Methods for reducing nicotine and marijuana dependency by administration of cannabinoids

Abstract

The present disclosure concerns methods for reducing nicotine dependency, i.e. by reducing tobacco smoking and promoting tobacco smoking secession; and by reducing marijuana dependency, i.e. by reducing marijuana smoking and promoting marijuana smoking cessation. More particularly the present disclosure concerns formulations of cannabinoids for use in reducing nicotine and marijuana dependency and promoting tobacco and marijuana smoking secession.

Description

[0001] Methods for reducing nicotine and marijuana dependency by administration of cannabinoids

[0002] TECHNOLOGICAL FIELD

[0003] The present disclosure concerns methods for reducing nicotine dependency, i.e. by reducing tobacco smoking and promoting tobacco smoking secession; and by reducing marijuana dependency, i.e. by reducing marijuana smoking and promoting marijuana smoking cessation. More particularly the present disclosure concerns formulations of cannabinoids for use in reducing nicotine and marijuana dependency and promoting tobacco and marijuana smoking secession.

[0004] BACKGROUND ART

[0005] References considered to be relevant as background to the presently disclosed subject matter are listed below:

[0006] C.J. Morgan et al., Addict. Behav. 2013, 38(9), 2433-2436

[0007] C. Hindocha et al., Addiction 2018, 113(9), 1696-1705

[0008] - L. Taylor et al., CNS drugs, 2018, 32(11), 1053-1067

[0009] J.R. Hughes et al., Addiction 2004, 99(1), 29-38

[0010] C.J. Jordan & Z.X. Xi, Expert Opin. Drug Discov. 2018, 13(7), 671-683

[0011] C. Hindocha et al., Sci. Rep. 2018, 8(1), 1-7

[0012] U S patent application publication no . 2019 / 0231833

[0013] US patent application publication no. 2019 / 0314326

[0014] I. Ujvary & L. Hanns, Cannabis Cannabinoid Res. 2016, 1(1), 90-101

[0015] Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter.

[0016] BACKGROUND

[0017] Cannabidiol (CBD) is a promising candidate for treating a range of diseases and disorders. CBD has been shown to mitigate key neurocircuit disturbances underlying these disorders, symptoms, and cognitive impairments. Though the mechanism of action of CBD is not fully understood, CBD has been shown to have an inhibitory effect at CB 1 and CB2 receptors and to correspondingly alter the “bias” of systems activated by CB1 agonists (i.e. endocannabinoids and THC). Like other non-psychoactive cannabinoids, CBD shows low affinity for CB1 and CB2 receptors, and is not an orthosteric ligand at those sites.

[0018] Historically, cannabinoids have been used anecdotally as a treatment for a wide array of conditions. However, more recent scientific research has begun to explore these compounds for reliable medicinal use. To date, the focus of this research has been predominantly on two compounds as potential therapeutics: tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is a psychoactive compound, presenting long lasting adverse side effects on the user. CBD, however, is non-psychoactive and is considered non-intoxicating and safe for various routes of administration. THC and CBD are most commonly found together as a mixture in various concentrations in plant sources, and as a result, most therapeutic applications currently known involve consumption of both compounds together. A need therefore exists for formulations and pharmaceutical compositions which comprise CBD and have almost undetectable levels of psychoactive cannabinoids such as THC, thereby minimizing the deleterious side effects of THC, such as intoxication.

[0019] One of the conditions suggested in literature to be potentially beneficially impacted by administration of cannabinoids is addictive tobacco or marijuana consumption, in particular smoking of tobacco and marijuana products. Although the prevalence of smoking has substantially declined in the past five decades, the use of tobacco products for instance, remains the most significant preventable cause of death worldwide, estimated to be more than 8 million human deaths each year, with over 500,000 tobacco-related deaths per year in the U.S. alone. Survey data indicate that in 2020, 8.9% of adults in California smoked at least 100 cigarettes in their lifetime and currently smoked daily or on some days.

[0020] Smoking cessation, of either tobacco or marijuana products, is among the most important actions a person can take to reduce the risk of various diseases, and more than 70% of those who smoke wish to quit. Although there are safe and effective treatments for smoking cessation, not everyone who attempts smoking cessation is successful, even with these treatments. Relapse rates are high, leaving a need for new approaches. Among people who try to quit smoking independently, only 3 to 6 percent successfully stop for 6 to 12 months, and most fail within 8 days (Hughes et al. 2004). Medications approved for smoking cessation are effective and safe, but the available medications and behavioral interventions have limited success. For example, continuous abstinence rates with varenicline, the most effective of the medications, are 18-30 percent (Jordan & Xi 2018), highlighting the need for alternative therapies.

[0021] To date, research on the impact of cannabinoids on smoking secession in human patients is scant. A small trial indicated that CBD, administered for one week by inhalation of aerosolized CBD ethanolic solution, reduced smoking (Morgan et al. 2013), and a single oral dose of pure CBD reduced attentional bias to smoking-related cues in another study (Hindocha et al. 2018).

[0022] As a class, cannabinoids are non-water soluble. This has posed a challenge both in the extraction of cannabinoids from natural sources and in formulating pharmaceutical compositions for oral administration. Cannabinoids are lipid soluble, and CBD has been delivered orally in oilbased capsules in human trials. However, due to CBD’s low water solubility, absorption from the gastrointestinal system is erratic and leads to variable pharmacokinetics (Taylor et al. 2018). Bioavailability of cannabinoids administered orally is generally low (less than 10% in some reports), largely dose dependent, and variable. More so, patient-based variability in bioavailability and absorption rates have been identified when administering CBD in oil form or in pure form, as well as for some commercial CBD-containing products, at times accompanied by a non-linear dose response and / or dependency on consumption of food during treatment (concomitant with, preadministration, or post-administration).

[0023] A need, therefore, exists for reliable pharmaceutical formulations of cannabinoids that have improved water solubility, which can be effectively delivered orally, and which improve the overall bioavailability, and more consistent absorption of orally administered cannabinoids, that would enable effective smoking cessation treatments.

[0024] GENERAL DESCRIPTION

[0025] Cannabinoids, and in particular CBD, have unique and complex pharmacology. Some cannabinoids, including CBD, are considered to be non-intoxicating, and have been used to inhibit drug-seeking behavior in animal models of addiction. Notably, CBD was found to inhibit the rewarding and reinforcing effects of cocaine, methamphetamine, morphine and cannabis, and a recent systematic review concluded that CBD might have promising potential for the treatment of substance use disorders.

[0026] The present disclosure provides pharmaceutical formulations for oral administration of cannabinoids, e.g. CBD, as a means of smoking cessation or reducing tobacco dependency in a tobacco products’ consumer. The present disclosure also provides formulations for oral administration of cannabinoids, e.g. CBD, as means of reducing marijuana smoking in a subject or marijuana dependency in cannabis products’ consumer. As also detailed below, utilizing the pharmaceutical formulations disclosed herein provides improved bioavailability and reduced variance in patient-dependent dose absorption, enabling a more stable and planned treatment protocol for smoking secession, ensuring proper dose delivery and effective consistent absorption after intake.

[0027] According to one of its aspects, the present disclosure provides a method of tobacco smoking cessation in a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0028] According to another one of its aspects, the present disclosure provides a method of reducing nicotine dependency in a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0029] According to another one of its aspects, the present disclosure provides a method of reducing smoking of tobacco cigarettes, by a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0030] According to another one of its aspects, the present disclosure provides a method of inducing abstinence from smoking of tobacco cigarettes by a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0031] According to another one of its aspects, the present disclosure provides a method of reducing marijuana smoking by a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0032] According to one of its aspects, the present disclosure provides a method of marijuana smoking cessation in a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0033] According to another one of its aspects, the present disclosure provides a method of reducing marijuana dependency in a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0034] According to another one of its aspects, the present disclosure provides a method of inducing abstinence from marijuana smoking by a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0035] By another aspect, there is provided a pharmaceutical formulation for use in a method of tobacco smoking cessation in a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0036] By another aspect, there is provided a pharmaceutical formulation for use in a method of reducing nicotine dependency in a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0037] By another aspect, there is provided a pharmaceutical formulation for use in a method of reducing smoking of tobacco cigarettes by a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0038] By yet another aspect, there is provided a pharmaceutical formulation for use in a method of inducing abstinence from smoking of tobacco cigarettes by a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0039] By another aspect, there is provided a pharmaceutical formulation for use in a method of reducing marijuana smoking by a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0040] By another aspect, there is provided a pharmaceutical formulation for use in a method of inducing marijuana smoking cessation in a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0041] By another aspect, there is provided a pharmaceutical formulation for use in a method of reducing marijuana dependency in a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0042] By yet another aspect, there is provided a pharmaceutical formulation for use in a method of inducing abstinence from marijuana smoking by a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

[0043] In other words, the present disclosure provides the use on pharmaceutical formulations of at least one cannabinoid, as will be disclosed herein, for reducing nicotine dependency and / or reducing tobacco smoking and / or inducing tobacco smoking secession and / or reducing marijuana smoking and / or inducing marijuana smoking cessation, by orally administering the pharmaceutical formulations.

[0044] The term tobacco refers to the dried leaves of plants from the genus Nicotiana (e.g. Nicotiana iabacum)'. typically smoked in the form of cigarettes, pipes, or cigars. The term also encompasses chewable products made from Nicotiana plants, such as chewing tobacco, dipping tobacco and snuf.

[0045] The term marijuana as used herein refers to the dried leaves and flowering tops of the Cannabis sativa or Cannabis indica plant which are, typically, used as smoking substance.

[0046] The present disclosure presents formulations comprising at least one cannabinoid.

[0047] Despite the apparent potential of cannabinoid, such as CBD, for use as a therapeutic agent, it has proven difficult to make use of reliably. Traditional methods of administering cannabinoids predominantly involve inhalation of cannabinoid containing smoke or vapors. In addition to the inherent negative health effects inherent in smoke and vapor inhalation, when administered in such a manner dose amounts tend to be inaccurate and variable. Additionally, the pharmacokinetics of CBD administered via inhalation is too variable to allow for consistent and reliable therapeutic administration. To date, methods of oral administration have suffered from extremely poor absorption and bioavailability of CBD, and or from significant patient-dependent variance in dose absorption.

[0048] The disclosed formulations overcome these limitations by allowing for an oral administration of at least one cannabinoid (CBD, CBG, CBC, CBDV, CBN, or the like), with increased bioavailability. The formulations described herein allow for an oral administration of one or more cannabinoids, such that the one or more cannabinoids have increased water solubility, quicker and more consistent absorption and faster onset of action time. Further, the formulations described herein have increased shelf-life stability.

[0049] As used herein, the term cannabinoid refers to therapeutically active compounds which are found in plants of the genus Cannabis (e.g. Cannabis sativa or Cannabis indica). The term includes compounds which are obtained and / or isolated from natural sources (e.g. plants), as well as compounds obtained synthetically. The term also encompasses derivative compounds which are the product of chemical modification to a naturally occurring cannabinoid, so long as the product retains its therapeutic activity. The cannabinoid can be substantially pure cannabinoid (e.g. pure CBD), a cannabinoid in crystalline form, a cannabinoid from a natural source (e.g. extracted or purified from cannabis plant or part thereof), a synthetic cannabinoid (e.g. synthesized from one or more reactions), and a cannabinoid extract (e.g. extract obtained by known extraction methods).

[0050] Exemplary cannabinoids for use in the present disclosure include, but are not limited to, cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerol (CBG), cannabigerol monomethylether (CBGM), cannabigerovarinic acid (CBGVA), cannabigerovarin (CBGV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabichromevarinic acid (CBCVA), cannabichromevarin (CBCV), cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDV A), cannabidiorcol (CBD-C1), delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9-tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinol (THC), delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), delta-9-tetrahydrocannabinol-C4 (THCA-C4), delta-9-tetrahydrocannabivarinic acid (THCVA), delta-9-tetrahydrocannabivarin (THCV), delta-9-tetrahydrocannabiorcolic acid (THCA-C1), delta-9-tetrahydrocannabiorcol (THC-C1), delta-7-cis-isotetrahydrocannabivarin, delta-8-tetrahydrocannabinolic acid A (A8- THCA), delta-8-tetrahydrocannabinol (A8-THC), cannabicyclolic acid (CBLA), cannabicyclol (CBL), cannabicyclovarin (CBLV), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEAB), cannabielsoin (CBE), cannabinolic acid (CBNA), cannabinol (CBN), cannabinol methylether (CBNM), cannabinol-C4 (CBN-C4), cannabivarin (CBV), cannabinol-C2 (CBNC2), cannabiorcol (CBN-C1), cannabinodiol (CBND), cannabinodivarin (CBVD), cannabitriol (CBT), 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, 8,9-dihydroxy-delta-6a- tetrahydrocannabinol, cannabitriolvarin (CBTV), ethoxy-cannabitriolvarin (CBTVE), dehydrocannabifuran (DCBF), cannabifuran (CBF), cannabichromanon (CBCN), cannabicitran (CBT), 10-oxo-delta-6a-tetrahydrocannabinol (OTHC), delta-9-cistetrahydrocannabinol (cis- THC), 3,4,5,6-tetrahtdro-7-hydroxy-a-a-2-trimethyl-9-n-propyl-2,6-methano-2H-l-benzoxocin- 5-methanol (OH-iso-HHCV), cannabiripsol (CBR), trihydroxy-delta-9-tetrahydroxycannabinol (triOH-THC), cannabidiol hydroxyquinone (CBDHQ), and any combination thereof.

[0051] In some embodiments, at least one of the cannabinoids is a non-psychoactive cannabinoid. In some embodiments, at least one of the cannabinoids is a non-psychoactive cannabinoid selected from cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabidivarin (CBDV), cannabinol (CBN), or derivatives thereof.

[0052] In some embodiments, the at least one cannabinoid is CBD or a CBD derivative. As used herein, the terms cannabidiol or CBD refer to a non-psychoactive cannabinoid of the same name, having a chemical formula C21H30O2 and an IUPAC name 2-(lR,6R)-3-methyl-6-prop-l-en-2- ylcyclohex-2-en-l-yl-5-pentylbenzene-l,3-diol. The term also encompasses derivative compounds which are the product of chemical modification to a naturally occurring cannabidiol, so long as the product retains its therapeutic activity.

[0053] In some embodiments, at least one of the cannabinoids is CBD or a CBD derivative, and the pharmaceutical formulation comprises less than 0.1 wt% tetrahydrocannabinol (THC). In some embodiments, at least one of the cannabinoids is CBD, and the pharmaceutical formulation is devoid of THC.

[0054] In some cases, the cannabinoid (e.g. CBD) is a natural cannabinoid, namely one obtained via extraction from, or treatment of, a cannabinoid producing plant. Examples of extraction methods include, but are not limited to, extraction by carrier oils, extraction by organic solvents, and / or super-critical CO2 extraction. In some embodiments, cannabinoid extraction may be carried out utilizing methods, techniques, and formulations as presented in US 2019 / 0231833, the content of which is incorporated herein by reference in its entirety as related to the extraction of cannabinoids. In some embodiments, the cannabinoid is extracted from a cannabinoid-containing plant or plant part. In some embodiments, the cannabinoid is extracted from a plant of the Cannabis genus. In some embodiments, the cannabinoid is extracted from a Cannabis sativa (hemp) plant.

[0055] In some embodiments, the cannabinoid is a synthetic cannabinoid. In some embodiments, the cannabinoid is a synthetic cannabinoid obtained via chemical synthesis or modification techniques.

[0056] In some embodiments, the at least one cannabinoid comprises a CBD derivative, for example a metabolite. In some embodiments, the at least one cannabinoid comprises a human metabolite of CBD (see, e.g., Ujvary & Hanns, Cannabis Cannabinoid Res. 2016; the contents of which are incorporated herein by reference in its entirety as relates to human metabolites of CBD).

[0057] In some embodiments, the formulation comprises between about 0.1 wt% and about 25 wt% of at least one cannabinoid. By some other embodiments, the formulation comprises between about 0.1 wt% and about 12 wt%, between about 5 wt% and about 12 wt %, between about 4 wt% and about 11 wt %, or between about 5 wt% and about 10 wt% of said at least one cannabinoid.

[0058] In some embodiments, the at least one cannabinoid (e.g. CBD) is present in the formulation in an amount between 0.1 wt% and 25 wt%, 0.1 wt% and 20 wt%, 0. 1 wt% and 15 wt%, 0. 1 wt% and 10 wt%, 0. 1 wt% and 10 wt%, 0. 1 wt% and 5 wt%, 0.1 wt% and 1 wt%, 1 wt% and 25 wt%, 1 wt% and 20 wt%, 1 wt% and 15 wt%, 1 wt% and 10 wt%, 1 wt% and 10 wt%, 1 wt% and 5 wt%, 5 wt% and 25 wt%, 5 wt% and 20 wt%, 5 wt% and 15 wt%, 5 wt% and 10 wt%, about 10 wt% and 25 wt%, 10 wt% and 20 wt%, 10 wt% and 15 wt%, 15 wt% and 25 wt%, or 15 wt% and 20 wt%. For example, the at least one cannabinoid may be present in the formulation in an amount of about 25, 24.9, 24.8, 24.7, 24.6, 24.5, 24.4, 24.3, 24.2, 24.1, 24, 23.9, 23.8, 23.7, 23.6, 23.5, 23.4, 23.3, 23.2, 23.1, 23, 22.9, 22.8, 22.7, 22.6, 22.5, 22.4, 22.3, 22.2, 22.1, 22, 21.9, 21.8, 21.7, 21.6, 21.5,

[0059] 21.4, 21.3, 21.2, 21.1, 21, 20.9, 20.8, 20.7, 20.6, 20.5, 20.4, 20.3, 20.2, 20.1, 20, 19.5, 18.5, 18,

[0060] 17.5, 17, 16.5, 16, 15.5, 15, 14.5, 14, 13.5, 13, 12.5, 12, 11.5, 11, 10.5, 10, 9.5, 9, 8.5, 8, 7.5, 7,

[0061] 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5 or 0.1 wt%.

[0062] The present disclosure includes water-soluble lipidic formulations capable of solubilizing a cannabinoid, which retain their water-soluble nature once loaded with the cannabinoid. These formulations, when incorporated into suitable pharmaceutical formulations increase the bioavailability of the cannabinoid over the cannabinoid administered alone and over cannabinoids dissolved in pure oils. For example, one formulation herein was shown to increase absorption of CBD by about 40% relative to CBD administered as a pure oil solution in a study in healthy volunteers. Methods of measuring bioavailability (e.g. the proportion of an active ingredient which reaches the blood stream of a subject able to perform the intended effect) of a therapeutic compound are well known in the art. In short, such methods may comprise the steps of administering a known amount of an active ingredient to a subject, making blood draws at regular intervals from said subject, measuring the concentration of the active ingredient in said subjects’ plasma, and graphing said concentration overtime. The process of measuring bioavailability may further comprise determining the area under the plasma concentration versus time curve (AUC) for either a specific period (AUCO-t) or extrapolated to infinity (AUCO-inf) and / or determining the maximum plasma concentration of the active ingredient (Cmax). Percent (%) bioavailability is determined by comparing the AUC for an active ingredient administered via a non-intravenous route to the intravenously delivered AUC, with the intravenous route assumed to offer 100% bioavailability. The overall bioavailability is considered to increase if the AUC or Cmax increases between 2 formulations at the same dose. Additionally, the time at which Cmax occurs (Tmax) and / or the elimination half-life (T1 / 2) may also be determined with such a procedure, and formulations which alter these pharmacokinetic properties may be advantageous for the treatment of a given indication.

[0063] In some embodiments, the AUC or Cmax of at least one cannabinoid (i.e. CBD) administered in at least one of the disclosed formulations is increased by at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, or more relative to the cannabinoid administered alone.

[0064] In some embodiments the AUC of at least one cannabinoid (i.e. CBD) administered in at least one of the disclosed formulations is at least 35 ngxh / ml, at least 37 ngxh / ml, at least 39 ngxh / ml, at least 41 ngxh / ml, at least 45 ngxh / ml, at least 50 ngxh / ml, at least 100 ngxh / ml, or more.

[0065] In some embodiments the Cmax of at least one cannabinoid (i.e. CBD) administered in at least one of the disclosed formulations is at least, 14 ng / ml, at least 17 ng / ml, at least 20 ng / ml, at least 25 ng / ml, at least 30 ng / ml, at least 35 ng / ml, at least 40 ng / ml, at least 45 ng / ml, at least 50 ng / ml, at least 75 ng / ml, at least 100 ng / ml, or more.

[0066] The pharmaceutical formulations of this disclosure are capable of solubilizing or otherwise carrying lipophilic active ingredients, such as cannabinoids, thereby increasing their bioavailability relative to the active ingredient administered alone. In some embodiments, the formulations remain water soluble when loaded with the one or more cannabinoids and are suitable for inclusion in pharmaceutical products for oral administration. In some embodiments, formulations of the present disclose are water free. In some embodiments, the formulation comprises about 0 wt% of water, less than 0.000001 wt% of water, less than 0.00001 wt% of water, less than 0.0001 wt% of water, less than 0.001 wt% of water, less than 0.01 wt% of water, less than 0.1 wt% of water, or less than 1 wt% of water. In some embodiments, the water free formulations are dilutable by aqueous liquids (e.g. water, buffer solutions, saline, etc.) as needed for effective administration or use according to the present disclosure, or the amount of water in the formulation may increase beyond about 1 wt% over time due to hydration by atmospheric water.

[0067] Without wishing to be bound by theory, the combination of excipients of the pharmaceutical formulations disclosed herein are capable of spontaneous self-assembly into liquid nanodomains when combined in the absence of water (or in the presence of no more than 1 wt% of water). These nanodomains serve as stable carriers for water-insoluble cannabinoids, rendering them water-soluble upon dilution of the formulation into an aqueous liquid.

[0068] Due to their small size (typically up to 400 nm (nanometers), e.g. between about 10 and 150 nm), the nanodomains possess a high surface-area-to-volume ratio. As schematically demonstrated in Figs. 1A-1C, the lipophilic cannabinoids are entrapped and stabilized close to the surface of the nanodomains - hence such a high surface-area-to-volume ratio results in a high loading capacity of the cannabinoids, resulting in nanodomains which are thermodynamically stable. Further, the small size of the nanodomains allows for them to spread over a large surface area of the gut and promotes penetration of the mucus-rich “unstirred water layer.” The nanodomains also appear to increase the rate of absorption in the gastrointestinal track when administered orally, leading to increased bioavailability of the cannabinoids. Without wishing to be bound by theory, the combination of excipients in the formulations of the present disclosure may render the cannabinoids, and particularly CBD, less susceptible to degradation or decomposition by the gastric fluid. These factors thus provide an increase in bioavailability of the active ingredient due to increased absorption, and a decrease in the time of maximum permeation of the drug.

[0069] As noted, formulations of the present disclosure comprise at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, and at least one co-surfactant.

[0070] In some embodiments, the formulation comprises one or more oils. In some embodiments the one or more oils may be either a synthetic or natural oil. In some embodiments, the oil may include, but is not limited to, medium-chain triglycerides (MCT), sesame oil, seed oils, nut oils, vegetable oils, olive oil, soybean oil, canola oil, cotton oil, palmolein, sunflower oil, com oil, rapeseed oil, grape seeds oil, hemp oil, pomegranate oil, avocado oil, peppermint oil, tomato oil, isopropyl myristate, oleyl lactate, coco caprylocaprate, hexyl laurate, oleyl amine, oleic acid, oleyl alcohol, linoleic acid, linoleyl alcohol, ethyl oleate, hexane, heptanes, nonane, decane, dodecane, D-limonene, neem oil, lavender oil, peppermint oil, anise oil, rosemary oil, sage oil, hibiscus oil, berries oil, menthol, capsaicin, pumpkin oil, triglycerides, esters of fatty acids, and mixtures thereof.

[0071] In some embodiments, the formulation comprises at least one oil which comprises mediumchain triglycerides (MCT). In some embodiments, the oil in the formulation is medium-chain triglycerides (MCT). In some embodiments, the formulation comprises at least one oil which comprises sesame oil. In some embodiments, the oil in the formulation is sesame seed oil. In some embodiments, the oil in the formulation is a mixture of two or more oils comprising at least medium -chain triglycerides (MCT) and sesame oil.

[0072] In some embodiments, the at least one oil may be present in the formulation at an amount ranging between about 0.5 wt% and about 20 wt%, about 0.5 wt% and about 18 wt%, about 0.5 wt% and about 16 wt%, about 0.5 wt% and about 14 wt%, about 0.5 wt% and about 12 wt%, about 0.5 wt% and about 10 wt%, about 0.5 wt% and about 8 wt%, about 1 wt% and about 20 wt%, about 1 wt% and about 18 wt%, about 1 wt% and about 16 wt%, about 1 wt% and about 14 wt%, about 1 wt% and about 12 wt%, about 1 wt% and about 10 wt%, about 1 wt% and about 8 wt%, about 2 wt% and about 20 wt%, about 2 wt% and about 18 wt%, about 2 wt% and about 16 wt%, about 2 wt% and about 14 wt%, about 2 wt% and about 12 wt%, about 2 wt% and about 10 wt%, about 2 wt% and about 8 wt%, about 4 wt% and about 20 wt%, about 4 wt% and 18 wt%, about 4 wt% and about 16 wt%, about 4 wt% and about 14 wt%, about 4 wt% and about 12 wt%, about 4 wt% and about 10 wt%, about 4 wt% and about 8 wt%, about 6 wt% and about 20 wt%, about 6 wt% and about 18 wt%, about 6 wt% and about 16 wt%, about 6 wt% and about 14 wt%, about 6 wt% and about 12 wt%, about 6 wt% and about 10 wt%, about 6 wt% and about 8 wt%, about 8 wt% and about 20 wt%, about 8 wt% and about 18 wt%, about 8 wt% and about 16 wt%, about 8 wt% and about 14 wt%, about 8 wt% and about 12 wt%, about 8 wt% and about 10 wt%, about 10 wt% and about 20 wt%, about 10 wt% and about 18 wt%, about 10 wt% and about 16 wt%, about 10 wt% and about 14 wt%, about 10 wt% and about 12 wt%, about 12 wt% and about 20 wt%, about 12 wt% and about 18 wt%, about 12 wt% and about 16 wt%, about 12 wt% and about 14 wt%, about 14 wt% and about 20 wt%, about 14 wt% and about 18 wt%, about 14 wt% and about 16 wt%, about 16 wt% and about 20 wt%, about 16 wt% and about 18 wt%, or about 18 wt% and 20 wt%.

[0073] In some embodiments, the one or more oils may be present in the formulation at an amount between about 0.5 wt% and about 20 wt %. In other embodiments, the one or more oils may be present in the formulation at an amount between about 1 wt% and about 10 wt%. In other embodiments the one or more oils may be present in the formulation in an amount between about 3 wt% and about 6 wt%.

[0074] In some embodiments, the one or more oils may be present in the formulation in a wt% of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 15, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 wt%.

[0075] In some embodiments the one or more oils may be present in an amount of about 3 wt%. In some embodiments the one or more oils may be present in an amount of about 4 wt%. In some embodiments the at least one oil may be present in an amount of about 5 wt%. In some embodiments the one or more oils may be present in an amount of about 6 wt%. In some embodiments the one or more oils may be present in an amount of about 11 wt%.

[0076] In some embodiments, the amount of oil present in the formulation may be measured as the mass of the one or more oils present in one (i. e. a single) tablet or capsule of the pharmaceutical formulation. In such embodiments, the amount of the one or more oils may be between about 5 mg and about 200 mg per one (single) tablet or capsule. In some embodiments, the one or more oils may be present in an amount between 5 mg and 10 mg, 5 mg and 20 mg, 5 mg and 30 mg, 5 mg and 40 mg, 5 mg and 50 mg, 5 mg and 60 mg, 5 mg and 70 mg, 5 mg and 80 mg, 5 mg and 90 mg, 5 mg and 100 mg, 5 mg and 110 mg, 5 mg and 120 mg, 5 mg and 130 mg, 5 mg and 140 mg, 5 mg and 150 mg, 5 mg and 160 mg, 5 mg and 170 mg, 5 mg and 180 mg, 5 mg and 190 mg, 10 mg and 20 mg, 10 mg and 30 mg, 10 mg and 40 mg, 10 mg and 50 mg, 10 mg and 60 mg, 10 mg and 70 mg, 10 mg and 80 mg, 10 mg and 90 mg, 10 mg and 100 mg, 10 mg and 110 mg, 10 mg and 120 mg, 10 mg and 130 mg, 10 mg and 140 mg, 10 mg and 150 mg, 10 mg and 160 mg, 10 mg and 170 mg, 10 mg and 180 mg, 10 mg and 190 mg, 10 mg and 200 mg, 20 mg and 30 mg, 20 mg and 40 mg, 20 mg and 50 mg, 20 mg and 60 mg, 20 mg and 70 mg, 20 mg and 80 mg, 20 mg and 90 mg, 20 mg and 100 mg, 20 mg and 110 mg, 20 mg and 120 mg, 20 mg and 130 mg, 20 mg and 140 mg, 20 mg and 150 mg, 20 mg and 160 mg, 20 mg and 170 mg, 20 mg and 180 mg, 20 mg and 190 mg, 20 mg and 200 mg, 30 mg and 40 mg, 30 mg and 50 mg, 30 mg and 60 mg, 30 mg and 70 mg, 30 mg and 80 mg, 30 mg and 90 mg, 30 mg and 100 mg, 30 mg and 110 mg, 30 mg and 120 mg, 30 mg and 130 mg, 30 mg and 140 mg, 30 mg and 150 mg, 30 mg and 160 mg, 30 mg and 170 mg, 30 mg and 180 mg, 30 mg and 190 mg, 30 mg and 200 mg, 40 mg and 50 mg, 40 mg and 60 mg, 40 mg and 70 mg, 40 mg and 80 mg, 40 mg and 90 mg, 40 mg and 100 mg, 40 mg and 110 mg, 40 mg and 120 mg, 40 mg and 130 mg, 40 mg and 140 mg, 40 mg and 150 mg, 40 mg and 160 mg, 40 mg and 170 mg, 40 mg and 180 mg, 40 mg and 190 mg, 40 mg and 200 mg, 50 mg and 60 mg, 50 mg and 70 mg, 50 mg and 80 mg, 50 mg and 90 mg, 50 mg and 100 mg, 50 mg and 110 mg, 50 mg and 120 mg, 50 mg and 130 mg, 50 mg and 140 mg, 50 mg and 150 mg, 50 mg and 160 mg, 50 mg and 170 mg, 50 mg and 180 mg, 50 mg and 190 mg, 50 mg and 200 mg, 60 mg and 70 mg, 60 mg and 80 mg, 60 mg and 90 mg, 60 mg and 100 mg, 60 mg and 110 mg, 60 mg and 120 mg, 60 mg and 130 mg, 60 mg and 140 mg, 60 mg and 150 mg, 60 mg and 160 mg, 60 and 170 mg, 60 mg and 180 mg, 60 mg and 190 mg, 60 mg and 200 mg, 70 mg and 80 mg, 70 mg and 90 mg, 70 mg and 100 mg, 70 mg and 110 mg, 70 mg and 120 mg, 70 mg and 130 mg, 70 mg and 140 mg, 70 mg and 150 mg, 70 mg and 160 mg, 70 mg and 170 mg, 70 mg and 180 mg, 70 mg and 190 mg, 70 mg and 200 mg, 80 mg and 90 mg, 80 mg and 100 mg, 80 mg and 110 mg, 80 mg and 120 mg, 80 mg and 130 mg, 80 mg and 140 mg, 80 mg and 150 mg, 80 mg and 160 mg, 80 mg and 170 mg, 80 mg and 180 mg, 80 mg and 190 mg, 80 mg and 200 mg, 90 mg and 100 mg, 90 mg and 110 mg, 90 mg and 120 mg, 90 mg and 130 mg, 90 mg and 140 mg, 90 mg and 150 mg, 90 mg and 160 mg, 90 mg and 170 mg, 90 mg and 180 mg, 90 mg and 190 mg, 90 mg and 200 mg, 100 mg and 110 mg, 100 mg and 120 mg, 100 mg and 130 mg, 100 mg and 140 mg, 100 mg and 150 mg, 100 mg and 160 mg, 100 mg and 170 mg, 100 mg and 180 mg, 100 mg and 190 mg, 100 mg and 200 mg, 110 mg and 120 mg, 110 mg and 130 mg, 110 mg and 140 mg, 110 mg and 150 mg, 110 mg and 160 mg, 110 mg and 170 mg, 110 mg and 180 mg, 110 mg and 190 mg, 110 mg and 200 mg, 120 mg and 130 mg, 120 mg and 140 mg, 120 mg and 150 mg, 120 mg and 160 mg, 120 mg and 170 mg, 120 mg and 180 mg, 120 mg and 190 mg, 120 mg and 200 mg, 130 mg and 140 mg, 130 mg and 150 mg, 130 mg and 160 mg, 130 mg and 170 mg, 130 mg and 180 mg, 130 mg and 190 mg, 130 mg and 200 mg, 140 mg and 150 mg, 140 mg and 160 mg, 140 mg and 170 mg, 140 mg and 180 mg, 140 mg and 190 mg, 140 mg and 200 mg, 150 mg and 160 mg, 150 mg and 170 mg, 150 mg and 180 mg, 150 mg and 190 mg, 150 mg and 200 mg, 160 mg and 170 mg, 160 mg and 180 mg, 160 mg and 190 mg, 160 mg and 200 mg, 170 mg and 180 mg, 170 mg and 190 mg, 170 mg and 200 mg, 180 mg and 190 mg, 180 mg and 200 mg, or between 190 mg and 200 mg per one (single) tablet or capsule.

[0077] In some embodiments, the amount of the one or more oils may be between about 50 and about 60 mg per one (single) tablet or capsule. In some embodiments the one or more oils are present in an amount between 50 mg and 60 mg, 51 mg and 60 mg, 52 mg and 60 mg, 53 mg and 60 mg, 54 mg and 60 mg, 55 mg and 60 mg, 56 mg and 60 mg, 57 mg and 60 mg, 58 mg and 60 mg, 59 mg and 60 mg, 50 mg and 59 mg, 51 mg and 59 mg, 52 mg and 59 mg, 53 mg and 59 mg,

[0078] 54 mg and 59 mg, 55 mg and 59 mg, 56 mg and 59 mg, 57 mg and 59 mg, 58 mg and 59 mg, 50 mg and 58 mg, 51 mg and 58 mg, 52 mg and 58 mg, 53 mg and 58 mg, 54 mg and 58 mg, 55 mg and 58 mg, 56 mg and 58 mg, 57 mg and 58 mg, 50 mg and 57 mg, 51 mg and 57 mg, 52 mg and 57 mg, 53 mg and 57 mg, 54 mg and 57 mg, 55 mg and 57 mg, 55 mg and 57 mg, 56 mg and 57 mg, 50 mg and 56 mg, 51 mg and 56 mg, 52 mg and 56 mg, 53 mg and 56 mg, 54 mg and 56 mg,

[0079] 55 mg and 56 mg, 50 mg and 55 mg, 51 mg and 55 mg, 52 mg and 55 mg, 53 mg and 55 mg, 54 mg and 55 mg, 50 mg and 54 mg, 51 mg and 54 mg, 52 mg and 54 mg, 53 mg and 54 mg, 50 mg and 53 mg, 51 mg and 53 mg, 52 mg and 53 mg, 50 mg and 52 mg, 51 mg and 52 mg, or between 50 mg and 51 mg per one tablet or capsule.

[0080] In some embodiments, the amount of the one or more oils may be about 54 mg per one tablet or capsule. In some embodiments, the amount of the one or more oils may be about 57 mg per one tablet or capsule. In some embodiments, the amount of the one or more oils may be about 60 mg per one tablet or capsule. In some embodiments, the amount of the one or more oils may be about 110 mg per one tablet or capsule.

[0081] The pharmaceutical formulation comprises at least one hydrophilic surfactant. As used herein, the term hydrophilic surfactant refers to ionic or non-ionic surfactants having a hydrophilic nature, i.e. a surfactant having an affinity for water.

[0082] In some embodiments, the hydrophilic surfactant may include, but is not limited to, ethoxylated sorbitan mono laurate, ethoxylated sorbitan monostearate / palmitate, ethoxylated sorbitan mono oleate / linoleate, ethoxylated sorbitan trioleate, ethoxylated castor oil, hydrogenated castor oil ethoxylated, ethoxylated monoglyceride stearate / plamitate, polyethylene glycol-8 (PEG- 8) caprylic / capric glycerides, oleoyl macrogolglycerides (e.g., Labrasol® ALF), polyoxyl 35 castor oil (e.g. Cremophor™ EL), Solutol® HS15 (Polyethylene glycol (15)-hydroxystearate), polysorbate 40, polysorbate 60, polysorbate 80, polyoxyethylene fatty acid esters (e.g. Myq® S40), ethoxylated hydroxystearate, polyglycerol esters (such as decaglycerol monolaurate, decaglycerol monooleate, hexaglycerol monooleate and hexaglycerol monolaurate), sucrose monooleate, sucrose monolaurate, ethoxylated monoglycerol esters, and ethoxylated fatty acids.

[0083] In some embodiments, the hydrophilic surfactant comprises polyoxyl 35 castor oil (e.g. Cremophor EL). In some embodiments, the hydrophilic surfactant comprises polysorbate 80. In some embodiments, the hydrophilic surfactant comprises PEG-8 caprylic / capric glycerides. According to some embodiments, the pharmaceutical formulation comprises a combination of two or more of polyoxyl 35 castor oil, polysorbate 80, PEG-8 caprylic / capric glycerides, and oleoyl macrogolglycerides.

[0084] In some embodiments, the formulation may comprise between about 30 wt% and about 85 wt%, 30 wt% and 35 wt%, 30 wt% and 40 wt%, 30 wt% and 45 wt%, 30 wt% and 50 wt%, 30 wt% and 55 wt%, 30 wt% and 60 wt%, 30 wt% and 65 wt%, 30 wt% and 70 wt%, 30 wt% and 75 wt%, 30 wt% and 80 wt%, 30 wt% and 85 wt%, 35 wt% and 40 wt%, 35 wt% and 45 wt%, 35 wt% and 50 wt%, 35 wt% and 55 wt%, 35 wt% and 60 wt%, 35 wt% and 65 wt%, 35 wt% and 70 wt%, 35 wt% and 75 wt%, 35 wt% and 80 wt%, 35 wt% and 85 wt%, 40 wt% and 45 wt%, 40 wt% and 50 wt%, 40 wt% and 55 wt%, 40 wt% and 60 wt%, 40 wt% and 65 wt%, 40 wt% and 70 wt%, 40 wt% and 75 wt%, 40 wt% and 80 wt%, 40 wt% and 85 wt%, 45 wt% and 50 wt%, 45 wt% and 55 wt%, 45 wt% and 60 wt%, 45 wt% and 65 wt%, 45 wt% and 70 wt%, 45 wt% and 75 wt%, 45 wt% and 80 wt%, 45 wt% and 85 wt%, 50 wt% and 55 wt%, 50 wt% and 60 wt%, 50 wt% and 65 wt%, 50 wt% and 70 wt%, 50 wt% and 75 wt%, 50 wt% and 80 wt%, 50 wt% and 85 wt%, 55 wt% and 60 wt%, 55 wt% and 65 wt%, 55 wt% and 70 wt%, 55 wt% and 75 wt%, 55 wt% and 80 wt%, 55 wt% and 85 wt%, 60 wt% and 65 wt%, 60 wt% and 70 wt%, 60 wt% and 75 wt%, 60 wt% and 80 wt%, 60 wt% and 85 wt%, 65 wt% and 70 wt%, 65 wt% and 75 wt%, 65 wt% and 80 wt%, 65 wt% and 85 wt%, 70 wt% and 75 wt%, 70 wt% and 80 wt%, 70 wt% and 85 wt%, 75 wt% and 80 wt%, 75 wt% and 85 wt%, or between 80 wt% and 85 wt%, of one or more hydrophilic surfactants.

[0085] In some embodiments, the formulation may comprise, between about 30 wt% and about 85 wt% of hydrophilic surfactants. In some other embodiments, the formulation may comprise between about 35 wt% and about 80 wt% of hydrophilic surfactants. In some embodiments, the formulation may comprise between about 45 wt% and about 80 wt% of hydrophilic surfactants. In some embodiments, the formulation may comprise between about 45 wt% and about 55 wt% of hydrophilic surfactants. In some embodiments, the formulation may comprise between about 70 wt% and about 80 wt% of hydrophilic surfactants.

[0086] In some embodiments, the formulation may comprise, about 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 wt% of hydrophilic surfactants. In some embodiments, the formulation may comprise, about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 wt% of hydrophilic surfactants. In some embodiments, the formulation may comprise, about 38 wt% of hydrophilic surfactants. In some embodiments, the formulation may comprise, about 28 wt% of hydrophilic surfactants. In some embodiments, the formulation may comprise, about 48 wt% of hydrophilic surfactants. In some embodiments, the formulation may comprise, about 12 wt% of hydrophilic surfactants.

[0087] According to some embodiments, the formulation comprises at least two hydrophilic surfactants, each selected independently from the hydrophilic surfactants disclosed herein, provided that the first surfactant is different from the second surfactant. In such embodiments, the formulation comprises a first hydrophilic surfactant having a range of about 30 wt% and about 50 wt% and a second hydrophilic surfactant having a range of about 10 wt% and about 30 wt%. In some embodiments, the formulation comprises about 38 wt % of a first hydrophilic surfactant and about 28 wt% of a second hydrophilic surfactant.

[0088] In some embodiments, the formulation comprises between about 30 wt% and about 50 wt% polyoxyl 35 castor oil as a first hydrophilic surfactant, between about 10 wt% and about 30 wt% of polysorbate 80 as a second hydrophilic surfactant. In some embodiments, the formulation comprises about 38 wt% of polyoxyl 35 castor oil and about 28 wt% polysorbate 80.

[0089] According to some other embodiments, the formulation comprises at least three hydrophilic surfactants, each selected independently from the hydrophilic surfactants disclosed herein, provided that the second surfactant is different from the first surfactant, and that the third surfactant is different from both the first and second surfactants. In such embodiments, the formulation comprises the first hydrophilic surfactant in a range of about 45 wt% and about 50 wt%, the second hydrophilic surfactant in a range of about 10 wt% and about 12 wt%, and the third hydrophilic surfactant in a range of about 10 wt% and about 12 wt%. In some embodiments, the formulation comprises about 48 wt% of the first hydrophilic surfactant, about 11 wt % of the second hydrophilic surfactant, and about 11 wt% of the third hydrophilic surfactant.

[0090] In some embodiments, the formulation comprises between about 45 wt% and about 50 wt% polyoxyl 35 castor oil as the first hydrophilic surfactant, between about 10 wt% and about 12 wt% polysorbate 80 as the second hydrophilic surfactant, and between about 10 wt% and about 12 wt% PEG-8 caprylic / capric glycerides as the third hydrophilic surfactant. In some embodiments, the formulation comprises about 48 wt% polyoxyl 35 castor oil, about 11 wt % polysorbate 80, and about 11 wt% of PEG-8 caprylic / capric glycerides.

[0091] In some embodiments, the amount of hydrophilic surfactants present in the formulation may be measured as the mass of the at least one hydrophilic surfactant present in one (single) tablet or capsule of the pharmaceutical formulation. In such embodiments, the amount of said at least one hydrophilic surfactant may be between about 300 mg and about 850 mg per one (single) tablet or capsule. For example, in some embodiments said at least one hydrophilic surfactant may be present in amounts between 300 mg and 800 mg, 300 mg and 750 mg, 300 mg and 700 mg, 300 mg and 650 mg, 300 mg and 600 mg, 300 mg and 550 mg, 300 mg and 500 mg, 300 mg and 450 mg, 300 mg and 400 mg, 300 mg and 350 mg, 350 mg and 850 mg, 350 mg and 800 mg, 350 mg and 750 mg, 350 mg and 700 mg, 350 mg and 650 mg, 350 mg and 600 mg, 350 mg and 550 mg, 350 mg and 500 mg, 350 mg and 450 mg, 350 mg and 400 mg, 400 mg and 850 mg, 400 mg and 800 mg, 400 mg and 750 mg, 400 mg and 700 mg, 400 mg and 650 mg, 400 mg and 600 mg, 400 mg and 550 mg, 400 mg and 500 mg, 400 mg and 450 mg, 450 mg and 850 mg, 450 mg and 800 mg, 450 mg and 750 mg, 450 mg and 700 mg, 450 mg and 650 mg, 450 mg and 600 mg, 400 mg and 550 mg, 400 mg and 500 mg, 400 mg and 450 mg, 450 mg and 850 mg, 450 mg and 800 mg, 450 mg and 750 mg, 450 mg and 700 mg, 450 mg and 650 mg, 450 mg and 600 mg, 450 mg and 550 mg, 450 mg and 500 mg, 500 mg and 850 mg, 500 mg and 800 mg, 500 mg and 750 mg, 500 mg and 700 mg, 500 mg and 650 mg, 500 mg and 600 mg, 500 mg and 550 mg, 550 mg and 850 mg, 550 mg and 800 mg, 550 mg and 750 mg, 550 mg and 700 mg, 550 mg and 650 mg, 550 mg and 600 mg, 600 mg and 850 mg, 600 mg and 800 mg, 600 mg and 750 mg, 600 mg and 700 mg, 600 mg and 650 mg, 650 mg and 850 mg, 650 mg and 750 mg, 650 mg and 700 mg, 700 mg and 850 mg, 700 mg and 800 mg, 700 mg and 750 mg, 750 mg and 850 mg, 750 mg and 800 mg, or 800 mg and 850 mg per one tablet or capsule.

[0092] In some embodiments the amount of said at least one hydrophilic surfactant may be between about 100 mg and about 300 mg per one tablet or capsule. For example, in some embodiments said at least one hydrophilic surfactant may be present in amounts between 100 mg and 150mg, 100 mg and 200 mg, 100 mg and 250 mg, 100 mg and 300 mg, 150 mg and 200 mg, 150 mg and 250 mg, 150 mg and 300 mg, 200 mg and 250 mg, 200 mg and 300 mg, or 250 mg and 300 mg per one tablet or capsule.

[0093] In some embodiments, the amount of hydrophilic surfactants present in the formulation may be between 700 mg and 800 mg per one tablet or capsule. For example, in some embodiments said at least one hydrophilic surfactant may be present in an amount of about 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, or 800 mg per one tablet or capsule.

[0094] In some embodiments, the amount of hydrophilic surfactants present in the formulation may be about 715 mg per one tablet or capsule. In some embodiments, the amount of hydrophilic surfactants present in the formulation may be about 755 mg per one tablet or capsule. In some embodiments, the amount of hydrophilic surfactants present in the formulation may be about 795 mg per one tablet or capsule. In some embodiments, the amount of hydrophilic surfactants present in the formulation may be about 380 mg per one tablet or capsule. In some embodiments, the amount of hydrophilic surfactants present in the formulation may be about 280 mg per one tablet or capsule. In some embodiments, the amount of hydrophilic surfactants present in the formulation may be about 484 mg per one tablet or capsule. In some embodiments, the amount of hydrophilic surfactants present in the formulation may be about 115 mg per one tablet or capsule. In some embodiments, the amount of hydrophilic surfactants present in the formulation may be about 116 mg per one tablet or capsule.

[0095] The pharmaceutical formulation comprises at least one co-surfactant. The co-surfactant, as used herein, refers to an auxiliary surfactant agent which differs from the hydrophilic surfactant in the formulation, and is capable (together with the hydrophilic surfactant) of lowering the interfacial tension between an oil phase and an aqueous phase to almost zero (or zero), allowing for the formation of a homogeneous mixture once the formulation is mixed with an aqueous liquid.

[0096] In some embodiments, the co-surfactant may comprise, but is not limited to, at least one polyol (i.e. an alcohol containing at least 2 hydroxyl groups), for example ethylene glycol, glycerol, polyethylene glycol, polypropylene glycol, sorbitol, mannitol, lactitol, xylitol and others. In some embodiments, the co-surfactant may be selected from glycerol, polypropylene glycol, polyethylene glycol, propylene glycol, polyglyceryl-3 oleate (Plurol® Oleique CC 947), ethoxy hydrogenated castor oil, sorbitan esters of saturated or unsaturated fatty acids (Spans®), phospholipids, and waxes (carnauba, beeswax, candelilla).

[0097] In some embodiments, the formulation may comprise between about 1 wt% and about 50 wt%, 1 wt% and 45 wt%, 1 wt% and 40 wt%, 1 wt% and 35 wt%, 1 wt% and 30 wt%, 1 wt% and 25 wt%, 1 wt% and 20 wt%, 1 wt% and 15 wt%, 1 wt% and 10 wt%, 1 wt% and 5 wt%, 5 wt% and 50 wt%, 5 wt% and 45 wt%, 5 wt% and 40 wt%, 5 wt% and 35 wt%, 5 wt% and 30 wt%, 5 wt% and 25 wt%, 5 wt% and 20 wt%, 5 wt% and 15 wt%, 5 wt% and 10 wt%, 5 wt% and 5 wt%, 10 wt% and 50 wt%, 10 wt% and 45 wt%, 10 wt% and 40 wt%, 10 wt% and 35 wt%, 10 wt% and 30 wt%, 10 wt% and 25 wt%, 10 wt% and 20 wt%, 10 wt% and 15 wt%, 15 wt% and 50 wt%, 15 wt% and 45 wt%, 15 wt% and 40 wt%, 15 wt% and 35 wt%, 15 wt% and 30 wt%, 15 wt% and 25 wt%, 15 wt% and 20 wt%, 20 wt% and 50 wt%, 20 wt% and 45 wt%, 20 wt% and 30 wt%, 20 wt% and 25 wt%, 25 wt% and 50 wt%, 25 wt% and 45 wt%, 25 wt% and 40 wt%, 25 wt% and 35 wt%, 25 wt% and 30 wt%, 30 wt% and 50 wt%, 30 wt% and 45 wt%, 30 wt% and 40 wt%, 30 wt% and 35 wt%, 35 wt% and 50 wt%, 35 wt% and 45 wt%, 35 wt% and 40 wt%, 40 wt% and 50 wt%, 40 wt% and 45 wt%, or 45 wt% and 50 wt% of co-surfactants. In some embodiments, the formulation may comprise between about 1 wt% and about 50 wt% of co-surfactants. In other embodiments, the formulation may comprise between about 2 wt% and about 45 wt% of co-surfactants. In still more embodiments, the formulation may comprise between about 2 wt% and about 5 wt% of co-surfactants.

[0098] In some embodiments, the formulation may comprise about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 12, 13, or 14 wt% of co-surfactants. In some embodiments, the formulation may comprise about 4 wt% of co-surfactants. In some embodiments, the formulation may comprise about 8 wt% of cosurfactants. In some embodiments, the formulation may comprise about 3 wt% of co-surfactants. In some embodiments, the formulation may comprise about 14 wt% of co-surfactants.

[0099] According to some embodiments, the formulation comprises at least two co-surfactants, each independently selected from the co-surfactants disclosed herein, provided that the first cosurfactant is different from the second co-surfactant.

[0100] According to some embodiments, the formulation comprises about 14 wt% of a first cosurfactant and about 3 wt% of a second co-surfactant. In some embodiments, the formulation comprises about 14 wt% of poly clyceryl-3 -oleate as the first co-surfactant and about 3 wt% of propylene glycol as the second co-surfactant.

[0101] According to other embodiments, the formulation comprises about 4 wt% of a first cosurfactant and about 8 wt% of a second co-surfactant. In some embodiments, the formulation comprises about 4 wt% of polyclyceryl-3-oleate as the first co-surfactant and about 8 wt% of propylene glycol as the second co-surfactant.

[0102] In some embodiments, the amount of one co-surfactant present in the formulation may be measured as the mass of the at least one co-surfactant present in one (single) tablet or capsule of the pharmaceutical formulation. In such embodiments, the amount of said at least one co-surfactant may be between about 10 mg and about 500 mg per one (single) tablet or capsule. For example, in some embodiments said at least one co-surfactant may be present in amounts between 10 mg and 500 mg, 10 mg and 450 mg, 10 mg and 400 mg, 10 mg and 350 mg, 10 mg and 300 mg, 10 mg and 250 mg, 10 mg and 200 mg, 10 mg and 150 mg, 10 mg and 100 mg, 10 mg and 50 mg, 50 mg and 500 mg, 50 mg and 450 mg, 50 mg and 400 mg, 50 mg and 350 mg, 50 mg and 300 mg, 50 mg and 250 mg, 50 mg and 200 mg, 50 mg and 150 mg, 50 mg and 100 mg, 100 mg and 500 mg, 100 mg and 450 mg, 100 mg and 400 mg, 100 mg and 350 mg, 100 mg and 300 mg, 100 mg and 250 mg, 100 mg and 200 mg, 100 mg and 150 mg, 150 mg and 500 mg, 150 mg and 450 mg, 150 mg and 400 mg, 150 mg and 350 mg, 150 mg and 300 mg, 150 mg and 250 mg, 150 mg and 200 mg, 200 mg and 500 mg, 200 mg and 450 mg, 200 mg and 400 mg, 200 mg and 350 mg, 200 mg and 300 mg, 200 mg and 250 mg, 250 mg and 500 mg, 250 mg and 450 mg, 250 mg and 400 mg, 250 mg and 350 mg, 250 mg and 300 mg, 300 mg and 500 mg, 300 mg and 450 mg, 300 mg and 400 mg, 300 mg and 350 mg, 350 mg and 500 mg, 350 mg and 450 mg, 350 mg and 400 mg, 400 mg and 500 mg, 400 mg and 450 mg, or 450 mg and 500 mg per one tablet or capsule.

[0103] In some embodiments, the co-surfactants may be present in the formulation in an amount between about 20 mg and 50 mg per one tablet or capsule. For example, the co-surfactants may be present in the formulation in an amount of about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 45, 46, 47, 48, 49 or 50 mg per one tablet or capsule. In some embodiments, the co-surfactants may be present in the formulation in an amount between about 25 mg and about 150 mg per one tablet or capsule.

[0104] In some embodiments, the co-surfactants may be present in the formulation in an amount of about 45 mg per one tablet or capsule. In other embodiments, the co-surfactants may be present in the formulation in an amount of about 85 mg per one tablet or capsule. In still more embodiments, the co-surfactants may be present in the formulation in an amount of about 140 mg per one tablet or capsule. In some embodiments, the co-surfactants may be present in the formulation in an amount of about 30 mg per one tablet or capsule.

[0105] The pharmaceutical formulation may optionally comprise at least one solvent. In some embodiments the at least one solvent is an organic compound, different from the oil, which is miscible in the oil and together therewith form a homogenous oily phase that dissolves and stabilizes the cannabinoid.

[0106] In some embodiments, the solvent may be selected from ethanol, propanol, isopropyl alcohol, acetic acid, propionic acid, fumaric acid, tartaric acid and its derivatives, lactic acid, maleic acid, and malic acid.

[0107] In some embodiments, the solvents may be present in the formulation in an amount between about 0.1 wt% and about 25 wt%, 0. 1 and 20 wt%, 0. 1 wt% and 15 wt%, 0.1 wt% and 10 wt%, 0. 1 wt% and 5 wt%, 1 wt% and 25 wt%, 1 wt% and 20 wt%, 1 wt% and 15 wt%, 1 wt% and 10 wt%, 1 wt% and 5 wt%, 5 wt% and 25 wt%, 5 wt% and 20 wt%, 5 wt% and 15 wt%, 5 wt% and 10 wt%, 10 wt% and 25 wt%, 10 wt% and 20 wt%, 10 wt% and 15 wt%, 15 wt% and 25 wt%, 15 wt% and 20 wt%, or 20 wt% and 25 wt%.

[0108] In some embodiments, the solvents may be present in the formulation in an amount ranging between about 0.1 wt% and about 25 wt%. In some embodiments, the formulation may comprise between about 0. 1 wt% and about 15 wt% of solvents. In some embodiments, the amount of solvents present in the formulation may be measured as the mass of the at least one solvent present in one (single) tablet or capsule of the pharmaceutical formulation. In such embodiments, the amount of solvents may be between about 1 mg and about 250 mg per one tablet or capsule. For example, in some embodiments said solvents may be present in amounts between about 1 mg and 250 mg, 1 mg and 200 mg, 1 mg and 150 mg, 1 mg and 100 mg, 1 mg and 50 mg, 10 mg and 250 mg, 10 mg and 200 mg, 10 mg and 150 mg, 10 mg and 100 mg, 10 mg and 50 mg, 50 mg and 250 mg, 50 mg and 200 mg, 50 mg and 150 mg, 50 mg and 100 mg, 100 mg and 250 mg, 100 mg and 200 mg, 100 mg and 150 mg, 150 mg and 250 mg, 150 mg and 200 mg, or 200 mg and 250 mg per one tablet or capsule.

[0109] In some embodiments, the formulation optionally contains at least one phospholipid. In some embodiments, the phospholipids may be selected from soy lecithin, rapeseed lecithin, com lecithin, sunflower lecithin, egg lecithin, Epicom ™ 200, Phosal™ 50 PG, dioleyl phosphatidylcholine (DOPC), oleyl palmytoyl phosphatidylcholine (POPC), and the corresponding serines and / or ethanol amines thereof.

[0110] In some embodiments, the formulation may comprise between about 1 wt% and about 10 wt% of phospholipids. In some embodiments, the phospholipids may be present in the formulation in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 wt%.

[0111] In some embodiments, the amount of at least one phospholipid present in the formulation may be measured as the mass of the at least one phospholipid present in one (single) tablet or capsule of the pharmaceutical formulation. In some embodiments, the amount of the phospholipids may be between about 10 mg and 100 mg per one tablet or capsule. In some embodiments, the phospholipids may be present in amounts between about 10 mg and about 100 mg, 10 mg and 80 mg, 10 mg and 60 mg, 10 mg and 40 mg, 10 mg and 20 mg, 20 mg and 100 mg, 20 mg and 80 mg, 20 mg and 60 mg, 20 mg and 40 mg, 40 mg and 100 mg, 40 mg and 80 mg, 40 mg and 60 mg, 60 and 100 mg, 60 mg and 80 mg, or 80 mg and 100 mg per one tablet or capsule.

[0112] In some embodiments, the formulation may optionally comprise at least one additive, selected from antioxidants (e.g. tocopherols), preservatives, membrane-piercing agents, transmembrane penetrating enhancers (such as transcutol, isosorbide, maltodextrins, cyclodextrins, etc.), oil / water soluble vitamins, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), and others.

[0113] In some embodiments, the additives may be present in the formulation in an amount of between about 0.01 wt% and about 15 wt%, 0.01 wt% and 10 wt%, 0.01 wt% and 5 wt%, 1 wt% and 15 wt%, 1 wt% and 10 wt%, 1 wt% and 5 wt%, 5 wt% and 15 wt%, 5 wt% and 10 wt%, or 10 wt% and 15 wt%.

[0114] In some embodiments, the additives may be present in the formulation in an amount of between about 0.01 wt% and about 10 wt%. In some embodiments, the additives may be present in the formulation in an amount of between about 5 wt% and about 7 wt%. In some other embodiments, the additives may be present in the invention in an amount of between about 8 wt% and about 10 wt%. In some embodiments, the additives may be present in the formulation in an amount of between about 0.01 wt% and about 5 wt%. In some embodiments, the additives may be present in the formulation in an amount of between about 0.05 wt%.

[0115] In some embodiments, the amount of at least one additive present in the formulation may be measured as the mass of the at least one additive present in one (single) tablet or capsule of the pharmaceutical formulation. In some embodiments, the amount of the at least one additive may be between about 1 mg and 150 mg per one tablet or capsule. In some embodiments, the least one additive may be present in amounts between about 1 mg and 150 mg, 1 mg and 100 mg, 1 mg and 50 mg, 10 mg and 150 mg, 10 mg and 100 mg, 10 mg and 50 mg, 50 mg and 150 mg, 50 mg and 100 mg, or 100 mg and 150 mg per one tablet or capsule.

[0116] In some embodiments, the at least one additive may be present in the formulation in an amount between about 0.1 mg and about 5 mg per one tablet or capsule.

[0117] In some embodiments, the formulation may comprise one or more formulation component as disclosed in US 2019 / 0314326, the content of which is incorporated herein by reference in its entirety as related to formulation, production, and use of formulations suitable for use in present disclosure.

[0118] In some embodiments, the formulation may comprise MCT, sesame oil, polyoxyl 35 castor oil, polysorbate 80, PEG-8 caprylic / capric glycerides, polyglyceryl-3 oleate, propylene glycol, BHT, or any combination thereof.

[0119] In some embodiments, the formulation may comprise per tablet, softgel, or capsule about 50-60 mg of medium-chain triglycerides or sesame oil, about 480-515 mg of polyoxyl 35 castor oil (e.g. Cremophor™ EL), about 110-125 mg of polysorbate 80 (e.g. Tween® 80), about 110-125 mg of PEG-8 caprylic / capric glycerides (oleoyl macrogolglycerides, e.g. Labrasol® ALF), about 40-50 mg of polyglyceryl-3 oleate (e.g. Plurol® Oleique CC 947), about 80-95 mg of propylene glycol, and / or about 0.1-1 mg of butylated hydroxytoluene (BHT).

[0120] In some embodiments, the formulation comprises per capsule, softgel, or tablet: about 45- 55 mg of CBD, CBG, CBC, CBDV, CBN, or a combination thereof; about 105-115 mg sesame oil; about 375-385 mg of polyoxyl 35 castor oil; about 275-285 mg of polysorbate 80; about 135- 145 mg of polyglyceryl-3 oleate; about 25-35 mg of propylene glycol; about 0.1-1 mg of butylated hydroxytoluene (BHT); or any combination thereof.

[0121] In some embodiments, the formulation comprises per capsule, softgel, or tablet: about 95- 105 mg of CBD, CBG, CBC, CBDV, CBN, or a combination thereof; about 50-60 mg of mediumchain triglycerides; about 480-490 mg of polyoxyl 35 castor oil; about 110-120 mg of polysorbate 80; about 110-120 mg of PEG-8 Caprylic / Capric Glycerides; about 40-50 mg of polyglyceryl-3 oleate; about 80-90 mg of propylene glycol; about 0.1-1 mg of butylated hydroxytoluene (BHT); or any combination thereof.

[0122] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 190-210mg of CBD, CBG, CBC, CBDV, CBN, or a combination thereof, about 45-65 mg of medium-chain triglycerides, about 370-400mg of polyoxyl 35 castor oil, about 100-130mg of polysorbate 80, about 105-125mg of PEG-8 Caprylic / Capric Glycerides, about 40- 50mg of polyglyceryl-3 oleate, about 75-95mg of propylene glycol, and about 0.01-lmg of butylated hydroxytoluene (BHT), or any combination thereof, per capsule.

[0123] In some embodiments, the pharmaceutical formulation may be made by preparing the formulation via mixing and / or homogenizing the at least one oil, the at least one surfactant, and the at least one co-surfactant (and where applicable also at least one solvent, and / or at least one phospholipid), optionally while heating the mixture, adding at least one suitably pure cannabinoid to the formulation, mixing, or homogenizing the cannabinoid-formulation mixture until the cannabinoid is dissolved in the formulation mixture; and optionally, purifying, diluting, or further compounding the cannabinoid formulation.

[0124] In some embodiments, the formulation is clear, transparent, and homogenous. In some embodiments, when diluted in an aqueous liquid, the diluted formulation is clear and transparent or slightly opaque without visible particles or droplets.

[0125] In some embodiments, the pH of the formulation, in a water-free or diluted form, may be between 6.0 and 7.5.

[0126] In some embodiments, no physical changes are observed with storage of the formulation. In some embodiments, the active ingredient remains associated with the surfactant and lipid phases during storage in both non-diluted and diluted forms.

[0127] In some embodiments, the formulation is chemically stable for at least 1 month, at least 3 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, or more than 3 years. In some embodiments, the formulation is shelf stable at ambient conditions for at least 1 year, at least 2 years, at least 3 years, or more than 3 years.

[0128] In some embodiments, the pharmaceutical formulation may comprise a variety of additional components, depending on the administration route and / or desired properties of the formulation. In some embodiments, the pharmaceutical formulation may comprise at least one additional component selected from, but not limited to, aqueous and non-aqueous diluents, water, isotonic sterile injection solutions, antioxidants, buffers, bacteriostats, suspending agents, solubilizers, thickening agents, gelling agent, emollients, moisturizers, stabilizers, preservatives, buffers, coloring agents, a fragrance, aromatic agents, flavoring agents, flavor masking agents, absorbers, fdters, electrolytes, proteins, chelating agents, or combinations thereof.

[0129] In some embodiments, the pharmaceutical formulation may be in the form of (a) liquid solutions, such as an effective amount of the cannabinoid loaded formulation, optionally dissolved in diluents, such as water, saline, or juice (e.g. orange juice); (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the cannabinoid, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; (e) concentrates or diluted microemulsions; and / or (f) spray. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, fluidizers (e.g. water) and com starch. Tablet forms can include one or more of lactose, sucrose, mannitol, com starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active formulation in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active formulation, such carriers as are known in the art.

[0130] In some embodiments, the pharmaceutical formulation is administered in a form selected from a gel, a spray, capsules, soft gel capsules, chewing gum, buccal-patch, or a solution.

[0131] In some embodiments, the pharmaceutical formulation is administered in the form of a tablet, a capsule, a soft gel capsule, or a solution. In some embodiments the pharmaceutical formulation may be administered in the form of an about 10-50 mg, 50-100 mg, 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350-400 mg, 400-450 mg, 450-500 mg, 500-550 mg, 550-600 mg, 650-700 mg, 700-750 mg, 750- 800 mg, 800-850 mg, 850-900 mg, 900-950 mg, 950-1000 mg, 1000-1050 mg, 1050-1100 mg, 1100-1150 mg, 1150-1200mg, 1200-1250 mg, 1250-1300 mg, 1300-1350 mg, 1350-1400 mg, 1400-1450 mg, or 1450-1500 mg tablet or capsule. In some embodiments the pharmaceutical formulation may be administered in the form of an about 1500-1600 mg, 1600-1700 mg, 1700- 1800 mg, 1800-1900 mg, or 1900-2000 mg capsule, softgel, or tablet.

[0132] In some embodiments the embodiments the pharmaceutical formulation may be in the form of an about 1500 mg capsule, softgel, or tablet. In some embodiments the pharmaceutical formulation may be in the form of an about 1 mL capsule.

[0133] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 10-400 mg of synthetic CBD or CBD, e.g. 10-350 mg of CBD, 10-300mg CBD, 10-250mg CBD, or even 10-200mg CBD.

[0134] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 10-150 mg of synthetic CBD or CBD extracted from hemp, about 50-60 mg of medium -chain triglycerides or sesame oil, about 480-515 mg of polyoxyl 35 castor oil, about 110-125 mg of polysorbate 80, about 110-125 mg of PEG-8 Caprylic / Capric Glycerides, about 40- 50 mg of polyglyceryl-3 oleate, about 80-95 mg of propylene glycol, about 0.1-1 mg of butylated hydroxytoluene (BHT), about 305-330 mg of gelatin, about 130-150 mg of glycerin, about 5-15 mg of caramel colorant, or any combination thereof, per capsule.

[0135] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 50 mg of synthetic CBD or CBD extracted from hemp, about 57 mg of sesame oil, about 511.1 mg of polyoxyl 35 castor oil (e.g. Cremophor® EL), about 121.6 mg of polysorbate 80 (e.g. Tween® 80), about 122.5 mg of PEG-8 Caprylic / Capric Glycerides, about 47.5 mg of polyglyceryl-3 oleate (e.g. Plurol® Oleique CC 947), about 90.25 mg of propylene glycol, about 0.475 mg of butylated hydroxytoluene (BHT), about 344 mg of gelatin, about 152 mg of glycerin, 12 mg of caramel colorant, or any combination thereof, per capsule.

[0136] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 100 mg of synthetic CBD or CBD extracted from hemp, about 54 mg of medium-chain triglycerides, about 484.2 mg of polyoxyl 35 castor oil, about 115.2 mg of polysorbate 80, about 116.1 mg of PEG-8 Caprylic / Capric Glycerides, about 45 mg of polyglyceryl-3 oleate, about 85.5 mg of propylene glycol, about 0.45 mg of butylated hydroxytoluene (BHT), about 344 mg of gelatin, about 152 mg of glycerin, about 12 mg of caramel colorant, or any combination thereof, per capsule.

[0137] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 45-55 mg of CBD, CBG, CBC, CBDV, CBN, or a combination thereof, about 105-115 mg sesame oil, about 375-385 mg of polyoxyl 35 castor oil, about 275-285 mg of polysorbate 80, about 135-145 mg of polyglyceryl-3 oleate, about 25-35 mg of propylene glycol, about 0.1-1 mg of butylated hydroxytoluene (BHT), or any combination thereof, per capsule.

[0138] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 95-105 mg of CBD, CBG, CBC, CBDV, CBN, or a combination thereof, about 50-60 mg of medium-chain triglycerides, about 480-490 mg of polyoxyl 35 castor oil, about 110-120 mg of polysorbate 80, about 110-120 mg of PEG-8 Caprylic / Capric Glycerides, about 40- 50 mg of polyglyceryl-3 oleate, about 80-90 mg of propylene glycol, about 0.1-1 mg of butylated hydroxytoluene (BHT), or any combination thereof, per capsule.

[0139] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 51 mg of synthetic CBD or CBD extracted from hemp, 110 mg of sesame oil, 380 mg of polyoxyl 35 castor oil, 280 mg of polysorbate 80, 140 mg of polyglyceryl-3 oleate, 30 mg of propylene glycol, 0.5 mg of butylated hydroxytoluene (BHT), or any combination thereof, per capsule.

[0140] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 102 mg of synthetic CBD or CBD extracted from hemp, 54 mg of medium-chain triglycerides, 484 mg of polyoxyl 35 castor oil, 115 mg of polysorbate 80, 116 mg of PEG-8 Caprylic / Capric Glycerides, 45 mg of polyglyceryl-3 oleate, 85 mg of propylene glycol, 0.5 mg of butylated hydroxytoluene (BHT), or any combination thereof, per capsule.

[0141] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 20 wt % of synthetic CBD or CBD extracted from hemp, 5.4 wt % of medium-chain triglycerides, 38.4 wt % of polyoxyl 35 castor oil, 11.51 wt % mg of polysorbate 80, 11.6 wt % of PEG-8 Caprylic / Capric Glycerides, 4.5 wt % of polyglyceryl-3 oleate, 8.5 wt % of propylene glycol, 0.05 wt % mg of butylated hydroxytoluene (BHT), or any combination thereof, per capsule.

[0142] As noted, the disclosure provides pharmaceutical formulations and their uses in methods of reducing nicotine -dependency, reducing smoking of tobacco products and / or marijuana, and in smoking secession. To effectively gauge successful treatment with the pharmaceutical formulation of the disclosure can be established via several known and acceptable methods.

[0143] In some embodiments, the subject’s cue-induced tobacco cravings are reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pretreatment cravings.

[0144] In some embodiments, the subject’s cue-induced tobacco cravings score will be reduced after administration of the disclosed pharmaceutical formulation by about 100% 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% relative to the subjects pre administration level.

[0145] In some embodiments, the subject’s cue-induced marijuana cravings are reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pretreatment cravings.

[0146] In some embodiments, the subject’s cue-induced marijuana cravings score will be reduced after administration of the disclosed pharmaceutical formulation by about 100% 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% relative to the subjects pre administration level.

[0147] In some embodiments, the Fagerstrom Test for Nicotine Dependence (FTND) score is reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pre-treatment score. The FTND score is based on a 6-iem survey that is closely linked to nicotine intake.

[0148] In some embodiments, the subject’s FTND score will be reduced after administration of the disclosed pharmaceutical formulation by about 100% 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% relative to the subjects pre administration level.

[0149] In some embodiments, the Minnesota Tobacco Withdrawal Scale (MNWS) score is reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pre-treatment score. This method of assessment measures the withdrawal symptoms (such as craving, irritability, anxiety, difficulty concentrating, restlessness, headache, drowsiness, GI disturbances, etc.). The symptoms are scored in an ordinal scale (from 0 - being symptom not present - to 3 being severe).

[0150] In some embodiments, the subject’s MNWS score will be reduced after administration of the disclosed pharmaceutical formulation by about 100% 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% relative to the subjects pre administration level.

[0151] In some embodiments, the weekly Patient Health Questionnaire -9 (PHQ-9) score is reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pre-treatment score. The PHQ-9 is a self-assessment 9-item scale that assesses the subject’s degree of depression.

[0152] In some embodiments, the subject’s PHQ-9 score will be reduced after administration of the disclosed pharmaceutical formulation by about 100% 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% relative to the subjects pre administration level.

[0153] In some embodiments, the weekly Generalized Anxiety Disorder-7 screener (GAD-7) score is reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pre-treatment score. GAD-7 is a self-assessment 7-item questionnaire used to measure or assess the severity of the subject’s anxiety.

[0154] In some embodiments, the subject’s GAD-7 score will be reduced after administration of the disclosed pharmaceutical formulation by about 100% 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% relative to the subjects pre administration level.

[0155] In some embodiments, the subject relapses to pre-treatment behaviors less frequently with administration of the pharmaceutical formulation to the subject, as compared to the frequency without administration.

[0156] In some embodiments, the total daily dose of cannabinoid administered to the subject is at least about 50 mg / day. In some embodiments, the total daily dose of cannabinoid administered to the subject ranges between about 50 mg / day and about 100 mg / day.

[0157] In some embodiments, the total daily dose of cannabinoid administered to the subject is at least about 100 mg / day. In some embodiments, the total daily dose of cannabinoid administered to the subject ranges from about 100 mg / day to about 2000 mg / day. In some embodiments, the total daily dose of cannabinoid ranges from about 200 mg / day to about 1800 mg / day. In some embodiments, the total daily dose of cannabinoid ranges from about 300 mg / day to about 1500 mg / day. In some embodiments, the total daily dose of cannabinoid ranges from about 350 mg / day to about 1200 mg / day. In some embodiments, the total daily dose of cannabinoid administered to the subject ranges from about 200 mg / day to about 500 mg / day. In some embodiments, the total daily dose of cannabinoid administered to the subject is from about 600 mg / day to about 1200 mg / day.

[0158] In some embodiments, the total daily dose of cannabinoid administered to the subject is about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 450 mg / day, about 500 mg / day, about 550 mg / day, about 600 mg / day, about 650 mg / day, about 700 mg / day, about 750 mg / day, about 800 mg / day, about 850 mg / day, about 900 mg / day, about 950 mg / day, about 1000 mg / day, about 1100 mg / day, or about 1200 mg / day.

[0159] In some embodiments, the total daily dose of cannabinoids is administered to the subject in a single daily dose. In some embodiments, said total daily dose of cannabinoids is administered to the subject as a split daily dose. In some embodiments, said total daily dose of cannabinoids is administered to the subject as a split daily dose comprising 2, 3, or 4 smaller doses. In some embodiments, said split daily dose comprises smaller doses having substantially equivalent cannabinoid concentrations. In some embodiments, said split daily dose comprises smaller doses having inequivalent cannabinoid concentrations.

[0160] As used herein, the term daily dose (and total daily dose) refers to the total amount of active ingredient to be administered to a subject in a given 24-hour period. The term single daily dose refers to administering the total amount of cannabinoids indicated by the method of treatment for a day to a subject at the same time. For example, a 600 mg dose of CBD taken once a day is a single daily dose administration schedule.

[0161] Split daily dose, as used herein, refers to administering the total amount of cannabinoids indicated by the method of treatment for a day to a subject over the course of the day in several increments. For example, a 600 mg dose of CBD taken as 300 mg of CBD in the morning and 300 mg of CBD at night is a split daily dose administration schedule.

[0162] In some embodiments, the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 200 mg / day.

[0163] In some embodiments, the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 300 mg / day.

[0164] In some embodiments, the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 400 mg / day. In some embodiments, the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 500 mg / day.

[0165] In some embodiments, the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 600 mg / day.

[0166] In some embodiments, the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 700 mg / day.

[0167] In some embodiments, the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 800 mg / day.

[0168] In some embodiments, the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 1200 mg / day.

[0169] In some embodiments, the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 1400 mg / day.

[0170] In some embodiments, the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 2000 mg / day.

[0171] In some embodiments, the total daily dose of at least one cannabinoid administered each day may change over the course of treatment. In some embodiments, the total daily dose of at least cannabinoid administered each day may decrease over the course of treatment. In some embodiments, the total daily dose of at least one cannabinoid administered each day may increase over the course of treatment. In some embodiments the total daily dose of cannabinoid may increase after one week of treatment. In some embodiments, the total daily dose of at least one cannabinoid may increase from about 200 mg / day to about 400 mg / day over the course of treatment. In some embodiments, the total daily dose of at least one cannabinoid may increase from about 200 mg / day to about 400 mg / day after one week of treatment. In some embodiments, the total daily dose of at least one cannabinoid may increase from about 200 mg / day to about 400 mg / day after two weeks of treatment. In some embodiments, the total daily dose of at least one cannabinoid may increase from about 350 mg / day to about 1400 mg / day over the course of treatment. In some embodiments, the total daily dose of at least one cannabinoid may increase from about 350 mg / day to about 700 mg / day over the course of treatment. In some embodiments, the total daily dose of at least one cannabinoid may increase from about 700 mg / day to about 1400 mg / day over the course of treatment. In some embodiments, the total daily dose of at least one cannabinoid increases from about 700 mg / day to about 2000 mg / day during treatment.

[0172] In some embodiments, the total daily dose of the at least one cannabinoid (e.g. CBD) may increase from about 350 mg / day to about 700 mg / day after 2 days of treatment. In some embodiments, the total daily dose of cannabinoid may increase from about 350 mg / day to about 700 mg / day after 2 days of treatment then from about 700 mg / day to about 1400 mg / day after 2 additional days of treatment (i.e. 4 days after start of treatment).

[0173] In some embodiments, the pharmaceutical formulation is administered orally as a split daily dose of about 350 mg / CBD administered in the morning and about 350 mg / day of CBD administered in the evening for a total daily dose of CBD of about 700 mg / day of CBD.

[0174] In some embodiments, the pharmaceutical formulation is administered orally as a split daily dose of about 700 mg / CBD administered in the morning and about 700 mg / day of CBD administered in the evening for a total daily dose of CBD of about 1400 mg / day of CBD .

[0175] In some embodiments, the pharmaceutical formulation is administered orally as a split daily dose of about 1000 mg / CBD administered in the morning and about 1000 mg / day of CBD administered in the evening for a total daily dose of CBD of about 2000 mg / day of CBD.

[0176] In some embodiments, the total daily dose of at least one cannabinoid may change at the discretion of an attending appropriately licensed medical practitioner over the course of treatment.

[0177] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 51 mg of synthetic CBD or CBD extracted from hemp, 110 mg of sesame oil, 380 mg of polyoxyl 35 castor oil, 280 mg of polysorbate 80, 140 mg of polyglyceryl-3 oleate, 30 mg of propylene glycol, 0.5 mg of butylated hydroxytoluene (BHT), or any combination thereof, per capsule. In some embodiments, the capsules are administered orally once a day for a total daily dose of about 200 mg / day CBD.

[0178] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 51 mg of synthetic CBD or CBD extracted from hemp, 110 mg of sesame oil, 380 mg of polyoxyl 35 castor oil, 280 mg of polysorbate 80, 140 mg of polyglyceryl-3 oleate, 30 mg of propylene glycol, 0.5 mg of butylated hydroxytoluene (BHT), or any combination thereof, per capsule. In some embodiments, the capsules are administered orally once a day for a total daily dose of about 400 mg / day CBD.

[0179] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 102 mg of synthetic CBD or CBD extracted from hemp, 54 mg of medium-chain triglycerides, 484 mg of polyoxyl 35 castor oil, 115 mg of polysorbate 80, 116 mg of PEG-8 Caprylic / Capric Glycerides, 45 mg of polyglyceryl-3 oleate, 85 mg of propylene glycol, 0.5 mg of butylated hydroxytoluene (BHT), or any combination thereof, per capsule. In some embodiments, the capsules are administered orally as a split daily dose of about 350 mg / day CBD administered in the morning and about 350 mg / day of CBD administered in the evening for a total daily dose of about 700 mg / day CBD.

[0180] In some embodiments, the pharmaceutical formulation is formulated as a soft gel capsule and may comprise about 102 mg of synthetic CBD or CBD extracted from hemp, 54 mg of medium-chain triglycerides, 484 mg of polyoxyl 35 castor oil, 115 mg of polysorbate 80, 116 mg of PEG-8 Caprylic / Capric Glycerides, 45 mg of polyglyceryl-3 oleate, 85 mg of propylene glycol, 0.5 mg of butylated hydroxytoluene (BHT), or any combination thereof, per capsule. In some embodiments, the capsules are administered orally as a split daily dose of about 700 mg / day CBD administered in the morning and about 700 mg / day of CBD administered in the evening for a total daily dose of about 1400 mg / day CBD.

[0181] By another aspect, there is provided a kit that comprises a pharmaceutical formulation of the disclosure and instructions for carrying out the methods of the disclosure. In some embodiments, said pharmaceutical formulation may be supplied in white high-density polyethylene (HDPE) bottles with child-resistant HDPE bottle caps. In some embodiments, the kits will be packaged and labeled in compliance with the Good Manufacturing Practice for drugs used in clinical trials. In some embodiments, said instructions will be provided electronically, via data-storage device, or in paper format.

[0182] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

[0183] As used herein, the term "about" is meant to encompass deviation of ±10% from the specifically mentioned value of a parameter, such as dosage, concentration, etc.

[0184] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range, including the end values of the range. The phrases "ranging / ranges between" a first indicate number and a second indicate number and "ranging / ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0185] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising" , will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any integer or step or group of integers and steps.

[0186] Generally it is noted that the term "... al least one... ” as applied to any component of formulations and methods of this disclosure should be read to encompass one, two, three, four, five, or even more different occurrences of said component in formulations and methods of this disclosure.

[0187] It is appreciated that certain features of this disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the disclosure. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0188] As used herein, the term subject (used interchangeably with the term patient) refers to any organism to which a formulation in accordance with the present disclosure may be administered, e.g. for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects comprise mammals (such as mice, rats, rabbits, non-human primates) and in particular humans.

[0189] Therapeutically effective amount and effective amount refer to any amount of an active ingredient (e.g. cannabinoid) that can cause the desired effect (e.g. clinical results) when administered to a subject. An effective amount may be determined according to considerations known in the art, and one skilled in the art will recognize that the effective amount can depend on a variety of factors including: the distribution profile within the body, a variety of pharmacological parameters (e.g. half-life in the body), undesired side effects (if any), factors such as age and gender, and other considerations.

[0190] As used herein, the terms "treatment", "treating", and their grammatical equivalents refer to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and / or reducing incidence of one or more symptoms or features of a particular infection, disease, disorder, and / or condition. Examples of treatment can include, but are not limited to: to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, to prevent the disease from occurring, or a combination thereof. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition, and / or to a subject who exhibits only early signs of a disease, disorder, and / or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0191] BRIEF DESCRIPTION OF THE DRAWINGS

[0192] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0193] Figs. 1A-1C show diagrams of liquid nanodomains loaded with CBD upon dilution with an aqueous phase. In a form of water in oil structure at low aqueous phase content (Fig. 1A), bicontinuous mesophase at intermediate aqueous phase content (Fig. IB), and oil in water nanostructures at high aqueous phase content (Fig. 1C).

[0194] DETAILED DESCRIPTION OF EMBODIMENTS

[0195] Example 1

[0196] All inactive ingredients included in the below formulations have been previously approved by the FDA for use as excipients in oral medications or food additives.

[0197] CBD was obtained via extraction from hemp by Mile High Labs (Broomfield, CO, USA). Excipients were emulsified, then CBD added. The mixture was then re-emulsified and encapsulated using standard commercial encapsulation techniques into capsules. The formulation is provided in Table 1.

[0198] For administration of Formulation 1, the capsules are broken open and then further diluted

[0199] 50 / 1 with water. Table 1: Exemplary Formulation 1 (amounts per 1500mg, ImL capsule)

[0200] The chemical and physical stability of Formulation 1 in softgel capsules has been evaluated at controlled room temperature (20°-25°C) over a period of 36 months and found to be remain stable. No change in assay or impurities was detected.

[0201] Several tests were conducted to determine the chemical characteristics of Formulation 1, both in concentrated (water free) and diluted forms. The concentrated Formulation was clear, transparent, and homogeneous. The diluted formulation is slightly opaque without visible particles or droplets coalescence. All liquid nanodomain droplets range in size up to 400 nm. The pH of both the concentrate and diluted formulations is between 6.0 and 7.5. No physical changes were observed with storage and CBD had a LogP of about 6 and remained associated with the surfactant and lipid phases during storage in both concentrated and diluted forms.

[0202] Example 2

[0203] Another version of a formulation produced similarly to Example 1 is provided in Table 2.

[0204] Table 2: Exemplary Formulation 1 (amounts per l500mg. ImL capsule) To characterize physical and chemical characteristics of the formulation visual and microscopic examinations were made of both the concentrated and 99 wt% water diluted forms to demonstrate single-phase, transparent attributes, compatibility with softgel and their components was tested, Dynamic Light Scattering (DLS) measurements were made to determine the nanodroplets average size, and LUMisizer® analysis was performed to assess physical stability of the nanodomains. Formulation 2 showed similar or better dilutability than Formulation 1 with no particle precipitation or oil-droplet formation. Encapsulation within gelatin soft gels was found to be feasible with no deformation of the capsule’s shell. Formulation 2 in softgel capsules has been evaluated at controlled room temperature (20°-25°C) over a period of 30 months and found to be remain stable. No change in assay or impurities was detected.

[0205] Example 3

[0206] The effects of oral administration of CBD on reduction of cigarette smoking in an 8-week randomized, placebo-controlled trial is evaluated. Testing involves participants 18-65 years of age (total sample: n = 120; 60 male and 60 female), who indicate a desire for smoking cessation. The participants are individuals who have tobacco use disorder and are receiving behavioral inpatient treatment for other substance use disorders (e.g., alcohol, cannabis). Participants receive Example 2 CBD formulation of this disclosure, at a dose of 800 mg per day or placebo (n = 60 / group).

[0207] Participants are provided support using messages from the National Cancer Institute’s Smokefiree.gov website.

[0208] Aim 1: evaluation of the effect of CBD formulation on reduction of cigarette use. The primary endpoint is reduction in cigarette use, indexed by self-reported cigarette s / day and plasma levels of cotinine. The secondary endpoint is abstinence from smoking, indexed categorically by self-report on questionnaires and confirmed biochemically by expired carbon monoxide (CO) during the last 2 weeks of the trial.

[0209] Aim 2: evaluation of the effects of CBD formulation on participant retention. The primary endpoint is retention in the trial, indicated by number of days that a participant continues in the protocol. Secondary endpoints is nicotine dependence and withdrawal (measured weekly on the Fagerstrom Test for Nicotine Dependence and Minnesota Withdrawal Scale, respectively), and mood states (measured weekly on the Patient Health Questionnaire -9 and Generalized Anxiety Disorder-7 screener). Exploratory aims: measuring CBD and other endocannabinoids post-administration of formulations of this disclosure. Plasma concentrations of CBD, N-arachidonoyl ethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) are measured at baseline and regularly throughout the trial (see Table 1). The primary endpoint is CBD plasma level. Secondary endpoints is levels of anandamide and 2-AG.

[0210] Participants exclusion criteria'.

[0211] • Physiological dependence on alcohol or any drug, requiring medical detoxification and / or showing signs of acute withdrawal symptoms from opioids, alcohol or benzodiazepines.

[0212] • Use of standard medications for smoking cessation, specifically nicotine (e.g., nicotine patch), varenicline, or bupropion.

[0213] • Participants who are taking the following medications: a) strong inducers of CYP3A4 or CYP2C19, which may decrease CBD plasma levels; and b) substrates of UGT1A9, UGT2B7, CYP2B6, CYP2C19 due to the potential of CBD to inhibit enzyme activity.

[0214] • Receiving therapy for opioid use disorder with buprenorphine or methadone to avoid potential drug-drug interactions

[0215] • Meeting DSM-5 criteria for schizophrenia, Bipolar I disorder, psychotic disorder, having active suicidal ideation, or suicide attempt in the past 12 months.

[0216] • AIDS or current HIV medication treatment with antiviral and / or non-antiviral therapy (due to the interaction of CBD with antiviral therapy).

[0217] • Clinically significant abnormalities on EKG (such as evidence of arrhythmia or MI).

[0218] • Clinically significant cardiovascular, hematologic, hepatic, renal, neurological, or endocrine abnormalities [specific exclusion criteria: AST greater than or equal to 3Xs ULN, Bilirubin > 1.5 X ULN, Prothrombin time / Intemational Normalized Ratio (INR) > 1.5.

[0219] • Pregnancy and / or lactation

[0220] • Women with values outside the reference ranges on a hormonal battery (estradiol, follicle- stimulating hormone, free thyroxine index, luteinizing hormone, prolactin, total T3 and total T4, thyroid-stimulating hormone), followed by an abnormal ovarian ultrasound.

[0221] Measures Collected

[0222] After screening (Days -7 to 0) and baseline (Day 0) assessments, the study comprises a 56- day (8-week) treatment period with follow up assessments at 1 and 3 months after termination of treatment as part of this trial. Measurements are obtained during daily and weekly assessments for the duration of the 8-week treatment period. Baseline assessment includes saliva sampling for assay of nicotine and its metabolites as an indication of heaviness of smoking, and self-reports of smoking -related behaviors on the following smoking-related questionnaires:

[0223] • Fagerstrom Test for Nicotine Dependence (FTND). This 6-item survey (~2 min) is closely linked to nicotine intake.

[0224] • Smoking History Questionnaire. This 25-item survey (~5 min) queries age at of initiation, longest quit attempt, number of quit attempts, reasons for quitting, and current smoking behavior (e.g. preferred brand, cigarettes per day, etc.).

[0225] • Minnesota Nicotine Withdrawal Scale (MNWS) measures withdrawal symptoms: craving, irritability, anxiety, difficulty concentrating, restlessness, headache, drowsiness, and GI disturbances.

[0226] • GAD-7. This is a self-administered seven-item questionnaire that is used to measure or assess the severity of generalized anxiety disorder (GAD).

[0227] • PHQ-9. This self-administered nine-item scale measures the degree of depression.

[0228] Assay of CBD, anandamide, 2-AG and Cotinine

[0229] Participants self-report cigarette use and adverse events each day (excluding weekends) using structured questionnaires. On Days 7, 14, 28 and 56, vital signs and blood samples are taken, for cotinine assay as an index of heaviness of smoking and for assay of cannabinoids (CBD, anandamide, 2-AG). At 1- and 3-month follow up, vital signs are taken, together with CO measurement in breath, and behavioral / self-report measures as on Days 7, 14, 28 and 56.

[0230] LC / MS-MRM assays are used for measurement of CBD and its derivatives of interest in plasma. Internal standards are added after sample extracts are processed and injected onto a multimode column with reversed phase, cation and anion exchange capabilities. After equilibration and elution, column effluents are passed through an electrospray ion source attached to a triple quadrupole mass spectrometer, and MRM signals are recorded. Peak areas, measured with manufacturer-supplied software, are checked and adjusted if needed. Each compound is quantified by interpolation from response curves from data obtained using internal standards and increasing concentrations of unlabeled authentic analytes.

[0231] Example 4

[0232] The effects of oral administration of CBD on reduction of marijuana smoking is carried out according to a similar protocol to that of Example 3.

Claims

CLAIMS:

1. A method of smoking cessation in a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

2. A method of reducing nicotine dependency in a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

3. A method of reducing smoking of tobacco cigarettes by a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

4. A method of inducing abstinence from smoking of tobacco cigarettes by a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

5. The method according to any one of claims 1 to 4, wherein the subject’s cue-induced tobacco smoking cravings are reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pre-treatment cravings.

6. The method of any one of claims 1 to 5, wherein the Fagerstrom Test for Nicotine Dependence (FTND) score is reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pre-treatment score.

7. The method of any one of claims 1 to 6, wherein the Minnesota Tobacco Withdrawal Scale score is reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pre-treatment score.

8. The method of any one of claims 1 to 7, wherein weekly Patient Health Questionnaire-9 (PHQ-9) score is reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pre-treatment score.

9. The method of any one of claims 1 to 8, wherein weekly Generalized Anxiety Disorder-7 screener (GAD-7) score is reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pre-treatment score.

10. A method of marijuana smoking cessation in a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

11. A method of reducing marijuana dependency in a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

12. A method of reducing smoking of marijuana by a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises: at least one cannabinoid, at least one oil,at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

13. A method of inducing abstinence from marijuana smoking by a subject, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation that comprises: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

14. The method according to any one of claims 10 to 13, wherein the subject’s cue-induced marijuana smoking cravings are reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pre-treatment cravings.

15. The method of any one of claims 10 to 14, wherein weekly Patient Health Questionnaire-9 (PHQ-9) score is reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pre-treatment score.

16. The method of any one of claims 10 to 15, wherein weekly Generalized Anxiety Disorder- 7 screener (GAD-7) score is reduced by the administration of the pharmaceutical formulation to the subject, as compared to the subject’s pre-treatment score.

17. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is at least about 50 mg / day.

18. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is from about 50 mg / day to about 100 mg / day.

19. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is at least about 100 mg / day.

20. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject greater than 800 mg / day.

21. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is from about 100 mg / day to 2000 mg / day.

22. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is from about 350 mg / day to 1400 mg / day.

23. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is from about 200 mg / day to 400 mg / day.

24. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is from about 700 mg / day to 1400 mg / day.

25. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is from about 850 mg / day to 1400 mg / day.

26. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is about 200 mg / day, about 350 mg / day, about 400 mg / day, about 600 mg / day, about 700 mg / day, about 1400 mg / day, or about 2000 mg / day.

27. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is about 200 mg / day.

28. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is about 350 mg / day.

29. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is about 400 mg / day.

30. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is about 700 mg / day.

31. The method of any one of claims 1 to 16, wherein the total daily dose of cannabinoid administered to the subject is about 1400 mg / day.

32. The method of any one of claims 1 to 16, wherein said total daily dose of cannabinoids is administered to the subject in a single daily dose.

33. The method of any one of claims 1 to 16, wherein said total daily dose of cannabinoids is administered to the subject as a split daily dose.

34. The method of any one of claims 1 to 16, wherein said total daily dose of cannabinoids is administered to the subject as a split daily dose comprising 2, 3, or 4 smaller doses.

35. The method of claim 33 or 34, wherein said split daily dose comprises smaller doses having substantially equivalent cannabinoid concentration.

36. The method of claim 33 or 34, wherein said split daily dose comprises smaller doses having inequivalent cannabinoid concentration.

37. The method of any one of claims 1 to 36, wherein said at least one cannabinoid is a nonpsychoactive cannabinoid.

38. The method of claim 37, wherein the non-psychoactive cannabinoid is selected from cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabidivarin (CBDV), cannabinol (CBN), and combinations thereof.

39. The method of any one of claims 1 to 38, wherein the formulation comprises between about 0. 1 wt% and about 25 wt% of at least one cannabinoid.

40. The method of claim 39, wherein the formulation comprises between about 0.1 wt% and about 12 wt% of at least one cannabinoid.

41. The method of claim 39, wherein the formulation comprises between about 5 wt% and about 12 wt % of at least one cannabinoid.

42. The method of claim 39, wherein the formulation comprises between about 4 wt% and about 11 wt % of at least one cannabinoid.

43. The method of claim 39, wherein the formulation comprises between about 5 wt% and about 10 wt% of at least one cannabinoid.

44. The method of any one of claims 1 to 43, wherein the formulation comprises between about 0.5 wt% and about 20 wt% of oils.

45. The method of claim 44, wherein the formulation comprises between about 1 wt% and about 10 wt% of oils.

46. The method of claim 44, wherein the formulation comprises between about 3 wt% and 6 wt% of oils.

47. The method of claim 44, wherein the formulation comprises about 5 wt% of oils.

48. The method of claim 44, wherein the formulation comprises about 11 wt% of oils.

49. The method of any one of claims 1 to 48, wherein the formulation comprises between 30 and 85 wt% of hydrophilic surfactants.

50. The method of claim 49, wherein the formulation comprises between about 35 and 80 wt % of hydrophilic surfactants.

51. The method of claim 49, wherein the formulation comprises between about 45 and 80 wt% of hydrophilic surfactants.

52. The method of claim 49, wherein the formulation comprises between about 45 and 55 wt% of hydrophilic surfactants.

53. The method of claim 49, wherein the formulation comprises between about 70 wt% and about 80 wt % of hydrophilic surfactants.

54. The method of claim 49, wherein the formulation comprises a first hydrophilic surfactant having a range of about 30 wt% and about 50 wt% and a second hydrophilic surfactant having a range of about 10 wt% and 30 wt%.

55. The method of claim 49, wherein the formulation comprises about 38 wt% of a first hydrophilic surfactant and about 28 wt% of a second hydrophilic surfactant.

56. The method of claim 49, wherein the formulation comprises a first hydrophilic surfactant having a range of about 45 wt% and about 50 wt%, a second hydrophilic surfactant having a range of about 10 wt% and about 12 wt %, and a third hydrophilic surfactant having a range of about 10 wt% and about 12 wt %.

57. The method of claim 49, wherein the formulation comprises about 48 wt% of a first hydrophilic surfactant, about 11 wt% of a second hydrophilic surfactant, and about 11 wt% of a third hydrophilic surfactant.

58. The method of any one of claims 1 to 57, wherein the formulation comprises between about 1 wt% and about 50 wt% of co-surfactants.

59. The method of claim 58, wherein the formulation comprises between about 2 wt% and about 45 wt% of co-surfactants.

60. The method of claim 58, wherein the formulation comprises between about 2 wt% and about 5 wt% of co-surfactants.

61. The method of claim 58, wherein the formulation comprises between about 2 wt% and about 14 wt% of co-surfactants.

62. The method of claim 58, wherein the formulation comprises about 14 wt% of a first cosurfactant and about 3 wt% of a second co-surfactant.

63. The method of claim 62, wherein the formulation comprises about 4 wt% of a first cosurfactant and about 8 wt% of a second co-surfactant64. The method of any one of claims 1 to 63, wherein the formulation comprises less than 1% water.

65. The method of any one of claims 1 to 64, wherein the formulation comprises between about 0. 1 wt% and about 25 wt% of solvents.

66. The method of any one of claims 1 to 65, wherein the formulation comprises between about 1 wt% and 10 wt% of phospholipids.

67. The method of any one of claims 1 to 66, wherein the formulation comprises between 0.01 and 10 wt% of additives.

68. The method of any one of claims 1 to 67, wherein the pharmaceutical formulation is administered as a tablet, a capsule, a soft gel capsule, or a solution.

69. The method of claim 68, wherein the cannabinoid is CBD.

70. The method of claim 69, wherein the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 350 mg / day.

71. The method of claim 69, wherein the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 200 mg / day.

72. The method of claim 69, wherein the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 400 mg / day.

73. The method of claim 69, wherein the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 700 mg / day.

74. The method of claim 69, wherein the pharmaceutical formulation is in the form of a soft gel capsule for administration orally as a split daily dose and provides a total daily dose of CBD of about 1400 mg / day.

75. The method of claim 69, wherein the total daily dose of CBD changes over the course of treatment.

76. The method of claim 75, wherein the total daily dose of CBD increases from 350 mg / day CBD to 2000 mg / day CBD during treatment.

77. The method of claim 75, wherein the total daily dose of CBD increases from 350 mg / day CBD to 700 mg / day CBD during treatment.

78. The method of claim 75, wherein the total daily dose of CBD increases from 700 mg / day CBD to 1400 mg / day CBD during treatment.

79. The method of claim 75, wherein the total daily dose of CBD increases from 350 mg / day CBD to 700 mg / day CBD, then from 700 mg / day CBD to 1400 mg / day CBD during treatment.

80. The method of claim 75, wherein the total daily dose of CBD increases from 350 mg / day CBD to 700 mg / day CBD after 2 days of treatment.

81. The method of claim 75, wherein the total daily dose of CBD increases from 350 mg / day CBD to 700 mg / day CBD after 2 days of treatment then from 700 mg / day to 1400 mg / day after 2 additional days of treatment.

82. The method of claim 69, wherein the pharmaceutical formulation provides a total daily dose of CBD of 200 mg / day.

83. The method of claim 69, wherein the pharmaceutical formulation provides a total daily dose of CBD of 400 mg / day.

84. The method of claim 69, wherein the pharmaceutical formulation is administered as a split daily dose of 350 mg / CBD administered in the morning and 350 mg / day of CBD administered in the evening for a total daily dose of CBD of 700 mg / day of CBD.

85. The method of claim 69, wherein the pharmaceutical formulation is administered as a split daily dose of 700 mg / CBD administered in the morning and 700 mg / day of CBD administered in the evening for a total daily dose of CBD of 1400 mg / day of CBD.

86. A pharmaceutical formulation for use in a method of reducing nicotine dependency in a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

87. A pharmaceutical formulation for use in a method of reducing smoking of tobacco cigarettes by a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

88. A pharmaceutical formulation for use in a method of inducing abstinence from smoking of tobacco cigarettes by a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, andless than 1 wt% water.

89. A pharmaceutical formulation for use in a method of reducing marijuana dependency in a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

90. A pharmaceutical formulation for use in a method of reducing smoking of marijuana by a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

91. A pharmaceutical formulation for use in a method of inducing abstinence from smoking of marijuana by a subject by orally administering said pharmaceutical formulation to the subject, the pharmaceutical formulation comprising: at least one cannabinoid, at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and less than 1 wt% water.

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