatty acid esters consists of (a) monoglycerides, diglycerides, and triglycerides and (b) a mixture of monoglycerides and diesters of PEG. In some embodiments, the PEG is PEG-32 (MW1500), PEG-150 (MW6000), or PEG-8 (MW400). In some embodiments, GELUCIRE ® 44 / 14, GELUCIRE ® 50 / 13, GELUCIRE ® 59 / 14 or Labrasol ALF also contains free PEG (e.g., PEG-32, PEG-150, or PEG-8).

[0093] In some implementations, GELUCIRE ® 48 / 16 PEG-containing fatty acid esters comprise a mixture of PEG monoesters and diesters. In some embodiments, GELUCIRE ®The 48 / 16 PEG-containing fatty acid ester consists of a mixture of PEG monoesters and diesters. In some embodiments, the PEG is PEG-32 (MW 1500). In some embodiments, GELUCIRE... ® 48 / 16 also contains free PEG (e.g., PEG-32).

[0094] In some embodiments, the PEG-containing fatty acid esters include one or more of oleate, linoleate, laurate, palmitate, stearate, caprylate, or decanoate (i.e., polyethylene glycol monolaurate and dilaurate, polyethylene glycol monopalmitate and dipalmitate, polyethylene glycol monostearate and distearate). Mixtures of these esters may also be used.

[0095] In some implementations, lauric acid (C12) is GELUCIRE ® The main fatty acid components of glycerides and polyethylene glycol esters in 44 / 14. ® 44 / 14 is referred to as a mixture of glyceryl dilaurate (dilaurate and glycerol) and PEG dilaurate (dilaurate and polyethylene glycol), and is commonly known as PEG-32 glyceryl dilaurate (Gattefosse), lauroyl polyethylene glycol-32 glyceryl ester EP, or lauroyl polyoxyglyceride ester USP / NF. GELUCIRE ® 44 / 14 is produced by reacting hydrogenated palm kernel oil with polyethylene glycol (average molecular weight 1500). In some embodiments, GELUCIRE... ® 44 / 14 contains approximately 20% monoglycerides, diglycerides, and triglycerides; approximately 72% mono- and di-fatty acid esters of polyethylene glycol 1500; and approximately 8% polyethylene glycol 1500. In some embodiments, GELUCIRE ® 44 / 14 is composed of oleic acid (C18:1) monoglycerides, diglycerides, and triglycerides, with the monoglyceride fraction being dominant.

[0096] In some implementations, GELUCIRE ® 44 / 14 contains lauric acid (C12) ester (30% to 50%), myristic acid (C14) ester (5% to 25%), palmitic acid (C16) ester (4% to 25%), stearic acid (C18) ester (5% to 35%), caprylic acid (C8) ester (less than 15%), and decanoic acid (C10) ester (less than 12%). GELUCIRE ® 44 / 14 may also contain free glycerol (typically less than about 1%) and <1 ppm ethylene oxide.

[0097] In some implementations, GELUCIRE ®48 / 16 is a polyethylene glycol monostearate (type I) NF and a PEG-32 (MW 1500) ester containing palmitic acid (C16) and stearic acid (C18). In some embodiments, GELUCIRE ® 48 / 16 is composed of PEG-32 (MW 1500) esters of palmitic acid (C16) and stearic acid (C18).

[0098] In some implementations, GELUCIRE ® 50 / 13 is a stearoyl polyoxy / polyethylene glycol 32 glycerol NF / EP, and contains monoglycerides, diglycerides, and triglycerides of palmitic acid (C16) and stearic acid (C18), as well as PEG-32 (MW1500) monoglycerides and diesters. In some embodiments, GELUCIRE ® 50 / 13 is composed of monoglycerides, diglycerides, and triglycerides of palmitic acid (C16) and stearic acid (C18), as well as monoglycerides and diesters of PEG-32 (MW1500).

[0099] In some implementations, GELUCIRE ® 59 / 14 contains small portions of monoglycerides, diglycerides, and triglycerides, and primarily comprises lauric acid (C12) and PEG-32 (MW 1500) monoglycerides and diesters of PEG-150 (MW 6000). In some embodiments, GELUCIRE ® 59 / 14 consists of small portions of monoglycerides, diglycerides and triglycerides, and is mainly composed of monoglycerides and diesters of lauric acid (C12) and PEG-32 (MW 1500) of PEG-150 (MW 6000).

[0100] In some embodiments, Labrasol ALF comprises small portions of monoglycerides, diglycerides, and triglycerides, and primarily comprises PEG-8 (MW 400) monoesters and diesters of caprylic acid (C8) and decanoic acid (C10).

[0101] GELUCIRE ® The functions of 44 / 14 include (a) solubilizers and bioavailability enhancers for poorly soluble compounds; (b) single excipient formulation systems: self-emulsifying into microemulsions in aqueous fluids—LFCS Type III (SMEDDS); (c) wetting agents; and (d) lipid binders in melt processes. Safety of use is inferred from adequate toxicological evaluation and priority for use in approved pharmaceutical products. GELUCIRE® Functions of 48 / 16 include (a) solubilizers and bioavailability enhancers for compounds with low log P (a measure of lipophilicity); (b) single excipient formulation systems: self-emulsifying into micellar solutions in aqueous fluids—LFCS type IV; (c) for melt processing (granulation, extrusion), granulation, and compression; and (d) wetting agents. Safety of use is inferred from the priority of use in approved pharmaceutical products. GELUCIRE ® The functions of 50 / 13 include (a) solubilizers and bioavailability enhancers for poorly soluble compounds; (b) single excipient formulation systems: self-emulsifying into crude emulsions in aqueous fluids—LFCS Type III (SMEDDS); (c) drug release modifiers; and (d) lipid binders in melt processes. Safety of use is inferred from toxicological data and priority of use in approved pharmaceutical products. GELUCIRE ® The functions of 59 / 14 include (a) a solubilizer and bioavailability enhancer for poorly soluble compounds; and (b) a single excipient formulation system: self-emulsifying into a microemulsion in an aqueous fluid—LFCS Type III (SMEDDS). Safety of use is inferred from adequate toxicological evaluation and priority in use in approved pharmaceutical products. The functions of Labrasol ALF include (a) a solubilizer and bioavailability enhancer for poorly soluble compounds; (b) a single excipient formulation system: self-emulsifying into a microemulsion in an aqueous fluid—LFCS Type III (SMEDDS); and (c) high purity ensuring stability and capsule compatibility. Safety of use is inferred from extensive toxicological data and priority in use in approved pharmaceutical products. The safety of use is inferred from food additive status and priority in use in approved pharmaceutical products.

[0102] In some implementations, GELUCIRE ® 44 / 14 has a melting range of 42.5°C–47.5°C, an HLB of 11, and a CMC of 72 mg / L ± 53 mg / L at 25°C. In some embodiments, GELUCIRE... ® 48 / 16 has a melting range of 46°C-50°C, an HLB of 12, and a CMC of 153 mg / L ± 31 mg / L at 25°C. In some embodiments, GELUCIRE... ® 50 / 13 has a melting range of 46°C-51°C, an HLB of 11, and a CMC of 100 mg / L ± 31 mg / L at 25°C. In some embodiments, GELUCIRE... ®59 / 14 has a melting range of 57°C-62°C, an HLB of 14±1, and a CMC of 40 mg / L at 25°C. In some embodiments, LabrasolALF has a viscosity of 80-110 (20°C) mPA.s, an HLB of 12, and a CMC of 42 mg / L±24 mg / L at 25°C.

[0103] Relative amounts of components in SEDDS formulations

[0104] For embodiments including PEG-containing fatty acid esters, in some embodiments, the ratio of fatty acid glycerides to PEG-containing fatty acid esters is about 30:70 to about 70:30 v / v. In one embodiment, the ratio of fatty acid glycerides to PEG-containing fatty acid esters is about 30:70 v / v. In one embodiment, the ratio of fatty acid glycerides to PEG-containing fatty acid esters is about 40:60 v / v. In one embodiment, the ratio of fatty acid glycerides to PEG-containing fatty acid esters is about 50:50 v / v. In one embodiment, the ratio of fatty acid glycerides to PEG-containing fatty acid esters is about 60:40 v / v. In one embodiment, the ratio of fatty acid glycerides to PEG-containing fatty acid esters is about 70:30 v / v.

[0105] In one embodiment, the cannabinoid formulation disclosed herein comprises cannabinoids (optionally CBD), PECEOL, etc. ® and GELUCIRE ® 44 / 14. In the implementation plan, PECEOL ® With GELUCIRE ® The 44 / 14 ratio can be from 30:70 to 70:30 (e.g., 30:70; 40:60; 50:50; 60:40; and 70:30). In these implementations, PECEOL ® With GELUCIRE ® The 44 / 14 ratio can be from 20:80 to 80:20 (e.g., 20:80, 30:70; 40:60; 50:50; 60:40; 70:30; and 80:20).

[0106] In one embodiment, the cannabinoid formulation disclosed herein comprises cannabinoids (optionally CBD), PECEOL, etc. ® and GELUCIRE ® 48 / 16. In these implementations, PECEOL ® With GELUCIRE ®The 48 / 16 ratio can be from 30:70 to 70:30 (e.g., 30:70; 40:60; 50:50; 60:40; and 70:30). In these implementations, PECEOL ® With GELUCIRE ® The 48 / 16 ratio can be from 20:80 to 80:20 (e.g., 20:80, 30:70; 40:60; 50:50; 60:40; 70:30; and 80:20).

[0107] In one embodiment, the cannabinoid formulation disclosed herein comprises cannabinoids (optionally CBD), PECEOL, etc. ® and GELUCIRE ® 50 / 13. In these implementations, PECEOL ® With GELUCIRE ® The 50 / 13 ratio can be from 30:70 to 70:30 (e.g., 30:70; 40:60; 50:50; 60:40; and 70:30). In these implementations, PECEOL ® With GELUCIRE ® The 50 / 13 ratio can be from 20:80 to 80:20 (e.g., 20:80, 30:70; 40:60; 50:50; 60:40; 70:30; and 80:20).

[0108] In one embodiment, the cannabinoid formulation disclosed herein comprises cannabinoids (optionally CBD), PECEOL, etc. ® and GELUCIRE ® 59 / 14. In these implementations, PECEOL ® With GELUCIRE ® The 59 / 14 ratio can be from 30:70 to 70:30 (e.g., 30:70; 40:60; 50:50; 60:40; and 70:30). In these implementations, PECEOL ® With GELUCIRE ® The 59 / 14 ratio can be from 20:80 to 80:20 (e.g., 20:80, 30:70; 40:60; 50:50; 60:40; 70:30; and 80:20).

[0109] In one embodiment, the cannabinoid formulation disclosed herein comprises cannabinoids (optionally CBD), PECEOL, etc. ® And Labrasol ALF. In these implementations, PECEOL ®The ratio to Labrasol ALF can be 30:70 to 70:30 (e.g., 30:70; 40:60; 50:50; 60:40; and 70:30). In these implementations, PECEOL ® The ratio to Labrasol ALF can be from 20:80 to 80:20 (e.g., 20:80, 30:70; 40:60; 50:50; 60:40; 70:30; and 80:20).

[0110] In some embodiments, glyceryl oleate and the polyethylene glycol-containing fatty acid ester are each present in the formulation at an amount of about 30% to about 50% by weight. In some embodiments, glyceryl oleate and the polyethylene glycol-containing fatty acid ester are each present in the formulation at an amount of about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50%. In some embodiments, the polyethylene glycol-containing fatty acid ester is Gelucire 44 / 14 or lauroyl polyethylene glycol glyceride.

[0111] In some embodiments, glyceryl oleate and the polyethylene glycol-containing fatty acid ester are each present in the formulation at about 34.58% by weight. In some embodiments, glyceryl oleate and the polyethylene glycol-containing fatty acid ester are each present in the formulation at about 36.4% by weight. In some embodiments, glyceryl oleate and the polyethylene glycol-containing fatty acid ester are each present in the formulation at about 38% by weight. In some embodiments, glyceryl oleate and the polyethylene glycol-containing fatty acid ester are each present in the formulation at an amount from about 39% to about 41% by weight. In some embodiments, glyceryl oleate and the polyethylene glycol-containing fatty acid ester are each present in the formulation at about 40% by weight. In some embodiments, the polyethylene glycol-containing fatty acid ester is Gelucire 44 / 14 or lauroyl polyethylene glycol glyceride.

[0112] This disclosure provides cannabinoid SEDDS formulations that may optionally contain one or more additional ingredients. These additional ingredients may include one or more of a surfactant and a cosolvent. In some embodiments, the surfactant is tocopherol polyethylene glycol succinate (TPGS). In some embodiments, TPGS is present in the formulation in an amount of about 3% to about 4% by weight. In some embodiments, TPGS is present in the formulation in about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, or about 4% by weight. In some embodiments, TPGS is present in the formulation in about 3.64% by weight. In some embodiments, TPGS is present in the formulation in about 4% by weight.

[0113] In some embodiments, the co-solvent contained in the formulation is ethanol. In some embodiments, ethanol is present in the formulation at about 7%, about 7.1%, about 7.2%, about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, or about 8%. In some embodiments, ethanol is present in the formulation at about 7.2% by weight. In other embodiments, the formulation does not contain ethanol.

[0114] In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 38% by weight, and TPGS is present in the formulation at about 4% by weight. In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 34.58% by weight, TPGS is present in the formulation at about 3.64% by weight, and ethanol is present in the formulation at about 7.2% by weight.

[0115] In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 36.4% by weight, and ethanol is present in the formulation at about 7.2% by weight. In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 40% by weight, and the formulation does not contain TPGS or ethanol.

[0116] In some embodiments, a single dose of the formulation contains at least 10 milligrams (mg) of cannabinoids. In some embodiments, a single dose of the formulation contains cannabinoids in the range of about 10 mg to about 3,000 mg. In some embodiments, a single dose of the formulation contains cannabinoids in the range of about 50 mg to about 2,000 mg. In some embodiments, a single dose may contain about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,250 mg, about 1,500 mg, about 2,000 mg, about 2,500 mg, or about 3,000 mg of cannabinoids. In some implementations, a single dose contains approximately 600 mg of cannabinoids.

[0117] In some embodiments, this disclosure provides formulations containing more than about 1% by weight of cannabinoids. In some embodiments, the formulation contains about 10% by weight to about 50% by weight of cannabinoids. In some embodiments, the formulation contains about 20% by weight of cannabinoids. In some embodiments, the formulation contains about 40% by weight of cannabinoids.

[0118] In some embodiments, a single dose of the formulation contains at least 10 mg of CBD. In some embodiments, a single dose of the formulation contains CBD in the range of about 10 mg to about 3,000 mg. In some embodiments, a single dose of the formulation contains CBD in the range of about 50 mg to 2,000 mg. In some embodiments, a single dose may contain about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,250 mg, about 1,500 mg, about 2,000 mg, about 2,500 mg, or about 3,000 mg of CBD. In some implementations, a single dose contains approximately 600 mg of CBD.

[0119] In some embodiments, this disclosure provides formulations containing more than about 5% by weight of CBD. In some embodiments, the formulation contains about 10% by weight to about 50% by weight of CBD. In some embodiments, the formulation contains about 20% by weight of CBD. In some embodiments, the formulation contains about 40% by weight of CBD.

[0120] This disclosure also provides formulations as described herein, which are formulated for oral administration. This disclosure also provides a capsule containing any of the formulations described herein. In some embodiments, the capsule is a soft gel capsule. Cannabinoid SEDDS formulations can be formulated in any suitable form for administering said formulations, such as, but not limited to, capsules, tablets, powders, pills, or solutions.

[0121] cannabinoids

[0122] Cannabinoids are natural and synthetic compounds that are structurally or pharmacologically associated with components of the cannabis plant or endogenous agonists (endocannabinoids) of the cannabinoid receptors CB1 or CB2. Cannabinoids exert their physiological effects through a variety of receptors, including but not limited to adrenergic receptors, cannabinoid receptors (CB1 and CB2), GPR55, GPR3, or GPR5. CB1 receptors are particularly widespread in the central nervous system, with high levels found in the neocortex, hippocampus, basal ganglia, cerebellum, and brainstem, and therefore, CBD has been proposed for the treatment of variants of neurological disorders (Scotter et al. Br. J. Pharmacol. 2010. (160):480-498).

[0123] The main cannabinoids present in the cannabis plant are tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), along with small amounts of their corresponding neutral (decarboxylated) cannabinoids. In addition, cannabis may contain lower levels of other minor cannabinoids.

[0124] CBD is the main cannabinoid component of cannabis species. Unlike other cannabinoids (such as THC), CBD does not bind to CB1 or CB2, or its binding to these receptors is negligible in inducing pharmacological effects. Therefore, CBD does not cause central or peripheral nervous system effects mediated by CB1 or CB2 receptors. CBD has little or no psychoactive (cannabiological) activity, and its molecular structure and properties differ significantly from those of other cannabinoids.

[0125] In some embodiments, CBD is isolated from the cannabis plant. In some embodiments, CBD is prepared synthetically. In some embodiments, CBD exists as (-)-trans-CBD.

[0126] Of the more than 100 natural cannabinoids identified in cannabis (Cannabis sativa), seven have been classified as CBD-type compounds, possessing the same absolute configuration as CBD. These are: CBD, cannabidiol (CBDA), cannabidiol (CBDV), cannabidiol (CBDVA), cannabidiol-C1 (CBD-C1), cannabidiol-C4 (CBD-C4), and cannabidiol monomethyl ether (CBDM). Cannabidiol (CBDA) is the primary form of CBD found in the cannabis plant. It is converted to CBD upon decarboxylation.

[0127] Cannabidiol-C1 (CBD-C1) (also known as hypocannabidiol) is a homologue of CBD with a shortened side chain containing four methylene bridges. CBD-C1 is naturally found in plants that produce small amounts of CBD. Hypocannabidiol (CBDV) is a homologue of CBD with a shortened side chain containing two methylene bridges. CBDV is a non-psychoactive cannabinoid and has been shown to have anticonvulsant activity in mouse models of epilepsy. Cannabidiol-C4 (CBD-C4) (also known as norcannabidiol) is a homologue of CBD with a shortened side chain containing one methylene bridge. CBD-C4 is naturally found in plants that produce small amounts of CBD.

[0128] CBD is a highly lipophilic drug with low water solubility (estimated <13 µg / mL) (logP ≈ 6). After undergoing adequate first-pass metabolism, CBD has an oral bioavailability of approximately 6%. Formally, CBD is classified as a Class II compound in the Biopharmaceutics Classification System (BCS) due to its low water solubility and high intestinal permeability. Therefore, strategies to improve the dissolution or dispersion rate of CBD will increase its bioavailability. To this end, numerous formulation methods for CBD have been explored, including solid dispersions, nanocrystals, and nanoemulsions. Lipid formulations have experienced the most remarkable success given the physicochemical properties of CBD.

[0129] To date, the only FDA-approved CBD formulation is Epidiolex. ®Epidiolex is a sesame oil-based solution designed for the treatment of rare childhood epilepsy and tuberous sclerosis. However, this and other CBD formulations have limited applicability: (1) some patients are allergic to sesame oil, posing safety concerns; (2) many indications require large doses of CBD, which are difficult to administer with sesame oil formulations, resulting in adherence limitations; (3) liquid formulations are inherently less precise; and sesame oil formulations degrade upon exposure to air, resulting in higher costs. Furthermore, Epidiolex includes ethanol, which has drawbacks when used in certain patient populations. Therefore, there is a need for lipid formulations (which can improve CBD absorption without relying on sesame oil as an excipient) to avoid potential allergies, allow for higher doses and better patient adherence, minimize variability, and reduce costs.

[0130] CBD has been recommended for the treatment of a variety of conditions or injuries, including but not limited to high clinical risk of psychosis, insomnia, psychosis in its first episode, psychosis in Parkinson's disease, schizophrenia, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, Alzheimer's disease, postpartum psychosis, phobia of strange environments, acute stress disorder, and schizoaffective disorder. Treatment of some of these conditions or injuries may require high doses of CBD. Oral administration via a convenient and painless route, ideally through an easily administered, highly effective soft gel, would improve patient acceptance and treatment adherence. Therefore, CBD formulations are needed that possess the following properties: high solubilizing effect and high stability during storage, with favorable safety, absorption, and bioavailability characteristics.

[0131] D-α-Tocopherol Polyethylene Glycol 1000 Succinate (TPGS)

[0132] Cannabinoid preparations may optionally contain one or more additional ingredients, including surfactants such as D-α-tocopherol polyethylene glycol succinate (TPGS).

[0133] Therefore, in some embodiments, the cannabinoid formulations of this disclosure comprise: (a) cannabinoids, optionally cannabidiol; (b) one or more fatty acid glycerides; (c) one or more polyethylene glycol-containing fatty acid esters; and (d) TPGS, optionally D-α-tocopherol polyethylene glycol 1000 succinate (TPGS 1000).

[0134] As used herein, the term “D-α-tocopherol polyethylene glycol succinate” and the abbreviation “TPGS” are used interchangeably and are defined as molecules with the following chemical structures:

[0135]

[0136] TPGS is an amphiphilic molecule prepared by esterification of a hydrophilic polyethylene glycol molecule (typically having an average molecular weight of 1000 and about 20-25 ethylene oxide chains) with the carboxyl group of a hydrophobic d-α-tocopherol hemisuccinate (acid). TPGS is a water-soluble compound (up to 20% w / v) and forms a micelle solution with a critical micelle concentration of 0.4 mM / L-0.6 mM / L (about 0.075%). The hydrophilic-lipophilic equilibrium of TPGS is about 15-19. Structurally, tocopherol polyethylene glycol succinate has polyethylene glycol (PEG) covalently coupled to tocopherol (e.g., α-tocopherol or vitamin E) via succinate linkers. Because PEG is a polymer, various polymer molecular weights can be used to prepare TPGS. In one embodiment, TPGS is tocopherol polyethylene glycol succinate 1000, wherein the average molecular weight of PEG is 1000. A suitable tocopherol polyethylene glycol succinate is vitamin E TPGS, which is commercially available from Eastman.

[0137] TPGS can be used as a surfactant or emulsifier for lipophilic substances. Emulsification and the subsequent increase in the surface area of ​​the lipophilic substance can increase the absorption and bioavailability of drugs in the gastrointestinal tract. TPGS can be included in formulations to enhance their thermal stability, which in turn can increase their shelf life.

[0138] In some embodiments, tocopherol polyethylene glycol succinate is present in the formulation at about 0.1% to about 10% by volume, based on the total volume of the formulation. In one embodiment, tocopherol polyethylene glycol succinate is present in the formulation at about 5% by volume, based on the total volume of the formulation.

[0139] Toxicological studies have shown that TPGS is safe for human consumption as a dietary or nutritional supplement. Furthermore, the antioxidant properties of TPGS can improve the stability of TPGS-containing formulations.

[0140] antioxidants

[0141] Cannabinoid formulations may optionally contain one or more antioxidants. In some embodiments, the antioxidants are selected from the group consisting of: TPGS, butylated hydroxytoluene (BHT), butylated hydroxyanisole, α-tocopherol (vitamin E), ascorbyl palmitate, ascorbic acid, sodium ascorbate, EDTA, cysteine ​​hydrochloride, citric acid, sodium citrate, sodium bisulfate, sodium metabisulfite, lecithin, propyl gallate, sodium sulfate, and monothioglycerol. In some embodiments, one or more antioxidants comprise TPGS. In some embodiments, one or more antioxidants comprise BHT. In some embodiments, one or more antioxidants comprise both TPGS and BHT. In embodiments, the cannabinoid formulations described herein comprise about 0.001% by weight to about 20% by weight of antioxidants. In some embodiments, the cannabinoid formulation described herein comprises about 0.001% by weight, about 0.002% by weight, about 0.003% by weight, about 0.004% by weight, about 0.005% by weight, about 0.006% by weight, about 0.007% by weight, about 0.008% by weight, about 0.009% by weight, about 0.01% by weight, about 0.02% by weight, about 0.03% by weight, about 0.04% by weight, about 0.05% by weight, about 0.06% by weight, about 0.07% by weight, about 0.08% by weight, about 0.09% by weight, and about 0.1% by weight. About 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, or about 20% by weight of antioxidants.

[0142] ethanol

[0143] Cannabinoid preparations may optionally contain one or more additional ingredients, including cosolvents such as ethanol.

[0144] Therefore, in some embodiments, the cannabinoid formulations of this disclosure comprise: (a) cannabinoids, optionally CBD; (b) one or more fatty acid glycerides; (c) one or more fatty acid esters containing polyethylene glycol; (d) ethanol; and optionally TPGS.

[0145] Co-solvents can enhance the emulsification process and affect the solubility of lipophilic compounds in simulated intestinal fluid. However, ethanol may also present safety or patient preference concerns. In some formulations, the product does not contain ethanol.

[0146] Sesame oil

[0147] Epidiolex, a sesame oil-based formulation ® This FDA-approved complex is used to treat rare childhood epilepsy and tuberous sclerosis. Sesame oil increases the solubility and systemic exposure of cannabinoids. Furthermore, sesame oil promotes the intestinal lymphatic transport of CBD, effectively avoiding the first-pass effect and thus resulting in higher bioavailability. However, high variability in absorption is observed. Furthermore, sesame oil may pose safety concerns for patients due to food allergies. In some formulations, the preparation does not contain sesame oil.

[0148] Medium-chain triglyceride (MCT) oil

[0149] Cannabinoid (e.g., CBD) formulations may optionally contain one or more additional ingredients, including triglycerides, such as MCT. Triglycerides (also known as triacylglycerols or triacylglycerol esters) are glycerides in which glycerol is esterified with three fatty acids. Based on their chain length, triglycerides can be classified into three categories: (i) short-chain triglycerides (SCT); (ii) medium-chain triglycerides (MCT); and (iii) long-chain triglycerides (LCT). Medium-chain triglycerides have fatty acids ranging from about C8 to about C10 (e.g., caprylic / capric triglycerides). Some exemplary commercially available medium-chain triglycerides are CAPTEX. ® (Available from Parchem, White Plains, NY), NESATOL ® (Available from Kreglinger Europe, Antwerp, Belgium), WAGLINOL ® (Available from Industrial Quimica Lasem, SA, Barcelona, ​​Spain), BERGABEST ® (Available from Sternchemie, Hamburg, Germany), MIGL YOL ® (Available from UniversalPreserv-A-Chem, Inc., Edison, NJ), NEOBEE ® (Available from Stepan Company, Northfield, Illinois) and CRODAMOL ® (Available from Croda, Edison, NJ).

[0150] Methods for manufacturing SEDDS

[0151] This disclosure provides a method for manufacturing SEDDS. In SEDDS, the self-emulsifying oily solution is referred to as a pre-concentrate. A bulk mixture of drug-free pre-concentrate can be prepared by mixing excipients at 45°C for about 30 min while stirring at about 300 rpm. A final pre-concentrate can be prepared by adding the drug-free pre-concentrate to a cannabinoid isolate to achieve a desired cannabinoid concentration. The mixture can then be stirred at about 400 rpm and about 45°C until substantially completely homogeneous. An illustrative embodiment of the method for manufacturing cannabinoid SEDDS formulations is shown in Figure 1.

[0152] Droplet dispersion

[0153] The disclosed cannabinoid SEDDS formulation contains cannabinoids, optionally CBD, which are both partially dissolved (dissolved) and present in solid particulate form to provide a fine solid dispersion. Dispersion of the formulation in an aqueous medium provides a nanoemulsion.

[0154] The formulation can be characterized by droplet size and polydispersity index (PDI) measured by dynamic light scattering (DLS) (Zetasizer Nano ZS, Malvern Instruments Ltd, UK) at approximately 37°C. The pre-concentrate can be dispersed in PBS (approximately 0.5% w / v) and stirred at approximately 100 rpm and approximately 37°C for approximately 2 hours.

[0155] The formulation, upon dispersion, can form submicron-sized droplets. In some embodiments, the formulation can form droplets with an initial diameter of about 280 nm to about 500 nm. In some embodiments, the formulation can form droplets with an initial diameter of about 380 nm to about 480 nm. In some embodiments, the formulation can form droplets with an initial diameter of about 375 nm to about 490 nm. In some embodiments, the formulation can form droplets with an initial diameter of about 429 nm.

[0156] Upon dispersion, the formulation may form droplets with a PDI value of about 0.2 to about 0.6. In some embodiments, the formulation may form droplets with a PDI value of about 0.25 to about 0.4. In some embodiments, the formulation may form droplets with a PDI value of about 0.2 to about 0.4. In some embodiments, the formulation may form droplets with a PDI value of about 0.30.

[0157] The formulation can be stored under refrigerated conditions (i.e., about 3°C ​​to about 5°C) or at room temperature (i.e., about 20°C to about 25°C). The formulation can be stored for at least about 3 months. The formulation can be stored for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, about 14 days, about 20 days, about 30 days, about 40 days, about 50 days, about 60 days, about 70 days, about 80 days, about 90 days, or about 100 days.

[0158] The formulation may form droplets after storage, and these droplets have approximately the same diameter as the droplets formed by the formulation before storage. In some embodiments, the formulation may form droplets with an initial diameter of about 280 nm to about 650 nm after storage. In some embodiments, the formulation may form droplets with an initial diameter of about 380 nm to about 570 nm after storage. In some embodiments, the formulation may form droplets with an initial diameter of about 380 nm to about 490 nm after storage. In some embodiments, the formulation may form droplets with an initial diameter of about 429 nm to about 489 nm after storage.

[0159] In some embodiments, the formulation, when stored under refrigerated conditions, can form droplets with an initial diameter of about 400 nm to about 650 nm. In some embodiments, the formulation, when stored under refrigerated conditions, can form droplets with an initial diameter of about 425 nm to about 580 nm. In some embodiments, the formulation, when stored at room temperature, can form droplets with an initial diameter of about 400 nm to about 510 nm. In some embodiments, the formulation, when stored under refrigerated conditions, can form droplets with an initial diameter of about 420 nm to about 490 nm.

[0160] In some embodiments, the formulation, after being stored at room temperature, can form droplets with an initial diameter of about 310 nm to about 560 nm. In some embodiments, the formulation, after being stored at room temperature, can form droplets with an initial diameter of about 380 nm to about 520 nm. In some embodiments, the formulation, after being stored at room temperature, can form droplets with an initial diameter of about 370 nm to about 430 nm. In some embodiments, the formulation, after being stored at room temperature, can form droplets with an initial diameter of about 390 nm to about 410 nm.

[0161] The formulation, upon storage, may form droplets with a PDI value substantially the same as those formed by the formulation before storage. In some embodiments, the formulation may form droplets with a PDI value of about 0.05 to about 0.6 upon storage. In some embodiments, the formulation may form droplets with a PDI value of about 0.14 to about 0.5 upon storage. In some embodiments, the formulation may form droplets with a PDI value of about 0.15 to about 0.45 upon storage under refrigerated conditions. In some embodiments, the formulation may form droplets with a PDI value of about 0.2 to about 0.35 upon storage at room temperature.

[0162] In some embodiments, the formulation may form droplets with a PDI value of about 0.1 to about 0.6 after being stored under refrigerated conditions. In some embodiments, the formulation may form droplets with a PDI value of about 0.14 to about 0.5 after being stored under refrigerated conditions. In some embodiments, the formulation may form droplets with a PDI value of about 0.15 to about 0.45 after being stored under refrigerated conditions.

[0163] In some embodiments, the formulation, when stored at room temperature, can form droplets with a PDI value of about 0.15 to about 0.55. In some embodiments, the formulation, when stored at room temperature, can form droplets with a PDI value of about 0.2 to about 0.5. In some embodiments, the formulation, when stored at room temperature, can form droplets with a PDI value of about 0.15 to about 0.46. In some embodiments, the formulation, when stored at room temperature, can form droplets with a PDI value of about 0.2 to about 0.35.

[0164] Drug solubilization

[0165] The disclosed cannabinoid SEDDS formulation effectively dissolves cannabinoids such that cannabinoids (optionally CBD) are present in the formulation at a concentration of at least about 1% by weight. In some embodiments, the formulation contains cannabinoids (e.g., CBD) in amounts greater than or equal to about 5% by weight, greater than or equal to about 10% by weight, greater than or equal to about 15% by weight, greater than or equal to about 20% by weight, greater than or equal to about 25% by weight, greater than or equal to about 30% by weight, greater than or equal to about 35% by weight, greater than or equal to about 40% by weight, greater than or equal to about 45% by weight, greater than or equal to about 50% by weight, or greater than or equal to about 55% by weight. In some embodiments, the formulation contains cannabinoids in amounts from about 1% to about 60% by weight, from about 20% by weight to about 50% by weight, from about 30% by weight to about 50% by weight, or from about 30% by weight to about 40% by weight. In some embodiments, the formulation contains cannabinoids in amounts from about 10% by weight to about 50% by weight. In some embodiments, the formulation contains cannabinoids in amounts from about 20% by weight to about 40% by weight. In some embodiments, the formulation contains about 20% by weight of cannabinoids. In some embodiments, the formulation contains about 25% by weight of cannabinoids. In some embodiments, the formulation contains about 30% by weight of cannabinoids. In some embodiments, the formulation contains about 35% by weight of cannabinoids. In some embodiments, the formulation contains about 40% by weight of cannabinoids. In some embodiments, the formulation contains about 45% by weight of cannabinoids. In some embodiments, the formulation contains about 50% by weight of cannabinoids.

[0166] The formulation can be stored under refrigerated conditions (i.e., about 3°C ​​to about 5°C) or at room temperature (i.e., about 20°C to about 25°C).

[0167] The stability of cannabinoid SEDDS can be evaluated at predetermined time points by, for example, diluting the pre-concentrated product in ethanol (1:1000), vortexing for about 20 seconds, sonicating in an ultrasonic bath (Sonoswiss AG, SW 3H, Switzerland) for about 5 minutes, and quantifying the cannabinoids by HPLC.

[0168] After storage, such as under refrigerated conditions (i.e., about 3°C ​​to about 5°C) or at room temperature (i.e., about 20°C to about 25°C), the formulation can maintain cannabinoid solubilization (measured as cannabinoid content (%)) at a level substantially the same as the cannabinoid content of the formulation before storage. In some embodiments, the formulation may have a cannabinoid content (drug content) of about 80% to about 110% after storage. In some embodiments, the formulation may have a cannabinoid content of about 91% to about 104% after storage.

[0169] In some embodiments, the formulation may have a cannabinoid content of about 94% to about 110% after being stored under refrigerated conditions. In some embodiments, the formulation may have a cannabinoid content of about 96% to about 104% after being stored under refrigerated conditions.

[0170] In some embodiments, the formulation may have a cannabinoid content of about 80% to about 104% after being stored at room temperature. In some embodiments, the formulation may have a cannabinoid content of about 91% to about 100% after being stored at room temperature. In some embodiments, the formulation may have a cannabinoid content of about 91% to about 95% after being stored at room temperature.

[0171] To determine the effectiveness of the representative cannabinoid formulations of the present invention as oral administration formulations, their stability was evaluated in simulated gastric fluid.

[0172] Simulates drug dispersion and solubility in gastric juice

[0173] The disclosed cannabinoid SEDDS formulation maintains a favorable dispersion profile and effectively dissolves cannabinoids (optionally CBD) in biologically relevant media (e.g., simulated gastric juices, including but not limited to fasting simulated gastric juice [FaSSGF], fasting simulated intestinal juice [FaSSIF], and feeding simulated intestinal juice [FeSSIF]).

[0174] FaSSGF, FaSSIF, and FeSSIF are dissolution media that mimic human intestinal fluid. Each contains the same type and levels of surfactants (bile salts and phospholipids) present in the gastrointestinal fluid it replicates, as well as the same average pH and similar osmolarity. Surfactants, pH, and osmolarity are important parameters to control when testing drugs or formulations. Surfactants form mixed micelles, which can significantly enhance the solubility and dissolution of drugs. pH and osmolarity can affect the solubility and dissolution of drugs. FaSSGF contains approximately 0.08 mM taurocholic acid, approximately 0.02 mM phospholipids, approximately 34 mM sodium, and approximately 59 mM chloride. FaSSIF contains approximately 3 mM taurocholic acid, approximately 0.75 mM phospholipids, approximately 148 mM sodium, approximately 106 mM chloride, and approximately 29 mM phosphate. FeSSIF contains approximately 15 mM taurocholic acid, approximately 3.75 mM phospholipids, approximately 319 mM sodium, approximately 203 mM chloride, and approximately 144 mM acetic acid. Powdered and buffer concentrates of FaSSGF, FaSSIF, and FeSSIF were purchased from Biorelevant.com Ltd.

[0175] In some embodiments, after dispersion in a bio-associated medium (0.5% w / v), the disclosed cannabinoid SEDDS formulation may have about 90% to about 100% cannabinoids (optionally CBD) dissolved within 30 minutes. In some embodiments, for all formulations, the dispersion of the formulation in FaSSGF may have at least about 90% cannabinoids dissolved within 30 minutes. In some embodiments, the dispersion of the formulation in FaSSGF may have at least about 80% cannabinoids dissolved within 2 hours. In some embodiments, the dispersion of the formulation in FaSSGF may have at least about 95% cannabinoids dissolved within 2 hours. In some embodiments, for all formulations, the dispersion of the formulation in FaSSIF may have at least 90% cannabinoids dissolved within 30 minutes. In some embodiments, the dispersion of the formulation in FaSSIF may have at least about 90% cannabinoids dissolved within 2 hours. In some embodiments, for all formulations, the dispersion of the formulation in FeSSIF may have at least about 60% cannabinoids dissolved within 30 minutes. In some embodiments, the dispersion of the formulation in FeSSIF may have at least about 40% cannabinoids dissolved at 2 hours.

[0176] In vitro digestion of cannabinoid SEDDS preparations

[0177] The solubilizing properties of the disclosed cannabinoids (e.g., CBD, SEDDS formulations) can be further characterized by in vitro digestion, for example, as described below (Kok et al. Eur. J. Pharm. Sci. 2022, 168, 106058; Williams et al. J. Pharm. Sci. 2012, 101 (9), 3360-3380; or Sassene et al. AAPS J. 2014, 16 (6), 1344-1357). Before adding pancreatic lipase (approximately 667 mg), the selected formulation was dispersed (2.5% w / v) in FaSSIF by stirring at approximately 100 rpm and approximately 37 °C for 10 minutes and digested for approximately 30 minutes. The sample was then separated into three layers by centrifugation (20,800 × g, 15 min): top layer (oil phase), middle layer (aqueous micelle phase), and bottom layer (precipitate phase). The cannabinoid content from each phase was analyzed by HPLC after dilution in methanol.

[0178] In some embodiments, the formulation exhibits minimal precipitation (<20%) and is predominantly distributed in the oil phase. In some embodiments, the formulation exhibits approximately 55% to approximately 75% of cannabinoids (e.g., CBD) distributed in the oil phase, approximately 18% to approximately 28% of cannabinoids distributed in the aqueous phase, and approximately 7% to approximately 21% of cannabinoids distributed in the precipitate phase. In some embodiments, the formulation exhibits approximately 62% of cannabinoids distributed in the oil phase, approximately 23% of cannabinoids distributed in the aqueous phase, and approximately 15% of cannabinoids distributed in the precipitate phase.

[0179] Pharmacokinetics

[0180] This disclosure provides cannabinoid (e.g., CBD) formulations that, compared to medium-chain triglyceride (MCT) cannabinoid formulations (also referred to herein as cannabinoid MCTs) (optionally MCT CBD formulations, also referred to herein as CBD MCTs), result in improved absorption and slower elimination after administration. In some embodiments, the formulations can produce, upon administration, the maximum plasma concentration (C) produced by administration of cannabinoid MCTs. max The maximum plasma concentration is approximately equal to, or at least as high as, or higher than that of, sesame oil (SO) cannabinoid formulations (also referred to herein as cannabinoid SO) (optionally SO CBD formulations, also referred to herein as CBD SO) produced upon administration. max The maximum plasma concentration is approximately equal to, or at least as high as, or higher than that of the formulation. In some embodiments, the formulation generates C after administration. max C can be a cannabinoid MCT maxApproximately 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, or 2.0 times. In some embodiments, the formulation generates C after administration. max C can be cannabinoid SO max Approximately 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, or 2.0 times. In some embodiments, the formulation generates C after administration. max C can be a cannabinoid MCT max Approximately 1.7 times that of [previous formulation]. In some implementations, the formulation generates C [after application]. max C can be a cannabinoid MCT max Approximately 1.1 times that.

[0181] In some embodiments, the formulation may: a) form droplets with diameters within a specified range upon dispersion, and b) produce a maximum plasma concentration (Cmax) greater than a certain value after administration. In some embodiments, the formulation may: a) form droplets with a diameter of about 280 nm to about 500 nm upon dispersion, and b) produce a maximum plasma concentration (Cmax) greater than 500 ng / mL, greater than 550 ng / mL, greater than 600 ng / mL, greater than 650 ng / mL, greater than 700 ng / mL, or greater than 750 ng / mL after administration. In some embodiments, the formulation may: a) form droplets with an initial diameter of about 380 nm to about 480 nm upon dispersion, and b) produce a maximum plasma concentration (Cmax) greater than 500 ng / mL, greater than 550 ng / mL, greater than 600 ng / mL, greater than 650 ng / mL, greater than 700 ng / mL, or greater than 750 ng / mL after administration. In some embodiments, the formulation may: a) form droplets with an initial diameter of about 375 nm to about 490 nm upon dispersion, and b) produce a maximum plasma concentration (Cmax) greater than 500 ng / mL, greater than 550 ng / mL, greater than 600 ng / mL, greater than 650 ng / mL, greater than 700 ng / mL, or greater than 750 ng / mL after administration. In some embodiments, the formulation may: a) form droplets with an initial diameter of about 429 nm upon dispersion, and b) produce a maximum plasma concentration (Cmax) greater than 500 ng / mL, greater than 550 ng / mL, greater than 600 ng / mL, greater than 650 ng / mL, greater than 700 ng / mL, or greater than 750 ng / mL after administration. In some embodiments, the formulation may: a) form droplets with an initial diameter of about 429 nm upon dispersion, and b) produce a maximum plasma concentration (Cmax) greater than 750 ng / mL after administration.

[0182] In some embodiments, the formulation can generate the area under the plasma concentration-time curve (AUC) from the time of administration (0h) to 8 hours later. 0-8 h These values ​​are approximately equal to, or at least as high as, or higher than, the values ​​produced by applying cannabinoid MCT. In some embodiments, the formulation may produce an AUC value after application similar to that produced by applying cannabinoid SO. 0-8 h Approximately equal, or at least the same or higher, AUC 0-8 h In some implementations, the AUC generated by the formulation after administration is... 0-8 h The value can be the AUC of cannabinoid MCT. 0-8 h The value is approximately 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, or 2.0 times. In some embodiments, the AUC generated after administration of the formulation is... 0-8 h The value can be the AUC of cannabinoid SO. 0-8 h The value is approximately 1.1 times, 1.2 times, 1.3 times, 1.4 times, or 1.5 times higher. In some embodiments, the AUC generated after administration of the formulation is... 0-8 h The value can be the AUC of cannabinoid MCT. 0-8 h The value is approximately 1.9 times higher. In some implementations, the AUC generated by the formulation after administration is... 0-8 h The value can be the AUC of cannabinoid SO. 0-8 h It is approximately 1.1 times the value.

[0183] In some embodiments, the formulation may have a time (Tmax) to reach maximum concentration in approximately 30 minutes, approximately 1 hour, approximately 1.25 hours, approximately 1.5 hours, approximately 1.75 hours, or approximately 2 hours after administration. max In some embodiments, the formulation may have a Tg period of approximately 1.75 hours after administration. max .

[0184] Unit dosage form and application

[0185] This disclosure provides formulations suitable for administering a wide range of cannabinoid dosages (optionally CBD dosages). In some embodiments, the formulations enable a higher loading of the cannabinoid active pharmaceutical ingredient, resulting in improved bioavailability and reduced pill or capsule size. Furthermore, the SEDDS formulations disclosed herein provide increased AUC concentrations compared to other formulations. The optimized formulations allow for more efficient and convenient administration of cannabinoid products, particularly for indications requiring a high therapeutic range. The formulations and unit dosage forms allow for the administration of higher doses of cannabinoids (e.g., CBD) than conventional formulations and unit dosage forms, including, for example, doses greater than 1000 ng, such as from about 1,000 mg to at least 3,000 mg, such as from about 1,500 mg to about 2,000 mg.

[0186] In some embodiments, a single dose of any formulation comprises about 10 mg to about 3,000 mg, about 20 mg to about 2,000 mg, about 30 mg to about 1,000 mg, about 40 mg to about 800 mg, or about 50 mg to about 600 mg of cannabinoids, optionally CBD. In some embodiments, a single dose of any formulation comprises about 100 mg to about 2,500 mg, about 500 mg to about 2,500 mg, about 1,000 mg to about 2,500 mg, about 1,500 mg to about 2,500 mg, about 500 mg to about 2,000 mg, about 1,000 mg to about 2,000 mg, or about 1,500 mg to about 2,000 mg of cannabinoids, such as CBD. In some implementations, a single dose (or unit dosage form) may contain cannabinoids, optionally CBD, in the range of about 50 mg to about 2,000 mg, about 500 mg to about 2,000 mg, about 1,000 mg to about 2,000 mg, or about 1,500 mg to about 2,000 mg, or about 50 mg to about 1,000 mg. In some embodiments, a single dose may contain about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,250 mg, about 1,500 mg, about 1,750 mg, about 2,000 mg, about 2,500 mg, or about 3,000 mg of cannabinoids, optionally CBD. In some embodiments, one, two, or three doses may be administered daily.

[0187] This disclosure provides unit dosage forms of cannabinoid preparations. In specific embodiments, the unit dosage forms are formulated for oral delivery, such as as a liquid or in tablets or capsules. In specific embodiments, the unit dosage form contains a therapeutically effective amount of the cannabinoid preparation, or two or more unit dosage forms together contain a therapeutically effective amount of the cannabinoid preparation. In some embodiments, each unit dosage form contains cannabinoids in the range of about 10 mg to about 3,000 mg, about 20 mg to about 2,000 mg, about 30 mg to about 1,000 mg, about 40 mg to about 800 mg, or about 50 mg to about 600 mg, optionally CBD. In some embodiments, the unit dosage form may contain cannabinoids in the range of about 50 mg to about 2,000 mg, about 500 mg to about 2,000 mg, about 1,000 mg to about 2,000 mg, or about 1,500 mg to about 2,000 mg, or about 50 mg to about 1,000 mg, optionally CBD. In some embodiments, any unit dosage form of the formulation contains about 100 mg to about 2,500 mg, about 500 mg to about 2,500 mg, about 1,000 mg to about 2,500 mg, about 1,500 mg to about 2,500 mg, about 500 mg to about 2,000 mg, about 1,000 mg to about 2,000 mg, or about 1,500 mg to about 2,000 mg of cannabinoids, such as CBD. In some embodiments, the unit dosage form may contain about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,250 mg, about 1,500 mg, about 1,750 mg, about 2,000 mg, about 2,500 mg, or about 3,000 mg of cannabinoids, optionally CBD. In some embodiments, two or more (e.g., two, three, or four) unit dosage forms together contain any of these total amounts of cannabinoids (e.g., CBD). In some implementations, the unit dose comprises a range of cannabinoids (e.g., CBD) formed from any two amounts disclosed herein, such as about 30 mg to about 300 mg.

[0188] In some embodiments, the disclosed cannabinoid formulation comprises at least about 250 mg of cannabinoid (e.g., CBD) per unit dosage form, and less than 1500 mg of total weight. In some embodiments, the disclosed cannabinoid formulation comprises at least about 300 mg of cannabinoid (e.g., CBD) per unit dosage form, and less than 1500 mg of total weight. In some embodiments, the disclosed cannabinoid formulation comprises at least about 400 mg of cannabinoid (e.g., CBD) per unit dosage form, and less than 1700 mg of total weight. In some embodiments, the disclosed cannabinoid formulation comprises at least about 500 mg of cannabinoid (e.g., CBD) per unit dosage form, and less than 2000 mg of total weight.

[0189] In some embodiments, this disclosure provides cannabinoid formulations that can be administered orally, for example, in soft or hard gelatin capsules, and form fine, relatively stable oil-in-water (o / w) emulsions, for example, upon aqueous dilution due to gentle agitation by gastrointestinal fluids. In specific embodiments, the unit dosage form is contained within a soft or hard gelatin capsule.

[0190] In some embodiments, this disclosure provides a capsule, such as a soft or hard gelatin capsule, comprising the disclosed cannabinoid preparation containing at least about 250 mg of cannabinoid (e.g., CBD) and less than 1500 mg of total weight. In some embodiments, the capsule comprising the disclosed cannabinoid preparation contains at least about 300 mg of cannabinoid (e.g., CBD) and less than 1500 mg of total weight. In some embodiments, the capsule comprising the disclosed cannabinoid preparation contains at least about 400 mg of cannabinoid (e.g., CBD) and less than 1700 mg of total weight. In some embodiments, the capsule comprising the disclosed cannabinoid preparation contains at least about 500 mg of cannabinoid (e.g., CBD) and less than 2000 mg of total weight. In a specific embodiment, the capsule comprises a gelatin cap or an outer gelatin layer.

[0191] This disclosure provides formulations and unit dosage forms suitable for daily administration of a wide range of cannabinoids (optionally CBD). In some embodiments, the cannabinoid formulation can be administered in amounts such as about 10 mg to about 3,000 mg of cannabinoid per day. In some embodiments, the cannabinoid formulation can be administered in amounts such as about 50 mg to about 2,000 mg of cannabinoid per day, or about 50 mg to about 1,000 mg of cannabinoid. In some embodiments, the cannabinoid formulation can be administered in amounts such as about 100 mg to about 2,500 mg, about 500 mg to about 2,500 mg, about 1,000 mg to about 2,500 mg, about 1,500 mg to about 2,500 mg, about 500 mg to about 2,000 mg, about 1,000 mg to about 2,000 mg, or about 1,500 mg to about 2,000 mg of cannabinoid (e.g., CBD) per day. In some embodiments, cannabinoid preparations may be administered in amounts such as about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,250 mg, about 1,500 mg, about 2,000 mg, about 2,500 mg, or about 3,000 mg of cannabinoids per day. In some embodiments, the dosage range of cannabinoids (e.g., CBD) formed from any two amounts disclosed herein is used, for example, from about 30 mg to about 300 mg.

[0192] In some embodiments of a method of treating a subject's illness or injury, wherein the illness or injury is a clinically high-risk psychosis, the cannabinoid preparation may be administered in doses such as about 600 mg to about 1,000 mg daily. In some embodiments of a method of treating a subject's illness or injury, wherein the illness or injury is insomnia, the cannabinoid preparation may be administered in doses such as 50 mg to 400 mg daily. In some embodiments of a method of treating a subject's illness or injury, wherein the illness or injury is generalized anxiety disorder, the cannabinoid preparation may be administered in doses such as 300 mg to 600 mg daily. In some embodiments of a method of treating a subject's illness or injury, wherein the illness or injury is panic disorder, the cannabinoid preparation may be administered in doses such as 300 mg to 600 mg daily. In some embodiments of a method of treating a subject's illness or injury, wherein the illness or injury is post-traumatic stress disorder, the cannabinoid preparation may be administered in a dose such as 100 mg to 600 mg daily. In some embodiments of a method of treating a subject's illness or injury, wherein the illness or injury is social anxiety disorder, the cannabinoid preparation may be administered in a dose such as 300 mg to 600 mg daily. In some embodiments of a method of treating a subject's illness or injury, wherein the illness or injury is first-episode psychosis, the cannabinoid preparation may be administered in a dose such as 600 mg to 1,000 mg daily. In some embodiments of a method of treating a subject's illness or injury, wherein the illness or injury is psychosis in Parkinson's disease, the cannabinoid preparation may be administered in a dose such as 300 mg to 1,500 mg daily. In some embodiments in which a cannabinoid preparation (optionally a CBD preparation) is administered in a method of treating a subject’s disease or injury, wherein the disease or injury is schizophrenia, the cannabinoid preparation may be administered in doses such as 600 mg to 1,500 mg per day.

[0193] This disclosure provides cannabinoid formulations that, upon oral administration, result in higher cannabinoid concentrations in the MLN than in the liver. In some embodiments, the formulation, upon oral administration, results in cannabinoid concentrations in the MLN that are substantially the same as those achieved with a cannabinoid sesame oil formulation. In some embodiments, the formulation, upon oral administration, results in lower cannabinoid concentrations in the spleen than in the MLN, brain, liver, or kidney. In some embodiments, the formulation, upon oral administration, results in cannabinoid concentrations in the MLN that are approximately 9 to approximately 14 times higher than in the spleen. In some embodiments, the formulation, upon oral administration, results in a tissue partition coefficient (Kp) in the MLN that is higher than that in the brain, liver, kidney, or spleen.

[0194] Effects of food on the pharmacokinetics of cannabinoid SEDDS formulations

[0195] This disclosure provides cannabinoid SEDDS formulations, optionally CBD SEDDS formulations, which are food-indeterminate to a measurable degree. Specifically, when administered with food, the formulation provides favorable pharmacokinetics for a period of up to 2 hours, up to 4 hours, or up to 8 hours or longer after food intake, or after fasting for at least 2 to 12 hours. In some embodiments, the formulation is administered at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, or at least about 10 hours after food intake and / or after fasting for up to about 2 hours before food intake. In some embodiments, food is not consumed until at least about 2 hours after administration of the formulation. In some embodiments, food is consumed about 2 hours before administration of the formulation. In some embodiments, the formulation is administered without food intake for at least 2 hours before and at least 2 hours after administration. In some embodiments, the formulation is administered without food intake for at least 4 hours before and at least 4 hours after administration. In some embodiments, after administration for at least 2 hours, 4 hours, 6 hours, 8 hours, or 10 hours after food ingestion, the cannabinoid Cmax produced by the disclosed cannabinoid SEDDS formulation is at least about 50% of the cannabinoid Cmax after oral administration of the formulation approximately simultaneously with food. In some embodiments, after administration for at least 2 hours, 4 hours, 6 hours, 8 hours, or 10 hours after food ingestion, and at least 2 hours before food ingestion, the cannabinoid AUC produced by the formulation is... ∞ AUC of cannabinoids after oral administration of the preparation at approximately the same time as food. ∞ At least about 50%.

[0196] Methods and treatments of applying cannabinoids

[0197] In some embodiments, the provided cannabinoid SEDDS formulation and unit dosage form may be used in methods for administering cannabinoids (optionally CBD) to a subject. In some embodiments, the formulation may be used to treat an illness or injury in a subject in need, which includes administering or providing the subject with a cannabinoid SEDDS formulation or one or more unit dosage forms. In some embodiments, the cannabinoid SEDDS formulation or unit dosage form is provided to the subject, whether the subject is fasting or not. In some embodiments, the subject has eaten or is eating at approximately the same time as the administration of the cannabinoid SEDDS formulation or one or more unit dosage forms. In some embodiments, the subject has eaten or is eating for at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, or at least about 10 hours prior to the administration of the cannabinoid SEDDS formulation or unit dosage form. In some embodiments, the cannabinoid SEDDS formulation or unit dosage form is administered to the subject approximately once daily, approximately twice daily, or approximately three times daily. In some implementations, subjects are administered cannabinoid SEDDS formulations or unit dosage forms for at least one or about one day, at least two or about two days, at least three or about three days, at least five days, at least one week, at least two weeks, at least one month, at least two months, at least four months, at least six months, at least one year, or longer.

[0198] In a specific embodiment, cannabinoids, optionally CBD, are administered orally to a subject in the form of three or fewer capsules (e.g., one or two capsules) comprising a formulation disclosed herein (e.g., as a SEDDS formulation), and in a specific embodiment, each capsule contains at least about 200 mg, at least about 250 mg, at least about 275 mg, at least about 300 mg, at least about 325 mg, at least about 350 mg, at least about 375 mg, at least about 400 mg, at least about 425 mg, at least about 450 mg, at least about 475 mg, or at least about 500 mg. In a specific embodiment, a total dose of about 400 mg to about 1500 mg (or about 600 mg to about 1000 mg) of cannabinoids, optionally CBD, is administered to the subject from three or fewer capsules.

[0199] In some embodiments, a dose of cannabinoids in a formulation disclosed herein (e.g., a SEDDS formulation) is administered orally to a subject in doses of up to about 1000 mg, up to about 200 mg, up to about 3000 mg, up to about 4000 mg, up to about 5000 mg, or up to about 6000 mg, such as in one or more capsules. In some embodiments, a dose range of cannabinoids (e.g., CBD) formed from any two amounts disclosed herein is administered, such as about 1000 mg to about 3000 mg.

[0200] In some embodiments, this disclosure provides a method for treating a disease or injury in a subject of need, the method comprising achieving a plasma AUC (e.g., AUC) sufficient to achieve at least 2000 ng·h / mL. 0-last or AUC 0-inf The amount of cannabinoid (e.g., CBD) SEDDS formulation or one or more unit dosage forms thereof is administered or provided to the subject. In some embodiments, the amount is sufficient to achieve a plasma AUC of about 2,000 ng·h / mL to about 3,000 ng·h / mL. In some embodiments, the amount is sufficient to achieve a plasma AUC of about 2,000 ng·h / mL to about 5,000 ng·h / mL.

[0201] In related embodiments, this disclosure provides a method for treating a disease or injury in a subject, the method comprising administering a cannabinoid, such as CBD, to the subject in an amount and form sufficient to achieve an AUC of at least 2,000 ng·h / mL (e.g., between about 2,000 ng·h / mL and about 4,000 ng·h / mL, between about 2,000 ng·h / mL and about 3,000 ng·h / mL, or between about 2,000 ng·h / mL and about 5,000 ng·h / mL).

[0202] In various embodiments of the treatments disclosed herein, the disease or injury is selected from the group including: high clinical risk of psychosis, insomnia, psychosis in the first episode, psychosis in Parkinson's disease, schizophrenia, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, Alzheimer's disease, postpartum psychosis, phobia of strange environments, acute stress disorder, and schizoaffective disorder. In some embodiments, the disease or injury is high clinical risk of psychosis. In some embodiments, the disease or injury is insomnia.

[0203] In various embodiments of the treatments disclosed herein, the disease or lesion is selected from the group including: generalized epilepsy, post-traumatic epilepsy, major depressive disorder, bipolar disorder, postpartum depression, endometriosis, premenstrual disorders, premenstrual anxiety disorders, menopausal mood changes, menopausal sleep disorders, menopausal cognitive changes, and obsessive-compulsive disorder. In some embodiments, the disease or lesion is selected from absence seizures, typical absence seizures, atypical absence seizures, atonic seizures, myoclonic seizures, infantile spasms (also known as West Syndrome), juvenile myoclonic epilepsy, and Lennox-Gastaut syndrome. Syndrome), progressive myoclonic epilepsy, tonic-clonic seizures, tonic seizures, clonic seizures, status epilepticus, focal perceptual impairment seizures, infantile myoclonic epilepsy, generalized epilepsy with febrile seizures, early infantile epileptic encephalopathy (also known as Ohtahara syndrome), early myoclonic encephalopathy, infantile epilepsy with migratory focal seizures, Dravet syndrome (also known as severe infantile myoclonic epilepsy), nodular epilepsy Sclerosis complex, refractory epilepsy, childhood absence epilepsy, myoclonic absence epilepsy, eyelid myoclonic epilepsy (also known as Jevons syndrome), epilepsy with myoclonic-atonic seizures (also known as myoclonic-atonic epilepsy or Doose syndrome), developmental / epileptic encephalopathy with sleep spike-and-wave activation (also known as sleep continuous spike-and-wave, sleep epileptic status epilepticus or Landau-Kleffner syndrome), febrile infection-associated epilepsy syndrome (FIRES), hemiconvulsion-hemiplegia-epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, isolated generalized tonic-clonic epilepsy, Rasmussen syndrome, progressive myoclonic epilepsy, Rett syndrome, CDKL5 deficiency, benign rolandicepilepsy, and refractory childhood epilepsy. In some implementations, the disease or injury is selected from Dravey syndrome, Lennox-Gasstor syndrome, tuberous sclerosis complex, refractory epilepsy, infantile spasms, CDKL5 deficiency, Aicardi syndrome, Dussen's syndrome, Dup15 syndrome, SYNGAP1 epileptic encephalopathy, drug-resistant focal seizures, Sturge-Weber syndrome, febrile infection-associated epilepsy syndrome, focal epilepsy, developmental and epileptic encephalopathy, and myoclonic absence epilepsy.

[0204] Example

[0205] Example 1: Composition of an oral self-emulsifying lipid formulation.

[0206] Four cannabinoid SEDDS formulations (i.e., A, B, C, and D) were developed (Figure 1), each containing 20% ​​w / w (CBD weight / total weight) (Table 1). SEDDS are isotropic mixtures of oils, surfactants, and / or co-solvents that spontaneously assemble into colloidal dispersions or emulsions when mixed with aqueous media, such as in a gastrointestinal environment. Self-emulsifying oily solutions are referred to as pre-concentrates.

[0207] A bulk mixture of drug-free preconcentrate was prepared by mixing the excipients at 45°C for 30 min while stirring at 300 rpm. A final preconcentrate was prepared by adding the drug-free preconcentrate to the CBD isolate to achieve a concentration of 20% w / w CBD. This mixture was stirred at 400 rpm and 45°C until completely homogeneous.

[0208] Each formulation contains Peceol and Gelucire 44 / 14 in a 50:50 (w / w) ratio. The formulations differ in the presence or absence of additional surfactants (TPGS) or co-solvents (anhydrous ethanol).

[0209] Table 1: Summary of Formulation Composition .

[0210]

[0211] Furthermore, a sesame oil formulation (CBD SO) was prepared based on a previous report (Kok, LY; Bannigan, P.; Sanaee, F.; Evans, JC; Dunne, M.; Regenold, M.; Ahmed, L.; Dubins, D.; Allen, C. Development and Pharmacokinetic Evaluation of a Self-Nanoemulsifying Drug Delivery System for the Oral Delivery of Cannabidiol. Eur. J. Pharm. Sci. 2022, 168, 106058. https: / / doi.org / 10.1016 / j.ejps.2021.106058). In short, the final composition of the formulation consisted of sucralose (0.05% w / w), strawberry flavoring (0.02% w / w), anhydrous ethanol (7.91% w / w), sesame oil (82.02% w / w), and CBD (10% w / w). Dissolve sucralose and strawberry flavoring in anhydrous ethanol and vortex for 20 seconds. Add sesame oil by gravimetric analysis and stir the solution at 250 rpm for 30 minutes. Then add the sesame oil solution to CBD to a concentration of 10% w / w and stir under the same conditions until completely homogeneous. Store CBD SO at room temperature away from direct light until further use.

[0212] The formulation of caprylic / capric triglyceride (CBDMCT) was prepared by adding oil to CBD to achieve a CBD concentration of 10% w / w. The MCT oil solution was stirred at 250 rpm until completely homogeneous and stored at room temperature away from direct light until further use.

[0213] Example 2: Characteristics and stability of cannabinoid SEDDS formulations

[0214] The CBD SEDDS formulations are characterized by droplet size and polydispersity index (PDI) measured by dynamic light scattering (DLS) (Zetasizer Nano ZS, Malvern Instruments Ltd, UK) at 37°C. The pre-concentrated product was dispersed in PBS (0.5% w / v) and stirred at 100 rpm and 37°C for 2 h. Upon mixing with PBS, the CBD SEDDS produced a milky, translucent dispersion with no visible signs of drug precipitation. The resulting droplet size was submicron, with initial diameters and PDI values ​​of approximately 400 nm and 0.40, 480 nm and 0.37, 430 nm and 0.30, and 460 nm and 0.25 for CBD SEDDS A, B, C, and D, respectively (Table 2).

[0215] Table 2: Summary of physicochemical properties and stability data of CBD SEDDS A, B, C, and D (mean ± SD). The pre-concentrated product (n=3) was stored under refrigeration (i.e., 3℃-5℃) and room temperature (i.e., 20℃-25℃) in the absence of light. Save for one month .

[0216]

[0217] The size of the dispersed droplets appeared to be directly related to the drug loading levels of the four formulations, with the blank formulation exhibiting a diameter approximately half that of the formulations studied (Figure 2). The dispersibility of the oil formulations (i.e., CBD SO, CBD MCT) was not evaluated because they were not found to disperse.

[0218] For a series of initially filtered dispersions (Figure 3A) and a selected unfiltered dispersion (Figure 3B), drug solubilization of formulations with different CBD contents was evaluated after dispersion in phosphate-buffered saline at 37°C (0.5% w / v) for 1 h. Formulations 1, 2, 3, and 4 correspond to CBD SEDDS A, CBD SEDDS B, CBD SEDDS C, and CBD SEDDS D. When loaded with 20% w / w CBD, formulations 1 and 3 in Figure 3B correspond to CBD SEDDS A and C, respectively. Formulation 2 in Figure 2B contains 45.6%:30.4%:4% w / w Peceol:Gelucire 44 / 14:TPGS, and formulation 4 in Figure 3B contains 48%:32% w / w Peceol:Gelucire 50 / 13. No dispersion showed significant drug precipitation. Filtering of dispersions was found to increase the variability of drug solubilization measurements, but the average solubilization was consistent with that of the unfiltered dispersions.

[0219] The stability of CBD SEDDS formulations in terms of dispersion profiles was evaluated under refrigerated and room temperature conditions. Storage of the preconcentrates under refrigerated or room temperature conditions for one month did not significantly alter droplet diameter or PDI (Table 2). After one month of storage at room temperature or under refrigerated conditions, the dispersion profiles of CBD SEDDS A, B, C, and D remained stable (Figure 4). After three months of storage at room temperature, the dispersion profiles of all four formulations were found to be stable (Figure 5).

[0220] The CBD content of the pre-concentrated products remained stable at room temperature for three months (Figure 6). Although all formulations maintained CBD concentrations within 10% of the initial measurements, lower overall variability was observed in the ethanol-containing formulations (CBD SEDDS B and D) compared to the formulations without co-solvents (CBD SEDDS A and C). The chemical stability of CBD in the SEDDS formulations was comparable to that in the sesame oil (SO) formulations (Figure 7).

[0221] Example 3: Dispersion of cannabinoid SEDDS formulation in simulated gastric juice

[0222] Evaluation of CBD SEDDS formulation dispersion in biologically relevant media: Fasting-state simulated gastric juice (FaSSGF), fasting-state simulated intestinal juice (FaSSIF), and fed-state simulated intestinal juice (FeSSIF) compared to phosphate-buffered saline (PBS). FaSSGF, FaSSIF, and FeSSIF are dissolution media that mimic human intestinal fluid. Each contains the same type and levels of surfactants (bile salts and phospholipids) present in the gastrointestinal fluids it replicates, as well as the same mean pH and similar osmolarity. Surfactants, pH, and osmolarity are important parameters to control when testing drugs or formulations. Surfactants form mixed micelles, which can significantly enhance drug solubility and dissolution. pH and osmolarity can affect drug solubility and dissolution. FaSSGF contains approximately 0.08 mM taurcholic acid, approximately 0.02 mM phospholipids, approximately 34 mM sodium, and approximately 59 mM chloride. FaSSIF contains approximately 3 mM taurine, approximately 0.75 mM phospholipid, approximately 148 mM sodium, approximately 106 mM chloride, and approximately 29 mM phosphate. FeSSIF contains approximately 15 mM taurine, approximately 3.75 mM phospholipid, approximately 319 mM sodium, approximately 203 mM chloride, and approximately 144 mM acetic acid. Powders and buffer concentrates of FaSSGF, FaSSIF, and FeSSIF were purchased from Biorelevant.com Ltd.

[0223] CBD SEDDS were dispersed (0.5% w / v) in a biorelevant medium (FaSSIF, FaSSGF, or FeSSIF) and stirred at 100 rpm and 37°C. At 5 min, 30 min, 60 min, and 120 min, 800 µL aliquots of the dispersion were taken and replenished with medium. The aliquots were diluted in methanol prior to HPLC analysis. All biorelevant media were prepared using buffer concentrates according to the supplier's information.

[0224] Different media effects were observed regarding the amount of CBD dissolved over the 2-hour period (Figure 8). Generally, the dispersion profiles of all formulations in FaSSIF appeared similar to those in PBS, with over 90% CBD dissolving during the study. For dispersions in FaSSGF, at least 90% of the CBD dissolved within 30 minutes for all formulations. From 1 hour onwards, the amount of CBD dissolved in all FaSSGF dispersions decreased but remained above 80% throughout the study. Conversely, the dispersion profiles in FeSSIF showed significantly lower amounts of dissolved CBD compared to dispersions in other biorelevant media. Based on the Fraser distance, the dispersions of CBD SEDDS A and C in FeSSIF were the least similar to any other formulation dispersed in any other medium (Figure 9A). Furthermore, the dispersions of CBD SEDDS A and C in FeSSIF showed significantly different areas under the curve (AUC) compared to the same formulation dispersed in FaSSIF (Figure 9B). These dispersions exhibited signs of paste formation, which became more pronounced at later time points in the study. The CBD SEDDS B and D dispersions in FeSSIF did not appear to show the same signs of paste formation.

[0225] Example 4: In vitro digestion of cannabinoid SEDDS formulations

[0226] For CBD SEDDS C and D, the handling of CBD 30 minutes after in vitro digestion was evaluated (Figure 10).

[0227] In summary, a dispersion of the selected CBD SEDDS (2.5% w / v) was prepared in 40 mL FaSSIF. Throughout the study, the medium was stirred at 100 rpm and 37 °C. The dispersion was stirred for 10 min, then pancreatic lipase (667 mg) was added to initiate digestion. After 30 min of digestion, 800 µL of the medium was aliquoted and separated into three layers by centrifugation (20, 800 × g, 15 min): a top layer (oil phase), a middle layer (aqueous micelle phase), and a bottom layer (precipitate phase). After dilution in methanol, the CBD content from each phase was analyzed by HPLC.

[0228] For CBD SEDDS C, CBD was distributed in the oil, aqueous, and precipitate phases at concentrations of 62% ± 6%, 23% ± 5%, and 15% ± 6%, respectively. The amounts of CBD recovered from the oil, aqueous, and precipitate phases of CBD SEDDS D were 72% ± 2%, 19% ± 1%, and 9% ± 2%, respectively. Generally, both formulations exhibited minimal precipitation. No precipitate phase was found in either formulation from the initial 10-minute dispersion (i.e., prior to digestion). Before the addition of pancreatic lipase, the aqueous phase of CBD SEDDS C contained significantly more CBD than that of CBD SEDDS D (p < 0.01), approximately 47% ± 4% and 24% ± 1%, respectively.

[0229] Example 5: In vivo pharmacokinetic parameters of cannabinoid preparations

[0230] The pharmacokinetics of CBD SEDDS C and CBD SEDDS D were evaluated after oral administration to rats at a dose of 20 mg / kg and compared with those of CBD MCT and SO (Figure 11).

[0231] For pharmacokinetic studies, rats were administered CBD medium-chain triglyceride oil (CBD MCT), CBD sesame oil medium (CBD SO), or one of two self-emulsifying drug delivery systems (i.e., CBD SEDDS C or CBD SEDDS D) via oral gavage at a dose of 20 mg / kg CBD (n=5 / formulation group). The SEDDS formulation was freshly prepared 30 min prior to each experiment by pre-diluting the pre-concentrate in deionized water (1:20 w / v) and then vortexing for 20 seconds. Blood samples (200 µL) were collected via the lateral saphenous vein at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, and 6 h (1.5 h and 3 h for the CBD MCT group) after administration to heparinized tubes. Eight h after administration, rats were euthanized by cardiac puncture and blood samples were collected, followed by decapitation. Blood samples collected during the study were centrifuged (1000 × g, 10 min, 4 °C; 15 min for terminal samples) to obtain plasma. The plasma was transferred to microcentrifuge tubes and stored at -80 °C for further analysis.

[0232] In subsequent pharmacokinetic and tissue distribution studies, rats in cohort 2 were administered CBD SO, CBD SEDDS C, and CBD SEDDS D formulations (n=5 / formulation group) to induce homing within a window near the expected maximum plasma concentration. In this study, blood samples were collected and stored at 0.5 h, 1 h, 1.5 h, 2 h, and 3 h in the same manner as before, with terminal blood collection performed 4 h after formulation administration.

[0233] A plasma aliquot (50 µL) was added to a microcentrifuge tube containing 2 µL of internal standard (THC; 100 µg / mL, in methanol), which was pre-dried under nitrogen evaporation (Glas-Col ZipVap, Terre Haute, IN, USA). 450 µL of acetonitrile:ethyl acetate (50:50 v / v) was added to each tube, vortexed for 10 min, and centrifuged (15,300 × g, 10 min, 4 °C). The supernatant (400 µL) was transferred to an autosampler vial and dried under nitrogen at 37 °C. The sample was then reconstituted in 150 µL of methanol, vortexed, centrifuged again under the same conditions, and transferred to an autosampler vial insert for subsequent analysis by HPLC-MS / MS.

[0234] Plasma concentration-time curves revealed comparable performance among the CBD SO, CBD SEDDS C, and CBD SEDDS D formulations, with each formulation showing significantly higher absorption and slower elimination compared to CBD MCT (Figure 12). Table 3 summarizes the corresponding pharmacokinetic parameters. No statistically significant differences were obtained between CBD SO or CBD MCT and any of the SEDDS formulations.

[0235] Table 3: Pharmacokinetic parameters. Data are expressed as mean ± SEM, n≥5. Tmax is expressed as median and range. .

[0236]

[0237] Although not statistically significant, the C-C from CBD SO, CBD SEDDS C, and CBD SEDDS D... max And systemic exposure is slightly higher than CBD MCT. The corresponding C values ​​for CBD SO, CBD SEDDS C, and CBD SEDDS D are... max C for CBD MCT max 1.5 times, 1.7 times, and 1.8 times. Regarding AUC 0-8 h In terms of values, CBD SO, CBD SEDDS C, and CBD SEDDS D are 1.8, 1.9, and 1.7 times that of CBD MCT, respectively. The median T values ​​for CBD SO and CBD SEDDS D are... max The median T of CBD SEDDS C is 1h. max The median T of CBD MCT is 1.75h. max It takes 1.5 hours. (Figures 13A to 13D). CBD SEDDS C and D of C max-The AUC values ​​were slightly higher than those for CBD SO. Within 8 hours of oral administration, the observed total exposure fractions were approximately 73% for CBD SEDDS C and 72% for CBD SEDDS D, while CBD SO and CBD MCT achieved 80% and 89% of their total exposures, respectively, within the same time period. Notably, lower variability was observed for CBD SEDDS and CBD MCT (Figures 14 and 15).

[0238] Example 6: Tissue distribution after oral administration of cannabinoid SEDDS formulation

[0239] Four hours after oral administration of 20 mg / kg of CBD in CBD SO, CBD SEDDSC, or CBD SEDDS D to rats in the second cohort described in Example 5, the distribution of CBD in the brain, liver, kidney, spleen, and MLN was assessed (Figure 16).

[0240] After bleeding, collect tissues as quickly as possible (i.e., brain, liver, kidney, spleen, and mesenteric lymph nodes (MLN)), rinse with PBS, and rapidly freeze in dry ice. Store the tissues at -80°C for further analysis. Weigh the tissue samples (approximately 100-250 mg) in glass vials and homogenize with PBS (1:4 w / v; 1:6 w / v for MLN) at 12,000 rpm for 5 min (Polytron). ® PT 2500 E, Kinematica AG, Luzern, Switzerland. The homogenate (150 µL; 30 µL for MLN) was transferred to a microcentrifuge tube pre-dried under nitrogen containing 2 µL of internal standard (THC; 100 µg / mL, in methanol), and 1.35 mL (270 µL for MLN) of acetonitrile:ethyl acetate (50:50 v / v) was added. The mixture was vortexed for 10 min and sonicated at room temperature for 10 min, then centrifuged (15,300 × g, 10 min, 4 °C). The supernatant (1.4 mL; 250 µL for MLN) was transferred to an autosampler vial and dried under nitrogen at 37 °C. The sample was then reconstituted in 150 µL of methanol, vortexed, centrifuged again under the same conditions, and transferred to an autosampler vial insert for subsequent analysis by HPLC-MS / MS.

[0241] For all formulations, the highest concentration of CBD was found in the MLN, approximately twice the level in the liver. CBD SO resulted in significantly higher CBD concentrations in the MLN compared to CBD SEDDS D (p<0.05), but not compared to CBD SEDDS C. The lowest CBD concentrations were found in the spleen for all formulations. MLN concentrations were 11.4 times higher for CBD SO, 13.2 times higher for CBD SEDDS C, and 9.5 times higher for CBD SEDDS D compared to the spleen.

[0242] The tissue partition coefficient values ​​were calculated as the ratio between the CBD concentration in each tissue and the corresponding plasma concentration at 4 hours (Table 4). For each formulation, MLN had the largest tissue partition coefficient. These findings confirm that, in lipid formulations containing LCT, lymphatic uptake of cannabinoids plays a significant role in their absorption following oral administration. Furthermore, these findings highlight that SO as a delivery medium is not essential for achieving the desired absorption effect with SEDDS formulations.

[0243] Table 4. Summary of organizational allocation coefficients. Data are expressed as mean ± SEM, n=5. The allocation coefficient values ​​(Kp) are calculated. The ratio between CBD concentration in each tissue and the corresponding plasma concentration at 4 hours .

[0244]

[0245] Example 7: Pharmacokinetic parameters of cannabinoid SEDDS formulations in fasted animals

[0246] The pharmacokinetics of CBD SEDDS C were evaluated in fasted and non-fasted Sprague-Dawley rats after oral administration at a dose of 20 mg / kg (Figures 17 and 18). Plasma concentration-time curves revealed that plasma CBD levels reached a higher peak in non-fasted animals compared to fasted animals. Table 5 summarizes the corresponding pharmacokinetic parameters. CBD C in non-fasted animals max The AUC in non-fasted animals was approximately 1.5 times higher than that in animals exposed to the whole body and 1.75 times higher than that in animals exposed to the whole body. 0-8 h The value is approximately 1.6 times, and the median T for non-prohibited animals is... max The median T for fasted animals is 1.75 hours. max The exposure time was 1 hour. Within 8 hours of oral administration, the observed total exposure fraction was approximately 73% for non-fasting animals and 92% for fasting animals.

[0247] Table 5. Pharmacokinetic parameters. Data are expressed as mean ± SEM (n≥5). Tmax is expressed as median and range. .

[0248]

[0249] Example 8: In vivo pharmacokinetic parameters of cannabinoid preparations

[0250] The increased bioavailability of the CBD SEDDS formulation compared to other CBD formulations was examined. Following the study design shown in Figure 19, the pharmacokinetics of the CBD SEDDS formulation (encapsulated micellar cannabidiol (EMCBD)) was evaluated after oral administration to fed or fasted rats at a dose of 20 mg / kg, and compared with the pharmacokinetics of cannabidiol active pharmaceutical ingredient (CBD API) and sesame oil (SO) formulations.

[0251] For groups 1 and 4 (CBD API), 121.8 mg of CBD isolate sample was combined with an appropriate amount of mediator consisting of 40% HPBCD. For groups 2 and 5 (EMCBD; SEDDS formulations), pre-drug concentrates (PDCs) were prepared as follows: 1 g each of Peceol and Gelucire were added to a vial, and the mixture was heated to 45°C for 30 minutes while stirring at 300 rpm. The final pre-concentrate was prepared by adding 1.00 g of drug-free PDC to 0.470 g of CBD isolate to achieve a concentration of 32% w / w. The mixture was stirred at 400 rpm and 45°C until completely homogeneous. The SEDDS formulations were then freshly prepared by pre-diluting the pre-concentrate in 30 mL of deionized water (1:80 w / v, e.g., 0.25 of the 32% w / w pre-concentrate in 20 mL of water) and then vortexing for 20 seconds. For groups 3 and 6 (CBD SO), approximately 0.005 g of sucralose and 0.002 g of strawberry flavoring were dissolved in 1 mL of anhydrous ethanol and vortexed for approximately 20 seconds. Approximately 8.92 mL of sesame oil was added by gravimetric analysis, and the product was stirred at 250 rpm for 30 minutes. The sesame oil mixture was then added to 0.330 g of the CBD isolate to achieve a concentration of 10% w / w, and stirred under the same conditions until completely homogeneous. The concentration of the CBD isolate in the administered solution was determined by LC-MS / MS.

[0252] Female Sprague-Dawley rats aged 52–61 days were administered 20 mg / kg CBD (n=8 / formulation group). Blood was collected from the jugular vein at 0.5 h, 1 h, 2 h, 3 h, 4 h, 8 h, and 24 h post-administration. Plasma samples were obtained after centrifugation and frozen until plasma concentrations of CBD were determined by LC-MS / MS. Non-compartmental pharmacokinetic analysis of the plasma concentrations of CBD isolates in rats was performed using PhoenixWinNonlin software (version 8.3, Certara USA, Inc). Nominal times were used for PK parameter calculations. Peak plasma concentration (Cmax) and the corresponding time to peak (Tmax) were determined directly from the plasma concentration versus time curve. Individual plasma concentrations in PO-administered animals below the lower limit of quantitation (LLOQ) before Tmax were set to zero, and those after Tmax were excluded from the PK parameter calculations. The terminal half-life (T1 / 2) and the area under the plasma concentration-time curve (AUC) from time zero to the final quantifiable concentration were calculated using the linear-up-log-down rule. 0-last ) and AUC extrapolated from time zero to infinity (AUC 0-inf The mean residence time (MRT) from time zero to the last quantifiable concentration (MRT0-last) and the mean residence time from time zero to infinity (MRT0-inf) were also included. All plasma concentrations and p-values ​​were reported with at least three significant figures. The treatment / food pair Cmax and AUC were estimated using a one-way ANOVA model with food treatment as a fixed factor and the in-transformed analytical values ​​as the dependent variable. 0-last The impact.

[0253] The average values ​​of the key PK parameters are summarized in Figure 20. Figures 21 through 25 provide a graphical representation of the average values ​​of the key PK parameters obtained from fed or fasted animals after administration of different CBD formulations.

[0254] Based on Cmax and AUC 0-last Following fasting administration, the CBD bioavailability of the SEDDS formulation (EMCBD) was higher than that of the HPBCD formulation (CBD API), and even higher after administration with food (Figures 21 and 24). Following fasting administration, the CBD AUC of the SEDDS formulation... 0-last It also has a higher CBD AUC than SO formulations (CBD WO). 0-lastFurthermore, the Cmax was even higher after administration with food (Figure 24). After administration with fasting, the Cmax of the SEDDS formulation was lower than that of the SO formulation, while after administration with food, the Cmax of the SEDDS formulation was higher than that of the SO formulation (Figure 21). The CBD bioavailability of the SEDDS formulation increased with food intake, while the slight food effects of the HPBCD and SO formulations were not significant relative to the observed inter-animal PK variability. These results demonstrate the excellent bioavailability of the CBD SEDDS formulation, which is enhanced by food intake.

[0255] All publications, U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, and foreign patent applications mentioned herein and / or listed in the application data sheet are incorporated herein by reference to disclose and describe methods and / or materials in connection with the cited publications. It should be understood that, in the event of any conflict, this disclosure supersedes any disclosure incorporated herein.

[0256] As stated above, although specific embodiments of the invention have been described herein for illustrative purposes, various modifications may be made without departing from the spirit and scope of the invention. Therefore, the invention is not limited.

Claims

1. A cannabinoid preparation comprising: cannabinoid; one or more fatty acid glycerides; and one or more fatty acid esters containing polyethylene glycol.

2. The formulation according to claim 1, wherein the cannabinoid is cannabidiol.

3. The formulation according to claim 1 or claim 2, wherein the cannabinoid is present in the formulation in an amount greater than about 5% by weight.

4. The formulation according to any one of claims 1 to 3, wherein the cannabinoid is present in the formulation in an amount of about 10% by weight to about 50% by weight.

5. The formulation according to any one of claims 1 to 4, wherein the cannabinoid is present in the formulation at about 20% by weight.

6. The formulation according to any one of claims 1 to 4, wherein the cannabinoid is present in the formulation at about 40% by weight.

7. The formulation according to any one of claims 1 to 6, wherein the ratio of the one or more fatty acid glycerides to the one or more polyethylene glycol-containing fatty acid esters is in the range of about 30:70 to about 70:

30.

8. The formulation according to any one of claims 1 to 7, wherein the one or more fatty acid glycerides include oleic acid glyceride (Peceol).

9. The formulation according to any one of claims 1 to 8, wherein the one or more polyethylene glycol-containing fatty acid esters comprises one or more of the following: lauroyl polyoxyglyceride (Gelucire 44 / 14), GELUCIRE ® 48 / 16, GELUCIRE ® 50 / 13, GELUCIRE ® 59 / 14 and Labrasol ALF.

10. The formulation according to any one of claims 7 to 9, wherein the fatty acid glyceride and the polyethylene glycol-containing fatty acid ester are each present in the formulation in an amount of about 30% to about 60% by weight.

11. The formulation of claim 10, wherein the fatty acid glyceride and the polyethylene glycol-containing fatty acid ester are each present in the formulation in an amount of about 39% by weight to about 41% by weight.

12. The formulation according to claim 11, wherein the fatty acid glyceride and the polyethylene glycol-containing fatty acid ester are each present in the formulation at about 40% by weight.

13. The formulation of claim 10, wherein the fatty acid glyceride and the polyethylene glycol-containing fatty acid ester are each present in the formulation at about 36.4% by weight, and wherein ethanol is present in the formulation at about 7.2% by weight.

14. The formulation of claim 10, wherein D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) is present in the formulation in an amount of about 3% to about 4% by weight.

15. The formulation of claim 14, wherein the fatty acid glyceride and the polyethylene glycol-containing fatty acid ester are each present in the formulation at about 38% by weight, and wherein TPGS is present in the formulation at about 4% by weight.

16. The formulation of claim 14, wherein the fatty acid glyceride and the polyethylene glycol-containing fatty acid ester are each present in the formulation at about 34.58% by weight, and wherein TPGS are present in the formulation at about 3.64% by weight, and wherein ethanol is present in the formulation at about 7.2% by weight.

17. The formulation according to any one of claims 9 to 16, wherein the polyethylene glycol-containing fatty acid ester comprises lauroyl polyoxyglyceride (Gelucire 44 / 14).

18. The formulation according to any one of claims 1 to 17, wherein the formulation comprises one or more antioxidants.

19. The formulation of claim 18, wherein one or more antioxidants comprise butylated hydroxytoluene (BHT).

20. The formulation according to any one of claims 1 to 19, wherein a single dose of the formulation comprises at least 50 mg of the cannabinoid.

21. The formulation of claim 20, wherein a single dose of the formulation comprises the cannabinoid in the range of about 50 mg to about 2,000 mg.

22. The formulation of claim 21, wherein a single dose comprises about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1250 mg, or about 1500 mg of the cannabinoid.

23. The formulation of claim 22, wherein a single dose comprises about 100 mg of the cannabinoid.

24. The formulation of claim 22, wherein a single dose comprises about 300 mg of the cannabinoid.

25. The formulation of claim 22, wherein a single dose comprises about 600 mg of the cannabinoid.

26. The formulation of claim 22, wherein a single dose comprises about 1,000 mg of the cannabinoid.

27. The formulation according to any one of claims 1 to 26, wherein the formulation is administered in a method of treating a disease or injury of a subject, wherein the formulation is administered in an amount such as an amount of about 50 mg to about 3,000 mg of the cannabinoid administered daily.

28. The formulation of claim 27, wherein the formulation is administered in a method of treating a subject’s disease or injury, wherein the formulation is administered in an amount of the cannabinoid such as about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,250 mg, about 1,500 mg, about 2,000 mg, about 2,500 mg, or about 3,000 mg per day.

29. The formulation of claim 28, wherein the formulation is administered in a method of treating a disease or injury of a subject, wherein the formulation is administered in an amount such as about 100 mg of the cannabinoid administered daily.

30. The formulation of claim 28, wherein the formulation is administered in a method of treating a disease or injury of a subject, wherein the formulation is administered in an amount such as about 300 mg of the cannabinoid administered daily.

31. The formulation of claim 28, wherein the formulation is administered in a method of treating a disease or injury of a subject, wherein the formulation is administered in an amount such as about 600 mg of the cannabinoid administered daily.

32. The formulation of claim 28, wherein the formulation is administered in a method of treating a disease or injury of a subject, wherein the formulation is administered in an amount such as about 1,000 mg of the cannabinoid administered daily.

33. The formulation according to any one of claims 1 to 32, wherein the formulation is formulated for oral administration.

34. The formulation according to any one of claims 1 to 33, wherein the formulation is a self-emulsifying drug delivery system.

35. The formulation according to any one of claims 1 to 34, wherein the formulation does not contain sesame oil or ethanol.

36. The formulation according to any one of claims 1 to 35, wherein after being stored at room temperature for up to three months, the cannabinoid concentration is maintained at an amount greater than about 80% of the initial concentration.

37. The formulation according to any one of claims 1 to 36, wherein the Cmax of the cannabinoid after oral administration of the formulation is at least approximately equal to the Cmax after oral administration of the cannabinoid sesame oil formulation.

38. The formulation according to any one of claims 1 to 37, wherein the systemic exposure (AUC) of cannabinoids after oral administration of the formulation is [missing information]. ∞ It is at least approximately equal to the systemic exposure following oral administration of cannabinoid sesame oil preparations.

39. The formulation according to any one of claims 1 to 38, wherein the Cmax of the cannabinoid after oral administration of the formulation for at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, or at least about 10 hours after ingestion of food, and at least about 2 hours before ingestion of food, is at least about 50% of the Cmax after oral administration of the formulation approximately at the same time as food.

40. The formulation according to any one of claims 1 to 39, wherein the systemic exposure (AUC) of cannabinoids after oral administration of the formulation is measured up to at least about 2 hours, up to at least about 4 hours, up to at least about 6 hours, up to at least about 8 hours, or up to at least about 10 hours after food ingestion and up to at least about 2 hours before food ingestion. ∞ () is at least about 50% of the systemic exposure following oral administration of the preparation at approximately the same time as food.

41. A formulation comprising more than about 5% by weight of cannabinoids.

42. The formulation according to claim 41, wherein the formulation comprises about 10% by weight to about 50% by weight of cannabinoids.

43. The formulation according to claim 42, wherein the formulation comprises about 20% by weight of cannabinoids.

44. The formulation according to claim 42, wherein the formulation comprises about 40% by weight of cannabinoids.

45. A capsule comprising the formulation according to any one of claims 1 to 44.

46. ​​The capsule of claim 45, wherein the capsule is a soft gel capsule.

47. A method for administering cannabinoids to a subject, the method comprising administering a formulation according to any one of claims 1 to 44 or a capsule according to claim 45 or claim 46.

48. A method of treating a disease or injury in a subject in need, the method comprising administering to the subject a formulation according to any one of claims 1 to 44 or a capsule according to claim 45 or claim 46.

49. The method of claim 48, wherein the disease or injury is selected from the group consisting of: high clinical risk of psychosis, insomnia, psychosis in the first episode, psychosis in Parkinson's disease, schizophrenia, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, Alzheimer's disease, postpartum psychosis, phobia of unfamiliar environments, acute stress disorder, and schizoaffective disorder.

50. The method of claim 49, wherein the disease or injury is of high clinical risk for mental illness.

51. The method of claim 50, wherein the method comprises administering the formulation of claim 12 to the subject.

52. The method of claim 49, wherein the disease or injury is insomnia.

53. The method of claim 52, wherein the method comprises administering the formulation of claim 12 to the subject.

Images