Oral preparations of cannabinoids

Abstract

This disclosure provides cannabinoid formulations having advantages such as high drug load and stability, as well as related methods for manufacturing and using these formulations. This disclosure also provides compositions for formulating therapeutic agents. The compositions are effective in solubilizing therapeutic agents, particularly those that are difficult to solubilize. In some embodiments, this disclosure provides cannabinoid formulations comprising a cannabinoid, one or more fatty acid glycerol esters, and one or more polyethylene glycol-containing fatty acid esters. In some embodiments, the cannabinoid is cannabidiol.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Application No. 63 / 530,613 filed on 3 August 2023 and U.S. Provisional Application No. 63 / 648,085 filed on 15 May 2024, each of which is incorporated herein by reference in whole for all purposes.

[0002] (Field of Invention) The present invention relates to a cannabinoid formulation and a method for using the same. [Background technology]

[0003] Oral drug administration is often preferred because it provides the most convenient and typically the least expensive route for patients and helps improve compliance. These advantages lead to high demand, reflected in the number of drugs approved for oral administration. Despite the advantages of oral delivery, challenges remain regarding the suitability of drugs for this route. A growing number of compounds with low solubility and / or permeability have been noted in the drug development pipeline. If these compounds are not properly formulated, their translational capacity is reduced by insufficient and variable oral bioavailability.

[0004] Many cannabinoids are natural and synthetic compounds structurally or pharmacologically related to components of the cannabis plant or endogenous agonists (endogenous cannabinoids) of cannabinoid receptors CB1 or CB2, and such formulations face challenges. Cannabinoids present in the cannabis plant include tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), as well as more than 100 natural cannabinoids, including cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivaric acid (CBDVA), cannabidiol-C1 (CBD-C1), cannabidiol-C4 (CBD-C4), and cannabidiol monomethyl ether (CBDM). Cannabidiol (CBD), one of the major cannabinoids derived from the cannabis plant, represents one such compound. It is a highly lipophilic drug with low water solubility (estimated to be <13 μg / mL) and undergoes extensive first-pass metabolism.

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[0005] To date, the only FDA-approved CBD formulation is Epidiolex®, a sesame oil-based solution indicated for the treatment of rare childhood epilepsy and tuberous sclerosis. However, sesame oil formulations are limited by variability in absorption, patient allergies, limited drug load, and low stability. Furthermore, Epidiolex® contains ethanol, which is unfavorable for use in certain patient populations. After opening, Epidiolex® must be used completely within 12 weeks. This limited shelf life increases the cost of the approved treatment. Therefore, there is a need for a formulation that can improve CBD absorption without relying on sesame oil as an excipient, given its associated drawbacks. [Overview of the project] [Means for solving the problem]

[0006] This disclosure provides compositions for formulating therapeutic agents. The compositions are effective in solubilizing therapeutic agents, particularly those that are difficult to solubilize.

[0007] In some embodiments, the present disclosure provides cannabinoid formulations comprising a cannabinoid, one or more fatty acid glycerol esters, and one or more polyethylene glycol-containing fatty acid esters.

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

[0009] In some embodiments, cannabinoids are present in the formulation in an amount greater than about 5% by weight. In some embodiments, cannabinoids are present in the formulation in an amount of about 10% to about 50% by weight. In some embodiments, cannabinoids are present in the formulation in an amount of about 20% by weight. In some embodiments, cannabinoids are present in the formulation in an amount of 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 include glyceryl oleate (Peceol). In some embodiments, the one or more polyethylene glycol-containing fatty acid esters include one or more of lauroyl polyoxylglyceride (Gelucire44 / 14), GELUCIRE® 48 / 16, GELUCIRE® 50 / 13, GELUCIRE® 59 / 14, and Labrasol ALF.

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

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

[0013] In some embodiments, the polyethylene glycol-containing fatty acid ester includes lauroyl polyoxyl glyceride (Gelucire 44 / 14).

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

[0015] In some embodiments, a single dose of the formulation includes at least 50 milligrams of cannabinoid. In some embodiments, a single dose of the formulation includes cannabinoid in the range of about 50 to about 2,000 milligrams. In some embodiments, the single dose includes 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 cannabinoid. In some embodiments, the single dose includes about 100 milligrams of cannabinoid. In some embodiments, the single dose includes about 300 milligrams of cannabinoid. In some embodiments, the single dose includes about 600 milligrams of cannabinoid. In some embodiments, the single dose includes about 1,000 milligrams of cannabinoid. <7000103><7000104><7000105>In some embodiments, when the formulation is administered in a manner to treat a disease or injury in a subject, the formulation is administered in amounts such as approximately 50 to approximately 3,000 milligrams of cannabinoids per day. In some embodiments, when the formulation is administered in a manner to treat a disease or injury in a subject, the formulation is administered in amounts such as approximately 50 milligrams, approximately 100 milligrams, approximately 200 milligrams, approximately 300 milligrams, approximately 400 milligrams, approximately 500 milligrams, approximately 600 milligrams, approximately 700 milligrams, approximately 800 milligrams, approximately 900 milligrams, approximately 1,000 milligrams, approximately 1,250 milligrams, approximately 1,500 milligrams, approximately 2,000 milligrams, approximately 2,500 milligrams, or approximately 3,000 milligrams of cannabinoids per day. In some embodiments, when the formulation is administered in a manner to treat a disease or injury in a subject, the formulation is administered in amounts such as approximately 100 mg of cannabinoids per day. In some embodiments, when the formulation is administered in a method of treating a disease or injury in a subject, the formulation is administered in a dose such as approximately 300 mg of cannabinoids per day. In some embodiments, when the formulation is administered in a method of treating a disease or injury in a subject, the formulation is administered in a dose such as approximately 600 mg of cannabinoids per day. In some embodiments, when the formulation is administered in a method of treating a disease or injury in a subject, the formulation is administered in a dose such as approximately 1,000 mg of cannabinoids 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 contain sesame oil or ethanol.

[0018] In some embodiments, the concentration of cannabinoids is maintained at an amount exceeding approximately 80% of the starting concentration after storage at room temperature for up to 3 months. In some embodiments, the Cmax of cannabinoids after oral administration of the formulation is at least approximately equivalent to the Cmax of cannabinoids after oral administration of the cannabinoid sesame oil formulation. In some embodiments, the systemic exposure (AUC) of cannabinoids after oral administration of the formulation is maintained. ∞ This is at least approximately equivalent to systemic exposure to cannabinoids after oral administration of cannabinoid sesame oil preparations.

[0019] In some embodiments, the Cmax of cannabinoids after oral administration of the formulation up to at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, or at least about 10 hours after food intake, and at least about 2 hours before food intake, is at least about 50% of the Cmax of cannabinoids after oral administration of the formulation approximately simultaneously with food intake. In some embodiments, the systemic exposure (AUC) of cannabinoids after oral administration of the formulation up to at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, or at least about 10 hours after food intake, and at least about 2 hours before food intake. 0-∞) This accounts for at least approximately 50% of systemic exposure to cannabinoids after oral administration of a formulation nearly simultaneously with food.

[0020] In some embodiments, the disclosure provides formulations containing more than about 5% by weight of cannabinoids. In some embodiments, the formulations contain about 10% to about 50% by weight of cannabinoids. In some embodiments, the formulations contain about 20% by weight of cannabinoids. In some embodiments, the formulations contain about 40% by weight of cannabinoids.

[0021] In some embodiments, the present disclosure provides capsules containing any of the formulations disclosed herein. In some embodiments, the capsules are soft gel capsules.

[0022] In some embodiments, the present disclosure provides a method for administering cannabinoids to a subject, which includes administering one of the formulations disclosed herein or one of the capsules disclosed herein.

[0023] In some embodiments, the Disclosure provides a method for treating a disease or injury in a person requiring treatment of the disease or injury, the method comprising administering one of the formulations disclosed herein or one of the capsules disclosed herein.

[0024] In some embodiments, the disease or injury is selected from the group including clinically high-risk psychosis, insomnia, first-episode psychosis, psychosis in Parkinson's disease, schizophrenia, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, Alzheimer's disease, postpartum psychosis, agoraphobia, acute stress disorder, and schizoaffective disorder. In some embodiments, the disease or injury is clinically high-risk psychosis. In some embodiments where the disease or injury is clinically high-risk 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, each present in the formulation at approximately 40% by weight. In some embodiments, the disease or injury is insomnia. In some embodiments where 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 approximately 40% by weight. [Brief explanation of the drawing]

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

[0026] [Figure 2] Bar graphs showing the mean ± SD droplet diameter for SEDDS formulations containing various concentrations of CBD. All formulations were dispersed in phosphate-buffered saline (0.5% w / v), and the resulting droplet sizes were measured after stirring at 100 rpm and 37°C for 2 hours. The mean polydispersity index was <0.5 for all formulations.

[0027] [Figure 3A] Drug solubilization of SEDDS formulations with various CBD content was performed after dispersing a series of pre-filtered dispersions (Figure 3A) in phosphate-buffered saline at 37°C for 1 hour (0.5% w / v). Formulations 1 and 3 correspond to CBD SEDDS A and C, respectively, when filled with 20% w / w CBD. None of the dispersions showed significant drug precipitation. Filtration of the dispersions was found to increase the variability of drug solubilization measurements, but the average solubilization was consistent with that of the unfiltered dispersions. [Figure 3B] Drug solubilization of SEDDS formulations with various CBD content was performed on selected unfiltered dispersions (Figure 3B) after dispersion in phosphate-buffered saline at 37°C for 1 hour (0.5% w / v). Formulations 1 and 3 correspond to CBD SEDDS A and C, respectively, when filled with 20% w / w CBD. None of the dispersions showed significant drug precipitation. Filtration of the dispersions was found to increase the variability of drug solubilization measurements, but the average solubilization was consistent with that of the unfiltered dispersions.

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

[0029] [Figure 5] Dispersion profiles (mean ± SD) of CBD SEDDS A, B, C, and D after storage for 3 months at room temperature (i.e., 20–25°C) in the absence of light. Preliminary concentrates (n=3) were dispersed in PBS at 0.5% w / v each day.

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

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

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

[0033] [Figure 9A] Heatmap of Fréchet distance values ​​for the dispersion profiles of each CBD SEDDS formulation (i.e., A, B, C, D) in various media (i.e., FaSSGF, FaSSIF, FeSSIF, PBS) (Figure 9A). Statistical analysis was performed using a stratified-ranked 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. [Figure 9B] Bar graphs (mean ± SD) of scaled area under the curve (AUC) values ​​for the variance profiles of each CBD SEDDS formulation (i.e., A, B, C, D) in various media (i.e., FaSSGF, FaSSIF, FeSSIF, PBS) (Figure 9B). Statistical analysis was performed using a sorted-ranked two-way ANOVA with Tukey's post-hoc comparison test. Statistical differences compared to CBD SEDDS C variant in FaSSIF: *p<0.05, ***p<0.001. Statistical differences compared to CBD SEDDS A variant in FaSSIF: *p<0.05.

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

[0035] [Figure 11] Schematic diagram of pharmacokinetic studies. CBD preparations were administered orally at a dose of 20 mg / kg on day 0, and blood samples were then taken from the saphenous vein at the indicated time points. n=5-10 animals / group. The preparations tested were CBD medium-chain triglyceride oil (MCT), CBD SO, CBD SEDDS C, and CBD SEDDS D.

[0036] [Figure 12] Figure 11 shows the plasma concentration-time profiles of CBD after oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D. Data are shown as mean ± SEM, n≧5. The inset shows a plasma concentration-time plot with a semi-logarithmic axis. At 2 hours, the top-to-bottom lines correspond to CBD SEDDS C, CBD SO, CBD SEDDS D, and CBD MCT.

[0037] [Figure 13A] As shown in Figure 11, a visual overview of pharmacokinetic parameters obtained after oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D. Box plots of time to observed maximum plasma concentration (Tmax) are shown (Figure 13A), with each observation represented by an "x". [Figure 13B] As shown in Figure 11, a visual overview of pharmacokinetic parameters obtained after oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D. Box plot of observed maximum CBD plasma concentration (Cmax) (Figure 13B). [Figure 13C] As shown in Figure 11, a visual overview of pharmacokinetic parameters obtained after oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D. Bar graph of area under the plasma concentration-time curve from 0 to 8 hours (mean ± SEM, n≧5) (Figure 13C). [Figure 13D] As shown in Figure 11, a visual overview of pharmacokinetic parameters obtained after oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D. Bar graph of the area under the extrapolated plasma concentration-time curve (mean ± SEM, n≧5) (Figure 13D).

[0038] [Figure 14] Box plots showing the plasma concentration-time profiles of CBD after oral administration of CBD MCT, CBD SO, CBD SEDDS C, and CBD SEDDS D, as shown in Figure 11. n≧5. Empty dots represent the mean value.

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

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

[0041] [Figure 17] Plasma concentration-time profiles of CBD after oral administration of 20 mg / kg CBD SEDDS C in fasted and non-fasted rats. Data are shown as mean ± SEM, n≧5. At time=2 hours, the upper line represents non-fasted rats, and the lower line represents fasted rats.

[0042] [Figure 18] Box plots showing the plasma concentration-time profiles of CBD after oral administration of 20 mg / kg CBD SEDDS C in fasted and non-fasted rats. n≧5. Empty dots represent the mean. For each time point, the bars from left to right correspond to non-fasted and fasted rats, respectively.

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

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

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

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

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

[0048] [Figure 24] Box plots showing the AUC0-end (ng.h / mL) of CBD in fed rats and fasted rats treated with different CBD formulations. For each formulation, the left bar represents fed rats, and the right bar represents fasted rats.

[0049] [Figure 25] Box plots showing the AUC0-infinity (ng.h / mL) of CBD in fed rats and fasted rats treated with different CBD formulations. For each formulation, the left bar represents fed rats, and the right bar represents fasted rats. [Modes for carrying out the invention]

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

[0051] Self-emulsifying drug delivery systems (SEDDSs) are an example of advanced lipid-based formulations that can be used to enhance the absorption of cannabinoids, including CBD. Simply put, SEDDSs are isotropic mixtures of oils, surfactants, and / or cosolvents that, when mixed with an aqueous medium, such as in the gastrointestinal tract environment, spontaneously assemble into a colloidal dispersion or emulsion. SEDDSs offer the potential to address the need for CBD-containing cannabinoid formulations by increasing their apparent solubility and delivering higher therapeutic doses. Definition:

[0052] The following terms are assumed to be well understood by those skilled in the art, but the following definitions are provided for the convenience of explaining the subject matter of this disclosure.

[0053] The terms "a" or "an" can refer to one or more of their entities, that is, to multiple referents. Similarly, the terms "a" or "an," "one or more," and "at least one" are used interchangeably herein. In addition, a reference to an "element" with the indefinite article "a" or "an" does not rule out the possibility of two or more elements existing unless the context explicitly requires that the element be unique.

[0054] As used herein and in the claims, the phrase “and / or” should be understood to mean “either or both” of the elements thus connected, i.e., elements that exist in some cases contiguously and in other cases separately. Multiple elements enumerated by “and / or” should be interpreted similarly, that is, “one or more” of the elements thus connected. Other elements other than those specifically identified by the “and / or” clause may exist at their discretion, whether related to or unrelated to the specifically identified elements. For this reason, as a non-restrictive example, a reference to “A and / or B” when used in conjunction with an unrestrictive word such as “including” may, in one embodiment, refer to A only (including elements other than B at their discretion), in another embodiment, refer to B only (including elements other than A at their discretion), and in yet another embodiment, refer to both A and B (including other elements at their discretion), and so on.

[0055] As used herein in this specification and in the claims, the phrase “at least one” with respect to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of all elements specifically enumerated in the list of elements, nor excluding combinations of elements in the list of elements. This definition also allows for the existence of elements other than those specifically identified in the list of elements, which are referred to by the phrase “at least one,” whether related to or unrelated to the specifically identified elements, at the discretion of the definition. Therefore, as a non-restrictive 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”) could mean, in one embodiment, at least one A that is absent (and optionally includes elements other than B) and optionally includes two or more elements; in another embodiment, at least one B that is absent (and optionally includes elements other than A) and optionally includes two or more elements; and in yet another embodiment, at least one A that optionally includes two or more elements, and at least one B that optionally includes two or more elements (and optionally includes other elements), and so on.

[0056] Throughout this application, the term “approximately” is used to indicate that a value includes inherent error variability in the device or method employed to determine that value, or variability present between the samples being measured. In some embodiments, the term “approximately” means within 5% of the reported numerical value. When used in conjunction with a range of values ​​or a set of values, the term “approximately” applies to the endpoints of the range or to each of the sequentially listed values, unless otherwise indicated.

[0057] As used herein, the verb “includes” and its conjugations as used herein and in the claims are used in their non-restrictive sense, meaning that the items following the word are included, but not excluded, except for items not specifically mentioned.

[0058] It should be further noted that the claims may be drafted to exclude any optional element. Therefore, this statement is intended to serve as an antecedent for the use of exclusive terms such as “simply,” “only,” or “consisting of,” or for the use of “negative” limitations in relation to the enumeration of the elements of the claims.

[0059] "Subject" refers to a living animal, particularly a mammal, that can be treated with the pharmaceutical compositions described herein. In some embodiments, the subject is a human. In some embodiments, the human subject is a human child, a human teenager, or a human adult. In some embodiments, the subject or patient is a non-human animal, including a mouse, rat, pig, dog, rabbit, monkey, or other non-human primate, or a research animal such as a goat.

[0060] As used herein, “Prescription” encompasses the term “Composition.” Therefore, “Prescription” may refer to a composition containing one or more cannabinoids. Additionally or alternatively, “Prescription” may refer to a composition containing one or more cannabinoids together with one or more pharmaceutically acceptable excipients.

[0061] As used herein, “activator” refers to a drug substance that produces a desired biological effect (e.g., cannabinoid, optionally CBD). It should be understood that, as used herein, CBD is an exemplary embodiment of a cannabinoid, and CBD formulations are exemplary embodiments of a cannabinoid formulation. The term “cannabidiol” and the abbreviation “CBD” are used interchangeably herein and refer to molecules conforming to the following structure. Furthermore, the activators of the formulations described herein include prodrugs and derivatives of CBD, in addition to biologically derived and synthetically derived CBD. [ka]

[0062] All weight percentages referred to herein (i.e., "% by weight", "% by weight", and "% w / w") are measured relative to the total weight of the formulation or particles, as per the context, unless otherwise indicated.

[0063] As used herein, “primary” should be understood to mean containing a greater weight percent than any other. For example, the primary form of a fatty acid glycerol ester (e.g., monoglyceride) is the one present in greater quantities than any other single form of that fatty acid glycerol ester.

[0064] As used herein, “dose” refers to the amount of a preparation containing one or more cannabinoids administered to a patient in a therapeutically effective amount. For example, a dose may be one tablet or one capsule containing one of the preparations disclosed herein.

[0065] As used herein, “to treat” and “to treat” mean reducing the severity and / or frequency of symptoms, eliminating symptoms and / or underlying causes, reducing the likelihood of symptoms and / or underlying causes occurring, and improving or addressing damage. Accordingly, “treating” a patient with the activators provided herein includes inhibiting a particular condition, disease or disorder in a susceptible individual, and treating an individual with clinical symptoms.

[0066] As used herein, “effective dose” refers to an amount that includes both the therapeutic effective dose and the preventive effective dose. As used herein, “therapeutic effective dose” refers to an amount that is effective in achieving the desired therapeutic outcome. The therapeutic effective dose of a given activator typically varies with respect to the type and severity of the disorder or disease being treated, as well as factors such as the patient's age, sex, and weight. SEDDS preparations

[0067] This disclosure provides formulations containing cannabinoids, including CBD. In some embodiments, the formulations are SEDDS formulations. As used herein, the terms “cannabinoid SEDDS formulation” and “cannabinoid SEDDS” are interchangeable and refer to the SEDDS formulations disclosed herein that contain cannabinoids. As used herein, “CBD SEDDS formulation” and “CBD SEDDS” are interchangeable and refer to the SEDDS formulations disclosed herein that contain CBD. SEDDS are isotropic mixtures of oils, surfactants, solvents, and co-solvent / surfactant. SEDDS can be used in formulation design to improve the absorption of highly lipophilic drug compounds, such as cannabinoids, after oral administration. When mixed with an aqueous medium, such as in the gastrointestinal tract environment, SEDDS spontaneously aggregate into a colloidal dispersion or emulsion. Furthermore, when the SEDDS composition is released into the lumen of the intestine, the composition disperses to form coarse, fine, or microemulsions, so that the drug remains in the intestinal solution, avoiding the dissolution process that often limits the absorption rate of hydrophobic drugs from a crystalline state. The use of SEDDS typically results in improved bioavailability and / or a more consistent temporal profile of intestinal absorption. A description of the composition of SEDDS can be found in CWPouton, Advanced Drug Delivery Reviews 25:47-58 (1997).

[0068] In the context of cannabinoids, including CBD, SEDDS has been demonstrated to improve systemic exposure compared to MCT oil or non-fat solutions (Cherniakov et al. Eur.J.Pharm..Sci., 2017, 109, 21-30; Knaub et al. Molecules. 2019, 24 (16), 2967; Nakano et al. Med.Cannabis Cannabinoids. 2019, 2 (1), 35-42; Kok et al. Eur.J.Pharm..Sci. 2022, 168, 106058; De Pra et al. Int.J.Pharm. 2021, 609, 121159). SEDDS formulations containing sesame oil have been reported to produce a more predictable plasma concentration-time profile, although they do not show a relative improvement in absorption compared to sesame oil as the sole vehicle (Izgelov et al. Eur.J.Pharm.Biopharm.2020,154,108-115). This disclosure provides SEDDS formulations that provide improved gastrointestinal absorption and systemic exposure of cannabinoids, including CBD, after oral administration. In some embodiments, these formulations do not contain sesame oil. In some embodiments, these formulations do not contain ethanol.

[0069] In some embodiments, the present disclosure provides cannabinoid formulations, which are cannabinoid formulations. Cannabinoids, CBD and other options as desired. One or more fatty acid glycerol esters, It contains one or more polyethylene glycol-containing fatty acid esters.

[0070] In some embodiments, the formulation contains cannabinoids, such as CBD, in an amount of about 1% by weight or more. In some embodiments, the formulation contains cannabinoids in an amount of about 5% by weight or more, about 10% by weight or more, about 15% by weight or more, about 20% by weight or more, about 25% by weight or more, about 30% by weight or more, about 35% by weight or more, about 40% by weight or more, about 45% by weight or more, about 50% by weight or more, or about 55% by weight or more. In some embodiments, the formulation contains cannabinoids in an amount of about 70% by weight or less, about 65% by weight or less, about 60% by weight or less, about 55% by weight or less, about 50% by weight or less, about 45% by weight or less, about 40% by weight or less, about 35% by weight or less, about 35% by weight or less, about 30% by weight or less, or about 25% by weight or less. In some embodiments, the formulation contains cannabinoids in an amount of about 1% by weight to about 60% by weight. In some embodiments, the formulation contains cannabinoids in amounts of about 10% to about 50% by weight. In some embodiments, the formulation contains cannabinoids in amounts of 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 formulation contains cannabinoids in amounts of about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight. In some embodiments, the formulation contains cannabinoids, e.g., CBD, in amounts of about 20% by weight. In some embodiments, the formulation contains cannabinoids, e.g., CBD, in amounts of about 30% by weight. In some embodiments, the formulation contains cannabinoids, e.g., CBD, in amounts of about 40% by weight. In some embodiments, the formulation contains cannabinoids, e.g., CBD, in amounts of about 40% by weight. For example, it ranges from approximately 15% to 40% by weight.

[0071] In some embodiments, the formulation contains CBD in an amount of about 1% by weight or more. In some embodiments, the formulation contains CBD in an amount of about 5% by weight or more, about 10% by weight or more, about 15% by weight or more, about 20% by weight or more, about 25% by weight or more, about 30% by weight or more, about 35% by weight or more, about 40% by weight or more, about 45% by weight or more, about 50% by weight or more, or about 55% by weight or more. In some embodiments, the formulation contains CBD in an amount of about 70% by weight or less, about 65% by weight or less, about 60% by weight or less, about 55% by weight or less, about 50% by weight or less, about 45% by weight or less, about 40% by weight or less, about 35% by weight or less, about 35% by weight or less, about 30% by weight or less, or about 25% by weight or less. In some embodiments, the formulation contains CBD in an amount of about 1% by weight to about 60% by weight. In some embodiments, the formulation contains CBD in an amount of about 10% by weight to about 50% by weight. In some embodiments, the formulation contains about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight of CBD. In some embodiments, the formulation contains about 20% by weight of CBD. In some embodiments, the formulation contains about 30% by weight of CBD. In some embodiments, the formulation contains about 40% by weight of CBD. In some embodiments, the formulation contains CBD within a range of weight percent formed from any two of the disclosed weight percent, for example, about 15% by weight to about 40% by weight.

[0072] This disclosure provides cannabinoid SEDDS formulations comprising one or more fatty acid glycerol esters and one or more polyethylene glycol (PEG)-containing fatty acid esters. In some embodiments, the formulation comprises one or more fatty acid glycerol esters and one or more PEG-containing fatty acid esters in a ratio ranging from about 30:70% by weight to about 70:30% by weight. In some embodiments, the formulation comprises one or more fatty acid glycerol esters and one or more PEG-containing fatty acid esters in a ratio ranging from about 40:60% by weight to about 60:40% by weight. In some embodiments, the formulation comprises one or more fatty acid glycerol esters and one or more polyethylene oxide-containing fatty acid esters in a ratio ranging from about 50:50% by weight. In some embodiments, one or more fatty acid glycerol esters include glyceryl oleate (e.g., Peceol®), and one or more PEG-containing fatty acid esters include PEG-containing fatty acid esters derived from fatty acids containing saturated and unsaturated fatty acids having 8 to 22 carbon atoms (e.g., Gelucire 44 / 14®). Fatty acid glycerol ester contained in SEDDS preparations

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

[0074] Fatty acid glycerol esters useful for formulations can be supplied from commercially available sources. Typical sources of fatty acid glycerol esters are mixtures of mono-, di-, and triesters, commercially available as PECEOL® (Gattefosse, Saint Priest Cedex, France), and are commonly referred to as "glyceryl oleate" or "glyceryl monooleate."

[0075] The functions of PECEOL® include solubilizing and bioavailability enhancing for lipophilic compounds. In some embodiments, PECEOL® is used to solubilize long-chain fatty acids (C) of type I (lipophilic), type II (SEDDS), and type III (SMEDDS) of the lipid formulation classification system (LFCS) related to lymphatic absorption. 18:1 It is a vehicle containing ). 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 from its generally recognized as safe (GRAS) status and priority of use in approved medicinal products.

[0076] In certain embodiments, when PECEOL® is used as a source of fatty acid glycerol esters in a formulation, the fatty acid glycerol esters consist of about 32 to about 52% by weight of fatty acid monoglycerides, about 30 to about 50% by weight of fatty acid diglycerides, and about 5 to about 20% by weight of fatty acid triglycerides. In some embodiments, PECEOL® contains mono-, di-, and triglycerides of oleic acid (C18:1), with the monoester fraction being dominant.

[0077] In certain embodiments, the formulations of the present disclosure may contain glycerol in an amount of less than about 10% by weight. Polyethylene glycol-containing fatty acid esters included in SEDDS preparations

[0078] As described above, CBD preparations contain one or more polyethylene glycol (PEG) modified lipids, such as PEG-containing phospholipids or one or more PEG-containing fatty acid esters, typically a mixture of PEG-containing phospholipids or a mixture of PEG-containing fatty acid esters.

[0079] Therefore, in one embodiment, the CBD formulation of the present disclosure comprises (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 containing polyethylene glycol groups (i.e., PEG groups) covalently bonded to a fatty acid via ester bonds. As used herein, the terms “polyethylene glycol,” “polyethylene oxide,” and “PEG” are used interchangeably. Examples of PEG-containing fatty acid esters include mono- and di-fatty acid esters of PEG. Preferred PEG-containing fatty acid esters are derived from fatty acids containing saturated and unsaturated fatty acids having 8 to 22 carbon atoms (i.e., PEG esters of C8-C22 fatty acids). In certain embodiments, preferred PEG-containing fatty acid esters are derived from fatty acids containing saturated and unsaturated fatty acids having 8 to 18 carbon atoms (i.e., PEG esters of C8-C18 fatty acids). In certain embodiments, preferred PEG-containing fatty acid esters contain saturated C8-C18 fatty acids.

[0081] The molecular weight of the PEG group in PEG-containing fatty acid esters can be varied to optimize the solubility of the therapeutic agent (e.g., cannabinoid, optionally CBD) in the formulation. Typical average molecular weights of PEG groups can range from approximately 350 to approximately 7000 g / mol. In one embodiment, the average molecular weight of the PEG group is approximately 1500. In another embodiment, the average molecular weight of the PEG group is approximately 6000. In yet another embodiment, the average molecular weight of the PEG group is approximately 400.

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

[0083] PEG-containing fatty acid esters useful for formulations can be provided by commercially available sources. Representative PEG-containing fatty acid esters (mixtures of mono- and diesters) are commercially available under the name GELUCIRE® (Gattefosse, Saint Priest Cedex, France). Exemplary 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 numbers in these GELUCIRE® names refer to the melting point and hydrophilic / lipophilic balance (HLB) of the substance, 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 (glycerides) of glycerol and (b) mono- and diesters (macrogol) of polyethylene glycol. 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 triglyceride esters and (b) mono- and diesters of PEG. In some embodiments, the PEG is PEG-32 (MW 1500), PEG-150 (MW 6000), or PEG-8 (MW 400). In some embodiments, GELUCIRE® 44 / 14, GELUCIRE® 50 / 13, GELUCIRE® 59 / 14, or Labrasol ALF further comprises free PEG (e.g., PEG-32, PEG-150, or PEG-8).

[0085] In some embodiments, the PEG-containing fatty acid ester of GELUCIRE® 48 / 16 comprises a mixture of PEG monoesters and diesters. In some embodiments, the PEG-containing fatty acid ester of GELUCIRE® 48 / 16 consists of a mixture of PEG monoesters and diesters. In some embodiments, the PEG is PEG-32 (MW1500). In some embodiments, GELUCIRE® 48 / 16 further comprises free PEG (e.g., PEG-32).

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

[0087] In some embodiments, lauric acid (C12) is the main fatty acid component of the glycerides and polyethylene glycol esters in GELUCIRE® 44 / 14. GELUCIRE® 44 / 14 is called 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 glyceride EP, or lauroyl polyoxylglyceride 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 contains 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 acid (C18:1), with the monoester fraction being dominant.

[0088] In some embodiments, GELUCIRE® 44 / 14 contains lauric acid (C12) ester (30-50%), myristic acid (C14) ester (5-25%), palmitic acid (C16) ester (4-25%), stearic acid (C18) ester (5-35%), caprylic acid (C8) ester (less than 15%), and capric acid (C10) ester (less than 12%). GELUCIRE® 44 / 14 may also contain free glycerol (typically less than about 1%) and ethylene oxide <1 ppm.

[0089] In some embodiments, GELUCIRE® 48 / 16 is polyethylene glycol monostearate (Type I) NF and comprises PEG-32 (MW1500) esters of palmitic acid (C16) and stearic acid (C18). In some embodiments, GELUCIRE® 48 / 16 consists of PEG-32 (MW1500) esters of palmitic acid (C16) and stearic acid (C18).

[0090] In some embodiments, GELUCIRE® 50 / 13 is stearoyl polyoxyl / macrogol 32 glyceride NF / EP, comprising mono-, di-, and triglycerides, as well as PEG-32 (MW1500) mono- and diesters of palmitic acid (C16) and stearic acid (C18). In some embodiments, GELUCIRE® 50 / 13 consists of mono-, di-, and triglycerides, as well as PEG-32 (MW1500) mono- and diesters of palmitic acid (C16) and stearic acid (C18).

[0091] In some embodiments, GELUCIRE® 59 / 14 comprises small amounts of mono-, di-, and triglycerides, as well as PEG-32 (MW1500) mono- and diesters of lauric acid (C12) and PEG-150 (MW6000).

[0092] In some embodiments, Labrasol ALF comprises small amounts of mono-, di-, and triglycerides, as well as PEG-8 (MW400) mono- and diesters, mainly of caprylic acid (C8) and capric acid (C10).

[0093] The functions of GELUCIRE® 44 / 14 include (a) a solubilizer and bioavailability enhancer for poorly soluble compounds, (b) a single excipient formulation system that self-emulsifies in aqueous fluids to form microemulsions LFCS type III (SMEDDS), (c) a wetting agent, and (d) a lipid binder in melt processes. Safety of use is inferred from extensive toxicological evaluations and priority of use in approved medicinal products. The functions of GELUCIRE® 48 / 16 include (a) a solubilizer and bioavailability enhancer for low logP (measure of lipophilicity) compounds, (b) a single excipient formulation system that self-emulsifies in aqueous fluids to form micellar solutions LFCS type IV, (c) use in melt processes (granulation, extrusion), granulation, and compression, and (d) a wetting agent. Safety of use is inferred from priority of use in approved medicinal products. The functions of GELUCIRE® 50 / 13 include (a) solubilizers and bioavailability enhancers for poorly soluble compounds, (b) single-excipient formulations that self-emulsify in aqueous fluids to form crude emulsions LFCS type III (SMEDDS), (c) drug release modifiers, and (d) lipid binders in melting processes. Safety of use is inferred from toxicological data and priority of use in approved medicinal products. The functions of GELUCIRE® 59 / 14 include (a) solubilizers and bioavailability enhancers for poorly soluble compounds, and (b) single-excipient formulations that self-emulsify in aqueous fluids to form microemulsions LFCS type III (SMEDDS). Safety of use is inferred from extensive toxicological evaluations and priority of use in approved medicinal products. Safety of use is inferred from priority of use in approved medicinal products. The functions of Labrasol ALF include (a) a solubilizer and bioavailability enhancer for poorly soluble compounds, (b) a single excipient formulation system that self-emulsifies in aqueous fluids to form microemulsions LFCS type III (SMEDDS), and (c) high purity with guaranteed stability and capsule compatibility. Safety of use is inferred from extensive toxicological data and priority of use in approved medicinal products. Safety of use is inferred from the status of food additives and priority of use in approved medicinal products.

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

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

[0096] In one embodiment, the cannabinoid formulation of the present disclosure comprises a cannabinoid (optionally CBD), PECEOL®, and GELUCIRE® 44 / 14. In embodiments, the ratio of PECEOL® to GELUCIRE® 44 / 14 may be 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 may be 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 present disclosure comprises a cannabinoid (optionally CBD), PECEOL®, and GELUCIRE® 48 / 16. In these embodiments, the ratio of PECEOL® to GELUCIRE® 48 / 16 may be 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® 48 / 16 may be 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 present disclosure comprises a cannabinoid (optionally CBD), PECEOL®, and GELUCIRE® 50 / 13. In these embodiments, the ratio of PECEOL® to GELUCIRE® 50 / 13 may be 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 may be 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 present disclosure comprises a cannabinoid (optionally CBD), PECEOL®, and GELUCIRE® 59 / 14. In these embodiments, the ratio of PECEOL® to GELUCIRE® 59 / 14 may be 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 may be 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 present disclosure comprises a cannabinoid (optionally CBD), PECEOL®, and Labrasol ALF. In these embodiments, the ratio of PECEOL® to Labrasol ALF may be 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 may be 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, glyceryl oleate and polyethylene glycol-containing fatty acid esters are present in the formulation in amounts ranging from about 30% to about 50% by weight, respectively. In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are present in the formulation in amounts ranging from 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%, respectively. In certain embodiments, the polyethylene glycol-containing fatty acid ester is Gelucire 44 / 14 or lauroyl polyoxylglyceride.

[0102] In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are present in the formulation at approximately 34.58% by weight, respectively. In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are present in the formulation at approximately 36.4% by weight, respectively. In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are present in the formulation at approximately 38% by weight, respectively. In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are present in the formulation at approximately 39% to approximately 41% by weight, respectively. In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are present in the formulation at approximately 40% by weight, respectively. In certain embodiments, the polyethylene glycol-containing fatty acid ester is Gelucire 44 / 14 or lauroyl polyoxylglyceride.

[0103] This disclosure provides cannabinoid SEDDS formulations that may optionally contain one or more additional components. These additional components may include one or more surfactants and cosolvents. In some embodiments, the surfactant is tocopherol polyethylene glycol succinate (TPGS). In some embodiments, TPGS is present in the formulation in an amount of about 3% to about 4% by weight. In some embodiments, TPGS is present in the formulation in an amount of about 3% by weight, about 3.1% by weight, about 3.2% by weight, about 3.3% by weight, about 3.4% by weight, about 3.5% by weight, about 3.6% by weight, about 3.7% by weight, about 3.8% by weight, about 3.9% by weight, or about 4% by weight. In some embodiments, TPGS is present in the formulation in an amount of about 3.64% by weight. In some embodiments, TPGS is present in the formulation in an amount of about 4% by weight.

[0104] In some embodiments, the co-solvent in the formulation is ethanol. In some embodiments, ethanol is present in the formulation at about 7%, about 7.1%, about 7.2%, about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, or about 8%. In some embodiments, ethanol is present in the formulation at about 7.2% by weight. In other embodiments, the formulation does not contain ethanol.

[0105] In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are present in the formulation at approximately 38% by weight each, and TPGS is present at approximately 4% by weight. In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are present in the formulation at approximately 34.58% by weight each, TPGS is present at approximately 3.64% by weight, and ethanol is present at approximately 7.2% by weight.

[0106] In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are present in the formulation at approximately 36.4% by weight, and ethanol is present at approximately 7.2% by weight. In some embodiments, glyceryl oleate and polyethylene glycol-containing fatty acid esters are present in the formulation at approximately 40% by weight, and the formulation does not contain TPGS or ethanol.

[0107] In some embodiments, a single dose of the formulation contains at least 10 milligrams (mg) of cannabinoids. In some embodiments, a single dose of the formulation contains cannabinoids ranging from about 10 mg to about 3,000 mg. In some embodiments, a single dose of the formulation contains cannabinoids ranging from about 50 to about 2,000 mg. In some embodiments, a single dose may contain approximately 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 1,250 mg, 1,500 mg, 2,000 mg, 2,500 mg, or 3,000 mg of cannabinoids. In some embodiments, a single dose may contain approximately 600 mg of cannabinoids.

[0108] In some embodiments, the disclosure provides formulations containing more than about 1% by weight of cannabinoids. In some embodiments, the formulations contain about 10% to about 50% by weight of cannabinoids. In some embodiments, the formulations contain about 20% by weight of cannabinoids. In some embodiments, the formulations contain about 40% by weight of cannabinoids.

[0109] In some embodiments, a single dose of the formulation contains at least 10 milligrams (mg) of CBD. In some embodiments, a single dose of the formulation contains CBD ranging from about 10 mg to about 3,000 mg. In some embodiments, a single dose of the formulation contains CBD ranging from about 50 to 2,000 mg. In some embodiments, a single dose may contain approximately 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 1,250 mg, 1,500 mg, 2,000 mg, 2,500 mg, or 3,000 mg of CBD. In some embodiments, a single dose may contain approximately 600 mg of CBD.

[0110] In some embodiments, the disclosure provides formulations containing more than about 5% by weight of CBD. In some embodiments, the formulations contain about 10% to about 50% by weight of CBD. In some embodiments, the formulations contain about 20% by weight of CBD. In some embodiments, the formulations contain about 40% by weight of CBD.

[0111] This disclosure further provides formulations described herein for oral administration. This disclosure further provides capsules containing any of the formulations described herein. In some embodiments, the capsule is a soft gel capsule. Cannabinoid SEDDS formulations can be formulated in any form suitable for administration, including but not limited to capsules, tablets, powders, pellets, or solutions. Cannabinoids

[0112] Cannabinoids are natural and synthetic compounds structurally or pharmacologically related to the components of the cannabis plant or to endogenous agonists (endogenous cannabinoids) of cannabinoid receptors CB1 or CB2. Cannabinoids exert their physiological effects through a variety of receptors, including but not limited to adrenaline receptors, cannabinoid receptors (CB1 and CB2), GPR55, GPR3, or GPR5. The CB1 receptor is particularly widespread in the central nervous system, found at high levels in the neocortex, hippocampus, basal ganglia, cerebellum, and brainstem; therefore, CBD has been proposed for the treatment of variants of neurological disorders (Scoter et al. Br.J.Pharmacol..2010.(160):480-498).

[0113] The main cannabinoids present in the cannabis plant are the cannabinoid acids tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), each containing small amounts of neutral (decarboxylated) cannabinoids. Furthermore, cannabis may contain lower levels of other minor cannabinoids.

[0114] CBD is the primary cannabinoid component of cannabis. Unlike other cannabinoids such as THC, CBD does not bind to CB1 or CB2 receptors, or its binding to these receptors is negligible in terms of inducing pharmacological effects. Therefore, CBD does not cause central or peripheral nervous system effects mediated by CB1 or CB2 receptors. CBD has little to no psychoactive (cannabinoid-like) activity, and its molecular structure and properties are substantially different from those of other cannabinoids.

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

[0116] Of the more than 100 natural cannabinoids identified in Cannabis sativa, seven are classified as CBD-type compounds, and these cannabinoids have the same absolute configuration as CBD. These are CBD, cannabidiolic acid (CBDA), cannabidivaline (CBDV), cannabidivaric acid (CBDVA), cannabidiol-C1 (CBD-C1), cannabidiol-C4 (CBD-C4), and cannabidiol monomethyl ether (CBDM). Cannabidiolic acid (CBDA) is the primary form of CBD found in the cannabis plant. It is converted to CBD after decarboxylation.

[0117] Cannabidiol-C1 (CBD-C1), also known as cannabidiorcol, is a homolog of CBD, with its side chain shortened by four methylene crosslinks. CBD-C1 is naturally present in plants that produce small amounts of CBD. Cannabidivarin (CBDV) is a homolog of CBD, with its side chain shortened by two methylene crosslinks. CBDV is a non-psychoactive cannabinoid and has been shown to have anticonvulsant activity in a mouse model of epilepsy. Cannabidiol-C4 (CBD-C4), also known as norcannabidiol, is a homolog of CBD, with its side chain shortened by one methylene crosslink. CBD-C4 is naturally present in plants that produce small amounts of CBD.

[0118] CBD is a highly lipophilic drug with low water solubility (estimated to be <13 μg / mL).

number

[0119] To date, the only FDA-approved CBD formulation is Epidiolex®, a sesame oil-based solution indicated for the treatment of rare childhood epilepsy and tuberous sclerosis. However, this CBD formulation and others have several drawbacks: (1) some patients are allergic to sesame oil, raising safety concerns; (2) many indications require higher doses of CBD, which are difficult to administer with sesame oil formulations, leading to compliance limitations; and (3) liquid formulations are inherently less precise, and sesame oil formulations degrade when exposed to air, increasing costs and thus limiting applicability. Furthermore, Epidiolex contains ethanol, which is unfavorable for use in certain patient populations. Therefore, there is a need for a lipid-based formulation that can improve CBD absorption without relying on sesame oil as an excipient, in order to avoid potential allergies, enable higher dosages and better patient compliance, minimize variability, and reduce costs.

[0120] CBD has been proposed as a treatment for multiple disorders or injuries, including but not limited to clinically high-risk psychoses, insomnia, first-episode psychosis, psychosis in Parkinson's disease, schizophrenia, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, Alzheimer's disease, postpartum psychosis, agoraphobia, acute stress disorder, and schizoaffective disorder. Some of these disorders or injuries may require high doses of CBD. Patient acceptance and adherence to treatment would be improved by a convenient and painless route of administration, ideally oral administration using an easily administered and highly potent soft gel. Therefore, CBD formulations with attributes such as high solubilization, high stability during storage, favorable safety, absorption, and bioavailability profiles are needed. D-α-Tocopherol Polyethylene Glycol 1000 Succinate (TPGS)

[0121] Cannabinoid preparations may optionally contain one or more additional components, including surfactants such as D-alpha-tocopheryl polyethylene glycol succinate (TPGS).

[0122] Accordingly, in some embodiments, the cannabinoid formulations of the present disclosure comprise (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-α-tocopherol polyethylene glycol 1000 succinate (TPGS1000).

[0123] As used herein, the terms “D-α-tocopherol polyethylene glycol succinate” and the abbreviation “TPGS” are used interchangeably and are defined as molecules conforming to the following chemical structure: [ka]

[0124] TPGS is an amphiphilic molecule prepared by esterification of a hydrophilic polyethylene glycol molecule (typically having an average molecular weight of 1000 and about 20-25 ethylene oxide chains) with the carboxyl group of a hydrophobic d-alpha-tocopherol hemisuccinate (acid). TPGS is a water-soluble compound (up to 20% w / v) and forms a micelle solution with a critical micelle concentration of 0.4-0.6 mM / L (about 0.075%). The hydrophilic-lipophilic balance of TPGS is about 15-19. Structurally, tocopherol polyethylene glycol succinate has polyethylene glycol (PEG) covalently bonded to tocopherol (e.g., α-tocopherol or vitamin E) via a succinate linker. Since PEG is a polymer, TPGS can be prepared using various polymer molecular weights. In one embodiment, TPGS is tocopherol polyethylene glycol succinate 1000, where the average molecular weight of PEG is 1000. One suitable tocopherol polyethylene glycol succinate is vitamin E TPGS, commercially available from Eastman.

[0125] TPGS can be used as a surfactant or emulsifier for lipophilic substances. Emulsification of lipophilic substances and subsequent increase in surface area can lead to increased gastrointestinal drug absorption and bioavailability. TPGS may be included in formulations to enhance their thermal stability, which can then increase their shelf life.

[0126] In certain embodiments, tocopherol polyethylene glycol succinate is present in the formulation at a volume percentage of about 0.1 to about 10, based on the total volume of the formulation. In one embodiment, tocopherol polyethylene glycol succinate is present in the formulation at a volume percentage of about 5, based on the total volume of the formulation.

[0127] Toxicological studies have shown that TPGS is safe for human intake as a dietary or nutritional supplement. Furthermore, the antioxidant properties of TPGS can improve the stability of TPGS-containing preparations. Antioxidants

[0128] Cannabinoid formulations may optionally contain one or more antioxidants. In some embodiments, the antioxidant is selected from the group consisting of TPGS, butylated hydroxytoluene (BHT), butylated hydroxyanisole, alpha-tocopherol (vitamin E), ascorbyl palmitate, ascorbic acid, sodium ascorbate, ethylenediaminotetraacetic acid, cysteine ​​hydrochloride, citric acid, sodium citrate, sodium bisulfate, sodium metabisulfite, lecithin, propyl gallate, sodium sulfate, and monothioglycerol. In some embodiments, one or more antioxidants include TPGS. In some embodiments, one or more antioxidants include BHT. In some embodiments, one or more antioxidants include TPGS and BHT. In embodiments, the cannabinoid formulations described herein contain about 0.001% to about 20% by weight of the antioxidant. In some embodiments, the cannabinoid formulations described herein are available in concentrations of approximately 0.001% by weight, approximately 0.002% by weight, approximately 0.003% by weight, approximately 0.004% by weight, approximately 0.005% by weight, approximately 0.006% by weight, approximately 0.007% by weight, approximately 0.008% by weight, approximately 0.009% by weight, approximately 0.01% by weight, approximately 0.02% by weight, approximately 0.03% by weight, approximately 0.04% by weight, approximately 0.05% by weight, approximately 0.06% by weight, approximately 0.07% by weight, approximately 0.08% by weight, approximately 0.09% by weight, and approximately 0.1% by weight. Contains antioxidants in amounts of approximately 0.2% by weight, approximately 0.3% by weight, approximately 0.4% by weight, approximately 0.5% by weight, approximately 0.6% by weight, approximately 0.7% by weight, approximately 0.8% by weight, approximately 0.9% by weight, approximately 1% by weight, approximately 2% by weight, approximately 3% by weight, approximately 4% by weight, approximately 5% by weight, approximately 6% by weight, approximately 7% by weight, approximately 8% by weight, approximately 9% by weight, approximately 10% by weight, approximately 11% by weight, approximately 12% by weight, approximately 13% by weight, approximately 14% by weight, approximately 15% by weight, approximately 16% by weight, approximately 17% by weight, approximately 18% by weight, approximately 19% by weight, or approximately 20% by weight. methanol

[0129] Cannabinoid preparations may optionally contain one or more additional components, including a co-solvent such as ethanol.

[0130] Accordingly, in some embodiments, the cannabinoid formulations of the present disclosure comprise (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] Co-solvents can enhance the emulsification process and affect the solubility of lipophilic compounds in simulated intestinal fluid. However, ethanol may also present safety or patient preference issues. In some embodiments, the formulation does not contain ethanol. Sesame oil

[0132] Epidiolex®, a sesame oil-based formulation, is FDA-approved for the treatment of rare childhood epilepsy and tuberous sclerosis. Sesame oil may increase the solubility and systemic exposure of cannabinoids. Furthermore, sesame oil promotes the intestinal lymphatic transport of CBD, effectively circumventing the first-pass effect and resulting in higher bioavailability. However, high variability in absorption may be observed. In addition, sesame oil may pose safety concerns for patients due to food allergies. In some embodiments, the formulation does not contain sesame oil. Medium-chain triglyceride oil (MCT)

[0133] Cannabinoids, such as CBD preparations, may optionally contain one or more additional components, including triglycerides such as MCTs. Triglycerides (also known as triacylglycerols or triacylglycerides) are glycerides in which glycerol is esterified with three fatty acids. Based on their chain length, triglycerides can be divided into three categories: (i) short-chain triglycerides (SCTs), (ii) medium-chain triglycerides (MCTs), and (iii) long-chain triglycerides (LCTs). Medium-chain triglycerides have fatty acids in the range of approximately C8 to approximately C10 (e.g., caprylic / capric triglyceride). Some exemplary commercially available medium-chain triglycerides are CAPTEX® (available from Parchem, White Plains, NY), NESATOL® (available from Kreglinger Europe, Antwerp, Belgium), WAGLINOL® (available from Industrial Quimica Lasem, SA, Barcelona, ​​Spain), BERGABEST® (available from Sternchemie, Hamburg, Germany), MIGL YOL® (available from Universal Preserv-A-Chem, Inc., Edison, NJ), NEOBEE® (available from Stepan Company, Northfield, Illinois), and CRODAMOL® (available from Croda, Edison, NJ). SEDDS manufacturing method

[0134] This disclosure provides a method for producing SEDDS. In SEDDS, a self-emulsifying oily solution is called a preconcentrate. A drug-free bulk mixture of preconcentrates can be prepared by mixing excipients at 45°C for about 30 minutes and stirring at about 300 rpm. A final preconcentrate can be prepared by adding the drug-free preconcentrate to a cannabinoid isolate so that the concentration of cannabinoids reaches the intended concentration. The mixture can then be stirred at about 400 rpm and about 45°C until it is nearly completely homogeneous. An exemplary embodiment of a method for producing a cannabinoid SEDDS formulation is shown in Figure 1.

[0135] droplet dispersion The disclosed cannabinoid SEDDS formulations include, optionally, CBD, a cannabinoid that is partially solubilized (dissolved) and exists as solid particles to provide a fine solid dispersion. The dispersion of the formulation in an aqueous medium provides a nanomicroemulsion.

[0136] The formulation can be characterized by droplet size and polydispersity index (PDI), measured by dynamic light scattering (DLS) (Zetasizer Nano ZS, Malvern Instruments Ltd, UK) at approximately 37°C. The preliminary concentrate can be dispersed in PBS (approximately 0.5% w / v) and stirred at approximately 100 rpm and approximately 37°C for approximately 2 hours.

[0137] The formulation may form submicron-sized droplets upon dispersion. In some embodiments, the formulation may form droplets with an initial diameter of approximately 280 nm to approximately 500 nm. In some embodiments, the formulation may form droplets with an initial diameter of approximately 380 nm to approximately 480 nm. In some embodiments, the formulation may form droplets with an initial diameter of approximately 375 nm to approximately 490 nm. In some embodiments, the formulation may form droplets with an initial diameter of approximately 429 nm.

[0138] The formulation may form droplets with a PDI value of approximately 0.2 to approximately 0.6 upon dispersion. In some embodiments, the formulation may form droplets with a PDI value of approximately 0.25 to approximately 0.4. In some embodiments, the formulation may form droplets with a PDI value of approximately 0.2 to approximately 0.4. In some embodiments, the formulation may form droplets with a PDI value of approximately 0.30.

[0139] The formulation can be stored under refrigerated conditions (i.e., approximately 3°C to 5°C) or at room temperature (i.e., approximately 20°C to 25°C). The formulation can be stored for at least approximately 3 months. The formulation can be stored for approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 20 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, or 100 days.

[0140] The formulation may, after storage, form droplets with approximately the same diameter as the droplets formed by the formulation before storage. In some embodiments, the formulation may, after storage, form droplets with an initial diameter of approximately 280 nm to approximately 650 nm. In some embodiments, the formulation may, after storage, form droplets with an initial diameter of approximately 380 nm to approximately 570 nm. In some embodiments, the formulation may, after storage, form droplets with an initial diameter of approximately 380 nm to approximately 490 nm. In some embodiments, the formulation may, after storage, form droplets with an initial diameter of approximately 429 to approximately 489 nm.

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

[0142] In some embodiments, the formulation may form droplets having an initial diameter of approximately 310 nm to approximately 560 nm after storage at room temperature. In some embodiments, the formulation may form droplets having an initial diameter of approximately 380 nm to approximately 520 nm after storage at room temperature. In some embodiments, the formulation may form droplets having an initial diameter of approximately 370 nm to approximately 430 nm after storage at room temperature. In some embodiments, the formulation may form droplets having an initial diameter of approximately 390 nm to approximately 410 nm after storage at room temperature.

[0143] The formulation may, after storage, form droplets having substantially the same PDI value as the droplets formed by the formulation before storage. In some embodiments, the formulation may, after storage, form droplets having a PDI value of about 0.05 to about 0.6. In some embodiments, the formulation may, after storage, form droplets having a PDI value of about 0.14 to about 0.5. In some embodiments, the formulation may, after storage under refrigerated conditions, form droplets having a PDI value of about 0.15 to about 0.45. In some embodiments, the formulation may, after storage at room temperature, form droplets with a PDI value of about 0.2 to about 0.35.

[0144] In some embodiments, the formulation may form droplets having a PDI value of about 0.1 to about 0.6 after storage under refrigerated conditions. In some embodiments, the formulation may form droplets having a PDI value of about 0.14 to about 0.5 after storage under refrigerated conditions. In some embodiments, the formulation may form droplets having a PDI value of about 0.15 to about 0.45 after storage under refrigerated conditions.

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

[0146] The disclosed cannabinoid SEDDS formulations effectively solubilize cannabinoids such that cannabinoids, optionally CBD, are present in the formulation at a concentration of at least about 1% by weight. In some embodiments, the formulation contains cannabinoids (e.g., CBD) in amounts of about 5% or more by weight, about 10% or more by weight, about 15% or more by weight, about 20% or more by weight, about 25% or more by weight, about 30% or more by weight, about 35% or more by weight, about 40% or more by weight, about 45% or more by weight, about 50% or more by weight, or about 55% or more by weight. In some embodiments, the formulation contains cannabinoids in amounts of 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 formulation contains cannabinoids in amounts of about 10% to about 50% by weight. In some embodiments, the formulation contains cannabinoids in an amount of about 20% to about 40% by weight. In some embodiments, the formulation contains cannabinoids in an amount of about 20% by weight. In some embodiments, the formulation contains cannabinoids in an amount of about 25% by weight. In some embodiments, the formulation contains cannabinoids in an amount of about 30% by weight. In some embodiments, the formulation contains cannabinoids in an amount of about 35% by weight. In some embodiments, the formulation contains cannabinoids in an amount of about 40% by weight. In some embodiments, the formulation contains cannabinoids in an amount of about 45% by weight. In some embodiments, the formulation contains cannabinoids in an amount of about 50% by weight.

[0147] The formulation can be stored under refrigerated conditions (i.e., approximately 3°C to 5°C) or at room temperature (i.e., approximately 20°C to 25°C).

[0148] The stability of cannabinoid SEDDS can be evaluated at a given time point, for example, by diluting a preliminary concentrate in ethanol (1:1000), vortexing for about 20 seconds, sonicating in an ultrasonic bath (Sonoswiss AG, SW 3H, Switzerland) for about 5 minutes, and quantifying the cannabinoids via HPLC.

[0149] The formulation can maintain, for example, cannabinoid solubilization, measured as cannabinoid content (%), at approximately the same level as the cannabinoid content of the formulation before storage, after storage 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). In some embodiments, the formulation may have a cannabinoid content (drug content) of about 80% to about 110% after storage. In some embodiments, the formulation may have a cannabinoid content of about 91% to about 104% after storage.

[0150] In some embodiments, the formulation may have a cannabinoid content of approximately 94% to approximately 110% after storage under refrigerated conditions. In some embodiments, the formulation may have a cannabinoid content of approximately 96% to approximately 104% after storage under refrigerated conditions.

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

[0152] To determine their efficacy as orally administered formulations, the stability of representative cannabinoid formulations of the present invention was evaluated in simulated gastric fluid. Dispersibility and solubility of drugs in simulated gastric juice

[0153] The disclosed cannabinoid SEDDS formulations maintain a favorable dispersion profile and effectively solubilize cannabinoids, optionally CBD, in biocompatible media (including, but not limited to, simulated gastric juices in a fasted state [FaSSGF], a fasted state simulated intestinal juice [FaSSIF], and a feeding state simulated intestinal juice [FeSSIF]).

[0154] FaSSGF, FaSSIF, and FeSSIF are dissolving media that mimic human intestinal fluid. Each contains the same types and levels of surfactants (bile salts and phospholipids) present in the gastrointestinal fluid it replicates, and has the same average pH and similar osmotic pressure. Surfactants, pH, and osmotic pressure are important parameters to control when testing drugs or formulations. Surfactants form mixed micelles that can greatly enhance the solubility and dissolution of drugs. pH and osmotic pressure can affect the solubility and dissolution of drugs. FaSSGF contains approximately 0.08 mM taurocholic acid, approximately 0.02 mM phospholipids, approximately 34 mM sodium, and approximately 59 mM chloride. FaSSIF contains approximately 3 mM taurocholic acid, approximately 0.75 mM phospholipids, approximately 148 mM sodium, approximately 106 mM chloride, and approximately 29 mM phosphate. FeSSIF contains approximately 15 mM taurocholic acid, approximately 3.75 mM phospholipid, approximately 319 mM sodium, approximately 203 mM chloride, and approximately 144 mM acetic acid. FaSSGF, FaSSIF, and FeSSIF powder and buffer concentrates were purchased from Biorelevant.com Ltd.

[0155] In some embodiments, after dispersion (0.5% w / v) in a biocompatible medium, approximately 90% to approximately 100% of the cannabinoids, optionally CBD, of the disclosed cannabinoid SEDDS formulation can be solubilized within 30 minutes. In some embodiments, a dispersion of the formulation in FaSSGF can solubilize at least approximately 90% of the cannabinoids for all formulations within 30 minutes. In some embodiments, a dispersion of the formulation in FaSSGF can solubilize at least approximately 80% of the cannabinoids within 2 hours. In some embodiments, a dispersion of the formulation in FaSSGF can solubilize at least approximately 95% of the cannabinoids within 2 hours. In some embodiments, a dispersion of the formulation in FaSSIF can solubilize at least 90% of the cannabinoids for all formulations within 30 minutes. In some embodiments, a dispersion of the formulation in FaSSIF can solubilize at least approximately 90% of the cannabinoids within 2 hours. In some embodiments, a dispersion of the formulation in FeSSIF can solubilize at least about 60% of the cannabinoids for all formulations within 30 minutes. In some embodiments, a dispersion of the formulation in FeSSIF can solubilize at least about 40% of the cannabinoids within 2 hours. In vitro digestion of cannabinoid SEDDS preparations

[0156] The solubilization properties of the disclosed cannabinoids, e.g., CBD, SEDDS formulations, can be further characterized by in vitro digestion, as described, for example, 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). Before adding pancreatic lipase (approximately 667 mg), the selected formulation is dispersed in FaSSIF (2.5% w / v) by stirring at approximately 100 rpm and 37°C for 10 minutes. After digestion for approximately 30 minutes, the sample can be separated into three layers by centrifugation (20,800 × g, 15 minutes): an upper layer (oil phase), an intermediate layer (aqueous micelle phase), and a lower layer (precipitated pellet phase). The cannabinoid content can then be analyzed from each phase by HPLC after dilution in methanol.

[0157] In some embodiments, the formulation exhibits minimal precipitation (<20%) and is primarily distributed in the oil phase. In some embodiments, the formulation has a distribution of approximately 55% to 75% cannabinoids, e.g., CBD, in the oil phase, approximately 18% to 28% cannabinoids in the aqueous phase, and approximately 7% to 21% cannabinoids in the pellet phase. In some embodiments, the formulation has a distribution of approximately 62% cannabinoids in the oil phase, approximately 23% cannabinoids in the aqueous phase, and approximately 15% cannabinoids in the pellet phase. Pharmacokinetics

[0158] This disclosure provides cannabinoids, such as CBD formulations, that, after administration, result in improved absorption and delayed excretion compared to medium-chain triglyceride oil (MCT) cannabinoid formulations, also known herein as cannabinoid MCTs (optionally, MCT CBD formulations, also known herein as CBD MCTs). In some embodiments, the formulations achieve, after administration, a maximum plasma concentration (C) that is approximately equal to, at least as high as, or higher than, that resulting from the administration of cannabinoid MCTs. 最大) can result in. In some embodiments, the formulation, after administration, has a maximum plasma concentration (C) that is approximately equal to, at least as high as, or higher than that resulting from the administration of a sesame oil (SO) cannabinoid formulation (optionally also referred to herein as cannabinoid SO), which is also optionally referred to herein as SO CBD formulation 最大 ) can result in. In some embodiments, the formulation, after administration, has a C of the cannabinoid MCT 最大 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 the C 最大 In some embodiments, the formulation, after administration, has a C of the cannabinoid SO 最大 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 the C 最大 In some embodiments, the formulation, after administration, has a C of the cannabinoid MCT 最大 that is about 1.7-fold greater than the C 最大 In some embodiments, the formulation, after administration, has a C of the cannabinoid MCT 最大 that is about 1.1-fold greater than the C 最大 can result in.

[0159] In some embodiments, the formulation may a) form droplets having a diameter within a specific range during dispersion, and b) deliver a maximum plasma concentration (Cmax) greater than a specific value after administration. In some embodiments, the formulation may a) form droplets with a diameter of approximately 280 nM to approximately 500 nM during dispersion, and b) deliver a maximum plasma concentration (Cmax) greater than 500 ng / mL, 550 ng / mL, 600 ng / mL, 650 ng / mL, 700 ng / mL, or 750 ng / mL after administration. In some embodiments, the formulation may a) form droplets with an initial diameter of approximately 380 nm to approximately 480 nm during dispersion, and b) deliver a maximum plasma concentration (Cmax) greater than 500 ng / mL, 550 ng / mL, 600 ng / mL, 650 ng / mL, 700 ng / mL, or 750 ng / mL after administration. In some embodiments, the formulation may a) form droplets with an initial diameter of approximately 375 nm to approximately 490 nm during dispersion, and b) yield a maximum plasma concentration (Cmax) greater than 500 ng / mL, 550 ng / mL, 600 ng / mL, 650 ng / mL, 700 ng / mL, or 750 ng / mL after administration. In some embodiments, the formulation may a) form droplets with an initial diameter of approximately 429 nm during dispersion, and b) yield a maximum plasma concentration (Cmax) greater than 500 ng / mL, 550 ng / mL, 600 ng / mL, 650 ng / mL, 700 ng / mL, or 750 ng / mL after administration. In some embodiments, the formulation may a) form droplets with an initial diameter of approximately 429 nm during dispersion, and b) yield a maximum plasma concentration (Cmax) greater than 750 ng / mL after administration.

[0160] In some embodiments, the formulation measures the area under the plasma concentration-time curve (AUC) from the time of administration (0 hours) to 8 hours after administration. 0-8時間 This can result in a value, and this AUC 0-8時間 The AUC is approximately equal to, at least as high as, or higher than, that resulting from the administration of cannabinoid MCT. In some embodiments, the formulation exhibits an AUC after administration that is approximately equal to, at least as high as, or higher than that resulting from the administration of cannabinoid SO. 0-8時間This can result in the following: In some embodiments, the formulation may result in the AUC of cannabinoid MCT after administration. 0-8時間 AUC that is approximately 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, or 2.0 times larger than the value. 0-8時間 It may yield a value. In some embodiments, the formulation may yield the AUC of cannabinoid SO after administration. 0-8時間 AUC that is approximately 1.1 times, 1.2 times, 1.3 times, 1.4 times, or 1.5 times larger than the value. 0-8時間 It may yield a value. In some embodiments, the formulation, after administration, yields the AUC of cannabinoid MCTs. 0-8時間 AUC approximately 1.9 times larger than the value 0-8時間 It may yield a value. In some embodiments, the formulation may yield a value for the AUC of cannabinoid SO after administration. 0-8時間 AUC approximately 1.1 times larger than the value 0-8時間 It can yield value.

[0161] In some embodiments, the formulation reaches its maximum concentration (T) approximately 30 minutes, 1 hour, 1.25 hours, 1.5 hours, 1.75 hours, or 2 hours after administration. 最大 ) may have. In some embodiments, the formulation is administered approximately 1.75 hours after administration. 最大 It may have. Unit dosage form and administration

[0162] This disclosure provides formulations suitable for administering a wide range of cannabinoid doses, and optionally, CBD doses. In some embodiments, the formulations allow for a higher drug load of the cannabinoid active pharmaceutical ingredient, resulting in improved bioavailability and reduced pill or capsule size. Furthermore, the SEDDS formulations disclosed herein offer increased AUC concentration compared to other formulations. Optimized formulations enable more efficient and convenient administration of cannabinoid products, particularly for indications requiring a high therapeutic range of doses. The formulations and unit dosage forms enable the administration of higher doses of cannabinoids (e.g., CBD) than conventional formulations and unit dosage forms, including, for example, doses greater than 1,000 ng, e.g., 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 contains approximately 10 mg to approximately 3,000 mg, approximately 20 mg to approximately 2,000 mg, approximately 30 mg to approximately 1,000 mg, approximately 40 mg to approximately 800 mg, or approximately 50 mg to approximately 600 mg of cannabinoids, optionally CBD. In some embodiments, a single dose of any of the formulations contains approximately 100 mg to approximately 2,500 mg, approximately 500 mg to approximately 2,500 mg, approximately 1,000 to approximately 2,500 mg, approximately 1,500 mg to approximately 2,500 mg, approximately 500 mg to approximately 2,000 mg, approximately 1,000 mg to approximately 2,000 mg, or approximately 1,500 mg to approximately 2,000 mg of cannabinoids, for example, CBD. In some embodiments, a single dose (or unit dosage form) may contain cannabinoids in the range of approximately 50 mg to approximately 2,000 mg, approximately 500 mg to approximately 2,000 mg, approximately 1,000 mg to approximately 2,000 mg, or approximately 1,500 mg to approximately 2,000 mg, or 50 mg to approximately 1,000 mg, optionally including CBD. In some embodiments, a single dose may contain approximately 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 1,250 mg, 1,500 mg, 1,750 mg, 2,000 mg, 2,500 mg, or 3,000 mg of cannabinoids, optionally CBD. In some embodiments, a single dose, two doses, or three doses per day may be administered.

[0164] This disclosure provides unit dosage forms of cannabinoid preparations. In certain embodiments, the unit dosage forms are formulated for oral delivery, for example, as a liquid, or in tablets or capsules. In certain embodiments, the unit dosage form contains a therapeutically effective amount of the cannabinoid preparation, or two or more unit dosage forms, for example, two, three, or four unit dosage forms together contain a therapeutically effective amount of the cannabinoid preparation. In some embodiments, each unit dosage form contains cannabinoids in the range of about 10 mg to about 3,000 mg, about 20 mg to about 2,000 mg, about 30 mg to about 1,000 mg, about 40 mg to about 800 mg, or about 50 mg to about 600 mg, optionally containing CBD. In some embodiments, the unit dosage form may contain cannabinoids in the range of about 50 mg to about 2,000 mg, about 500 mg to about 2,000 mg, about 1,000 mg to about 2,000 mg, or about 1,500 mg to about 2,000 mg, or 50 mg to about 1,000 mg, optionally containing CBD. In some embodiments, any unit dosage form of the formulation may contain cannabinoids in the range of 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, or about 1,500 mg to about 2,000 mg, for example, CBD. In some embodiments, a unit dosage form may contain approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 500 mg, approximately 600 mg, approximately 700 mg, approximately 800 mg, approximately 900 mg, approximately 1,000 mg, approximately 1,250 mg, approximately 1,500 mg, approximately 1,750 mg, approximately 2,000 mg, approximately 2,500 mg, or approximately 3,000 mg of cannabinoids, optionally CBD. In some embodiments, two or more unit dosage forms, for example, two, three, or four, together contain any of these total amounts of cannabinoids, for example CBD. In some embodiments, a unit dose comprises a range of cannabinoids formed from any two of the amounts disclosed herein, for example, CBD, e.g., about 30 mg to about 300 mg.

[0165] In certain embodiments, the unit dosage form of the disclosed cannabinoid formulation contains at least about 250 mg of cannabinoid, e.g., CBD, and a total weight of less than 1500 mg. In certain embodiments, the unit dosage form of the disclosed cannabinoid formulation contains at least about 300 mg of cannabinoid, e.g., CBD, and a total weight of less than 1500 mg. In certain embodiments, the unit dosage form of the disclosed cannabinoid formulation contains at least about 400 mg of cannabinoid, e.g., CBD, and a total weight of less than 1700 mg. In certain embodiments, the unit dosage form of the disclosed cannabinoid formulation contains at 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 administered orally, for example, in soft or hard gelatin capsules, and that can form a fine, relatively stable oil-in-water (o / w) emulsion upon water dilution, for example, by gentle agitation of gastrointestinal fluid. In certain embodiments, the unit dosage form is contained within a soft or hard gelatin capsule.

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

[0168] This disclosure provides formulations and unit dosage forms suitable for administering a wide range of daily doses of cannabinoids, optionally CBD. In some embodiments, cannabinoid formulations may be administered in amounts ranging from about 10 mg to about 3,000 mg of cannabinoids per day. In some embodiments, cannabinoid formulations may be administered in amounts ranging from about 50 mg to about 2,000 mg, or about 50 mg to about 1,000 mg of cannabinoids per day. In some embodiments, the cannabinoid preparation may be administered in amounts such as approximately 100 mg to approximately 2,500 mg, approximately 500 mg to approximately 2,500 mg, approximately 1,000 to approximately 2,500 mg, approximately 1,500 mg to approximately 2,500 mg, approximately 500 mg to approximately 2,000 mg, approximately 1,000 mg to approximately 2,000 mg, or approximately 1,500 mg to approximately 2,000 mg of cannabinoids, such as CBD, per day. In some embodiments, cannabinoid preparations may be administered in amounts such as approximately 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 1,250 mg, 1,500 mg, 2,000 mg, 2,500 mg, or 3,000 mg of cannabinoid per day. In some embodiments, a dose range of cannabinoids, such as CBD, e.g., approximately 30 mg to 300 mg, is administered, formed from any two of the amounts disclosed herein.

[0169] In some embodiments where a cannabinoid preparation, optionally a CBD preparation, is administered in a manner to treat a disease or injury in a subject, and the disease or injury is a clinically high-risk psychosis, the cannabinoid preparation may be administered in amounts such as approximately 600 to approximately 1,000 mg per day. In some embodiments where a cannabinoid preparation, optionally a CBD preparation, is administered in a manner to treat a disease or injury in a subject, and the disease or injury is insomnia, the cannabinoid preparation may be administered in amounts such as 50 to 400 mg per day. In some embodiments where a cannabinoid preparation, optionally a CBD preparation, is administered in a manner to treat a disease or injury in a subject, and the disease or injury is generalized anxiety disorder, the cannabinoid preparation may be administered in amounts such as 300 to 600 mg per day. In some embodiments where a cannabinoid preparation, optionally a CBD preparation, is administered in a method to treat a disease or injury in a subject, and the disease or injury is panic disorder, the cannabinoid preparation may be administered in a dose such as 300-600 mg per day. In some embodiments where a cannabinoid preparation, optionally a CBD preparation, is administered in a method to treat a disease or injury in a subject, and the disease or injury is post-traumatic stress disorder, the cannabinoid preparation may be administered in a dose such as 100-600 mg per day. In some embodiments where a cannabinoid preparation, optionally a CBD preparation, is administered in a method to treat a disease or injury in a subject, and the disease or injury is social anxiety disorder, the cannabinoid preparation may be administered in a dose such as 300-600 mg per day. In some embodiments where a cannabinoid preparation, optionally a CBD preparation, is administered in a method to treat a disease or injury in a subject, and the disease or injury is first-episode psychosis, the cannabinoid preparation may be administered in a dose such as 600 to 1,000 mg per day. In some embodiments where a cannabinoid preparation, optionally a CBD preparation, is administered in a method to treat a disease or injury in a subject, and the disease or injury is psychosis in Parkinson's disease, the cannabinoid preparation may be administered in a dose such as 300 to 1,500 mg per day.In a method of treating a disease or injury in a subject, in which cannabinoid preparations, optionally CBD preparations, are administered, and in some embodiments, where the disease or injury is schizophrenia, the cannabinoid preparations may be administered in amounts such as 600 to 1,500 mg per day.

[0170] This disclosure provides cannabinoid formulations that, after oral administration, can result in cannabinoid concentrations in the MLN that are higher than those in the liver. In some embodiments, the formulations can result in cannabinoid concentrations in the MLN that are substantially the same as those achieved by cannabinoid sesame oil formulations after oral administration. In some embodiments, the formulations can result in cannabinoid concentrations in the spleen that are lower than those in the MLN, brain, liver, or kidneys after oral administration. In some embodiments, the formulations can result in cannabinoid concentrations in the MLN that are about 9 to 14 times higher than those in the spleen after oral administration. In some embodiments, the formulations can result in a tissue distribution coefficient (Kp) in the MLN that is higher than that of the brain, liver, kidneys, or spleen after oral administration. The effect of food on the pharmacokinetics of cannabinoid SEDDS preparations

[0171] This disclosure provides cannabinoid SEDDS formulations, optionally CBD SEDDS formulations, that are measurably food-independent. Specifically, the formulations provide favorable pharmacokinetics when administered with food, within 2 hours, 4 hours, or 8 hours, or longer than, or after at least 2 to 12 hours of fasting following food intake. In certain embodiments, the formulations are administered after fasting of 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 following food intake, and / or at least about 2 hours before food intake. In some embodiments, food is not consumed until at least about 2 hours after administration of the formulation. In some embodiments, food is consumed within about 2 hours before administration of the formulation. In some embodiments, the formulations are administered without food intake for at least 2 hours before and at least 2 hours after administration. In some embodiments, the formulations are administered without food intake for at least 4 hours before and at least 4 hours after administration. In some embodiments, the disclosed cannabinoid SEDDS formulations yield a cannabinoid C maxima of at least about 50% of the cannabinoid C maxima after oral administration of a formulation administered approximately simultaneously with food, after administration up to at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, or at least about 10 hours after food ingestion. In some embodiments, formulations administered up to at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, or at least about 10 hours after food ingestion, and up to at least 2 hours before food ingestion, yield a cannabinoid AUC of at least about 50% of the cannabinoid AUC after oral administration of a formulation administered approximately simultaneously with food. ∞ At least approximately 50% of the cannabinoid AUC ∞ It brings about. Methods of administering and treating with cannabinoids

[0172] In some embodiments, the provided cannabinoid SEDDS formulations and unit dosage forms can be used in methods for administering cannabinoids, optionally CBD, to a subject. In some embodiments, the formulations may be used for the treatment of a disease or injury in a subject requiring treatment, comprising administering or providing the cannabinoid SEDDS formulation or one or more unit dosage forms to the subject. In certain embodiments, the cannabinoid SEDDS formulation or unit dosage form is provided to the subject with or without fasting of the subject. In certain embodiments, the subject is eating or eating food at or around the same time as being administered the cannabinoid SEDDS formulation or one or more unit dosage forms. In certain embodiments, the subject is eating or eating food for at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, or at least about 10 hours prior to being administered the cannabinoid SEDDS formulation or unit dosage form. In certain embodiments, the subject is administered the cannabinoid SEDDS formulation or unit dosage form about once a day, about twice a day, or about three times a day. In certain embodiments, subjects are administered cannabinoid SEDDS formulations or unit dosage forms for at least or about 1 day, at least or about 2 days, at least or about 3 days, at least or about 5 days, at least or about 1 week, at least or about 2 weeks, at least or about 1 month, at least or about 2 months, at least or about 4 months, at least or about 6 months, at least or about 1 year, or longer.

[0173] In certain embodiments, the subject is orally administered cannabinoids, optionally CBD, in the form of three or fewer capsules (e.g., one or two capsules) containing the formulations disclosed herein (e.g., as SEDDS formulations), wherein in certain embodiments, each capsule contains at least about 200 mg, at least about 250 mg, at least about 275 mg, at least about 300 mg, at least about 325 mg, at least about 350 mg, at least about 375 mg, at least about 400 mg, at least about 425 mg, at least about 450 mg, at least about 475 mg, or at least about 500 mg. In certain embodiments, the subject is administered cannabinoids, optionally CBD, in a total dose of about 400 mg to about 1500 mg (or about 600 mg to about 1000 mg) in three or fewer capsules.

[0174] In certain embodiments, subjects are orally administered cannabinoids in doses of up to approximately 1000 mg, up to approximately 200 mg, up to approximately 3000 mg, up to approximately 4000 mg, up to approximately 5000 mg, or up to approximately 6000 mg in one or more capsules of the formulations disclosed herein (e.g., SEDDS formulations). In some embodiments, cannabinoids in dose ranges formed from any two of the amounts disclosed herein, for example, CBD, are administered in doses of up to approximately 1000 mg to approximately 3000 mg.

[0175] In certain embodiments, the Disclosure provides a method for treating a disease or injury in a subject requiring treatment, the method comprising a plasma AUC of at least 2000 ng.h / mL (e.g., AUC 0-最後 or AUC 0-無限大 This includes administering or providing a cannabinoid (e.g., CBD) SEDDS formulation or one or more unit dosage forms thereof to a target in an amount sufficient to achieve the following: In certain embodiments, this 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, this amount is sufficient to achieve a plasma AUC of about 2,000 ng.h / mL to about 5,000 ng.h / mL.

[0176] In a related embodiment, the Disclosure provides a method for treating a disease or injury in a subject, the method comprising providing a cannabinoid, such as CBD, to the subject in an amount and form sufficient to achieve an AUC of at least 2,000 ng·h / mL, for example, about 2,000 ng·h / mL to about 4,000 ng·h / mL, about 2,000 ng·h / mL to about 3,000 ng·h / mL, or about 2,000 ng·h / mL to about 5,000 ng·h / mL.

[0177] In various embodiments of the treatment methods disclosed herein, the disease or injury is selected from the group including clinically high-risk psychosis, insomnia, first-episode psychosis, psychosis in Parkinson's disease, schizophrenia, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, Alzheimer's disease, postpartum psychosis, agoraphobia, acute stress disorder, and schizoaffective disorder. In some embodiments, the disease or injury is clinically high-risk psychosis. In some embodiments, the disease or injury is insomnia.

[0178] In various embodiments of the therapeutic methods disclosed herein, the disease or injury is selected from the group including generalized epilepsy, post-traumatic epilepsy, major depressive disorder, bipolar depression, postpartum depression, endometriosis, premenstrual disorder, premenstrual dysphoric disorder, menopausal mood changes, menopausal sleep disorders, menopausal cognitive changes, and obsessive-compulsive disorder. In some embodiments, the disease or injury is absence seizure, typical absence seizure, atypical absence seizure, toneaconic seizure, myoclonic seizure, infantile convulsions (also known as West syndrome), juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, progressive myoclonic seizure, tonic-clonic seizure, tonic seizure, clonic seizure, status epilepticus, focal sensory disturbance seizure, infantile myoclonic epilepsy, hereditary epilepsy with febrile seizures plus, early infantile epileptic brain disorder (also known as Ohtahara syndrome), early myoclonic brain disorder, infantile epilepsy with migratory focal seizures, Dravet syndrome ( (also known as severe myoclonic epilepsy of infants), tuberous sclerosis, treatment-resistant epilepsy, childhood absence epilepsy, epilepsy with myoclonus absence, epilepsy with eyelid myoclonus (also known as Sievons syndrome), epilepsy with myoclonus-astonic seizures (also known as myoclonus-astonic epilepsy or Dose syndrome), developmental / epileptic brain disorder with sleep-induced spike wave excitation (also known as continuous sleep-induced spike wave, sleep-induced electroepileptic status epilepticus, or Landau-Kleffner syndrome), epileptic syndrome associated with febrile infections (febrile The following conditions are selected: infection-related epilepsy syndrome (FIRES), hemiconvulsive hemiplegia epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, epilepsy with generalized tonic-clonic seizures only, Rasmussen syndrome, progressive myoclonic epilepsy, Rett syndrome, CDKL5 deficiency, benign Rolandic epilepsy, and refractory childhood epilepsy.In some embodiments, the disease or injury is selected from Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis, treatment-resistant epilepsy, infantile seizures, CDKL5 deficiency, Aicardi syndrome, Dose syndrome, Dup15 syndrome, SYNGAP1 epileptic brain disorder, drug-resistant focal seizures, Sturge-Weber syndrome, epileptic syndromes associated with febrile infection, focal epilepsy, developmental and epileptic brain disorders, and epilepsy with myoclonus absence. [Examples]

[0179] Example 1: Composition of an oral self-emulsifying lipid-based formulation. Four cannabinoid SEDDS formulations (i.e., A, B, C, and D) were developed (Figure 1), each containing 20% ​​w / w (CBD weight / total weight) (Table 1). SEDDS are isotropic mixtures of oil, surfactant, and / or cosolvent that, when mixed with an aqueous medium in the gastrointestinal tract environment, spontaneously form a colloidal dispersion or emulsion. Self-emulsifying oily solutions are called preconcentrates.

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

[0181] Each formulation contained Peceol to Gelucire 44 / 14 in a 50:50 (w / w) ratio. The formulations varied with or without the presence of either an additional surfactant (TPGS) or a co-solvent (anhydrous ethanol). [Table 1]

[0182] In addition, the sesame oil preparation (CBD SO) was prepared based on a previous report (Kok, LY, Bannigan, P., Sanaee, F., Evans, JC, Dunne, M., Regenold, M., Ahmed, L., Dubins, D., Allen, C., Development and pharmacokinetic evaluation of a self-nanoemulsifying drug delivery system for oral delivery of cannabidiol, Eur.J.Pharm.Sci.2022,168,106058.https: / / doi.org / 10.1016 / j.ejps.2021.106058). Briefly, the final composition of the preparation 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 added by weight, and the solution was stirred at 250 rpm for 30 minutes. The sesame oil solution was then added to the CBD to a concentration of 10% w / w, and stirred under the same conditions until completely homogenized. The CBD SO was stored at room temperature, away from direct light, until further use.

[0183] Preparations in caprylic / capric triglyceride (CBD MCT) were prepared by adding oil to CBD to achieve a CBD concentration of 10% w / w. The MCT oil solution was stirred at 250 rpm until completely homogeneous and stored at room temperature, away from direct light, until further use. Example 2: Characteristics and stability of cannabinoid SEDDS formulations

[0184] CBD SEDDS formulations were characterized by droplet size and polydispersity index (PDI) measured by dynamic light scattering (DLS) (Zetasizer Nano ZS, Malvern Instruments Ltd, UK) at 37°C. Pre-concentrates were dispersed in PBS (0.5% w / v) and stirred at 100 rpm and 37°C for 2 hours. Upon mixing with PBS, the CBD SEDDS produced a milky white, translucent dispersion without visible signs of drug precipitation. The resulting droplets were submicron in size and had initial diameters and PDI values ​​of approximately 400 nm and 0.40, 480 nm and 0.37, 430 nm and 0.30, and 460 nm and 0.25 for CBD SEDDS A, B, C, and D, respectively (Table 2). [Table 2]

[0185] The size of the dispersed droplets appeared to be directly related to the drug load level across the four formulations, with the blank formulation exhibiting approximately half the diameter of the formulations examined (Figure 2). Oil formulations (i.e., CBD SO, CBD MCT) were found to be non-dispersible and therefore their dispersibility was not evaluated.

[0186] Drug solubilization was evaluated for formulations with various CBD content after dispersion in phosphate-buffered saline at 37°C for 1 hour (0.5% w / v) for a series of pre-filtered dispersions (Figure 3A) and selected unfiltered dispersions (Figure 3B). Formulations 1, 2, 3, and 4 correspond to CBD SEDDS A, CBD SEDDS B, CBD SEDDS C, and CBD SEDDS D, respectively. Formulations 1 and 3 in Figure 3B correspond to CBD SEDDS A and C, respectively, when filled with 20% w / w CBD. Formulation 2 in Figure 2B contains Peceol:Gelucire44 / 14:TPGS in 45.6%:30.4%:4% w / w, and Formulation 4 in Figure 3B contains Peceol:Gelucire50 / 13 in 48%:32% w / w. None of the dispersions showed significant drug precipitation. Filtration of the dispersion was found to increase the variability of drug solubilization measurements, but the average solubilization was consistent with that of the unfiltered dispersion.

[0187] The stability of the dispersion profiles of the CBD SEDDS formulations was evaluated under refrigerated and room temperature conditions. Storage of preconcentrates under refrigerated or room temperature conditions did not dramatically change droplet diameter or PDI over a one-month period (Table 2). The dispersion profiles of CBD SEDDS A, B, C, and D remained stable after one month of storage at either room temperature or refrigerated conditions (Figure 4). The dispersion profiles of all four formulations were found to remain stable after three months of storage at room temperature (Figure 5).

[0188] The CBD content of the preliminary concentrate remained stable at room temperature for 3 months (Figure 6). All formulations maintained CBD concentrations within 10% of the initial measurement, but overall lower variability was observed in the ethanol-containing formulations (CBD SEDDS B and D) compared to the co-solvent-free formulations (CBD SEDDS A and C). The chemical stability of CBD in the SEDDS formulations was comparable to that in the sesame oil (SO) formulations (Figure 7). Example 3: Dispersion of cannabinoid SEDDS preparation in simulated gastric juice

[0189] Dispersions of CBD SEDDS formulations were evaluated in biomimetic media such as fasting-state simulated gastric juice (FaSSGF), fasting-state simulated intestinal juice (FaSSIF), and feeding-state simulated intestinal juice (FeSSIF), and compared to phosphate-buffered saline (PBS). FaSSGF, FaSSIF, and FeSSIF are dissolving media that mimic human intestinal juice. Each contains the same types and levels of surfactants (bile salts and phospholipids) present in the gastrointestinal juice it replicates, and has the same mean pH and similar osmotic pressure. Surfactants, pH, and osmotic pressure are important parameters to control when testing a drug or formulation. Surfactants form mixed micelles that can greatly enhance the solubility and solubility of a drug. pH and osmotic pressure can affect the solubility and solubility of a drug. FaSSGF contains approximately 0.08 mM taurocholic acid, approximately 0.02 mM phospholipids, approximately 34 mM sodium, and approximately 59 mM chloride. FaSSIF contains approximately 3 mM taurocholic acid, approximately 0.75 mM phospholipid, approximately 148 mM sodium, approximately 106 mM chloride, and approximately 29 mM phosphate. FeSSIF contains approximately 15 mM taurocholic acid, approximately 3.75 mM phospholipid, approximately 319 mM sodium, approximately 203 mM chloride, and approximately 144 mM acetic acid. FaSSGF, FaSSIF, and FeSSIF powders and buffer concentrates were purchased from Biorelevant.com Ltd.

[0190] CBD SEDDS were dispersed in a biocompatible medium (FaSSIF, FaSSGF, or FeSSIF) at 0.5% w / v and stirred at 100 rpm and 37°C. 800 μL aliquots of the dispersion were taken at 5, 30, 60, and 120 minutes, and the medium was replenished. After diluting the dispersion aliquots with methanol, HPLC analysis was performed. All biocompatible media were prepared using buffer concentrates according to the supplier's instructions.

[0191] Differential effects of the media were observed regarding the amount of CBD solubilized over a two-hour period (Figure 8). Generally, the dispersion profiles of all formulations in FaSSIF appeared similar to those in PBS, with over 90% of CBD solubilized during the study period. For dispersions in FaSSGF, at least 90% of CBD was solubilized within 30 minutes for all formulations. After one hour, the amount of CBD solubilized in all FaSSGF dispersions began to decrease, but remained above 80% throughout the study period. In contrast, the dispersion profiles in FeSSIF showed significantly lower amounts of CBD solubilized compared to dispersions in other biomedical media. The dispersions of CBD SEDDS A and C in FeSSIF differed most from any other formulation dispersed in any other medium, based on the Fréchet distance (Figure 9A). Furthermore, the dispersion of CBD SEDDS A and C in FeSSIF differed significantly in terms of the area under the dispersion profile curve (AUC) compared to the same formulations dispersed in FaSSIF (Figure 9B). These dispersions exhibited signs of creaming, which became more pronounced during the later stages of the study. The 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 preparations

[0192] The pharmacokinetics of CBD after 30 minutes of in vitro digestion were evaluated for CBD SEDDS C and D (Figure 10).

[0193] Briefly, a dispersion of selected CBD SEDDS (2.5% w / v) was prepared in 40 mL of FaSSIF medium. Throughout the study, the medium was stirred at 100 rpm and 37°C. The dispersion was stirred for 10 minutes, followed by the addition of pancreatic lipase (667 mg) to initiate digestion. After 30 minutes of digestion, an 800 μL aliquot of the medium was taken and separated into three layers by centrifugation (20,800 × g, 15 min): an upper layer (oil phase), an intermediate layer (aqueous micelle phase), and a lower layer (precipitated pellet phase). The CBD content from each phase was analyzed by HPLC after dilution in methanol.

[0194] For CBD SEDDS C, CBD was distributed in the oil phase, aqueous phase, and pellet phase at concentrations of 62±6%, 23±5%, and 15±6%, respectively. For CBD SEDDS D, the amounts of CBD recovered from the oil phase, aqueous phase, and pellet phase were 72±2%, 19±1%, and 9±2%, respectively. Overall, the two formulations exhibited minimal precipitation. Neither formulation contained a pellet phase in the control sample from the first 10 minutes of dispersion (i.e., before digestion). Before the addition of pancreatic lipase, the aqueous phase of CBD SEDDS C contained significantly higher levels of CBD than the aqueous phase of CBD SEDDS D (p<0.01), at approximately 47±4% and 24±1%, respectively. Example 5: Pharmacokinetic parameters of cannabinoid preparations in vivo

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

[0196] For pharmacokinetic studies, rats were administered either CBD medium-chain triglyceride oil (CBD MCT), CBD sesame oil vehicle (CBD SO), or one of two self-emulsifying drug delivery systems (i.e., CBD SEDDS C or CBD SEDDS D) by forced oral administration at a dose of 20 mg / kg of CBD (n=5 per formulation group). SEDDS formulations were freshly prepared 30 minutes prior to each experiment by pre-diluting a pre-concentrate with deionized water (1:20 w / v) followed by vortex mixing for 20 seconds. Blood samples (200 μL) were collected via the lateral saphenous vein at 0.25, 0.5, 1, 2, 4, and 6 hours after administration into heparinized tubes (at 1.5 and 3 hours for the CBD MCT group). Eight hours after administration, rats were sacrificed by cardiac puncture, blood was collected, and then decapitation was performed. Blood samples collected during the study were centrifuged (1000×g, 10 minutes, 4°C, 15 minutes for the final sample) to obtain plasma, which was then transferred to a microcentrifuge tube and stored at -80°C until further analysis.

[0197] The second rat cohort was administered CBD SO, CBD SEDDS C, and CBD SEDDS D formulations (n=5 per formulation group) to return to a window near the expected maximum plasma concentration in subsequent pharmacokinetic and tissue distribution studies. In this study, blood samples were collected and stored at 0.5, 1, 1.5, 2, and 3 hours as before, with the final blood collection taking place 4 hours after formulation administration.

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

[0199] Plasma concentration-time profiles showed comparable performance among the CBD SO, CBD SEDDS C, and CBD SEDDS D formulations, with each of these formulations exhibiting significantly higher absorption and slower elimination compared to CBD MCT (Figure 12). Table 3 summarizes the corresponding pharmacokinetic parameters. No statistically significant differences were found between CBD SO or CBD MCT and any of the SEDDS formulations. [Table 3]

[0200] Although not statistically significant, the C of CBD from CBD SO, CBD SEDDS C, and CBD SEDDS D 最大And whole-body exposure was slightly higher than that of CBD MCT. CBD SO, CBD SEDDS C, and CBD SEDDS D 最 The AUC was 1.5 times, 1.7 times, and 1.8 times larger than that of CBD MCT. 0-8時間 Regarding the values, CBD SO, CBD SEDDS C, and CBD SEDDS D were 1.8 times, 1.9 times, and 1.7 times larger, respectively, than those of CBD MCT. 最大 The median was 1 hour, but it was 1.75 hours for CBD SEDDS C and 1.5 hours for CBD MCT (Figures 13A-13D). 最大 The AUC values ​​were slightly higher for CBD SO than for CBD SO. Within 8 hours of oral administration, the percentage of total exposure observed was approximately 73% for CBD SEDDS C and 72% for CBD SEDDS D. In contrast, CBD SO and CBD MCT achieved 80% and 89% of their total exposure within the same period. It is noteworthy that lower variability was observed for CBD SEDDS C and CBD MCT (Figures 14 and 15). Example 6: Tissue distribution after oral administration of cannabinoid SEDDS preparations

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

[0202] After bleeding, tissue samples (i.e., brain, liver, kidneys, spleen, and mesenteric lymph nodes (MLN)) were collected as quickly as possible, rinsed with PBS, and rapidly frozen in dry ice. The tissues were stored at -80°C until further analysis. Tissue samples (approximately 100-250 mg) were weighed into glass vials and homogenized at 12,000 rpm for 5 minutes using PBS (1:4 w / v, 1:6 w / v for MLN) (Polytron® PT 2500 E, Kinematica AG, Luzern, Switzerland). The homogenate (150 μL, 30 μL for MLN) was transferred to a microcentrifuge tube containing 2 μL of pre-dried internal standard (THC, 100 μg / mL in methanol) under nitrogen, and 1.35 mL (270 μL for MLN) of acetonitrile:ethyl acetate (50:50 v / v) was added. The mixture was vortex-mixed for 10 minutes, then placed in an ultrasonic bath at room temperature for 10 minutes, followed by centrifugation (15,300 × g, 10 min, 4°C). The supernatant (1.4 mL, 250 μL for MLN) was transferred to an autosampler vial and dried under nitrogen at 37°C. The sample was then reconstituted in 150 μL of methanol, vortex-mixed, and centrifuged again under the same conditions before being transferred to an autosampler vial insert for subsequent analysis by HPLC-MS / MS.

[0203] For all formulations, the highest CBD concentration was found in the MLN, which was approximately twice the level in the liver. CBD SO yielded significantly higher CBD concentrations in the MLN compared to CBD SEDDS D, but not in CBD SEDDS C (p<0.05). The lowest CBD concentration was found in the spleen across all formulations. Compared to spleen CBD concentrations, MLN concentrations were 11.4 times higher for CBD SO, 13.2 times higher for CBD SEDDS C, and 9.5 times higher for CBD SEDDS D.

[0204] The tissue distribution coefficient was calculated as the ratio between the CBD concentration in each tissue and its respective plasma concentration at 4 hours (Table 4). The tissue distribution coefficient was highest for MLN for each formulation. These findings support the fact that lymphatic uptake of cannabinoids plays a crucial role in their absorption after oral administration in LCT-containing lipid-based formulations. Furthermore, these findings clearly indicate that SO as a delivery vehicle is not necessary to achieve the desired absorption effect in SEDDS formulations. [Table 4] Example 7: Pharmacokinetic parameters of cannabinoid SEDDS formulations in fasted animals

[0205] The pharmacokinetics of CBD SEDDS C were evaluated in fasted and non-fasted Sprague-Dawley rats after oral administration of 20 mg / kg (Figures 17 and 18). Plasma concentration-time profiles revealed that plasma CBD levels reached a higher peak in non-fasted animals compared to fasted animals. Table 5 summarizes the corresponding pharmacokinetic parameters. 最大 And whole-body exposure was approximately 1.5 times and 1.75 times higher in non-fasting animals compared to fasting animals. AUC 0-8時間 The value was approximately 1.6 times larger in non-fasting animals, T 最大 The median exposure time was 1.75 hours in non-fasting animals and 1 hour in fasting animals. Within 8 hours of oral administration, the percentage of total exposure observed was approximately 73% in non-fasting animals and 92% in fasting animals. [Table 5] Example 8: Pharmacokinetic parameters of cannabinoid preparations in vivo

[0206] We investigated the increased bioavailability of CBD SEDDS formulations compared to other CBD preparations. The pharmacokinetics of CBD SEDDS formulations (encapsulated micellar cannabidiol (EMCBD)) were evaluated and compared with the pharmacokinetics of cannabidiol active pharmaceutical ingredient (CBD API) and sesame oil (SO) formulations after oral administration at a dose of 20 mg / kg to fed or fasted rats, according to the study design shown in Figure 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. For groups 2 and 5 (EMCBD, SEDDS formulations) and pre-drug concentrates (PDCs), 1 g of Peceol and Gelucire were added to vials, respectively, and then the mixtures were prepared by heating at 45°C for 30 minutes while stirring at 300 rpm. The final pre-drug concentrate was prepared by adding 1.00 g of drug-free PDC to 0.470 g of CBD isolate, resulting in a concentration of 32% w / w. This mixture was stirred at 400 rpm and 45°C until completely homogeneous. Next, the SEDDS formulation was freshly prepared by pre-diluting the preconcentrate with 30 mL of deionized water (1:80 w / v, for example, 0.25 of a 32% w / w preconcentrate in 20 mL of water) before administration, 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 to a concentration of 10% w / w, and stirred under the same conditions until completely homogenized. The concentration of the CBD isolate in the administration solution was determined by LC-MS / MS.

[0208] Female Sprague-Dawley rats aged 52–61 days were administered a dose of 20 mg / kg of CBD (n=8 per formulation group). Blood was collected from the jugular vein at 0.5, 1, 2, 3, 4, 8, and 24 hours after administration. Plasma samples were obtained after centrifugation and frozen until the plasma concentration of CBD was determined by LC-MS / MS. Plasma concentrations of CBD isolates in rats were subjected to non-compartmental pharmacokinetic analysis using Phoenix WinNonlin software (version 8.3, Certara USA, Inc). Nominal time was used for PK parameter times. Peak plasma concentration (Cmax) and the corresponding peak time (Tmax) were determined directly from the plasma concentration-time profile. Individual plasma concentration values ​​for PO-administered animals that fell below the lower limit of quantification (LLOQ) before Tmax were set to zero, and those after Tmax were excluded from PK parameter calculations. Terminal phase half-life (T1 / 2), area under the plasma concentration-time curve (AUC) from time zero to the last quantifiable concentration (AUC) 0-最後 ) and the AUC (AUC) extrapolated from time zero to infinity. 0-無限大 The mean residence time (MRT) from time zero to the last quantifiable concentration (MRT0-last), and the mean residence time (MRT) from time zero to infinity (MRT0-infinity) were calculated using a linear uplog-down rule. All plasma concentrations and PK parameters are reported with at least three significant figures. C-maxima and AUC were calculated using a one-way ANOVA model with food treatment as the fixed factor and In-transformed analysis values ​​as the dependent variable. 0-最後 The effects of treatment / food on [the condition] were estimated.

[0209] The mean values ​​of major PK parameters are summarized in Figure 20. Figures 21-25 provide graphs showing the mean values ​​of major PK parameters obtained from fed or fasted animals after administration of different CBD formulations.

[0210] Maximum C and AUC 0-最後Based on this, the bioavailability of CBD was higher for the SEDDS formulation (EMCBD) than for the HPBCD formulation (CBD API) after fasting administration, and even higher after feeding administration (Figures 21 and 24). CBD AUC 0-最後 Furthermore, Cmax was higher with the SEDDS formulation than with the SO formulation (CBD WO) after fasting administration, and even higher after feeding administration (Figure 24). The Cmax of the SEDDS formulation was lower than that of the SO formulation after fasting administration, but was higher with the SEDDS formulation than with the SO formulation after feeding administration (Figure 21). The bioavailability of CBD increased with food intake along with the SEDDS formulation, but the slight food effect on the HPBCD and SO formulations was not associated with the observed inter-animal PK variability. These results demonstrate the superior bioavailability of the CBD SEDDS formulation, which was enhanced by food intake.

[0211] All publications, U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, and foreign patent applications referenced herein and / or listed in the application data sheet are incorporated herein by reference to disclose and describe methods and / or materials in relation to those cited in the publications. It is understood that this disclosure takes precedence over any disclosure in the incorporated publications, to the extent of any conflict.

[0212] While specific embodiments of the present invention have been described herein for illustrative purposes, it will be understood from the above that various modifications can be made without departing from the spirit and scope of the invention. Therefore, the present invention is not limited.

Claims

1. Cannabinoids and One or more fatty acid glycerol esters, A cannabinoid preparation comprising one or more polyethylene glycol-containing fatty acid esters.

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

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

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

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

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

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

30.

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

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

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

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

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

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

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

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

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

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

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

19. The formulation according to claim 18, wherein the one or more antioxidants include butylated hydroxytoluene (BHT).

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

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

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

23. The formulation according to claim 22, comprising a single dose of approximately 100 milligrams of the cannabinoid.

24. The formulation according to claim 22, comprising a single dose of approximately 300 milligrams of the cannabinoid.

25. The formulation according to claim 22, comprising a single dose of approximately 600 milligrams of the cannabinoid.

26. The formulation according to claim 22, comprising a single dose of approximately 1,000 milligrams of the cannabinoid.

27. The preparation according to any one of claims 1 to 26, wherein the preparation is administered in a method for treating a disease or injury in a subject, and the preparation is administered in an amount such that approximately 50 to approximately 3,000 milligrams of the cannabinoid are administered per day.

28. The preparation according to claim 27, wherein the preparation is administered in a method for treating a disease or injury in a subject, and the preparation is administered in an amount such as administering 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 preparation according to claim 28, wherein the preparation is administered in a method for treating a disease or injury in a subject, and the preparation is administered in an amount such as administering about 100 mg of the cannabinoid per day.

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

31. The preparation according to claim 28, wherein the preparation is administered in a method for treating a disease or injury in a subject, and the preparation is administered in an amount such as administering about 600 mg of the cannabinoid per day.

32. The preparation according to claim 28, wherein the preparation is administered in a method for treating a disease or injury in a subject, and the preparation is administered in an amount such as administering about 1,000 mg of the cannabinoid per day.

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

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

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

36. The formulation according to any one of claims 1 to 35, wherein the concentration of the cannabinoid is maintained at an amount exceeding approximately 80% of the starting concentration after storage at room temperature for up to three months.

37. The formulation according to any one of claims 1 to 36, wherein the C-max of cannabinoids after oral administration of the formulation is at least approximately equivalent to the C-max of cannabinoids after oral administration of the cannabinoid sesame oil formulation.

38. Systemic exposure (AUC) to cannabinoids after oral administration of the aforementioned formulation. ∞ The formulation according to any one of claims 1 to 37, wherein the exposure to cannabinoids after oral administration of a cannabinoid sesame oil formulation is at least substantially equivalent to systemic exposure to cannabinoids.

39. The formulation according to any one of claims 1 to 38, wherein the Cmax of cannabinoids after oral administration of the formulation up to at least about two hours, at least about four hours, at least about six hours, at least about eight hours, or at least about ten hours after food intake, and at least about two hours before food intake, is at least about 50% of the Cmax of cannabinoids after oral administration of the formulation at approximately the same time as food intake.

40. Systemic exposure (AUC) to cannabinoids after oral administration of the formulation up to at least approximately 2 hours, at least approximately 4 hours, at least approximately 6 hours, at least approximately 8 hours, or at least approximately 10 hours after food intake, and at least approximately 2 hours before food intake. ∞ The formulation according to any one of claims 1 to 39, wherein the amount of the oral administration of the formulation approximately simultaneously with food accounts for at least about 50% of the systemic exposure to cannabinoids after oral administration of the formulation.

41. A preparation containing more than approximately 5% by weight of cannabinoids.

42. The formulation according to claim 41, comprising approximately 10% to approximately 50% by weight of cannabinoids.

43. The formulation according to claim 42, comprising approximately 20% by weight of cannabinoids.

44. The formulation according to claim 42, comprising approximately 40% by weight of cannabinoids.

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

46. The capsule according to claim 45, wherein the capsule is a soft gel capsule.

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

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

49. The method according to claim 48, wherein the disease or injury is selected from the group including clinically high-risk psychosis, insomnia, first-episode psychosis, psychosis in Parkinson's disease, schizophrenia, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, Alzheimer's disease, postpartum psychosis, agoraphobia, acute stress disorder, and schizoaffective disorder.

50. The method according to claim 49, wherein the disease or injury is a clinically high-risk psychosis.

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

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

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

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