Oral formulations of cannabinoids

Abstract

The present disclosure provides formulations of cannabinoid with advantages such as high drug-loading and stability, and related methods of manufacturing and using the formulations.

Description

ORAL FORMULATIONS OF CANNABINOIDSCROSS REFERENCE TO RELATED APPLICATIONS

[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 in its entirety for all purposes.FIELD OF THE INVENTION

[0002] The present invention relates to formulations of cannabinoids and methods of use thereof.BACKGROUND

[0003] It is well-known that oral drug administration is often preferred, as it presents the most convenient and typically least expensive route for patients, lending to improved compliance. These benefits translate to a high demand, reflected in the number of drugs approved for oral administration. Despite the advantages of oral delivery, drug suitability for this route remains a growing challenge. It has been noted that an increasing number of compounds in the pharmaceutical development pipeline have poor solubility and / or permeability properties. Without adequate formulation of these compounds, their translational potential is diminished by poor and variable oral bioavailability.

[0004] Many cannabinoids, which are natural and synthetic compounds structurally or pharmacologically related to the constituents of the cannabis plant or the endogenous agonists (endocannabinoids) of the cannabinoid receptors CB1 or CB2, face such formulation challenges. Cannabinoids present in cannabis plants include over 100 natural cannabinoids including tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), as well as cannabidiol-like compounds Cannabidiolic acid (CBDA), Cannabidivarin (CBDV), Cannabidivarin acid (CBDVA), Cannabidiol-Cl (CBD-C1), Cannabidiol-C4 (CBD-C4) and Cannabidiol monomethyl ether (CBDM). Cannabidiol (CBD), one of the main cannabinoids from the Cannabis plant, represents one suchcompound. As a highly lipophilic drug (logP ~ 6) with low water solubility (estimated to be < 13 pg / mL), and subject to extensive first-pass metabolism, CBD has an oral bioavailability around 6%. Formally, CBD is categorized as a Biopharmaceutical Classification System (BCS) class II compound due to its low aqueous solubility and high intestinal permeability. Therefore, strategies that can improve the dissolution or dispersion rate of CBD would increase its bioavailability. Given the physicochemical properties of CBD, lipid-based formulations have experienced the most resounding success.

[0005] To date, the only FDA-approved CBD formulation is Epidiolex®, a sesame oilbased solution indicated for the treatment of rare childhood epilepsies and tuberous sclerosis complex. However, sesame oil formulations are limited by varying absorption, patient allergies, limited drug loading, and poor stability. In addition, Epidiolex ® includes ethanol, which presents disadvantages for use in certain patient populations. Once opened, Epidiolex® must be used completely within 12 weeks; this limited life increases the cost of approved treatments. Consequently, there is a need for formulations that can improve the absorption of CBD without relying on sesame oil, with its concomitant disadvantages, as an excipient.SUMMARY

[0006] The present disclosure provides compositions for formulating therapeutic agents. The compositions are effective for solubilizing therapeutic agents, particularly difficult-to-solubilize therapeutic agents.

[0007] In some embodiments, the present disclosure provides a cannabinoid formulation, comprising: a cannabinoid; one or more fatty acid glycerol esters; and one or more polyethylene gly col-containing fatty acid esters.

[0008] In some embodiments, the cannabinoid is cannabidiol.

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

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

[0011] In some embodiments, the fatty acid glycerol esters and polyethylene glycol- containing fatty acid esters are each present in the formulation in an amount from about 30% to about 60% by weight. In some embodiments, the fatty acid glycerol esters and polyethylene glycol-containing fatty acid esters are each present in the formulation in an amount from about 39% to about 41% by weight. In some embodiments, the fatty acid glycerol esters and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 40% by weight. In some embodiments, the fatty acid glycerol esters and polyethylene glycol-containing fatty acid esters 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-a-tocopherol polyethylene glycol 1000 succinate (TPGS) is present in the formulation in an amount from about 3% to about 4% by weight. In some embodiments, the fatty acid glycerol esters and polyethylene glycol- containing fatty acid esters are each present in the formulation at about 38% by weight, and wherein TPGS is present in the formulation at about 4% by weight. In some embodiments, the fatty acid glycerol esters and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 34.58% by weight, and wherein TPGS is present in the formulation at about 3.64% by weight, and wherein ethanol is present in the formulation at about 7.2% by weight.

[0013] In some embodiments, the polyethylene glycol-containing fatty acid esters comprise lauroyl polyoxylglycerides (Gelucire 44 / 14).

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

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

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

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

[0018] In some embodiments, the cannabinoid concentration is maintained at an amount greater than about 80% of the starting concentration, after storage at room temperature for up to three months. In some embodiments, the Cmax of cannabinoid following oral administration of the formulation is at least about equivalent to that following oral administration of a cannabinoid sesame oil formulation. In some embodiments, the systemic exposure (AUCoo) of cannabinoid following oral administration of the formulation is at least about equivalent to that following oral administration of a cannabinoid sesame oil formulation.

[0019] In some embodiments, the Cmax of cannabinoid following oral administration of the formulation 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 ingestion of food and up to at least about 2 hours prior to ingestion of food is at least about 50% of that following oral administration of the formulation at about the same time as food. In some embodiments, the systemic exposure (AUCo-°°) of cannabinoid following oral administration of the formulation 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 ingestion of food and up to at least about 2 hours prior to ingestion of food is at least about 50% of that following oral administration of the formulation at about the same time as food.

[0020] In some embodiments, the present disclosure provides a formulation comprising greater than about 5% cannabinoid by weight. In some embodiments, the formulation comprises about 10% to about 50% cannabinoid by weight. In some embodiments, the formulation comprises about 20% cannabinoid by weight. In some embodiments, the formulation comprises about 40% cannabinoid by weight.

[0021] In some embodiments, the present disclosure provides a capsule comprising any of the formulations disclosed herein. In some embodiments, the capsule is a soft-gel capsule.

[0022] In some embodiments, the present disclosure provides a method for administering cannabinoid to a subject, comprising administering any of the formulations disclosed herein or any of the capsules disclosed herein.

[0023] In some embodiments, the present disclosure provides a method of treating a disease or injury in a subject in need thereof, 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 comprising Clinical High Risk of Psychosis, insomnia, first episode psychosis, psychosis in Parkinson’s disease, schizophrenia, general anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, Alzheimer’s disease, postpartum psychosis, agoraphobia, acute stress disorder, and schizoaffective disorder. In some embodiments, the disease or injury is Clinical High Risk of Psychosis. In some embodiments wherein the disease or injury is Clinical High Risk of Psychosis, the method comprises administering a formulation comprising: a cannabinoid; one or more fatty acid glycerol esters; and one or more polyethylene glycol-containing fatty acid esters; wherein the fatty acid glycerol esters and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 40% by weight. In some embodiments, the disease or injury is insomnia. In some embodiments wherein the disease or injury is insomnia, the method comprises administering a formulation comprising: a cannabinoid; one or more fatty acid glycerol esters; and one or more polyethylene glycol-containing fatty acid esters; wherein the fatty acid glycerol esters and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 40% by weight.BRIEF DESCRIPTION OF THE DRAWINGS

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

[0026] FIG. 2. Bar chart of droplet diameter (mean ± SD) for SEDDS formulations with varying concentrations of CBD. All formulations were dispersed in phosphate buffered saline (0.5% w / v), and the resulting droplet size was measured following 2 h of stirring at 100 rpm and 37 °C. Average poly dispersity index values were < 0.5 for the various formulations.

[0027] FIGs. 3A and 3B. Drug solubilization for SEDDS formulations with varying CBD content following dispersion (0.5% w / v) for 1 h at 37 °C in phosphate buffered saline for a series of preliminary filtered dispersions (FIG. 3A) and selected unfiltered dispersions (FIG. 3B). Formulations 1 and 3 correspond to CBD SEDDS A and C, respectively, when loaded at 20% w / w CBD. None of the dispersions exhibited noticeable drug precipitation. Filtering dispersions was found to increase variability ofthe drug solubilization measurements, but the average solubilization was consistent with unfiltered dispersions.

[0028] FIG. 4. Dispersion profiles of CBD SEDDS A, B, C, and D (mean ± SD) following storage at room temperature (i.e., 20-25 °C) and under refrigerated conditions in the absence of light, for 0, 14, or 30 days. Preconcentrates (n = 3) were dispersed at 0.5% w / v in PBS on each day.

[0029] FIG. 5. Dispersion profiles of CBD SEDDS A, B, C, and D (mean ± SD) following storage at room temperature (i.e., 20-25 °C) in the absence of light, over the course of three months. Preconcentrates (n = 3) were dispersed at 0.5% w / v in PBS on each day.

[0030] FIG. 6. CBD drug content (mean ± SD) in CBD SEDDS A, B, C, and D preconcentrates (n = 3) under storage at room temperature (i.e., 20-25 °C) in the absence of light, over the course of three months. Values are scaled to the CBD content at the initial time point. For each timepoint, the bars from left to right correspond to the legend from top to bottom.

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

[0032] FIG. 8. Dispersion profiles of CBD SEDDS A, B, C, and D (mean ± SD) in fasted state simulated gastric fluid (FaSSGF), fasted state simulated intestinal fluid (FaSSIF), fed state simulated intestinal fluid (FeSSIF), and phosphate buffered saline (PBS). Preconcentrates (n = 3) were dispersed at 0.5% w / v in each respective medium. For each formulation, at the 60 minute timepoint, the circles from top to bottom correlate to FASSIF, PBS, FaSSGF, and FeSSIF.

[0033] FIGs. 9A and 9B. Heatmap of Frechet distance values (FIG. 9A) and bar plot of scaled area under the curve (AUC) values (mean ± SD) (FIG. 9B) for dispersion profiles of each CBD SEDDS formulation (i.e., A, B, C, D) in various media (i.e., FaSSGF, FaSSIF, FeSSIF, PBS). Statistical analysis was performed using an aligned ranked transform two-way ANOVA with Tukey’s post hoc comparison test. Statistical differences compared to CBD SEDDS C dispersed in FaSSIF; * p < 0.05; *** p < 0.001. Statistical differences compared to CBD SEDDS A dispersed in FaSSIF; * p < 0.05.

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

[0035] FIG. 11. Schematic of pharmacokinetic study. CBD formulations were administered at 20 mg / kg by oral gavage on day 0, then blood was sampled from the saphenous vein at the indicated time points. n=5-10 animals per group. Formulations tested were: CBD medium chain triglyceride oil (MCT), CBD SO, CBD SEDDS C, and CBD SEDDS D.

[0036] FIG. 12. Plasma concentration-time profiles of CBD following oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D as in Fig. 11. Data are shown as mean ± SEM, n > 5. Inset depicts the plasma concentration-time plot with a semi-log axis. At the two hour timepoint, the lines from top to bottom correspond to: CBD SEDDS C, CBD SO, CBD SEDDS D, and CBD MCT.

[0037] FIGs. 13A-13D. Visual summary of pharmacokinetic parameters obtained following oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D as in Fig. 11. Boxplot of time to maximum observed plasma concentration (Tmax), with individual observations represented as crosses (FIG. 13A); boxplot of maximum observed CBD plasma concentration (Cmax) (FIG. 13B); bar plot of area under the plasma concentration-time curve from 0-8 h (mean ± SEM, n > 5) (FIG. 13C); bar plot of area under the extrapolated plasma concentration-time curve (mean ± SEM, n > 5) (FIG. 13D).

[0038] FIG. 14. Box plot representation of the plasma concentration-time profiles of CBD following oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D as in Fig. 11. n > 5. Empty points represent the mean value.

[0039] FIG. 15. Individual plasma concentration-time profiles of CBD following oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D as in FIG. 11.

[0040] FIG. 16. CBD concentration in tissues 4 h following oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D as in Fig. 11. Data are shown as mean ± SEM, n = 5. Statistical differences 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] FIG. 17. Plasma concentration-time profiles of CBD following oral administration of 20mg / kg CBD SEDDS C in fasted and non-fasted rats. Data areshown as mean ± SEM, n > 5. At time = 2 h, the top line is No Fast, and the bottom line is Fasted.

[0042] FIG. 18. Box plot representation of the plasma concentration-time profiles of CBD following oral administration of 20mg / kg CBD SEDDS C in fasted and nonfasted rats, n > 5. Empty points represent the mean value. For each time point the bars from left to right correspond to No fast and Fasted, respectively.

[0043] FIG. 19. Summary of study of pharmacokinetics of different formulations of CBD administered orally to rats.

[0044] FIG. 20. Average values of key PK parameters in rats treated with different formulations of CBD

[0045] FIG. 21. Boxplot representation of Cmax (ng / mL) of CBD in fed or fasted rats treated with different formulations of CBD. For each formulation, the left bar is fed, and the right bar is fasted.

[0046] FIG. 22. Boxplot representation of Tmax (h) of CBD in fed or fasted rats treated with different formulations of CBD. For each formulation, the left bar is fed, and the right bar is fasted.

[0047] FIG. 23. Boxplot representation of Tl / 2 (h) of CBD in fed or fasted rats treated with different formulations of CBD. For each formulation, the left bar is fed, and the right bar is fasted.

[0048] FIG. 24. Boxplot representation of AUCo-iast (ng.h / mL) of CBD in fed or fasted rats treated with different formulations of CBD. For each formulation, the left bar is fed, and the right bar is fasted.

[0049] FIG. 25. Boxplot representation of AUCo-inf (ng.h / mL) of CBD in fed or fasted rats treated with different formulations of CBD. For each formulation, the left bar is fed, and the right bar is fasted.DETAILED DESCRIPTION

[0050] The present disclosure provides compositions for formulating therapeutic agents. The compositions are effective for solubilizing therapeutic agents, particularly difficult-to-solubilize therapeutic agents. The compositions advantageously enhance the bioavailability of the therapeutic agents while also providing for high concentrations of the therapeutic agents. The disclosure also provides therapeutic agent formulations based on the compositions that are effective for the delivery of therapeutic agents,particularly oral administration of therapeutic agents. The disclosure provides cannabinoid formulations, including CBD formulations, based on the compositions. The disclosed formulations effectively solubilize cannabinoids, including CBD, thus providing formulations having increased cannabinoid concentrations and, at the same time, provide for enhanced bioavailability of cannabinoids including CBD.

[0051] Self-emulsifying drug delivery systems (SEDDS) are one example of an advanced lipid-based formulation that can be used to enhance the absorption of cannabinoids including CBD. In simple terms, SEDDS are an isotropic mixture of oils, surfactants, and / or cosolvents that spontaneously assemble into a colloidal dispersion or emulsion upon mixing with aqueous media, such as in the environment of the gastrointestinal tract. SEDDS offer the potential to address the formulation needs of cannabinoids including CBD, namely by increasing its apparent solubility and also delivering high therapeutic doses.Definitions:

[0052] While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

[0053] The term “a” or “an” refers to one or more of that entity, i.e., can refer to a plural referent. As such, the terms “a” or “an”, “one or more” and “at least one” are used interchangeably herein. In addition, reference to “an element” by the indefinite article “a” or “an” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there is one and only one of the elements.

[0054] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements otherthan A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0055] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. 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”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, 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); etc.

[0056] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device or the method being employed to determine the value, or the variation that exists among the samples being measured. In some embodiments, the term “about” means within 5% of the reported numerical value. When used in conjunction with a range or series of values, the term “about” applies to the endpoints of the range or each of the values enumerated in the series, unless otherwise indicated.

[0057] As used herein, the verb “comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.

[0058] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only", “consisting of’ and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.

[0059] A “subject” is a living animal, particularly a mammal, which can be treated with a pharmaceutical composition described herein. In some embodiments, the subject is ahuman. In some embodiments, the human subject is a human child, a human teenager, or a human adult. In some embodiments, the subject or patient is a non-human animal, including research animals such as a mouse, a rat, a pig, a dog, a rabbit, a monkey or other non-human primate, or a goat.

[0060] “Formulation” as used herein encompasses the term “composition.” Accordingly, formulation may refer to a composition containing one or more cannabinoids. Additionally or alternatively, formulation may refer to a composition containing one or more cannabinoids, together with one or more pharmaceutically acceptable excipients.

[0061] “Active agent” as used herein refers to a drug substance (e.g., a cannabinoid, optionally CBD) that produces a desired biological effect. It is to be understood that CBD is an illustrative embodiment of a cannabinoid, and that a CBD formulation is an illustrative embodiment of a cannabinoid formulation, as used herein. The term “cannabidiol” and the abbreviation “CBD” are used interchangeably herein and refer to a molecule according to the following structure. Further, active agents of the formulations described herein include prodrugs and derivatives of CBD, in addition to biologically-derived and synthetically-derived CBD.

[0062] All weight percentages (i.e., “% by weight” and “wt. %” and “% w / w”) referenced herein, unless otherwise indicated, are measured relative to the total weight of the formulation or microparticle, depending on the context.

[0063] “Predominant” as used herein should be understood to mean comprising a greater % by weight than any other. For example, a predominant form of a fatty acidglycerol ester (e.g., monoglyceride) is one that is present in an amount greater than any other single form of said fatty acid glycerol ester.

[0064] “Dose” as used herein refers to an amount of a formulation that is administered to a patient and contains a therapeutically effective amount of the one or more cannabinoids. For example, a dose may be one tablet or one capsule containing a formulation disclosed herein.

[0065] “Treating” and “treatment” as used herein refer to reduction in severity and / or frequency of symptoms, elimination of symptoms and / or underlying cause, reduction in likelihood of the occurrence of symptoms and / or underlying cause, and improvement or remediation of damage. Thus, “treating” a patient with an active agent as provided herein includes inhibiting a particular condition, disease or disorder in a susceptible individual as well as treatment of a clinically symptomatic individual.

[0066] As used herein, “effective amount” refers to an amount covering both therapeutically effective amounts and prophylactically effective amounts. As used herein, “therapeutically effective amount” refers to an amount that is effective to achieve the desired therapeutic result. A therapeutically effective amount of a given active agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the patient.SEDDS Formulations

[0067] The present disclosure provides formulations comprising cannabinoids, including CBD. In some embodiments, the formulations are SEDDS formulations. As used herein, the term “cannabinoid SEDDS formulation” and “cannabinoid SEDDS” are used interchangeably and refer to a SEDDS formulation as disclosed herein comprising a cannabinoid. As used herein, “CBD SEDDS formulation” and “CBD SEDDS” are used interchangeably and refer to a SEDDS formulation as disclosed herein comprising CBD. SEDDS are isotropic mixtures of oils, surfactants, solvents, and co-solvents / surfactants. SEDDS can be used for the design of formulations in order to improve absorption of highly lipophilic drug compounds, such as cannabinoids, following oral administration. SEDDS spontaneously assemble into a colloidal dispersion or emulsion upon mixing with aqueous media, such as in the environment of the gastrointestinal tract. Further, when a SEDDS composition is released into the lumen of the gut, the composition disperses to form a coarse, fine, or micro emulsion, so that the drug remains in solution in the gut, avoiding the dissolution step thatfrequently limits the rate of absorption of hydrophobic drugs from the crystalline state. The use of SEDDS usually leads to improved bioavailability and / or a more consistent temporal profile of absorption from the gut. A description of compositions of SEDDS can be found in C. W. Pouton, Advanced Drug Delivery Reviews 25: 47-58 (1997).

[0068] In the context of cannabinoids, including CBD, SEDDS have demonstrated the ability to improve systemic exposure relative to MCT oil or lipid-free solutions (Chemiakov 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 Pra et al. Int. J. Pharm. 2021, 609, 121159). A SEDDS formulation containing sesame oil was also reported to generate a more predictable plasma-concentration time profile relative to sesame oil as the only vehicle, albeit without relative absorption improvement (Izgelov et al. Eur. J. Pharm. Biopharm. 2020, 154,108-115). The present disclosure provides SEDDS formulations that offer improved gastrointestinal absorption and systemic exposure of cannabinoids, including CBD, following oral administration. In some embodiments, these formulations do not comprise sesame oil. In some embodiments, these formulations do not comprise ethanol.

[0069] In some embodiments, the present disclosure provides cannabinoid formulations, comprising: a cannabinoid, optionally CBD; one or more fatty acid glycerol esters; and one or more polyethylene glycol -containing fatty acid esters.

[0070] In some embodiments, the formulations comprise a cannabinoid, e.g., CBD, in an amount greater than or equal to about 1% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount greater than or equal to about 5%, greater than or equal to about 10%, greater than or equal to about 15%, greater than or equal to about 20%, greater than or equal to about 25%, greater than or equal to about 30%, greater than or equal to about 35%, greater than or equal to about 40%, greater than or equal to about 45%, greater than or equal to about 50%, or greater than or equal to about 55% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount less than or equal to about 70%, less than or equal to about 65%, less than or equal to about 60%, less than or equal to about 55%, less than or equal to about 50%, less than or equal to about 45%, less than or equal to about 40%, less than or equal to about 35%, less than or equal to about 35%, less than or equal to about30%, or less than or equal to about 25% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount from about 1% to about 60% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount from about 10% to about 50% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount from about 20% to about 40% by weight, about 10% to about 60% by weight, about 20% to about 60% by weight, or about 30% to about 60% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount at about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight. In some embodiments, the formulations comprise a cannabinoid, e.g., CBD, at about 20% by weight. In some embodiments, the formulations comprise a cannabinoid, e.g., CBD, at about 30% by weight. In some embodiments, the formulations comprise a cannabinoid, e.g., CBD, at about 40% by weight. In some embodiments, the formulations comprise a cannabinoid, e.g., CBD, within a range of % by weight formed from any two of the disclosed % weights. For example, about 15% to about 40% by weight.

[0071] In some embodiments, the formulations comprise CBD, in an amount greater than or equal to about 1% by weight. In some embodiments, the formulations comprise CBD in an amount greater than or equal to about 5%, greater than or equal to about 10%, greater than or equal to about 15%, greater than or equal to about 20%, greater than or equal to about 25%, greater than or equal to about 30%, greater than or equal to about 35%, greater than or equal to about 40%, greater than or equal to about 45%, greater than or equal to about 50%, or greater than or equal to about 55% by weight. In some embodiments, the formulations comprise CBD in an amount less than or equal to about 70%, less than or equal to about 65%, less than or equal to about 60%, less than or equal to about 55%, less than or equal to about 50%, less than or equal to about 45%, less than or equal to about 40%, less than or equal to about 35%, less than or equal to about 35%, less than or equal to about 30%, or less than or equal to about 25% by weight. In some embodiments, the formulations comprise CBD in an amount from about 1% to about 60% by weight. In some embodiments, the formulations comprise CBD in an amount from about 10% to about 50% by weight. In some embodiments, the formulations comprise CBD at about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight. In some embodiments, the formulations comprise CBD at about 20% by weight. In some embodiments, the formulations comprise CBD at about 30% by weight. In some embodiments, theformulations comprise CBD at about 40% by weight. In some embodiments, the formulations comprise CBD within a range of % by weight formed from any two of the disclosed % weights. For example, about 15% to about 40% by weight.

[0072] The present disclosure provides cannabinoid SEDDS formulations that comprise one or more fatty acid glycerol esters and the one or more polyethylene glycol (PEG)-containing fatty acid esters. In some embodiments, the formulations comprise one or more fatty acid glycerol esters and one or more PEG-containing fatty acid esters at a ratio in the range of about 30:70% by weight to about 70:30% by weight. In some embodiments, the formulations comprise one or more fatty acid glycerol esters and one or more PEG-containing fatty acid esters at a ratio in the range of about 40:60% by weight to about 60:40% by weight. In some embodiments, the formulations comprise one or more fatty acid glycerol esters and one or more polyethylene oxide-containing fatty acid esters at a ratio of about 50:50% by weight. In some embodiments, the one or more fatty acid glycerol esters comprise glyceryl oleate (e.g., Peceol®) and the one or more PEG-containing fatty acid esters comprise PEG-containing fatty acid esters derived from fatty acids including saturated and unsaturated fatty acids having from eight (8) to twenty-two (22) carbon atoms (e.g., Gelucire 44 / 14®).Fatty acid glycerol esters comprised by SEDDS formulations

[0073] The disclosed cannabinoid SEDDS formulations include one or more fatty acid glycerol esters. As used herein the term “fatty acid glycerol esters” refers to esters formed between glycerol and one or more fatty acids including mono-, di-, and tri -esters (i.e., glycerides). Suitable fatty acids include saturated and unsaturated fatty acids having from eight (8) to twenty-two (22) carbons atoms (i.e., C8-C22 fatty acids). In certain embodiments, suitable fatty acids include C8-C18 fatty acids.

[0074] The fatty acid glycerol esters useful in the formulations can be provided by commercially available sources. A representative source for the fatty acid glycerol esters is a mixture of mono-, di-, and triesters commercially available as PECEOL® (Gattefosse, Saint Priest Cedex, France), commonly referred to as “glyceryl oleate” or “glyceryl monooleate.”

[0075] Functionalities of PECEOL® include that of a solubilizer for lipophilic compounds and a bioavailability enhancer. In some embodiments, PECEOL® is a vehicle containing long-chain fatty acids (Cisn) for lipid formulation classification system (LFCS) Type I (oily), Type II (SEDDS), and Type III (SMEDDS), associatedwith lymphatic absorption. In some embodiments, PECEOL® is an oily vehicle for oral or topical formulations. In some embodiments, PECEOL® has a viscosity of 220 (20°C) mPa.s and an HLB of 1. Safety of use is inferred by generally recognized as safe (GRAS) status and precedence of use in approved pharmaceutical products.

[0076] In certain embodiments, when PECEOL® is used as the source of fatty acid glycerol esters in the formulations, the fatty acid glycerol esters comprise from about 32 to about 52% by weight fatty acid monoglycerides, from about 30 to about 50% by weight fatty acid diglycerides, and from about 5 to about 20% by weight fatty acid triglycerides. In some embodiments, PECEOL® comprises mono-, di- and triglycerides of oleic (C18: l) acid, the monoester fraction being predominant.

[0077] In certain embodiments, the formulations of the disclosure can include glycerol in an amount less than about 10% by weight.Polyethylene glycol-containing fatty acid esters comprised by SEDDS formulations

[0078] As noted above, the CBD formulations include one or more polyethylene glycol (PEG)-modified lipids such as PEG-containing phospholipids or one or more PEG- containing fatty acid esters, and typically, a mixture of PEG-containing phospholipids or a mixture of PEG-containing fatty acid esters.

[0079] Accordingly, in one embodiment, the CBD formulations of the disclosure include (a) a cannabinoid, optionally cannabidiol; (b) one or more fatty acid glycerol esters; and (c) one or more PEG-containing fatty acid esters.

[0080] As used herein, the term “polyethylene glycol-containing fatty acid ester” refers to a fatty acid ester that includes a polyethylene glycol group (i.e., PEG group) covalently coupled to the fatty acid through 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 from eight (8) to twenty-two (22) carbons atoms (i.e., a PEG ester of a C8-C22 fatty acid). In certain embodiments, suitable PEG-containing fatty acid esters are derived from fatty acids including saturated and unsaturated fatty acids having from eight (8) to eighteen (18) carbon atoms (i.e., a PEG ester of a C8- C18 fatty acid). In certain embodiments, suitable PEG-containing fatty acid esters include saturated C8-C18 fatty acids.

[0081] The molecular weight of the PEG group of the PEG-containing fatty acid ester can be varied to optimize the solubility of the therapeutic agent (e.g., a cannabinoid, optionally CBD) in the formulation. Representative average molecular weights for the PEG groups can be from about 350 to about 7000 g / mol. In one embodiment, the average molecular weight for the PEG group is about 1500. In another embodiment, the average molecular weight for the PEG group is about 6,000. In another embodiment, the average molecular weight for the PEG group is about 400.

[0082] In this embodiment, the cannabinoid formulations include one or more PEG- containing fatty acid esters, and typically, a mixture of PEG-containing fatty acid esters (mono- and di-fatty acid esters of PEG).

[0083] The PEG-containing fatty acid esters useful in the formulations can be provided by commercially available sources. Representative PEG-containing fatty acid esters (mixtures of mono- and diesters) are commercially available under the designation GELUCIRE® (Gattefosse, Saint Priest Cedex, France). Illustrative examples of suitable PEG-containing fatty acid esters include GELUCIRE® 44 / 14, GELUCIRE® 48 / 16, GELUCIRE® 50 / 13, GELUCIRE® 59 / 14, and Labrasol ALF. The numerals in these GELUCIRE® designations refer to the melting point and hydrophilic / lipophilic balance (HLB) of this material, respectively.

[0084] In some embodiments, the PEG-containing fatty acid esters of GELUCIRE® 44 / 14, GELUCIRE® 50 / 13, GELUCIRE® 59 / 14, or Labrasol ALF comprise a mixture of (a) mono-, di-, and triesters of glycerol (glycerides) and (b) mono- and diesters of polyethylene glycol (macrogols). In some embodiments, the PEG-containing fatty acid esters of GELUCIRE® 44 / 14, GELUCIRE® 50 / 13, GELUCIRE® 59 / 14, or Labrasol ALF consist of a mixture of (a) mono-, di-, and triglyceride esters and (b) mono- and diesters of PEG. In some embodiments, the PEG is PEG-32 (MW 1500), PEG-150 (MW6000), or PEG-8 (MW400). In some embodiments, the GELUCIRE® 44 / 14, GELUCIRE® 50 / 13, GELUCIRE® 59 / 14, or Labrasol ALF additionally comprise free PEG (e g., PEG-32, PEG-150, or PEG-8).

[0085] In some embodiments, the PEG-containing fatty acid esters of GELUCIRE® 48 / 16, comprise a mixture of mono- and diesters of PEG. In some embodiments, the PEG-containing fatty acid esters of GELUCIRE® 48 / 16 consist of a mixture of mono- and diesters of PEG. In some embodiments, the PEG is PEG-32 (MW 1500). In some embodiments, the GELUCIRE® 48 / 16 additionally comprises free PEG (e.g., PEG- 32).

[0086] In some embodiments, the PEG-containing fatty acid esters comprise one or more of an oleic acid ester, a linoleic acid ester, a lauric acid ester, a palmitic acid ester, a stearic acid ester, a caprylic acid ester, or a capric acid ester (i.e., mono- and di-lauric acid esters of polyethylene glycol, mono- and di-palmitic acid esters of polyethylene glycol, mono- and di-stearic acid esters of polyethylene glycol). Mixtures of these esters can also be used.

[0087] In some embodiments, lauric acid (C12) is the predominant fatty acid component of the glycerides and polyethylene glycol esters in GELUCIRE® 44 / 14. GELUCIRE® 44 / 14 is referred to as a mixture of glyceryl dilaurate (lauric acid diester with glycerol) and PEG dilaurate (lauric acid diester with polyethylene glycol), and is commonly known as PEG-32 glyceryl laurate (Gattefosse) lauroyl macrogol-32 glycerides EP, or lauroyl polyoxyl glycerides USP / NF. GELUCIRE® 44 / 14 is produced by the reaction of hydrogenated palm kernel oil with polyethylene glycol (average molecular weight 1500). In some embodiments, GELUCIRE® 44 / 14 includes about 20% mono-, di- and, triglycerides, about 72% mono- and di-fatty acid esters of polyethylene glycol 1500, and about 8% polyethylene glycol 1500. In some embodiments, GELUCIRE® 44 / 14 consists of mono-, di- and triglycerides of oleic (Cl 8: 1) acid, the monoester fraction being predominant.

[0088] In some embodiments, GELUCIRE® 44 / 14 includes lauric acid (C12) esters (30 to 50%), myristic acid (C14) esters (5 to 25%), palmitic acid (C16) esters (4 to 25%), stearic acid (Cl 8) esters (5 to 35%), caprylic acid (C8) esters (less than 15%), and capric acid (CIO) esters (less than 12%). GELUCIRE® 44 / 14 may also include free glycerol (typically less than about 1%), and < Ippm ethylene oxide.

[0089] In some embodiments, GELUCIRE® 48 / 16 is a polyethylene glycol monostearate (type I) NF and comprises PEG-32 (MW 1500) esters of palmitic acid (C16) and stearic acid (C18). In some embodiments, GELUCIRE® 48 / 16 consists of PEG-32 (MW 1500) esters of palmitic acid (Cl 6) and stearic acid (Cl 8).

[0090] In some embodiments, GELUCIRE® 50 / 13 is a stearoyl polyoxyl / macrogol 32 glycerides NF / EP and comprises mono-, di-, and triglycerides and PEG-32 (MW1500) mono- and diesters of palmitic acid (Cl 6) and stearic acid (Cl 8). In some embodiments, GELUCIRE® 50 / 13 consists of mono-, di-, and triglycerides and PEG-32 (MW1500) mono- and diesters of palmitic acid (Cl 6) and stearic acid (Cl 8).

[0091] In some embodiments, GELUCIRE® 59 / 14 comprises a small fraction of mono, di- and triglycerides and mainly PEG-32 (MW 1500) mono- and diesters of lauric acid(C12) and of PEG-150 (MW 6000). In some embodiments, GELUCIRE® 59 / 14 consists of a small fraction of mono, di- and triglycerides and mainly PEG-32 (MW 1500) mono- and diesters of lauric acid (C12) and of PEG-150 (MW 6000).

[0092] In some embodiments, Labrasol ALF comprises a small fraction of mono-, di- and triglycerides and mainly PEG-8 (MW 400) mono- and diesters of caprylic (C8) and capric (CIO) acids. In some embodiments, Labrasol ALF consists of a small fraction of mono-, di- and triglycerides and mainly PEG-8 (MW 400) mono- and diesters of caprylic (C8) and capric (CIO) acids.

[0093] Functionalities of GELUCIRE® 44 / 14 include (a) solubilizer for poorly-soluble compounds and bioavailability enhancer; (b) single excipient formulation system: selfemulsifies in aqueous fluid into microemulsion — LFCS Type III (SMEDDS); (c) wetting agent; and (d) lipid binder in melt processes. Safety of use is inferred by extensive toxicological evaluations and precedence of use in approved pharmaceutical products. Functionalities of GELUCIRE® 48 / 16 include (a) solubilizer for low log P (a measure of lipophilicity) compounds and bioavailability enhancer; (b) single excipient formulation system: self-emulsifies in aqueous fluid into micellar solution — LFCS Type IV; (c) use in melt processes (granulation, extrusion), granulation, and compression; and (d) wetting agent. Safety of use is inferred by precedence of use in approved pharmaceutical products. Functionalities of GELUCIRE® 50 / 13 include (a) solubilizer for poorly-soluble compounds and bioavailability enhancer; (b) single excipient formulation system: self-emulsifies in aqueous fluid into coarse emulsion — LFCS Type III (SMEDDS); (c) modulator of drug release; and (d) lipid binder in melt processes. Safety of use is inferred by toxicological data and precedence of use in approved pharmaceutical products. Functionalities of GELUCIRE® 59 / 14 include (a) solubilizer for poorly-soluble compounds and bioavailability enhancer; and (b) single excipient formulation system: self-emulsifies in aqueous fluid into microemulsion — LFCS Type III (SMEDDS). Safety of use is inferred by extensive toxicological evaluations and precedence of use in approved pharmaceutical products. Safety of use is inferred by precedence of use in approved pharmaceutical products. Functionalities of Labrasol ALF include (a) solubilizer for poorly-soluble compounds and bioavailability enhancer; (b) single excipient formulation system: self-emulsifies in aqueous fluid into microemulsion — LFCS Type III (SMEDDS); (c) high purity guaranteed for stability and capsule compatibility. Safety of use is inferred by extensive toxicological data and precedence of use in approved pharmaceutical products. Safetyof use is inferred by food additive status and precedence of use in approved pharmaceutical products.

[0094] In some embodiments, GELUCIRE® 44 / 14 has a melting range of 42.5 - 47.5 °C, an HLB of 11, and a CMC of 72 ± 53 mg / L, 25°C. In some embodiments, GELUCIRE® 48 / 16 has a melting range of 46 - 50 °C, an HLB of 12, and a CMC of 153 ± 31 mg / L, 25°C. In some embodiments, GELUCIRE® 50 / 13 has a melting range of 46 - 51 °C, an HLB of 11, and a CMC of 100 ± 31 mg / L, 25°C. In some embodiments, GELUCIRE® 59 / 14 has a melting range of 57 - 62 °C, an HLB of 14+1, and a CMC of 40 mg / L, 25°C. °C. In some embodiments, Labrasol ALF has a viscosity of 80-110 (20 °C) mPA.s, an HLB of 12, and a CMC of 42 ± 24 mg / L, 25°C.Relative amounts of components in SEDDS formulations

[0095] For embodiments that include PEG-containing fatty acid esters, in certain embodiments, the ratio of the fatty acid glycerol esters to PEG-containing fatty acid esters is from about 30:70 to about 70:30 v / v. In one embodiment, the ratio of the fatty acid glycerol esters to PEG-containing fatty acid esters is about 30:70 v / v. In one embodiment, the ratio of the fatty acid glycerol esters to PEG-containing fatty acid esters is about 40:60 v / v. In one embodiment, the ratio of the fatty acid glycerol esters to PEG-containing fatty acid esters is about 50:50 v / v. In one embodiment, the ratio of the fatty acid glycerol esters to PEG-containing fatty acid esters is about 60:40 v / v. In one embodiment, the ratio of the fatty acid glycerol esters to PEG-containing fatty acid esters is about 70:30 v / v.

[0096] In one embodiment, the cannabinoid formulation of the disclosure includes a cannabinoid (optionally CBD), PECEOL®, and GELUCIRE® 44 / 14. In embodiments, the ratio of PECEOL® to GELUCIRE® 44 / 14 can be from 30:70 to 70:30 (e.g., 30:70; 40:60; 50:50; 60:40; and 70:30). In these embodiments, the ratio of PECEOL^' to GELUCIRE® 44 / 14 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).

[0097] In one embodiment, the cannabinoid formulation of the disclosure includes a cannabinoid (optionally CBD), PECEOL®, and GELUCIRE® 48 / 16. In these embodiments, the ratio of PECEOL® to GELUCIRE® 48 / 16 can be from 30:70 to 70:30 (e.g., 30:70; 40:60; 50:50; 60:40; and 70:30). In these embodiments, the ratio ofPECEOL® to GELUCIRE® 48 / 16 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).

[0098] In one embodiment, the cannabinoid formulation of the disclosure includes a cannabinoid (optionally CBD), PECEOL®, and GELUCIRE® 50 / 13. In these embodiments, the ratio of PECEOL® to GELUCIRE® 50 / 13 can be from 30:70 to 70:30 (e.g., 30:70; 40:60; 50:50; 60:40; and 70:30). In these embodiments, the ratio of PECEOL® to GELUCIRE® 50 / 13 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).

[0099] In one embodiment, the cannabinoid formulation of the disclosure includes a cannabinoid (optionally CBD), PECEOL®, and GELUCIRE® 59 / 14. In these embodiments, the ratio of PECEOL® to GELUCIRE® 59 / 14 can be from 30:70 to 70:30 (e.g., 30:70; 40:60; 50:50; 60:40; and 70:30). In these embodiments, the ratio of PECEOL® to GELUCIRE® 59 / 14 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).

[0100] In one embodiment, the cannabinoid formulation of the disclosure includes a cannabinoid (optionally CBD), PECEOL®, and Labrasol ALF. In these embodiments, the ratio of PECEOL® to Labrasol ALF can be from 30:70 to 70:30 (e.g., 30:70; 40:60; 50:50; 60:40; and 70:30). In these embodiments, the ratio of PECEOL® 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).

[0101] In some embodiments, the glyceryl oleate and polyethylene glycol-containing fatty acid esters are each present in the formulation in an amount from about 30% to about 50% by weight. In some embodiments the glyceryl oleate and polyethylene glycol-containing fatty acid esters are each present in the formulation at 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 certain embodiments, the polyethylene glycol-containing fatty acid esters are Gelucire 44 / 14 or lauroyl polyoxyl glycerides.

[0102] In some embodiments, the glyceryl oleate and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 34.58% by weight. In some embodiments, the glyceryl oleate and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 36.4% by weight. In some embodiments, the glyceryl oleate and polyethylene glycol-containing fatty acid esters are each presentin the formulation at about 38% by weight. In some embodiments, the glyceryl oleate and polyethylene glycol-containing fatty acid esters are each present in the formulation in an amount in from about 39% to about 41% by weight. In some embodiments, the glyceryl oleate and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 40% by weight. In certain embodiments, the polyethylene glycol-containing fatty acid esters are Gelucire 44 / 14 or lauroyl polyoxyl glycerides.

[0103] The present disclosure provides cannabinoid SEDDS formulations that may optionally include 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 from about 3% to about 4% by weight. In some embodiments, TPGS is present in the formulation at 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 at about 3.64% by weight. In some embodiments, TPGS is present in the formulation at about 4% by weight.

[0104] In some embodiments, the cosolvent comprised by 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 comprise ethanol.

[0105] In some embodiments, the 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, the 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.

[0106] In some embodiments, the 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, the 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 comprise TPGS or ethanol.

[0107] In some embodiments, a single dose of the formulation comprises at least 10 milligrams (mg) of a cannabinoid. In some embodiments, a single dose of the formulation comprises in the range of about 10 mg to about 3,000 mg of a cannabinoid. In some embodiments, a single dose of the formulation comprises in the range of about 50 to about 2,000 mg of a cannabinoid. In some embodiments, a single dose may comprise 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 a cannabinoid. In some embodiments, a single dose comprises about 600 mg of a cannabinoid.

[0108] In some embodiments, the disclosure provides formulations comprising greater than about than about 1% of a cannabinoid by weight. In some embodiments, the formulations comprise about 10% to about 50% of a cannabinoid by weight. In some embodiments, the formulations comprise about 20% of a cannabinoid by weight. In some embodiments, the formulations comprise about 40% of a cannabinoid by weight.

[0109] In some embodiments, a single dose of the formulation comprises at least 10 milligrams (mg) of CBD. In some embodiments, a single dose of the formulation comprises in the range of about 10 mg to about 3,000 mg of CBD. In some embodiments, a single dose of the formulation comprises in the range of about 50 to 2,000 mg of CBD. In some embodiments, a single dose may comprise 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 embodiments, a single dose comprises about 600 mg of CBD.

[0110] In some embodiments, the disclosure provides formulations comprising greater than about than about 5% CBD by weight. In some embodiments, the formulations comprise about 10% to about 50% CBD by weight. In some embodiments, the formulations comprise about 20% CBD by weight. In some embodiments, the formulations comprise about 40% CBD by weight.[OHl] The present disclosure further provides formulations as described herein that are formulated for oral administration. The present disclosure further provides a capsulecomprising any of the formulations described herein. In some embodiments, the capsule is a soft-gel capsule. The cannabinoid SEDDS formulation may be formulated in any suitable form for administration of said formulation, such as, but not limited to, a capsule, a tablet, a powder, a pellet, or a solution.Cannabinoids

[0112] Cannabinoids are natural and synthetic compounds structurally or pharmacologically related to the constituents of the cannabis plant or the 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. The CB1 receptor is particularly widespread in the central nervous system with high levels found in the neocortex, hippocampus, basal ganglia, cerebellum and brainstem and accordingly, CBD has been proposed to treat a variant of nervous system disorders (Scotter et al. Br. J. Pharmacol. 2010. (160):480-498.

[0113] The main cannabinoids present in cannabis plants are cannabinoid acids tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA) with small amounts of their respective neutral (decarboxylated) cannabinoids. In addition, cannabis may contain lower levels of other minor cannabinoids.

[0114] CBD is a major cannabinoid constituent of Cannabis species. Unlike other cannabinoids, such as THC, CBD does not bind CB 1 or CB2, or its binding to the receptors is negligible in terms of inducing a pharmacological effect. Thus, CBD does not cause the central or peripheral nervous system effects mediated by the CB 1 or CB2 receptors. CBD has little or no psychotropic (cannabimimetic) activity and its molecular structure and properties are substantially different from those of other cannabinoids.

[0115] In some embodiments CBD is isolated from a cannabis plant. In some embodiments CBD is prepared synthetically. In some embodiments, CBD is present as (-)-trans-CBD.

[0116] Of the over 100 natural cannabinoids identified in Cannabis saliva, seven have been classified as CBD-type compounds, these cannabinoids have the same absolute configuration as CBD. These are: CBD, Cannabidiolic acid (CBDA), Cannabidivarin (CBDV), Cannabidivarin acid (CBDVA), Cannabidiol -Cl (CBD-C1), Cannabidiol-C4 (CBD-C4) and Cannabidiol monomethyl ether (CBDM). Cannabidiolic acid (CBDA)is the main form in which CBD exists in the cannabis plant. It is converted into CBD after decarboxylation.

[0117] Cannabidiol-Cl (CBD-C1) also known as cannabidiorcol is a homolog of CBD, with the side-chain shortened by four methylene bridges. CBD-C1 occurs naturally in plants producing CBD in minor quantities. Cannabidivarin (CBDV) is a homolog of CBD, with the side-chain shortened by two methylene bridges. CBDV is a nonpsychoactive cannabinoid and has been shown to have anti-convulsant activity in a mouse model of epilepsy. Cannabidiol-C4 (CBD-C4) also known as nor-cannabidiol is a homolog of CBD, with the side-chain shortened by one methylene bridge. CBD-C4 occurs naturally in plants producing CBD in minor quantities.

[0118] CBD is a highly lipophilic drug (logP ~ 6) with low water solubility (estimated to be < 13 pg / mL). Subject to extensive first-pass metabolism, CBD has an oral bioavailability around 6%. Formally, CBD is categorized as a Biopharmaceutical Classification System (BCS) class II compound due to its low aqueous solubility and high intestinal permeability. Therefore, strategies that can improve the dissolution or dispersion rate of CBD would increase its bioavailability. To this end, numerous formulation approaches have been explored for CBD, including solid dispersions, nanocrystals, and nanoemulsions. Given the physicochemical properties of CBD, lipid- based formulations have experienced the most resounding success.

[0119] To date, the only FDA-approved CBD formulation is Epidiolex®, a sesame oilbased solution indicated for the treatment of rare childhood epilepsies and tuberous sclerosis complex. However, this and other CBD formulations have limited applicability: (1) some patients are allergic to sesame oil creating safety concerns; (2) many indications require larger doses of CBD that are difficult to administer with sesame oil formulations creating compliance limitations; (3) liquid formulation are inherently less precise; and sesame oil formulations degrade upon exposure to air, creating higher costs. In addition, Epidiolex includes ethanol, which presents disadvantages for use in certain patient populations. Consequently, there is a need for lipid-based formulations that can improve the absorption of CBD without relying on sesame oil as an excipient, to avoid potential allergy, allow for higher dosing and better patient compliance, minimize variability, and decrease costs.

[0120] CBD has been suggested as a treatment for multiple diseases or injuries including, but not limited to, Clinical High Risk of Psychosis, insomnia, first episode psychosis, psychosis in Parkinson’s disease, schizophrenia, general anxiety disorder,social anxiety disorder, panic disorder, post-traumatic stress disorder, Alzheimer’s disease, postpartum psychosis, agoraphobia, acute stress disorder, and schizoaffective disorder. Treatment of some of these diseases or injuries may necessitate high doses of CBD. Patient acceptance and adherence to treatment would be improved by a convenient and painless route of administration, ideally oral administration with an easy to administer soft gel of high potency. As such, CBD formulations with the following attributes are needed: high solubilization of CBD and highly stable during storage, with favorable safety, absorption, and bioavailability profiles.D-q-tocopherol polyethylene glycol 1000 succinate (TPGS)

[0121] The cannabinoid formulations may optionally include one or more additional ingredients including a surfactant such as a D-alpha-tocopheryl polyethylene glycol succinate (TPGS).

[0122] Accordingly, in some embodiments, the cannabinoid formulations of the disclosure include (a) a cannabinoid, optionally cannabidiol; (b) one or more fatty acid glycerol esters; (c) one or more polyethylene glycol-containing fatty acid esters; and (d) TPGS, optionally D-a-tocopherol polyethylene glycol 1000 succinate (TPGS 1000).

[0123] As used herein, the term “D-a-tocopherol polyethylene glycol succinate” and the abbreviation “TPGS” are used interchangeably, and are defined as a molecule according to the chemical structure below:

[0124] TPGS is an amphipathic molecule, prepared by the esterification of a hydrophilic polyethylene glycol molecule (usually with a mean molecular weight 1000, and about 20-25 ethylene oxide chains) with the carboxylic group of hydrophobic d- alpha-tocopherol hemisuccinate (acid). TPGS is a water soluble compound (to 20% w / v) and forms micellar solutions with a critical micelle concentration of 0.4-0.6 mM / L (about 0.075%). The hydrophilic-lipophilic balance of TPGS is about 15-19. Structurally, tocopherol polyethylene glycol succinates have a polyethylene glycol (PEG) covalently coupled to tocopherol (e.g., a-tocopherol or vitamin E) through a succinate linker. Because PEG is a polymer, a variety of polymer molecular weightscan be used to prepare the TPGS In one embodiment, the TPGS is tocopherol polyethylene glycol succinate 1000, in which the average molecular weight of the PEG is 1000. One suitable tocopherol polyethylene glycol succinate is vitamin E TPGS commercially available from Eastman.

[0125] TPGS may be used as a surfactant or emulsifying agent for lipophilic substances. The emulsification and subsequent increase in surface area of the lipophilic substance may result in increased gastrointestinal drug absorption and bioavailability. The TPGS may be included in the formulation to enhance the thermal stability of the formulation, which in turn, can increase the formulation’s shelf-life.

[0126] In certain embodiments, the tocopherol polyethylene glycol succinate is present in the formulation from about 0.1 to about 10 percent by volume based on the total volume of the formulation. In one embodiment, the tocopherol polyethylene glycol succinate is present in the formulation in about 5 percent by volume based on the total volu e of the formulation.

[0127] Toxicological studies have shown that TPGS is safe for ingestion by humans as a dietary or nutritional supplement. Moreover, the antioxidative properties of TPGS may improve the stability of TPGS containing formulations.Antioxidants

[0128] The cannabinoid formulations may optionally include one or more antioxidants. In some embodiments, the antioxidants are selected from the group consisting of TPGS, butylated hydroxytoluene (BHT); butylated hydroxyanisole; alpha-tocopherol (Vitamin E); ascorbyl palmitate; ascorbic acid; sodium ascorbate; ethylenediamino tetraacetic acid; cysteine hydrochloride; citric acid; sodium citrate; sodium bisulfate; sodium metabisulfite; lecithin; propyl gallate; sodium sulfate; and monothioglycerol. In some embodiments, the one or more antioxidants comprise TPGS. In some embodiments, the one or more antioxidants comprise BHT. In some embodiments, the one or more antioxidants comprise TPGS and BHT. In embodiments, the cannabinoid formulations described herein comprise from about 0.001% to about 20% by weight of an antioxidant. In some embodiments, the cannabinoid formulations described herein comprise about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight of an antioxidant.Ethanol

[0129] The cannabinoid formulations may optionally include one or more additional ingredients including a cosolvent such as ethanol.

[0130] Accordingly, in some embodiments, the cannabinoid formulations of the disclosure include (a) a cannabinoid, optionally CBD; (b) one or more fatty acid glycerol esters; (c) one or more polyethylene glycol-containing fatty acid esters; (d) ethanol, and optionally TPGS.

[0131] Cosolvents can enhance the emulsification process and influence the solubility of lipophilic compounds in simulated intestinal fluid. However, ethanol may also present an issue for safety or patient preference. In some embodiments, the formulations do not comprise ethanol.Sesame oil

[0132] A sesame oil-based formulation, Epidiolex®, is FDA-approved for the treatment of rare childhood epilepsies and tuberous sclerosis complex. Sesame oil may increase solubility and systemic exposure of a cannabinoid. Further, sesame oil facilitates intestinal lymphatic transport of CBD, effectively evading the first-pass effect to result in higher bioavailability. However, high variability in terms of absorption may be observed. Further, sesame oil may present an issue for patient safety, due to food allergies. In some embodiments, the formulations do not comprise sesame oil.Medium chain triglyceride oil (MCT)

[0133] The cannabinoid, e.g., CBD, formulations may optionally include one or more additional ingredients including a triglyceride, such as an MCT. Triglycerides (also known as triacylglycerol or triacylglyceride) are glycerides in which the glycerol is esterified with three fatty acids. Based on their chain length, triglycerides can be divided into three categories: (i) short chain triglycerides (SCT); (ii) medium chain triglycerides (MCT); and (iii) long chain triglycerides (LCT). Medium chain triglycerides have fattyacids ranging from about C8 to about CIO (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, S.A., Barcelona, Spain), BERGABEST® (available from Sternchemie, Hamburg, Germany), MIGL YOL® (available from Universal Preserv-A-Chem, Inc., Edison, NJ), NEOBEE® (available from Stepan Company, Northfield, Illinois), and CRODAMOL® (available from Croda, Edison, NJ).Methods of manufacturing SEDDS

[0134] The present disclosure provides methods of manufacturing SEDDS. In SEDDS, the oily solution that self-emulsifies is termed the preconcentrate. A bulk mixture of the drug-free preconcentrate may be prepared by mixing the excipients at 45 °C for about 30 min, stirring at about 300 rpm. The final preconcentrate may be prepared by adding the drug-free preconcentrate to the cannabinoid isolate, such that the concentration of cannabinoid reaches the intended concentration. The mixture may then be stirred at about 400 rpm and about 45 °C until approximately fully homogeneous. An illustrative embodiment of a method of manufacturing a cannabinoid SEDDS formulation is shown in FIG. 1Droplet dispersion

[0135] The disclosed cannabinoid SEDDS formulations include a cannabinoid, optionally CBD, that is both partially solubilized (dissolved) and present as solid particles to provide a fine solid dispersion. Dispersion of the formulations in aqueous media provides a nano-microemulsion.

[0136] The formulations may be characterized by droplet size and poly dispersity index (PDI) measured by dynamic light scattering (DLS) (Zetasizer Nano ZS, Malvern Instruments Ltd, UK) at about 37 °C. The preconcentrates may be dispersed in PBS (about 0.5% w / v) and stirred at about 100 rpm and about 37 °C for about 2 hours.

[0137] The formulations may, upon dispersal, form droplets that are submicron in size. In some embodiments, the formulations may form droplets of about 280 nm to about 500 nm initial diameter. In some embodiments, the formulations may form droplets of about 380 nm to about 480 nm initial diameter. In some embodiments, the formulationsmay form droplets of about 375nm to about 490 nm initial diameter. In some embodiments, the formulations may form droplets of about 429 nm initial diameter.

[0138] The formulations may, upon dispersal, form droplets with PDI values of about 0.2 to about 0.6. In some embodiments, the formulations may form droplets with PDI values of about 0.25 to about 0.4. In some embodiments, the formulations may form droplets with PDI values of about 0.2 to about 0.4. In some embodiments, the formulations may form droplets with PDI values of about 0.30.

[0139] The formulations may 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 formulations may be stored for at least about 3 months. The formulations may 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.

[0140] The formulations, following storage, may form droplets of about the same diameter as droplets formed by the formulations prior to storage. In some embodiments, the formulations, following storage, may form droplets of about 280 nm to about 650 nm initial diameter. In some embodiments, the formulations, following storage may form droplets of about 380 nm to about 570 nm initial diameter. In some embodiments, the formulations, following storage may form droplets of about 380 nm to about 490 nm initial diameter. In some embodiments, the formulations, following storage may form droplets of about 429 to about 489 nm initial diameter.

[0141] In some embodiments, the formulations, following storage under refrigerated conditions, may form droplets of about 400 nm to about 650 nm initial diameter. In some embodiments, the formulations, following storage under refrigerated conditions, may form droplets of about 425 nm to about 580 nm initial diameter. In some embodiments, the formulations, following storage at room temperature, may form droplets with about 400 nm to about 510 nm initial diameter. In some embodiments, the formulations, following storage under refrigerated conditions, may form droplets with about 420nm to about 490 nm initial diameter.

[0142] In some embodiments, the formulations, following storage at room temperature, may form droplets with about 310 nm to about 560 nm initial diameter. In some embodiments, the formulations, following storage at room temperature, may form droplets with about 380 nm to about 520 nm initial diameter. In some embodiments,the formulations, following storage at room temperature, may form droplets with about 370 nm to about 430 nm initial diameter. In some embodiments, the formulations, following storage at room temperature, may form droplets with about 390 nm to about 410 nm initial diameter.

[0143] The formulations, following storage, may form droplets with about the same PDI values as droplets formed by the formulations prior to storage. In some embodiments, the formulations, following storage, may form droplets with PDI values of about 0.05 to about 0.6. In some embodiments, the formulations, following storage, may form droplets with PDI values of about 0.14 to about 0.5. In some embodiments, the formulations, following storage under refrigerated conditions, may form droplets with PDI values of about 0.15 to about 0.45. In some embodiments, the formulations, following storage at room temperature, may form with PDI values of about 0.2 to about 0.35.

[0144] In some embodiments, the formulations, following storage under refrigerated conditions, may form droplets with PDI values of about 0.1 to about 0.6. In some embodiments, the formulations, following storage under refrigerated conditions, may form droplets with PDI values of about 0.14 to about 0.5. In some embodiments, the formulations, following storage under refrigerated conditions, may form droplets with PDI values of about 0.15 to about 0.45.

[0145] In some embodiments, the formulations, following storage at room temperature, may form droplets with PDI values of about 0.15 to about 0.55. In some embodiments, the formulations, following storage at room temperature, may form with PDI values of about 0.2 to about 0.5. In some embodiments, the formulations, following storage at room temperature, may form droplets with PDI values of about 0.15 to about 0.46. In some embodiments, the formulations, following storage at room temperature, may form with PDI values of about 0.2 to about 0.35.Drug solubilization

[0146] The disclosed cannabinoid SEDDS formulations effectively solubilize a cannabinoid such that the cannabinoid, optionally CBD, is present within the formulation at a concentration of at least about 1% by weight. In some embodiments, the formulations comprise a cannabinoid (e.g., CBD) in an amount greater than or equal to about 5%, greater than or equal to about 10%, greater than or equal to about 15%, greater than or equal to about 20%, greater than or equal to about 25%, greater than orequal to about 30%, greater than or equal to about 35%, greater than or equal to about 40%, greater than or equal to about 45%, greater than or equal to about 50%, or greater than or equal to about 55% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount from about 1% to about 60% by weight, about 20% to about 50% by weight, about 30% to about 50% by weight, or about 30% to about 40% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount from about 10% to about 50% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount from about 20% to about 40% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount at about 20% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount at about 25% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount at about 30% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount at about 35% by weight. In some embodiments, the formulations comprise a cannabinoid at about 40% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount at about 45% by weight. In some embodiments, the formulations comprise a cannabinoid in an amount at about 50% by weight.

[0147] The formulations may 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).

[0148] The stability of the cannabinoid SEDDS may be evaluated at a predetermined time point by, for example, diluting the preconcentrate in ethanol (1 : 1000), vortex mixing for about 20 seconds, sonicating in an ultrasonic bath (Sonoswiss AG, SW 3H, Switzerland) for about 5 min, and quantifying the cannabinoid via HPLC.

[0149] The formulations, following storage, e.g., 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), may maintain cannabinoid solubilization, measured as cannabinoid content (%), at approximately the same level as the cannabinoid content of the formulation prior to storage. In some embodiments, the formulations, following storage, may have a cannabinoid content (drug content) of about 80% to about 110%. In some embodiments, the formulations, following storage, may have a cannabinoid content of about 91% to about 104%.

[0150] In some embodiments, the formulations, following storage under refrigerated conditions, may have a cannabinoid content of about 94% to about 110%. In someembodiments, the formulations, following storage under refrigerated conditions, may have a cannabinoid content of about 96% to about 104%.

[0151] In some embodiments, the formulations, following storage at room temperature, may have a cannabinoid content of about 80% to about 104%. In some embodiments, the formulations, following storage at room temperature, may have a cannabinoid content of about 91% to about 100%. In some embodiments, the formulations, following storage at room temperature, may have a cannabinoid content of about 91% to about 95%.

[0152] To determine their effectiveness as orally administered formulations, the stability of representative cannabinoid formulations of the invention was evaluated in simulated gastric fluid.Drug dispersion and solubility in simulated gastric fluid

[0153] The disclosed cannabinoid SEDDS formulations maintain favorable dispersion profiles and effectively solubilize the cannabinoid, optionally CBD, in biorelevant media (e.g., simulated gastric fluid including, but not limited to, fasted state simulated gastric fluid [FaSSGF], fasted state simulated intestinal fluid [FaSSIF], and fed state simulated intestinal fluid [FeSSIF].

[0154] FaSSGF, FaSSIF, and FeSSIF are dissolution media that simulate human gut fluids. Each contains the same types and levels of surfactants (bile salt and phospholipid) 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 enhance drug solubility and dissolution greatly. pH and osmolarity can affect drug solubility and dissolution. FaSSGF comprises about 0.08 mM taurocholate, about 0.02 mM phospholipids, about 34 mM sodium, and about 59 mM chloride. FaSSIF comprises about 3 mM taurocholate, about 0.75 mM phospholipids, about 148 mM sodium, about 106 mM chloride, and about 29 mM phosphate. FeSSIF comprises about 15 mM taurocholate, about 3.75 mM phospholipids, about 319 mM sodium, about 203 mM chloride, and about 144 mM acetic acid. Powder and buffer concentrates of FaSSGF, FaSSIF, and FeSSIF were purchased from Biorelevant.com Ltd.

[0155] In some embodiments, following dispersion (0.5% w / v) in biorelevant media, the disclosed cannabinoid SEDDS formulations may have about 90% to about 100% ofthe cannabinoid, optionally CBD, solubilized within 30 minutes. In some embodiments, dispersions of the formulations in FaSSGF may have at least about 90% of the cannabinoid solubilized within 30 min for all formulations. In some embodiments, dispersions of the formulations in FaSSGF may have at least about 80% of the cannabinoid solubilized at 2 hours. In some embodiments, dispersions of the formulations in FaSSGF may have at least about 95% of the cannabinoid solubilized at 2 hours. In some embodiments, dispersions of the formulations in FaSSIF may have at least 90% of the cannabinoid solubilized within 30 minutes for all formulations. In some embodiments, dispersion of the formulations in FaSSIF may have at least about 90% of the cannabinoid solubilized at 2 hours. In some embodiments, dispersions of the formulations in FeSSIF may have at least about 60% of the cannabinoid solubilized within 30 minutes for all formulations. In some embodiments, dispersion of the formulations in FeSSIF may have at least about 40% of the cannabinoid solubilized at 2 hours.In vitro digestion of cannabinoid SEDDS Formulations

[0156] The solubilization properties of the disclosed cannabinoid, e.g., CBD, SEDDS formulations may be further characterized by in vitro digestion, for example, as described in (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). Following dispersion (2.5% w / v) of selected formulations in FaSSIF by stirring at about 100 rpm and about 37 °C for 10 minutes prior to the addition of pancreatic lipase (about 667 mg), and digestion for about 30 minutes, samples may be separated by centrifugation (20,800 x g, 15 min) into three layers: a top layer (oily phase), middle layer (aqueous micellar phase), and bottom layer (precipitated pellet phase), and cannabinoid content may be analyzed via HPLC from each phase after dilution in methanol.

[0157] In some embodiments, the formulations exhibit minimal precipitation (< 20%) and distribute primarily to the oil phase. In some embodiments, the formulations exhibit distribution of about 55% to about 75% cannabinoid, e.g., CBD, to the oil phase, about 18% to about 28% cannabinoid to the aqueous phase, and about 7% to about 21% cannabinoid to the pellet phase. In some embodiments, the formulations exhibit distribution of about 62% cannabinoid to the oil phase, about 23% cannabinoid to the aqueous phase, and about 15% cannabinoid to the pellet phase.Pharmacokinetics

[0158] The present disclosure provides cannabinoid, e.g. CBD, formulations that, following administration, may result in improved absorption and slower elimination compared to a medium chain triglyceride oil (MCT) cannabinoid formulation, also called cannabinoid MCT herein (optionally a MCT CBD formulation, also called CBD MCT herein). In some embodiments, the formulations, following administration, may result in a maximum plasma concentration (Cmax) that is about equal, at least as high, or higher than that resulting from administration of cannabinoid MCT. In some embodiments, the formulations, following administration, may result in a maximum plasma concentration (Cmax) that is about equal, at least as high, or higher than that resulting from administration of a sesame oil (SO) cannabinoid formulation, also called cannabinoid SO herein (optionally a SO CBD formulation, also called CBD SO herein). In some embodiments, the formulations, following administration, may result in a Cmax that is about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, 1.5-fold, about 1.6- fold, about 1.7-fold, about 1.8-fold, about 1.9-fold, or about 2.0-fold greater than that of a cannabinoid MCT. In some embodiments, the formulations, following administration, may result in a Cmax that is about 1.1-fold, about 1.2-fold, about 1.3- fold, about 1.4-fold, 1.5-fold, about 1.6-fold, about 1.7-fold, about 1.8-fold, about 1.9- fold, or about 2.0-fold greater than that of a cannabinoid SO. In some embodiments, the formulations, following administration, may result in a Cmax that is about 1.7-fold greater than that of a cannabinoid MCT. In some embodiments, the formulations, following administration, may result in a Cmax that is about 1.1-fold greater than that of a cannabinoid MCT.

[0159] In some embodiments, the formulations may: a) form, upon dispersal, droplets with a diameter within a specified range, and b) result, following administration, in a maximum plasma concentration (Cmax) greater than a certain value. In some embodiments, the formulations may: a) form, upon dispersal, droplets with a diameter of about 280 nM to about 500 nM in diameter, and b) result, following administration, in a maximum plasma concentration (Cmax) of 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. In some embodiments, the formulations may: a) form, upon dispersal, droplets with a diameter of about 380 nm to about 480 nm initial diameter, and b) result, following administration, in a maximum plasma concentration (Cmax) ofgreater 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. In some embodiments, the formulations may: a) form, upon dispersal, droplets with a diameter of about 375nm to about 490 nm initial diameter, and b) result, following administration, in a maximum plasma concentration (Cmax) of 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. In some embodiments, the formulations may: a) form, upon dispersal, droplets with a diameter of about 429 nm initial diameter, and b) result, following administration, in a maximum plasma concentration (Cmax) of 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. In some embodiments, the formulations may: a) form, upon dispersal, droplets with a diameter of about 429 nm initial diameter, and b) result, following administration, in a maximum plasma concentration (Cmax Cmax) of greater than 750 ng / mL.

[0160] In some embodiments, the formulations, following administration, may result in an area under the plasma concentration-time curve (AUC) from the time of administration (Oh) to 8 hours later (AUCo-8 h) values that are about equal, at least as high, or higher than that resulting from administration of cannabinoid MCT. In some embodiments, the formulations, following administration, may result in an AUCo-8 h that is about equal, at least as high, or higher than that resulting from administration of cannabinoid SO. In some embodiments, the formulations, following administration, may result in AUCo-8 h values that are about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, 1.5-fold, about 1.6-fold, about 1.7-fold, about 1.8-fold, about 1.9-fold, or about 2.0-fold greater than that of cannabinoid MCT. In some embodiments, the formulations, following administration, may result in AUCo-8 h values that are about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, or 1.5-fold greater than that of cannabinoid SO. In some embodiments, the formulations, following administration, may result in AUCo-8 h values that are about 1.9-fold greater than that of cannabinoid MCT. In some embodiments, the formulations, following administration, may result in AUCo-8 h values that are about 1.1 -fold greater than that of cannabinoid SO.

[0161] In some embodiments, the formulations, following administration, may have a time to reach maximum concentration (Tmax) that is about 30 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, or about 2 hours. In someembodiments, the formulations, following administration, may have a Tmax that is about 1.75h.Unit Dosage Forms and Administration

[0162] The present disclosure provides formulations suitable for administering a wide range of cannabinoid doses, optionally CBD doses. In some embodiments, the formulations enable higher drug loading of the cannabinoid active pharmaceutical ingredient, resulting in improved bioavailability and a reduced pill or capsule size. In addition, the SEDDS formulations disclosed herein provide increased AUC concentrations as compared to other formulations. The optimized formulations allow for a more efficient and convenient administration of the cannabinoid product, particularly for indications that require a high dose therapeutic range. The formulations and unit dosage forms allow the administration of higher doses of cannabinoid (e.g., CBD) than conventional formulations and unit dosage forms, including, e.g., doses greater than 1000 ng, e.g., doses of about 1,000 mg to at least about 3,000 mg, e.g., about 1,500 mg to about 2,000 mg.

[0163] In some embodiments, a single dose of any of the formulations 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 cannabinoid, optionally CBD. In some embodiments, a single dose of any of the formulations comprises about 100 mg to about 2,500 mg, about 500 mg to about 2,500 mg, about 1,000 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, about 1,500 mg to about 2,000 mg of cannabinoid, e.g., CBD. In some embodiments, a single dose (or unit dosage form) may comprise 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 50 mg to about 1,000 mg, of cannabinoid, optionally CBD. In some embodiments, a single dose may comprise 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 cannabinoid, optionally CBD. In some embodiments, one dose, two doses, or three doses may be administered per day.

[0164] The disclosure provides unit dosage forms of the cannabinoid formulations. In particular embodiments, the unit dosage form is formulated for oral delivery, e.g., as a liquid or in a tablet or capsule. In particular embodiments, a unit dosage form comprises a therapeutically effective amount of the cannabinoid formulation, or two or more, e.g., two or three or four, unit dosage forms together comprise a therapeutically effective amount of the cannabinoid formulation. In some embodiments, each unit dosage form comprises 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 of cannabinoid, optionally CBD. In some embodiments, a unit dosage form may comprise 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 50 mg to about 1,000 mg, of cannabinoid, optionally CBD. In some embodiments, a unit dosage form of any of the formulations comprises about 100 mg to about 2,500 mg, about 500 mg to about 2,500 mg, about 1,000 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, about 1,500 mg to about 2,000 mg of cannabinoid, e.g., CBD. In some embodiments, a unit dosage form may comprise 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 cannabinoid, optionally CBD. In some embodiments, two or more, e.g., two or three or four, unit dosage forms together comprise any of these total amounts of cannabinoid, e.g., CBD. In some embodiments, a unit dose comprises a range of a cannabinoid, e.g., CBD, formed from any two of the amounts disclosed herein, e.g., about 30 mg to about 300 mg.

[0165] In certain embodiments, a unit dosage form of the disclosed cannabinoid formulations comprises at least about 250 mg of cannabinoid, e.g., CBD, and a total weight of less than 1500 mg. In certain embodiments, a unit dosage form of the disclosed cannabinoid formulations comprises at least about 300 mg of cannabinoid, e.g., CBD, and a total weight of less than 1500 mg. In certain embodiments, a unit dosage form of the disclosed cannabinoid formulations comprises at least about 400 mg of cannabinoid, e.g., CBD, and a total weight of less than 1700 mg. In certain embodiments, a unit dosage form of the disclosed cannabinoid formulations comprisesat least about 500 mg of cannabinoid, e.g., CBD, and a total weight of less than 2000 mg.

[0166] In certain embodiments, the present disclosure provides cannabinoid formulations that can be orally administered, e.g., in soft or hard gelatin capsules and form fine relatively stable oil-in-water (o / w) emulsions, e.g., upon aqueous dilution owing to the gentle agitation of the gastrointestinal fluids. In particular embodiments, a unit dosage form is present within a soft or hard gelatin capsule.

[0167] In certain embodiments, the disclosure provides a capsule, e.g., a soft or hard gelatin capsule, comprising a disclosed cannabinoid formulation comprising at least about 250 mg of cannabinoid, e.g., CBD, and a total weight of less than 1500 mg. In certain embodiments, a capsule comprising a disclosed cannabinoid formulation comprises at least about 300 mg of cannabinoid, e.g., CBD, and a total weight of less than 1500 mg. In certain embodiments, a capsule comprising a disclosed cannabinoid formulation comprises at least about 400 mg of cannabinoid, e.g., CBD, and a total weight of less than 1700 mg. In certain embodiments, a capsule comprising a disclosed cannabinoid formulation comprises at least about 500 mg of cannabinoid, e.g., CBD, and a total weight of less than 2000 mg. In particular embodiments, the capsule comprises a gelatin cap or outer gelatin layer.

[0168] The present disclosure provides formulations and unit dosage forms suitable for administering a wide range of amounts of cannabinoid, optionally CBD, per day. In some embodiments, the cannabinoid formulation may be administered in an amount such as to administer in the range of about 10 mg to about 3,000 mg of cannabinoid per day. In some embodiments, the cannabinoid formulation may be administered in amount such as to administer about 50 mg to about 2,000 mg, or about 50 mg to about 1,000 mg, of cannabinoid per day. In some embodiments, the cannabinoid formulation may be administered in an amount such as to administer about 100 mg to about 2,500 mg, about 500 mg to about 2,500 mg, about 1,000 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, about 1,500 mg to about 2,000 mg of cannabinoid, e.g., CBD, per day. In some embodiments, the cannabinoid formulation may be administered in amount such as to administer 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 1,250mg, about 1,500 mg, about 2,000 mg, about 2,500 mg, or about 3,000 mg of cannabinoid per day. In some embodiments, a range of dose of a cannabinoid, e.g., CBD, formed from any two of the amounts disclosed herein, e.g., about 30 mg to about 300 mg, is administered.

[0169] In some embodiments in which the cannabinoid formulation, optionally the CBD formulation, is administered in a method of treating a disease or injury in a subject, wherein the disease or injury is Clinical High Risk for Psychosis, the cannabinoid formulation may be administered in an amount such as to administer about 600 to about 1,000 mg per day. In some embodiments in which the cannabinoid formulation, optionally the CBD formulation, is administered in a method of treating a disease or injury in a subject, wherein the disease or injury is insomnia, the cannabinoid formulation may be administered in an amount such as to administer 50-400 mg per day In some embodiments in which the cannabinoid formulation, optionally the CBD formulation, is administered in a method of treating a disease or injury in a subject, wherein the disease or injury is generalized anxiety disorder, the cannabinoid formulation may be administered in an amount such as to administer 300-600 mg per day. In some embodiments in which the cannabinoid formulation, optionally the CBD formulation, is administered in a method of treating a disease or injury in a subject, wherein the disease or injury is panic disorder, the cannabinoid formulation may be administered in an amount such as to administer 300-600 mg per day. In some embodiments in which the cannabinoid formulation, optionally the CBD formulation, is administered in a method of treating a disease or injury in a subject, wherein the disease or injury is post-traumatic stress disorder, the cannabinoid formulation may be administered in an amount such as to administer 100-600 mg per day. In some embodiments in which the cannabinoid formulation, optionally the CBD formulation, is administered in a method of treating a disease or injury in a subject, wherein the disease or injury is social anxiety disorder, the cannabinoid formulation may be administered in an amount such as to administer 300-600 mg per day. In some embodiments in which the cannabinoid formulation, optionally the CBD formulation, is administered in a method of treating a disease or injury in a subject, wherein the disease or injury is first-episode psychosis, the cannabinoid formulation may be administered in an amount such as to administer 600-1,000 mg per day. In some embodiments in which the cannabinoid formulation, optionally the CBD formulation, is administered in a method of treating a disease or injury in a subject, wherein thedisease or injury is psychosis in Parkinson’s, the cannabinoid formulation may be administered in an amount such as to administer 300-1,500 mg per day. In some embodiments in which the cannabinoid formulation, optionally the CBD formulation, is administered in a method of treating a disease or injury in a subject, wherein the disease or injury is schizophrenia, the cannabinoid formulation may be administered in an amount such as to administer 600-1,500 mg per day

[0170] The present disclosure provides cannabinoid formulations that, following oral administration, may result in cannabinoid concentrations in MLN that are higher than those in the liver. In some embodiments, the formulations, following oral administration, may result in a cannabinoid concentration within the MLN that is approximately the same as that attained with a cannabinoid sesame oil formulation. In some embodiments, the formulations, following oral administration, may result in cannabinoid concentrations in the spleen that are lower than the MLN, brain, liver, or kidney. In some embodiments, the formulations, following oral administration, may result in a cannabinoid concentration in the MLN that are about 9-fold to about 14-fold higher than the cannabinoid concentration in the spleen. In some embodiments, the formulations, following oral administration, may result in a tissue partition coefficient (Kp) for MLN that is higher than that of brain, liver, kidney, or spleen.Effect of Food on Cannabinoid SEDDS Formulation Pharmacokinetics

[0171] The present disclosure provides cannabinoid SEDDS formulations, optionally CBD SEDDS formulations, that are, to a measurable degree, food-agnostic. Specifically, the formulations provide favorable pharmacokinetics when administered with food, within up to 2 hours, up to 4 hours, or up to 8 hours or longer of food ingestion, or following fasting for at least 2-12 hours. In certain embodiments, the formulations are administered following fasting 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 / or up to at least about 2 hours prior to ingestion of food. In some embodiments, food is not ingested until at least about 2 hours following administration of the formulations. In some embodiments, food is ingested within about 2 hours prior to administration of the formulations. In some embodiments, the formulations are administered absent the ingestion of food for at least 2 hours prior to administration and at least 2 hours following administration. In some embodiments, the formulations are administered absent the ingestion of food for at least 4 hours prior to administration andat least 4 hours following administration. In some embodiments, the disclosed cannabinoid SEDDS formulations, following administration 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 ingestion of food, result in a cannabinoid Cmax at least about 50% of that following oral administration of the formulation at about the same time as food. In some embodiments, the formulations following administration 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 ingestion of food and up to at least 2 hours prior to ingestion of food, result in a cannabinoid AUCoo at least about 50% of that following oral administration of the formulation at about the same time as food.Methods of Administering Cannabinoid and Methods of Treatment

[0172] In some embodiments, the provided cannabinoid SEDDS formulations and unit dosage forms may be used in a method for administering a cannabinoid, optionally CBD, to a subject. In some embodiments, the formulations may be used for treatment of a disease or injury in a subject in need thereof, comprising administering or providing the cannabinoid SEDDS formulation or one or more unit dosage form to the subject. In certain embodiments, the cannabinoid SEDDS formulation or unit dosage form is provided to the subject with or without the subject fasting. In certain embodiments, the subject has eaten food or eats food at about the same time as the subject is administered the cannabinoid SEDDS formulation or one or more unit dosage form. In certain embodiments, the subject has eaten food or eats food 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 before the subject is administered the cannabinoid SEDDS formulation or unit dosage form(s). In certain embodiments, the subject is administered the cannabinoid SEDDS formulation or unit dosage form(s) about once a day, about twice a day, or about three times a day. In certain embodiments, the subject is administered the cannabinoid SEDDS formulation or unit dosage form(s) for at least or about one day, at least or about two days, at least or about three days, at least or about five days, at least or about one week, at least or about two weeks, at least or about one month, at least or about two months, at least or about four months, at least or about six months, at least or about one year, or longer.

[0173] In particular embodiments, the subject is orally administered a cannabinoid, optionally CBD, in the form of three or less capsules (e.g., one or two capsules) comprising a formulation disclosed herein (e.g., as SEDDS formulation), and in particular embodiments, each capsule comprises 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 particular embodiments, the subject is administered a total dose of about 400 mg to about 1500 mg (or about 600 mg to about 1000 mg) of the cannabinoid, optionally CBD, in the three or less capsules.

[0174] In certain embodiments, a subject is orally administered a dosage 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 of a cannabinoid in a formulation disclosed herein (e.g., a SEDDS formulation), e.g., in one or more capsules. In some embodiments, a range of dose of a cannabinoid, e.g., CBD, formed from any two of the amounts disclosed herein, e.g., about 1000 mg to about 3000 mg, is administered.

[0175] In certain embodiments, the disclosure provides a method for treatment of a disease or injury in a subject in need thereof, comprising administering or providing a cannabinoid (e.g., CBD) SEDDS formulation or one or more unit dosage form thereof to the subject in an amount sufficient to achieve a plasma AUC (e.g., AUCo-iast or AUCo- inf) of at least 2000 ng.h / mL. In certain 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 certain embodiments, the amount is sufficient to achieve a plasma AUC of about 2,000 ng.h / mL to about 5,000 ng.h / mL.

[0176] In related embodiments, the disclosure provides a method of treating a disease or injury in a subject, comprising providing to the subject a cannabinoid, e.g., CBD, 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 to about 5,000 ng.h / mL.

[0177] In various embodiments of the methods of treatment disclosed herein, the disease or injury is selected from the group comprising Clinical High Risk for Psychosis, insomnia, first-episode psychosis, psychosis in Parkinson’s disease, schizophrenia, general anxiety disorder, social anxiety disorder, panic disorder, post- traumatic stress disorder, Alzheimer’s disease, postpartum psychosis, agoraphobia,acute stress disorder, and schizoaffective disorder. In some embodiments, the disease or injury is Clinical High Risk for Psychosis. In some embodiments, the disease or injury is Insomnia.

[0178] In various embodiments of the methods of treatment disclosed herein, the disease or injury is selected from the group comprising generalized epilepsy, post- traumatic epilepsy, major depression, bipolar depression, postpartum depression, endometriosis, premenstrual disorder, premenstrual dysphoric disorder, mood changes during menopause, sleep disturbances during menopause, cognitive changes during menopause, and obsessive-compulsive disorder. In some embodiments, the disease or injury is selected from absence seizures, typical absence seizures, atypical absence seizures, atonic seizures, myoclonic seizures, infantile spasms (also called West Syndrome), juvenile myoclonic epilepsy, Lennox-Gastaut Syndrome, progressive myoclonic epilepsy, tonic-clonic seizures, tonic seizures, clonic seizers, status epilepticus, focal impaired awareness seizures, myoclonic epilepsy in infancy, genetic epilepsy with febrile seizures plus, early infantile epileptic encephalopathy (also called Ohtahara syndrome), early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, Dravet syndrome (also called severe myoclonic epilepsy in infancy), tuberous sclerosis complex, treatment-resistant epilepsy, childhood absence epilepsy, epilepsy with myoclonic absences, epilepsy with eyelid myoclonia (also called Jeavons syndrome), epilepsy with myoclonic-atonic seizures (also called myoclonic atonic epilepsy or Doose syndrome), developmental / epileptic encephalopathy with spike wave activation in sleep (also called continuous spike-wave in sleep, electrical status epilepticus in sleep, or Landau-Kleffner syndrome), febrile infection-related epilepsy syndrome (FIRES), hemiconvulsion-hemiplegia-epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, epilepsy with generalized tonic-clonic seizures alone, Rasmussen syndrome, progressive myoclonus epilepsies, Rett syndrome, CDKL5 deficiency disorder, benign rolandic epilepsy, and intractable childhood epilepsy. In some embodiments, the disease or injury is selected from Dravet syndrome, Lennox-Gastaut Syndrome, tuberous sclerosis complex, treatment-resistant epilepsy, infantile spasms, CDKL5 deficiency disorder, Aicardi syndrome, Doose syndrome, Dupl5 syndrome, SYNGAP1 epileptic encephalopathy, drug-resistant focal seizures, Sturge-Weber syndrome, febrile infection-related epilepsy syndrome, focal epilepsy, developmental and epileptic encephalopathies, and epilepsy with myoclonic absences.EXAMPLESExample 1 : Compositions of Oral Self-emulsifying Lipid-based Formulations.

[0179] Four cannabinoid SEDDS formulations (i.e., A, B, C, D) were developed (FIG. 1), each containing 20% w / w (CBD weight / total weight) (Table 1). SEDDS are an isotropic mixture of oils, surfactants, and / or cosolvents that spontaneously assemble into a colloidal dispersion or emulsion upon mixing with aqueous media, such as in the environment of the gastrointestinal tract. The oily solution that self-emulsifies is termed the preconcentrate.

[0180] A bulk mixture of the drug-free preconcentrate was prepared by mixing the excipients at 45 °C for 30 min, stirring at 300 rpm. The final preconcentrate was prepared by adding the drug-free preconcentrate to the CBD isolate, such that the concentration was 20% w / w CBD. This mixture was stirred at 400 rpm and 45 °C until fully homogeneous.

[0181] Each formulation contained a 50:50 (w / w) ratio of Peceol to Gelucire 44 / 14. The formulations varied in terms of the presence or absence of either an additional surfactant (TPGS) or cosolvent (anhydrous ethanol).Table 1: Summary of formulation compositions.Excipient (% w / w) Formulation CBD (% w / w) -Peceol Gelucire 44 / 14 TPGS EthanolCBD SEDDS A 20 38 38 4 —CBD SEDDS B 20 34.58 34.58 3.64 7.2CBD SEDDS C 20 40 40 — —CBD SEDDS D 20 36.4 36.4 — 7.2

[0182] In addition, a sesame oil formulation (CBD SO) was prepared based on previous reports (Kok, L. Y.; Bannigan, P.; Sanaee, F.; Evans, J. C.; 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 brief, 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). Sucralose and strawberry flavoring were dissolved in anhydrous ethanol, and vortex mixed for 20 seconds. Sesame oil was addedgravimetrically, and the solution was stirred at 250 rpm for 30 min. The sesame oil solution was then added to CBD such that the concentration was 10% w / w and stirred under the same conditions until fully homogeneous. CBD SO was stored away from direct light at room temperature until further use.

[0183] A formulation in caprylic / capric triglycerides (CBD MCT) was prepared by adding the oil to CBD such that the CBD concentration was 10% w / w. The MCT oil solution was stirred at 250 rpm until fully homogenous and stored away from direct light at room temperature until further use.Example 2: Characteristics and Stability of Cannabinoid SEDDS Formulations

[0184] The CBD SEDDS formulations were characterized by droplet size and poly dispersity index (PDI) measured by dynamic light scattering (DLS) (Zetasizer Nano ZS, Malvern Instruments Ltd, UK) at 37°C. The preconcentrates were 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 milky, translucent dispersions with no visible signs of drug precipitation. The resulting droplets were submicron in size, with initial diameter 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).Table 2: Summary of physicochemical properties and stability data for CBD SEDDS A, B, C, and D (mean ± SD). Preconcentrates (n = 3) were stored in the absence of light, under refrigerated conditions (i.e., 3-5 °C) and room temperature (i.e., 20-25 °C) for one month.2 weeks 1 monthTo 4 °C 25 °C 4 °C 25 °CCBD SEDDS ADrug content (%) 92.8 ± 4.6 103.2 ± 3.1 95.3 ± 3.4 98.0 ± 3.2 99.4 ± 4.1Drug solubilized at 1 h 97.6 ± 6.8 96.8 ± 12.9 91 .8 ± 2.8 96.2 ± 3.5 94.5 ± 11.8(%)Diameter (nm) 389 ± 103 573 ± 74 347 ± 21 457 ± 26 380 ± 64PDI 0.40 ± 0.12 0.50 ± 0.10 0.39 ± 0.09 0.39 ± 0.09 0.41 ± 0.13CBD SEDDS BDrug content (%) 98.2 ± 3.0 97.4 ± 2.9 95.8 ± 1 .7 97.9 ± 2.0 95.2 ± 1 .0Drug solubilized at 1 h 99.4 ± 5.6 95.2 ± 11.6 98.6 ± 4.0 93.2 ± 8.7 105.0 ± 2.1(%)Diameter (nm) 477 ± 35 502 ± 42 509 ± 48 571 ± 45 512 ± 26PDI 0.37 ± 0.07 0.41 ± 0.05 0.41 ± 0.16 0.37 ± 0.07 0.50 ± 0.07CBD SEDDS CDrug content (%) 93.0 ± 1.7 103.4 ± 6.5 95.0 ± 0.7 96.4 ± 1.4 91.6 ± 10.4Drug solubilized at 1 h 98.1 ± 6.7 94.5 ± 3.4 106.0 ± 3.2 98.1 ± 2.3 96.3 ± 2.1(%)Diameter (nm) 429 ± 59 489 ± 20 392 ± 20 429 ± 30 403 ± 22PDI 0.30 ± 0.10 0.45 ± 0.11 0.20 ± 0.05 0.15 ± 0.04 0.34 ± 0.12CBD SEDDS DDrug content (%) 94.6 ± 0.8 95.0 ± 0.7 95.6 ± 1.0 97.0 ± 1.0 96.1 ± 1.3Drug solubilized at 1 h 97.1 ± 11.4 99.0 ± 7.8 89.5 ± 2.2 97.7 ± 2.2 100.5 ± 5.4(%)Diameter (nm) 458 ± 23 443 ± 19 477 ± 48 487 ± 44 422 ± 22PDI 0.25 ± 0.07 0.18 ± 0.07 0.29 ± 0.05 0.14 ± 0.06 0.25 ± 0.04

[0185] The size of the dispersion droplets appeared to be directly related to the drug loading level across the four formulations, with blank formulations exhibiting roughly half the diameter of the formulations investigated (FIG. 2). Oil formulations (i.e., CBD SO, CBD MCT) were not evaluated in terms of their dispersibility as they were not found to disperse.

[0186] Drug solubilization was assessed for formulations with varying CBD content following dispersion (0.5% w / v) for 1 h at 37°C in phosphate buffered saline for a series of preliminary filtered dispersions (FIG. 3A) and selected unfiltered dispersions (FIG. 3B). Formulations 1, 2, 3 and 4 correspond to CBD SEDDS A, CBD SEDDS B, CBD SEDDS C, and CBD SEDDS D. Formulations 1 and 3 in FIG. 3B correspond to CBD SEDDS A and C, respectively, when loaded at 20% w / w CBD. Formulation 2 in FIG. 2B comprises Peceol: Gelucire 44 / 14: TPGS at 45.6%: 30.4%: 4% w / w and Formulation 4 in FIG. 3B comprises Peceol: Gelucire 50 / 13 at 48%: 32% w / w. None of the dispersions exhibited noticeable drug precipitation. Filtering dispersions was found to increase variability of the drug solubilization measurements, but the average solubilization was consistent with unfiltered dispersions.

[0187] Stability of the CBD SEDDS formulations, with respect to dispersal profiles, was assessed under refrigerated conditions and at room temperature. Storage of the preconcentrates under refrigerated conditions or room temperature did not drastically change the droplet diameter or PDI over the course of one month (Table 2). Dispersion profiles of CBD SEDDS A, B, C, and D were maintained stably following storage ateither room temperature or under refrigerated conditions for one month (FIG. 4). Dispersion profiles for all four formulations were found to be stable following storage at room temperature for three months (FIG. 5).

[0188] The CBD content of the preconcentrates remained stable at room temperature for three months (FIG. 6). While all formulations maintained a CBD concentration within 10% of the initial measurement, overall lower variability was observed for formulations containing ethanol (CBD SEDDS B and D) relative to those without the cosolvent (CBD SEDDS A and C). The chemical stability of CBD in the SEDDS formulations was comparable to stability in a sesame oil (SO) formulation (FIG. 7).Example 3: Dispersion of Cannabinoid SEDDS Formulations in Simulated Gastric Fluid

[0189] Dispersion of the CBD SEDDS formulations was assessed in biorelevant media: fasted state simulated gastric fluid (FaSSGF), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF), compared to phosphate buffered saline (PBS). FaSSGF, FaSSIF, and FeSSIF are dissolution media that simulate human gut fluids. Each contains the same types and levels of surfactants (bile salt and phospholipid) 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 enhance drug solubility and dissolution greatly. pH and osmolarity can affect drug solubility and dissolution. FaSSGF comprises about 0.08 mM taurocholate, about 0.02 mM phospholipids, about 34 mM sodium, and about 59 mM chloride. FaSSIF comprises about 3 mM taurocholate, about 0.75 mM phospholipids, about 148 mM sodium, about 106 mM chloride, and about 29 mM phosphate. FeSSIF comprises about 15 mM taurocholate, about 3.75 mM phospholipids, about 319 mM sodium, about 203 mM chloride, and about 144 mM acetic acid. Powder and buffer concentrates of FaSSGF, FaSSIF, and FeSSIF were purchased from Biorelevant.com Ltd.

[0190] CBD SEDDS were dispersed (0.5% w / v) in biorelevant media (FaSSIF, FaSSGF, or FeSSIF) and stirred at 100 rpm and 37 °C. At 5, 30, 60, and 120 min, 800 pL aliquots of the dispersion were removed and the media was replenished. The dispersion aliquots were diluted in methanol prior to HPLC analysis. All biorelevant media were prepared according to supplier information, using buffer concentrates.

[0191] Differential media effects were observed with regard to the amount of CBD solubilized over the course of 2 h (FIG. 8). In general, dispersion profiles for all formulations in FaSSIF appeared similar to those in PBS, with over 90% CBD solubilized for the duration of the study. For dispersions in FaSSGF, at least 90% of CBD was solubilized within 30 min for all formulations. Beginning at 1 h, the CBD solubilized in all FaSSGF dispersions decreased, but remained above 80% throughout the duration of the study. In contrast, dispersion profiles in FeSSIF showed a markedly lower quantity of CBD was solubilized relative to the other biorelevant media dispersions. Dispersions of CBD SEDDS A and C in FeSSIF were the most dissimilar, based on Frechet distance, from any other formulations dispersed in any other media (FIG. 9A). Further, dispersions of CBD SEDDS A and C in FeSSIF were significantly different in terms of the dispersion profile area under the curve (AUC) relative to the same formulations dispersed in FaSSIF (FIG. 9B). These dispersions exhibited signs of creaming, which was more pronounced during the later timepoints of the study. CBD SEDDS B and D dispersions in FeSSIF did not appear to show the same signs of creaming.Example 4: In Vitro Digestion of Cannabinoid SEDDS Formulations

[0192] The disposition of CBD following in vitro digestion for 30 minutes was evaluated for CBD SEDDS C and D (FIG. 10).

[0193] In brief, a dispersion (2.5% w / v) of selected CBD SEDDS was prepared in 40 mL FaSSIF. The media was stirred at 100 rpm and 37 °C throughout the duration of the study. The dispersion was allowed to stir for 10 min, followed by the addition of pancreatic lipase (667 mg) to initiate digestion. After 30 min of digestion, 800 pL aliquots of the media were removed and separated by centrifugation (20,800xg, 15 min) into three layers: a top layer (oily phase), middle layer (aqueous micellar phase), and bottom layer (precipitated pellet phase). CBD content from each phase was analyzed via HPLC after dilution in methanol.

[0194] For CBD SEDDS C, CBD was distributed at 62 ± 6%, 23 ± 5%, and 15 ± 6% in the oil, aqueous, and pellet phases, respectively. The amount of CBD recovered from the oil, aqueous, and pellet phases of CBD SEDDS D was 72 ± 2%, 19 ± 1%, and 9 ± 2%, respectively. In general, the two formulations exhibited minimal precipitation. Neither formulation was found to contain a pellet phase in control samples from the initial 10 min dispersion (i.e., prior to digestion). Before the addition of pancreaticlipase, the aqueous phase of CBD SEDDS C contained significantly higher CBD than that of CBD SEDDS D (p < 0.01), with approximately 47 ± 4% and 24 ± 1%, respectively.Example 5: Pharmacokinetic Parameters of Cannabinoid Formulations In Vivo

[0195] The pharmacokinetics of CBD SEDDS C and D were evaluated and compared to that of CBD MCT and SO following oral administration to rats at a dose of 20 mg / kg (FIG. 11)

[0196] For pharmacokinetic studies, rats were administered a CBD medium chain triglyceride oil (CBD MCT), CBD sesame oil vehicle (CBD SO), or one of two selfemulsifying drug delivery systems (i.e., CBD SEDDS C or CBD SEDDS D) by oral gavage at a dose of 20 mg / kg CBD (n = 5 per formulation group). The SEDDS formulations were freshly prepared 30 min before each experiment, by pre-diluting the preconcentrates in deionized water (1 :20 w / v) followed by vortex mixing for 20 seconds. Blood samples (200 pL) were collected via the lateral saphenous vein at 0.25, 0.5, 1, 2, 4, and 6 h (with 1.5 and 3 h timepoints for the CBD MCT group) after administration into heparinized tubes. At 8 h after administration, rats were sacrificed through cardiac puncture and blood was collected, followed by decapitation. Blood samples collected during the study were centrifuged (1000 x g, 10 min, 4 °C; 15 min for terminal sample) to obtain plasma, which were transferred to microcentrifuge tubes and stored at -80 °C pending further analysis.

[0197] A second cohort of rats were administered the CBD SO, CBD SEDDS C, and CBD SEDDS D formulations (n = 5 per formulation group) in a subsequent pharmacokinetic and tissue distribution study to home in on the window around the expected maximum plasma concentration. In this study, blood samples were collected and stored in the same manner as before at 0.5, 1, 1.5, 2, and 3 h, with terminal blood collection at 4 h following administration of the formulation.

[0198] Plasma aliquots (50 pL) were added to microcentrifuge tubes containing 2 pL of internal standard (THC; 100 pg / mL in methanol) pre-dried under a nitrogen evaporator (Glas-Col ZipVap, Terre Haute, IN, USA). Each tube was filled with 450 pL of acetonitrile: ethyl acetate (50:50 v / v), then vortex mixed for 10 min and centrifuged (15,300 x g, 10 min, 4 °C). The supernatant (400 pL) was transferred to an autosampler vial and dried under nitrogen at 37 °C. The samples were then reconstituted in 150 pL of methanol, vortex mixed, and centrifuged again under the same conditions,before being transferred to autosampler vial inserts for subsequent analysis via HPLC- tandem mass spectrometry (HPLC-MS / MS).

[0199] The plasma concentration-time profiles revealed comparable performance between the CBD SO, CBD SEDDS C, and CBD SEDDS D formulations, and both noticeably higher absorption and slower elimination for each of these formulations compared to CBD MCT (FIG. 12). Table 3 summarizes the corresponding pharmacokinetic parameters. No statistical differences were obtained between CBD SO or CBD MCT and either SEDDS formulation.Table 3: Pharmacokinetic parameters. Data are presented as mean ± SEM, n > 5.Tmax is presented as median and range.Formulation CmaxTmax(h) AUCM hAUC0_8hAUCo_ t1 / 2(h) kei(h1) AUCo_iast / (ng / mL) [range] (h x ng / mL) (h x ng / mL) (h x ng / mL) AUCo_CBD MCT 449 ± 1.5 967 ± 142 1198 ± 168 1328 ± 159 2.7 ± 0.8 0.31 ± 0.05 0.89 ± 0.0361 [1-2]CBD SO 688 ± 1 1615 ± 419 2146 ± 671 2634 ± 766 2.9 ± 1.3 0.45 ± 0.07 0.80 ± 0.05146 [0.25-2]CBD SEDDS C 768 ± 1.75 1926 ± 226 2291 ± 310 3133 ± 338 3.2 ± 0.9 0.37 ± 0.08 0.73 ± 0.0595 [0.5-2]CBD SEDDS D 784 ± 1 1741 ± 301 2087 ± 388 3405 ± 762 3.9 ± 1.5 0.32 ± 0.06 0.72 ± 0.07198 [0.5-2]

[0200] Though not statistically significant, the Cmax and systemic exposure of CBD from the CBD SO, CBD SEDDS C, and CBD SEDDS D was modestly higher than CBD MCT. Respective Cmaxfor CBD SO, CBD SEDDS C, and CBD SEDDS D were 1.5-fold, 1.7-fold, and 1.8-fold greater than that of CBD MCT. In terms of AUCo-s h values, CBD SO, CBD SEDDS C, and CBD SEDDS D were 1.8-fold, 1.9-fold, and 1.7-fold greater than that of CBD MCT, respectively. The median Tmax for CBD SO and CBD SEDDS D was 1 h, whereas it was 1.75 h for CBD SEDDS C and 1.5 h for CBD MCT. (FIGs. 13A-13D). The Cmaxand AUC values for CBD SEDDS C and D were marginally higher than CBD SO. Within 8 h of oral administration, the fraction of total exposure observed was approximately 73% for CBD SEDDS C and 72% for CBD SEDDS D. By contrast, CBD SO and CBD MCT achieved 80% and 89% of their total exposure within the same period. It is worth noting that lower variability was observed for CBD SEDDS C and CBD MCT (FIG. 14 and FIG. 15).Example 6: Tissue Distribution After Oral Administration of Cannabinoid SEDDS Formulations

[0201] The distribution of CBD in brain, liver, kidney, spleen, and MLN was assessed at 4 hours after oral administration to the second cohort of rats described in Example 5 of 20mg / kg of CBD in CBD SO, CBD SEDDS C, or CBD SEDDS D (FIG. 16).

[0202] As quickly as possible after exsanguination, tissues (i.e., brain, liver, kidney, spleen, mesenteric lymph node (MLN) were collected, rinsed with PBS, and flash frozen in dry ice. The tissues were stored at -80 °C pending further analysis. Tissue samples (approximately 100-250 mg) were weighed in glass vials and homogenized 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 pL; 30 pL for MLN) was transferred to a microcentrifuge tube containing 2 pL of internal standard (THC; 100 pg / mL in methanol) pre-dried under nitrogen, and 1.35 mL (270 pL for MLN) of acetonitrile: ethyl acetate (50:50 v / v) was added. The mixture was vortex mixed for 10 min and placed in an ultrasonic bath for 10 min at room temperature before being centrifuged (15,300 x g, 10 min, 4 °C). The supernatant (1.4 mL; 250 pL for MLN) was transferred to an autosampler vial and dried under nitrogen at 37 °C. The samples were then reconstituted in 150 pL of methanol, vortex mixed, and centrifuged again under the same conditions, before being transferred to autosampler vial inserts for subsequent analysis via HPLC-MS / MS.

[0203] For all formulations, the highest concentrations of CBD were found in MLN, which were approximately double the levels in the liver. CBD SO resulted in a significantly higher concentration of CBD in the MLN compared with CBD SEDDS D (p < 0.05), but not CBD SEDDS C. The lowest CBD concentrations were found in the spleen across all formulations. Compared to the CBD concentration in the spleen, MLN concentrations were 11.4-fold higher for CBD SO, 13.2-fold higher for CBD SEDDS C, and 9.5-fold higher for CBD SEDDS D.

[0204] Tissue partition coefficient values were calculated were calculated as the ratio between the CBD concentration in each tissue and the respective plasma concentration at 4 hours (Table 4). The tissue partition coefficient was largest for MLN for each of the formulations. These findings corroborate that cannabinoid uptake by lymph plays a significant role in its absorption following oral administration in LCT-containing lipid- based formulations. Moreover, they underscore that SO as a delivery vehicle is not necessary to achieve the desired absorption effects with SEDDS formulations.Table 4. Summary of Tissue Partition Coefficients. Data are presented as mean ± SEM, n = 5. Partition coefficient values (Kp) were calculated as the ratio between the CBD concentration in each tissue and the respective plasma concentration at 4 hours.Tissue partition coefficient (Kp) FormulationBrain Liver Kidney Spleen MLNCBD SO 29.2 ± 3.0 148.1 ± 78.8 30.0 ± 2.9 16.7 ± 2.3 305.4 ± 151.2CBD SEDDS C 11.6 ± 2.0 45.0 ± 7.9 15.7 ± 3.4 7.0 ± 0.9 94.2 ± 8.4CBD SEDDS D 16.7 ± 1.8 37.4 ± 3.0 26.7 ± 7.2 9.7 ± 2.2 92.8 ± 19.5Example 7: Pharmacokinetic Parameters of Cannabinoid SEDDS Formulations inFasted Animals

[0205] The pharmacokinetics of CBD SEDDS C was assessed in fasted and non-fasted Sprague-Dawley rats following oral administration to rats at a dose of 20 mg / kg (FIG. 17, FIG. 18) The plasma concentration-time profiles reveal that plasma CBD levels reach a higher peak in non-fasted versus fasted animals. Table 5 summarizes the corresponding pharmacokinetic parameters. The Cmax and systemic exposure of CBD were approximately 1.5-fold and 1.75-fold higher, respectively in non-fasted animals compared with fasted animals. AUCo values were approximately 1.6-fold greater in non-fasted animals, and the median Tmax was 1.75 hours in non-fasted animals, whereas it was 1 hour in fasted animals. Within 8 h of oral administration, the fraction of total exposure observed was approximately 73% for in non-fasted animals and 92% in fasted animals.Table 5. Pharmacokinetic parameters. Data are presented as mean ± SEM, n > 5).Tmax is presented as median and range.Fasted Cmax Tmax (h) AUCo-4 h AUCo-8 h AUCo-°° kel (hAUCo-last / (ng / mL) [range] (h x ng / mL) (h x ng / mL) (h x ng / mL) AUCo-°°No 768 ± 95 1.75 [0.5-2] 1926 ± 226 2291 ± 310 3133 ± 338 0.37 ± 0.08 0.73 ± 0.05Yes 521 ± 86 1 [0.5-1.5] 1192 ± 232 1450 ± 292 1566 ± 305 0.35 ± 0.03 0.92 ± 0.01Example 8: Pharmacokinetic Parameters of Cannabinoid Formulations In Vivo

[0206] The increased bioavailability of a CBD SEDDS formulation as compared to other CBD formulations was examined. The pharmacokinetics of a CBD SEDDS formulation (encapsulated micellar cannabidiol (EMCBD)) was evaluated andcompared to that of cannabidiol active pharmaceutical ingredient (CBD API) and a sesame-oil (SO) formulation following oral administration to fed or fasting rats at a dose of 20 mg / kg according to the study design shown in FIG. 19.

[0207] For Groups 1 and 4 (CBD API), a 121.8 mg sample of CBD Isolate was combined with an appropriate amount of vehicle consisting of 40% HPBCD. Groups 2 and 5 EMCBD; SEDDS formulation), a pre-drug concentrate (PDC) was formulated by adding 1 g each of Peceol and Gelucire to a vial followed by heating to 45 °C for 30 min. while stirring at 300 rpm. The final preconcentrate was prepared by adding 1.00 g of the drug-free PDC to 0.470 g of CBD Isolate, such that the concentration was 32% w / w. This mixture was stirred at 400 rpm and 45 °C until fully homogenous. The SEDDS formulation was then freshly prepared before dosing, by pre-diluting the preconcentrates in 30 mL of deionized water (1 :80 w / v, e.g., 0.25 of the 32% w / w preconcentrate in 20 mL water) followed by vortex mixing 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 gravimetrically, and the product was stirred at 250 rpm for 30 minutes. The sesame oil mixture was then added to 0.330 g of CBD Isolate such that the concentration was 10% w / w and stirred under the same conditions until fully homogenous. The concentrations of CBD Isolate in dosing solutions were determined by LC-MS / MS.

[0208] Female Sprague-Dawley rats, aged between 52-61 days, were administered a dose of 20 mg / kg CBD (n = 8 per formulation group). Blood was collected at 0.5, 1, 2, 3, 4, 8, and 24 h post-dose from jugular vein. Plasma samples were yielded after centrifugation, and frozen until plasma concentrations of CBD were determined by LC- MS / MS. The plasma concentration of CBD Isolate in rats was subjected to a noncompartmental pharmacokinetic analysis by using the Phoenix WinNonlin software (version 8.3, Certara USA, Inc). Nominal times were used in the PK parameter times. Peak plasma concentrations (Cmax) and the corresponding peak times (Tmax) were determined directly from the plasma concentration versus time profiles. Individual plasma concentration values for PO dosed animals that were below the lower limit of quantitation (LLOQ) before Tmax were set to zero, and those after Tmax were excluded from the PK parameter calculation. Terminal half-life (T 1 / 2), the area under the plasma concentration-time curve (AUC) from time zero to last quantifiable concentration (AUCo-iast) and AUC from time zero extrapolated to infinity (AUCo-inf), mean residencetime (MRT) from time zero to the last quantifiable concentration (MRTO-last) and from time zero to infinity (MRTO-inf) were calculated using the linear up log down rule. All plasma concentrations and PK parameters are reported with at least three significant figures. A one-way ANOVA model with the treatment of food as a fixed factor and the In-transformed analysis value as a dependent variable was used to estimate the treatment / food effect on Cmax and AUCo-iast.

[0209] The average values for the key PK parameters are summarized in FIG. 20. FIGs. 21-25 provide graphical representations of average values of key PK parameters obtained from fed or fasted animals following administration of the different CBD formulations.

[0210] Based on Cmax and on AUCo-iast, CBD bioavailability was higher with the SEDDS formulation (EMCBD) than with the HPBCD formulation (CBD API) after fasted administration and even more after fed administration (FIGs. 21 and 24). CBD AUCo-iast was also higher with the SEDDS formulation than with the SO formulation (CBD WO) after fasted administration and even more after fed administration (FIG. 24). Cmax with the SEDDS formulation was lower than with the SO formulation after fasted administration, while it was higher with the SEDDS formulation than with the SO formulation after fed administration (FIG. 21). CBD bioavailability was increased by food intake with the SEDDS formulation, while the slight food effect for the HPBCD formulation and SO formulation was not relevant relative to the observed inter-animal PK variability. These results demonstrate superior bioavailability of the CBD SEDDS formulations, which was enhanced by food intake.

[0211] All publications, U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, mentioned herein and / or listed in the Application Data Sheet are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction.

[0212] From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited.

Claims

CLAIMS1. A cannabinoid formulation, comprising: a cannabinoid; one or more fatty acid glycerol esters; and one or more polyethylene glycol -containing fatty acid esters.

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

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

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

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

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

8. The formulation of any of claims 1-7, wherein the one or more fatty acid glycerol esters comprise glyceryl oleate (Peceol).

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

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

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

12. The formulation of claim 11, wherein the fatty acid glycerol esters and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 40% by weight.

13. The formulation of claim 10, wherein the fatty acid glycerol esters and polyethylene glycol-containing fatty acid esters 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-a-tocopherol polyethylene glycol 1000 succinate (TPGS) is present in the formulation in an amount from about 3% to about 4% by weight.

15. The formulation of claim 14, wherein the fatty acid glycerol esters and polyethylene glycol-containing fatty acid esters 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 glycerol esters and polyethylene glycol-containing fatty acid esters are each present in the formulation at about 34.58% by weight, and wherein TPGS is 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 of any of claims 9-16, wherein the polyethylene glycol-containing fatty acid esters comprise lauroyl polyoxylglycerides (Gelucire 44 / 14).

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

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

20. The formulation of any of claims 1-19, wherein a single dose of the formulation comprises at least 50 milligrams of the cannabinoid.

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

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

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

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

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

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

27. The formulation of any of claims 1-26, wherein the formulation is administered in a method of treating a disease or injury in a subject, wherein the formulation is administered in an amount such as to administer about 50 to about 3,000 milligrams of the cannabinoid per day.

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

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

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

31. The formulation of claim 28, wherein the formulation is administered in a method of treating a disease or injury in a subject, wherein the formulation is administered in an amount such as to administer about 600 mg of the cannabinoid per day32. The formulation of claim 28, wherein the formulation is administered in a method of treating a disease or injury in a subject, wherein the formulation is administered in an amount such as to administer about 1,000 mg of the cannabinoid per day.

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

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

35. The formulation of any of claims 1-34, wherein the formulation does not comprise sesame oil or ethanol.

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

37. The formulation of any of claims 1-36, wherein the Cmax of cannabinoid following oral administration of the formulation is at least about equivalent to that following oral administration of a cannabinoid sesame oil formulation.

38. The formulation of any of claims 1-37, wherein the systemic exposure (AUCoo) of cannabinoid following oral administration of the formulation is at least about equivalent to that following oral administration of a cannabinoid sesame oil formulation.

39. The formulation of any of claims 1-38, wherein the Cmax of cannabinoid following oral administration of the formulation 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 ingestion of food and up to at least about 2 hours prior to ingestion of food is at least about 50% of that following oral administration of the formulation at about the same time as food.

40. The formulation of any of claims 1-39, wherein the systemic exposure (AUCoo) of cannabinoid following oral administration of the formulation 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 ingestion of food and up to at least about 2 hours prior to ingestion of food is at least about 50% of that following oral administration of the formulation at about the same time as food.

41. A formulation comprising greater than about 5% cannabinoid by weight.

42. The formulation of claim 41, comprising about 10% to about 50% cannabinoid by weight.

43. The formulation of claim 42, comprising about 20% cannabinoid by weight.

44. The formulation of claim 42, comprising about 40% cannabinoid by weight.

45. A capsule comprising the formulation of any of claims 1-44.

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

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

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

49. The method of claim 48, wherein the disease or injury is selected from the group comprising Clinical High Risk of Psychosis, insomnia, first episode psychosis, psychosis in Parkinson’s disease, schizophrenia, general anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, Alzheimer’s disease, postpartum psychosis, agoraphobia, acute stress disorder, and schizoaffective disorder.

50. The method of claim 49, wherein the disease or injury is Clinical High Risk of Psychosis.

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

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

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

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