WO2025054536A1 - Cannabinoid delivery - Google Patents

Abstract

Disclosed herein is a multilayer dosage form, such as a tablet or particle, comprising a delayed release core containing cannabidiol (CBD) encompassed by an immediate release layer containing Δ⁹ -tetrahydrocannabinol (THC). The dosage form effects immediate pain relief benefit of THC and sustained pain relief benefit of THC and CBD combination for treatment of migraine. The dosage form achieves more effective migraine treatment than THC alone, CBD alone, and even the immediate combination of THC and CBD obtained directly from cannabis. Also disclosed herein is a method for treating a subject afflicted with migraine by administration of a composition comprising an immediate release formulation comprising THC and a sustained release formulation comprising CBD to afford both immediate and long-acting symptom relief.

Description

CANNABINOID DELIVERY

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63/537,147, filed September 7, 2023, and U.S. Provisional Application No. 63/538,679, filed September 15, 2023, the contents of which applications are hereby incorporated as if fully set forth herein.

TECHNICAL FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to the field of pharmaceutical compositions and therapeutic methods, specifically addressing the treatment of migraine and its associated symptoms. The disclosure involves the pulmonary administration of cannabinoid-based formulations, particularly those comprising A⁹-tetrahydrocannabinol (THC) for immediate release and cannabidiol (CBD) for sustained release, respectively. The formulations provide rapid relief from migraine symptoms through the immediate release of THC, while the sustained release of CBD ensures extended therapeutic effects, making them effective for managing acute migraine episodes.

BACKGROUND

[0003] Migraine is a prevalent and debilitating neurological disorder that affects approximately 1 billion people worldwide, representing 12-15% of the global population. This disorder is characterized by severe headaches, often accompanied by symptoms such as nausea, vomiting, photophobia, and phonophobia, significantly impairing the quality of life for those affected. The economic burden of migraines is substantial, with annual costs in the United States alone estimated to exceed $28 billion in 2018. These costs include both direct healthcare expenses, such as physician visits and medications, and indirect costs, including lost productivity and absenteeism (Bonafede et al., 2018).

[0004] Many medications that are used to treat acute migraine (such as triptans, DHE, and CGRP antagonists) are ineffective for other painful conditions, such as chronic pain. Many medications, such as gabapentinoids, antidepressants, and opioids, that are useful in the treatment of chronic pain are ineffective for treating acute migraine or they can make migraine worse.

[0005] Despite the availability of various treatment options, many patients continue to experience inadequate relief from migraine symptoms, which has driven the exploration of new therapeutic approaches. The sudden and severe nature of migraine attacks necessitates treatments that can provide rapid relief, helping to prevent the progression of symptoms and quickly restore patient functionality.

[0006] Cannabinoids, a class of compounds derived from the cannabis plant, have gained attention for their potential therapeutic effects in treating a range of conditions, including migraines. These compounds are believed to interact with specific receptors in the body that influence processes central to the development of migraine symptoms, including pain, nausea, photophobia, phonophobia, and inflammation. Cannabis is known to be effective in the treatment of migraine, such as when first- and second-line treatments fail (Poudel et al., 2021). Drawbacks of cannabis use, however, reside in the variability of THC and CBD contents amongst cannabis strains and varied outcomes that depend, in part, upon routes of cannabis administration (e.g., smoking, vaping, dabs). Furthermore, varied patient sensitivities to the psychoactive effects of THC, especially for cannabis-naive patients and in chronic use of cannabis, can limit the overall efficacy of cannabis for treatment of migraine.

SUMMARY

[0007] Pulmonary administration of cannabinoids allows for the rapid absorption of active ingredients through the lungs, which provides rapid relief of symptoms. Additionally, pulmonary administration bypasses certain metabolic processes that can reduce the effectiveness of medications offering a more reliable therapeutic response in the management of acute migraine episodes.

[0008] The present disclosure addresses the needs above by providing a method entailing rapid onset of action and durable symptom relief, particularly during acute migraine episodes. The method comprises the pulmonary administration of a composition that includes both an immediate release formulation A⁹-tetrahydrocannabinol (THC) and a sustained release formulation of cannabidiol (CBD). The method provides rapid onset of relief from migraine symptoms through the immediate release of THC, while the sustained release of CBD offers prolonged therapeutic effects, thereby enhancing the overall management of migraine episodes.

[0009] The method is particularly advantageous due to its ability to deliver the active ingredients directly to the lungs, facilitating rapid absorption into the bloodstream and ensuring both immediate and extended therapeutic benefits.

[0010] The present disclosure also addresses these drawbacks and others by providing in one embodiment a multilayer dosage form comprising:

(a) a delayed-release core comprising a therapeutically effective amount of cannabidiol (CBD) and a pharmaceutically acceptable excipient;

(b) an immediate release layer disposed upon and fully enveloping the entirety of the core, comprising a therapeutically effective amount of A⁹ -tetrahydrocannabinol (THC) and a pharmaceutically acceptable excipient.

[0011] The present disclosure also provides in another embodiment a method for treating a subject suffering from migraine. The method comprises administering to the subject the multilayer dosage form as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Fig 1. Representative multilayer particle of THC and CBD for pulmonary inhalation, intranasal administration, or oral administration.

[0013] Fig 2. Representative multilayer tablet or pill of THC and CBD for oral administration. DETAILED DESCRIPTION

[0014] Provided herein are cannabinoid compositions suitable for pulmonary administration for the treatment of migraine, and methods of treatment of migraines using said compositions.

[0015] Definitions

[0016] As used herein, the term “migraine” refers to a neurological disorder characterized by intense, often debilitating headaches that typically occur on one side of the head, though they can affect both sides. The headache is usually accompanied by additional symptoms including nausea, vomiting, and extreme sensitivity to light (photophobia), sound (phonophobia), or smells (osmophobia). Migraine attacks can last anywhere from a few hours to several days and can significantly impact an individual's ability to carry out daily activities.

[0017] As used herein, the term “migraineur” refers to an individual who experiences migraines, including any of the associated symptoms, phases, or subtypes described herein. A migraineur may suffer from episodic or chronic migraines and may experience varying degrees of severity and frequency of migraine attacks.

[0018] As used herein, the term "composition" refers to any combination of two or more substances, which may include active ingredients, carriers, excipients, or additives, blended together to form a product intended for various purposes, including therapeutic, diagnostic, or preventive applications. A "pharmaceutically acceptable composition" is one that is suitable for administration to humans or animals, being non-toxic, nonirritating, and effective for its intended use. Pharmaceutically acceptable compositions may be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

[0019] As used herein, the term “THC” refers to the compound (-)-trans-A⁹- tetrahydrocannabinol or -A⁹-tetrahydrocannabinol (IUPAC name: (6aR, 10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8, 10a-tetrahydro-6H- benzo[c]chromen-l-ol), a phyto-cannabinoid primarily responsible for the psychoactive effects associated with cannabis. THC has the structure:

[0020] THC exerts its effects through partial agonism of CB1 receptors, predominantly located in the central nervous system. This interaction influences the release of neurotransmitters and modulates neural pathways involved in pain perception, appetite, mood, and memory. In the context of migraine treatment, A⁹-THC’s ability to reduce pain through central nervous system modulation is of particular interest. Additionally, A9-THC’s antiinflammatory properties contribute to its potential therapeutic application in mitigating the inflammatory components of migraine pathophysiology (Pertwee, 2008).

[0021] As used herein, the term “CBD” refers to cannabidiol (IUPAC name: 2-[(lR, 6R)-6-isopropenyl-3 -methylcyclohex -2-en-l -yl]-5-pentylbenzene- 1,3 -diol), a non-psychoactive phytocannabinoid that interacts with multiple receptor systems within the body, including cannabinoid receptors, serotonin receptors, and transient receptor potential channels. CBD has the structure:

[0022] Unlike THC, CBD has a low affinity for CB1 receptors but exerts indirect effects by inhibiting the degradation of endogenous cannabinoids and modulating receptor activity. CBD is known for its anti-inflammatory, analgesic, and anxiolytic properties, making it a candidate for therapeutic use in migraine treatment. CBD’s ability to influence the release of neurotransmitters and inflammatory mediators involved in migraine pathogenesis positions it as a compound of interest for the development of new therapeutic strategies aimed at managing migraines (Pacher et al., 2006).

[0023] As used herein, the term “cannabinoids” refer to a class of chemically diverse compounds that interact with cannabinoid receptors, specifically CB 1 and CB2, within the endocannabinoid system, and are particularly relevant in the modulation of pain pathways and inflammation, which are critical factors in the pathophysiology of migraine. These compounds can be classified into three primary categories: endocannabinoids, which are naturally produced within the body (e.g., anandamide and 2-arachidonoylglycerol); phytocannabinoids, which are naturally occurring in the cannabis plant (e.g., THC) and CBD; and synthetic cannabinoids, which are artificially synthesized for therapeutic purposes. Other examples of cannabinoids include, but are not limited to: cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerol monomethyl ether (CBGM), cannabichromene (CBC), cannabichromanone (CBCN), cannabichromenicacid (CBCA), cannabivarichromene (CBCV), cannabichromevarinic acid (CBCV A), isotetrahydrocannabinol (iso-THC), cannabinol (CBN), cannabinolic acid (CBNA), cannabinol methyl ether (CBNM), cannabinol C4 (CBN-C4), cannabinol C2 (CBN-C2),annabinol Cl (CBN-C1), cannabinodiol (CBND), cannabielsoin (CBE), cannabielsoic, acid A (CBEA-A), Cannabielsoic acid B (CBEA-B), cannabicyclol (CBL), cannabicycloic acid (CBLA), cannabicyclovarin (CBLV), cannabitriol (CBT), cannabitriolvarin (CBTV), ethoxy-cannabitriolvarin (CBTVE), cannabivarin (CBV), cannabinodivarin (CBVD), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGV A), cannabifuran (CBF), dehydrocannabifuran (DCBF), and cannabirispol (CBR). Without being bound by any particular theory, it is believed that the therapeutic application of cannabinoids in the treatment of migraines is based on their anti-inflammatory and neuromodulatory effects (Pertwee et al.., 2008; Pacher et al., 2006; Baron, 2018).

[0024] As used herein, the term "phytocannabinoid" refers to any naturally occurring cannabinoid compound that is biosynthesized by the cannabis plant (Cannabis sativa . Phytocannabinoids are produced in the glandular trichomes of the plant and include, but are not limited to, A9- tetrahydrocannabinol (THC), cannabidiol (CBD), and other cannabinoids. These compounds are responsible for the various pharmacological effects associated with cannabis. Phytocannabinoids differ from synthetic cannabinoids, which are chemically synthesized, in that they are directly extracted from the cannabis plant.

[0025] As used herein, the term “CB 1 receptor” refers to a G protein-coupled receptor (GPCR) that is primarily expressed in the central nervous system (CNS), including the brain and spinal cord, as well as in peripheral tissues such as adipose tissue, liver, and muscles. The CB1 receptor is activated by endogenous cannabinoids, such as anandamide and 2-arachidonoylglycerol, as well as by phytocannabinoids like A9-tetrahydrocannabinol (THC). Activation of CB1 receptors plays a crucial role in modulating neurotransmitter release, thereby influencing various physiological processes such as pain perception, appetite, mood, and memory. The CB1 receptor is primarily responsible for the psychoactive effects of cannabinoids. (Mackie, 2008,; Pertwee et al., 2006).

[0026] As used herein, the term “CB2 receptor” refers to a G protein-coupled receptor (GPCR) that is primarily expressed in peripheral tissues, particularly within the immune system, including the spleen, tonsils, and immune cells such as macrophages, B cells, and T cells. Unlike the CB1 receptor, CB2 receptors are minimally expressed in the central nervous system. Activation of CB2 receptors is associated with anti-inflammatory and immunomodulatory effects, and they play a significant role in regulating immune responses and inflammation. Endogenous cannabinoids, as well as phytocannabinoids like cannabidiol (CBD), can activate CB2 receptors, influencing processes such as pain modulation, inflammation, and immune system function. (Munro, et al., 1993; Atwood et al. 2010).

[0027] As used herein, the term “migraine triggers” refers to factors or stimuli that can initiate or worsen a migraine attack, including specific smells, environmental changes, or physical activities.

[0028] As used herein, the term “prodrome phase” refers to the early stage of a migraine that occurs hours or days before the headache, including subtle symptoms such as mood changes, food cravings, neck stiffness, frequent yawning, or increased urination.

[0029] As used herein, the term “headache phase” refers to the main phase of a migraine characterized by intense pain, typically accompanied by symptoms such as nausea, vomiting, photophobia, phonophobia, and osmophobia.

[0030] As used herein, the term “postdrome phase” refers to the phase following the resolution of the headache in a migraine, during which individuals may feel drained, fatigued, or unusually refreshed. Some may experience a mild residual headache or a feeling of euphoria.

[0031] As used herein, the term “episodic migraine” refers to the nature of migraine attacks as occurring intermittently, with each episode being selflimited. The duration of untreated or unsuccessfully treated migraine attacks can range from several hours to several days (e.g., about four hours to about three days).

[0032] As used herein, the term “vestibular migraine” refers to a subtype of migraine characterized by vertigo, dizziness, or balance disturbances that may occur with or without headache. These symptoms are associated with dysfunction in the vestibular system, which is responsible for maintaining balance and spatial orientation.

[0033] As used herein, the term “hemiplegic migraine” refers to a rare subtype of migraine characterized by temporary, reversible paralysis or weakness on one side of the body, often accompanied by other migraine symptoms such as headache, aura, and visual disturbances.

[0034] As used herein, the term “abdominal migraine” refers to a subtype of migraine primarily affecting children, characterized by recurrent episodes of abdominal pain, nausea, and vomiting, typically without the presence of a headache. These episodes are believed to be related to the same neurological mechanisms that cause migraines.

[0035] As used herein, the term “chronic migraine” refers to a type of migraine characterized by headaches occurring on 15 or more days per month, with at least 8 days involving migraine-like features, for a period of more than three months. Chronic migraine often involves severe and disabling pain that can significantly impact daily functioning.

[0036] As used herein, the term “migraine with brainstem aura” refers to a subtype of migraine that includes symptoms originating from the brainstem, such as vertigo, dysarthria (difficulty speaking), diplopia (double vision), or ataxia (lack of coordination). These symptoms occur before or during the headache phase of the migraine.

[0037] As used herein, the term “menstrual migraine” refers to a subtype of migraine that occurs in relation to the menstrual cycle, typically beginning two days before and up to three days after the onset of menstruation. Menstrual migraines are thought to be triggered by hormonal fluctuations, particularly the drop in estrogen levels.

[0038] As used herein, the term “nausea and vomiting” refers to the common symptoms that accompany migraines, where nausea may be accompanied by vomiting that can be severe, sometimes leading to dehydration if vomiting is frequent.

[0039] As used herein, the term “photophobia” refers to a condition characterized by an abnormal or heightened sensitivity to light, resulting in discomfort or pain in response to light exposure. [0040] As used herein, the term “phonophobia” refers to an abnormal or heightened sensitivity to sound, leading to discomfort, pain, or distress in response to auditory stimuli.

[0041] As used herein, the term “osmophobia” refers to an abnormal or heightened sensitivity to odors, which can result in discomfort, nausea, or aggravation of symptoms in response to certain smells.

[0042] As used herein, the term “olfactory hallucination” refers to the perception of odors that are not present in the environment.

[0043] As used herein, the term “nausea” refers to a sensation of discomfort in the stomach, often accompanied by an urge to vomit.

[0044] As used herein, the term “vomiting” refers to the forceful expulsion of stomach contents through the mouth, typically following a sensation of nausea.

[0045] As used herein, the term “vertigo” refers to a sensation of spinning or dizziness, often accompanied by a loss of balance.

[0046] As used herein, the term “unilateral cephalalgia” or “unilateral cephalalgia” refers to headache pain that is localized to one side of the head. The pain associated with a unilateral cephalalgia is often throbbing or pulsating in nature and can range from moderate to severe intensity.

[0047] As used herein, the term “mechanical allodynia” refers to a condition where non-painful stimuli, such as light touch or brushing, are perceived as painful.

[0048] As used herein, the term “aura” refers to a set of sensory, motor, or speech disturbances that can occur before or during a migraine attack. Aura is usually temporary, lasting from a few minutes to an hour. Common symptoms of migraine aura include visual disturbances such as scintillating scotomas, bright flashes or spots in the visual field, temporary loss of vision in specific areas (blind spots), and tunnel vision. Aura may also involve sensory changes such as unilateral tingling or numbness, speech or language difficulties like aphasia, and other disturbances such as vertigo, tinnitus, or unilateral weakness.

[0049] As used herein, the term “scintillating scotomas” refers to visual disturbances characterized by flickering, zigzagging lines or shapes that often start in the center of the vision and gradually expand outward.

[0050] As used herein, the term “tunnel vision” refers to a visual disturbance where an individual experiences a sensation of seeing through a narrow tube, with peripheral vision darkened or blurred.

[0051] As used herein, the term “aphasia” refers to a speech or language difficulty that may be experienced during a migraine aura, characterized by difficulty in understanding or producing speech.

[0052] As used herein, the term “functional disability” refers to the difficulty in performing routine work-related and non-work-r elated tasks, due to the severity of symptoms of a disease or medical condition.

[0053] As used herein, the term "aerosol" refers to a suspension of fine solid particles or liquid droplets in a gas. Aerosols can be naturally occurring or artificially created and may be used in pharmaceutical applications to deliver active ingredients to the respiratory system. A "pharmaceutically acceptable aerosol" is one that is safe for inhalation, effectively delivers the active ingredient to the desired site of action and is stable and free from harmful contaminants under conditions of use.

[0054] As used herein, the term "suspension" refers to a system in which solid particles are dispersed within a liquid medium, where the solid particles are not dissolved but remain distributed throughout the liquid. Suspensions can be used in a wide range of applications where the active ingredient needs to be delivered in particulate form. A "pharmaceutically acceptable suspension" is one that is safe for administration, stable under the conditions of use, and effective for delivering the intended therapeutic or diagnostic effect. [0055] As used herein, the term "solution" refers to a homogeneous mixture where one or more substances are dissolved completely in a solvent, forming a single-phase system. Solutions are commonly used when uniform distribution of the dissolved substance is required. A "pharmaceutically acceptable solution" is one that is safe and effective for its intended use, free from harmful contaminants, and stable under normal conditions of storage and use.

[0056] As used herein, the term "mixture" refers to a combination of two or more substances that are physically combined but not chemically bonded, where the individual components retain their distinct properties. Mixtures can be homogeneous or heterogeneous, depending on the uniformity of the distribution of their components. A "pharmaceutically acceptable mixture" is one that is appropriate for administration to humans or animals, being nontoxic, non-irritating, and effective for its intended therapeutic or diagnostic purpose.

[0057] As used herein, the term “sustained release mechanism” refers to a pharmacological delivery system designed to release a drug or active compound at a controlled rate, extending its therapeutic effect over a prolonged period compared to immediate release formulations. In the context of pulmonary administration, sustained release mechanisms are engineered to maintain consistent drug concentrations within the therapeutic window in the respiratory tract or systemically, thereby minimizing fluctuations that could lead to sub-therapeutic effects or adverse reactions. This controlled release can be achieved through various strategies, such as diffusion-controlled systems, erosion-controlled systems, or osmotically controlled release systems. The sustained release mechanism is particularly useful in maintaining the initial therapeutic effects of an immediate release component over an extended period, thereby prolonging the overall efficacy of the treatment (Robinson et al., 1987; Rathbone et al., 2002).

[0058] As used herein, the term “sustained delivery vehicle” refers to a pharmaceutical carrier or system that is designed to release an active ingredient, such as cannabidiol (CBD), at a controlled and extended rate over a prolonged period of time. This controlled release mechanism allows for the maintenance of therapeutic levels of the active ingredient in the body, reducing the need for frequent dosing and enhancing patient compliance. Sustained delivery vehicles can take various forms, including but not limited to, microparticles, nanoparticles, liposomes, hydrogels, micelles, polymeric implants, microspheres, nanocapsules, dendrimers, and biodegradable scaffolds, each of which can be engineered to achieve specific release profiles depending on the therapeutic requirements. The sustained release provided by these vehicles can range from several hours to several days, depending on the formulation and delivery method employed (Robinson et al., 1987; Langer et al., 2003).

[0059] As used herein, the term “psychoactive effect” refers to an effect on the central nervous system that results in alterations to mood, cognition, perception, or behavior following the administration of a compound or drug.

[0060] As used herein, the term "hydrophobic" refers to a substance or material that repels water or does not mix easily with water. Hydrophobic substances tend to be non-polar and are often used in formulations to interact with non-aqueous solvents or to prevent dissolution in water-based environments.

[0061] As used herein, the term "hydrophilic" refers to a substance or material that readily interacts with or dissolves in water. Hydrophilic substances are typically polar and can form hydrogen bonds with water, making them compatible with aqueous environments.

[0062] As used herein, the term “Active Pharmaceutical Ingredient (API)” refers to any substance or mixture of substances intended to furnish pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body. The API is the component of a pharmaceutical product that provides the intended therapeutic effect. [0063] As used herein, the term "hydrogel" refers to a three-dimensional network of hydrophilic polymers that can absorb and retain water or biological fluids. Hydrogels are used in pharmaceutical applications for API delivery by encapsulating compounds and releasing them in a controlled manner. Hydrogels can be formed from natural or synthetic polymers and are used in medical applications.

[0064] As used herein, the term "microparticle" refers to a small particle with a size ranging from 1 micron to 1000 microns in diameter. Microparticles can serve as carriers for pharmaceutical APIs, allowing for controlled release of active ingredients. They are made from materials such as polymers and can be used in API delivery systems for oral, injectable, or inhalable formulations.

[0065] As used herein, the term "nanoparticle" refers to a particle with a size ranging from 1 to 100 nanometers in diameter. Nanoparticles are used in pharmaceutical formulations to improve bioavailability, stability, and targeting of APIs. They may be composed of materials such as, but not limited to, lipids, polymers, or silica and are used in API delivery systems for targeted or controlled release.

[0066] As used herein, the term "micelle" refers to an aggregate of amphiphilic molecules, such as surfactants, that arrange themselves into a spherical form in aqueous solutions. Micelles are used to solubilize poorly water-soluble APIs. The hydrophobic core of the micelle encapsulates lipophilic APIs, while the hydrophilic surface permits dispersion in water.

[0067] As used herein, the term "liposome" refers to a spherical vesicle composed of one or more phospholipid bilayers. Liposomes encapsulate APIs, allowing for controlled release or targeted delivery. Liposomes may be used as API delivery systems and are capable of encapsulating both hydrophilic and hydrophobic APIs.

[0068] As used herein, the term “nebulizer” refers to a medical device that converts a liquid composition into a fine aerosol mist suitable for inhalation into the lungs. Nebulizers can utilize various mechanisms, including ultrasonic energy, compressed air, or oxygen, to generate the aerosol from the liquid formulation. The aerosolized composition is then inhaled by the patient, allowing for the delivery of therapeutic agents directly to the respiratory tract.

[0069] As used herein, the term "dry powder" refers to a finely divided solid form of a pharmaceutical compound, typically used in inhalers for pulmonary administration. In a dry powder inhaler (DPI), the powder is dispersed into the air upon actuation and inhaled by the patient into the lungs. Unlike aerosols that rely on propellants, dry powder formulations are typically inhaled by the patient using their own breath force to deliver the medication. As used herein, a “pharmaceutically acceptable dry powder” refers to a dry powder that is suitable for therapeutic administration to humans or animals, complying with safety, purity, and efficacy standards.

[0070] As used herein, the term “propellant” refers to a substance used to expel the contents of a container by generating pressure. Propellants are often utilized in aerosol formulations to disperse pharmaceutical compounds in a fine mist or spray form. As used herein, the term “pharmaceutically acceptable propellant” refers to a propellant that is safe for use in pharmaceutical products intended for human or animal administration. Such propellants must meet the necessary safety standards for their intended route of administration. Examples of pharmaceutically acceptable propellants include, but are not limited to, hydrofluoroalkanes (HFA-134a, UFA-227), carbon dioxide (CO2), nitrous oxide (N2O), nitrogen (N2), dimethyl ether (DME), propane, butane, and isobutane.

[0071] As used herein, the term “metered dose inhaler (MDI)” refers to a portable inhalation device that delivers a specific amount of a therapeutic composition in aerosol form, typically using a propellant to disperse the active ingredients. Each actuation of the MDI releases a metered dose of the composition, which is inhaled by the patient for targeted delivery to the lungs.

[0072] As used herein, the term “dry powder inhaler (DPI)” refers to an inhalation device that delivers a therapeutic composition in the form of a dry powder. The DPI may use a carrier substance to facilitate dispersion of the composition during inhalation. The release of the powder is typically breath- actuated, allowing the patient to inhale the active ingredients directly into the lungs.

[0073] As used herein, the term “nasal atomizer” refers to a device that delivers a therapeutic composition into the nasal passages in the form of a fine mist or spray. The atomizer may operate through manual actuation or other mechanisms to aerosolize the composition for intranasal administration, allowing for localized or systemic absorption of the active ingredients through the nasal mucosa.

[0074] As used herein, the term “pharmaceutical composition” refers to a chemical or biological composition suitable for administration to a subject (e.g., mammal). Such compositions may be specifically formulated for administration via one or more of a number of routes, including but not limited to buccal, cutaneous, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. In addition, administration can by means of capsule, drops, foams, gel, gum, injection, liquid, patch, pill, porous pouch, powder, tablet, or other suitable means of administration.

[0075] As used herein, the term “pharmaceutical excipient” or a “pharmaceutically acceptable excipient” comprises a carrier, sometimes a liquid, in which an active therapeutic agent is formulated. The excipient generally does not provide any pharmacological activity to the formulation, though it may provide chemical and/or biological stability, and release characteristics. Examples of suitable formulations can be found, for example, in Remington, The Science and Practice of Pharmacy, 20th Edition, (Gennaro, A. R., Chief Editor), Philadelphia College of Pharmacy and Science, 2000, which is incorporated by reference in its entirety. [0076] As used herein “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are physiologically compatible. In one embodiment, the carrier is suitable for pulmonary administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, sublingual, or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0077] As used herein, the term “dosage” refers to the specific amount or quantity of an active pharmaceutical ingredient (API) or therapeutic composition that is administered to a subject at one time or over a specified period. The dosage is determined based on various factors, including the potency of the API, the condition being treated, the route of administration, and the characteristics of the subject, such as age, weight, and overall health. Dosage may be expressed in units such as micrograms (pg), milligrams (mg), or grams (g), and it can refer to a single dose or the total amount administered over a treatment course.

[0078] As used herein, the term "about" refers to a range of values±20%, or ±10% of a specified value. For example, the phrase "the percentage is about 5% w/w" includes ±20% of 5, or from 4% to 6%, or from 4.5% to 5.5%.

[0079] As used herein, the term “weight percent (w/w%)” refers to the concentration of a particular component in a mixture or composition, expressed as a percentage of the total weight of the mixture or composition. Weight percent is calculated by dividing the weight of the specific component by the total weight of the mixture or composition, and then multiplying the result by 100. This measure is commonly used to describe the concentration of active ingredients, excipients, or other components in pharmaceutical formulations.

[0080] As used herein, the term “molar basis” refers to the proportion or ratio of components in a mixture or reaction, expressed in terms of moles. When components are compared on a molar basis, their quantities are considered in terms of the number of moles rather than their mass or volume. This term is often used to describe the relative amounts of different substances in a chemical reaction, formulation, or mixture, where the stoichiometric relationships are based on the number of molecules or atoms involved.

[0081] As used herein, the term “aerosol generating device” refers to a device configured to produce a vapor or aerosol from a liquid or solid composition. Aerosol generating devices are typically used to deliver a solid or liquid (including semi-liquid) composition to a subject in need thereof in an inhalable form (i.e., in a substantially gaseous form). Aerosol generating devices include nebulizers and inhalers, which typically produce aerosols through the application of mechanical force on the compositions (e.g., by gas flow or vacuum), as well as vaporizers and electronic cigarettes, which typically use heating units to produce aerosols by vaporizing the composition.

[0082] As used herein, the term “subject” refers to any human or animal receiving treatment or administration of a therapeutic composition. The subject may be a patient suffering from a disease or condition that requires treatment, or a healthy individual receiving a composition for preventive measures. In the context of this disclosure, the subject may be referred to as a human or an animal, depending on the intended application.

[0083] As used herein, the term “patient” refers to a human or animal subject who is receiving medical treatment or therapeutic intervention for a disease, condition, or disorder. The patient may be suffering from a specific illness requiring treatment or may be receiving preventive care or routine medical attention. [0084] As used herein, the term “pharmaceutically acceptable solvent” refers to a solvent that is compatible with the API and suitable for use in pharmaceutical formulations. A pharmaceutically acceptable solvent must be non-toxic, non-irritating, and safe for the intended route of administration. Examples of pharmaceutically acceptable solvents include, but are not limited to, water, ethanol, glycerin, polyethylene glycol, and various oils.

[0085] As used herein, the term “respiratory system” refers to the system of organs in the body responsible for the intake of oxygen and the expiration of carbon dioxide. The respiratory system generally includes all the air passages from the nose to the pulmonary alveoli. In mammals, it is generally considered to include the lungs, bronchi, bronchioles, trachea, nasal passages, and diaphragm. For purposes of the present disclosure, delivery of a drug to the "respiratory system" indicates that a drug is delivered to one or more of the air passages of the respiratory system, in particular to the lungs.

[0086] As used herein, the term “nasal mucosa” refers to the mucous membrane lining the nasal cavity, which is composed of epithelial cells, goblet cells, and underlying connective tissue. The nasal mucosa is involved in the protection of the respiratory tract by trapping and clearing inhaled particles, pathogens, and other foreign materials. It also plays a role in the absorption of substances, including drugs administered via intranasal routes.

[0087] As used herein, the term “therapeutic effect” refers to the beneficial effects of a treatment, such as the reduction of symptoms, improvement in health, or management of a condition or disease, achieved through the administration of an API or composition.

[0088] As used herein, the term “sustained therapeutic effect” refers to the prolonged beneficial effects of a treatment that are maintained over an extended period of time following the administration of an API or composition. This effect is typically achieved through formulations or delivery methods that allow for the gradual release and absorption of the API, providing continuous therapeutic action. [0089] As used herein, the terms “formulation” and “composition” generally refer to any mixture, solution, suspension, or the like that contains at least one API, and, optionally, a carrier. The carrier may be any carrier acceptable for pulmonary administration that is compatible for delivery with the API.

[0090] As used herein, the term “encapsulated” refers to the process by which an active pharmaceutical ingredient (API), composition, or other substance is enclosed within a carrier material or protective coating. Encapsulation is used to protect the API from degradation, control its release, or target its delivery to specific sites within the body.

[0091] As used herein, the term “incorporated” refers to the process by which an active pharmaceutical ingredient (API), composition, or other substance is integrated or combined into a formulation, mixture, or carrier. Incorporation involves blending, mixing, or dispersing the API within a vehicle or matrix to ensure uniform distribution and facilitate the intended therapeutic effect.

[0092] As used herein, the term “dosage unit form,” refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. In therapeutic use for treatment of conditions in mammals (e.g., humans) for which the compounds of the present disclosure or an appropriate pharmaceutical composition thereof are effective, the compounds of the present disclosure may be administered in an effective amount. The dosages as suitable for this disclosure may be a composition, a pharmaceutical composition or any other compositions described herein.

[0093] As used herein, the term "administration" refers to the process by which a composition is introduced into the body of a subject. The administration may be via any of the following routes: buccal, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. Exemplary routes of administration are pulmonary and oral. The administration can be local, where the composition is administered directly, close to, in the locality, near, at, about, or in the vicinity of, the site(s) of disease, e.g., inflammation, or systemic, wherein the composition is given to the patient and passes through the body widely, thereby reaching the site(s) of disease. Local administration can be administration to the cell, tissue, organ, and/or organ system, which encompasses and/or is affected by the disease, and/or where the disease signs and/or symptoms are active or are likely to occur. Administration can be topical with a local effect, composition is applied directly where its action is desired. Administration can be enteral wherein the desired effect is systemic (non-local), composition is given via the digestive tract. Administration can be parenteral, where the desired effect is systemic, composition is given by other routes than the digestive tract.

[0094] \As used herein, the term “treatment” encompasses the therapeutic intervention of a patient with an existing disease state, a patient who is susceptible to a future disease state, or a patient who has been previously treated for a disease state. Treatment includes interventions aimed at controlling, stopping, or reducing the target disease state, as well as addressing its effects and metabolic impacts on the patient. Treatment also includes the prevention of the disease state, prevention of metastasis or other spread of the disease, and prevention of the growth of a tumor or expansion of the disease state. Additionally, treatment may involve the reduction of recurrence, prevention of recurrence, or otherwise the inhibition or amelioration of the recurrence of a disease state.

[0095] As used herein, the term “therapeutically effective amount” of dosage form is governed by considerations including the particular subject being treated, the clinical condition of the subject, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. In general, a “therapeutically effective amount” is the minimum dose necessary to exert a migraine benefit, such as freedom or relief from headache pain, freedom or relief from the most bothersome symptom, and reduction in monthly headache and/or migraine days; and/or exert migraine relief, such as a reduction in migraine pain intensity, duration of migraine pain, and combinations thereof. However, it is to be understood that the total daily usage of the compounds and compositions described herein may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically- effective dose level for any particular patient will depend upon a variety of factors, including the condition being treated and the severity of the condition; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician. It is also appreciated that the therapeutically effective amount can be selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the compounds described herein.

[0096] Methods of Use

[0097] The disclosure provides in an embodiment a method of treating a migraine or reducing one or more symptoms thereof in a subject afflicted with migraine, comprising the pulmonary administration of a composition to the subject, wherein the composition comprises: i) an immediate release formulation comprising A⁹- tetrahydrocannabinol (THC), and ii) a sustained release formulation comprising cannabidiol (CBD).

[0098] The disclosure also provides, in an embodiment, a method for treating a subject suffering from migraine. The method comprises administering to the subject the multilayer dosage form as described herein. In some embodiments, the migraine is episodic migraine with or without aura. In other embodiments, the migraine is chronic migraine with or without aura. In some embodiments, the disclosure relates to acute migraine treatment. The disclosure also relates to migraine prevention. Even though the disclosure relates to a method for treating migraine the disclosure also relates to the treatment of all painful conditions, including acute pain, post-operative pain, and chronic pain conditions.

[0099] In some embodiments, the subject is a mammal. In further embodiments, the mammal is a human.

[00100] In some embodiments, the composition comprises THC and CBD in a molar ratio of THC to CBD ranging between 1: 1 and 1:5. For example, the THC to CBD ratio may be 1 : 1.8 on a molar basis.

[00101] In certain embodiments, the composition comprises THC and CBD in a weight/weight percentage (w/w%) ratio of THC to CBD ranging between 1 : 1 and 1 : 5. For example, the THC to CBD ratio may be 1: 1.8 w/w%.

[00102] In some embodiments, the composition administered to the subject is formulated as a solution, liquid suspension, or dry powder.

[00103] In certain embodiments, the composition further includes a pharmaceutically acceptable solvent.

[00104] In some embodiments, the sustained release formulation comprises cannabidiol (CBD) and a sustained delivery vehicle. [00105] In some embodiments, the sustained delivery vehicle is selected from the group consisting of hydrogel, microparticle, nanoparticle, micelle, and liposome.

[00106] In various embodiments, the sustained release formulation of CBD is provided in the form of a hydrogel, microparticle, nanoparticle, micelle, or liposome.

[00107] In some embodiments, the liposome used in the sustained release formulation is a cationic liposome or a liposome-polymer hybrid nanoparticle.

[00108] In certain embodiments, the sustained release formulation comprises one or more pharmaceutically acceptable excipients, such as hydroxypropyl-P-cyclodextrin, lactose, mannitol, glucose, sorbitol, sucrose, and trehalose.

[00109] In some embodiments, administration comprises pulmonary administration. In other embodiments, administration comprises oral administration.,

[00110] In various embodiments, the pulmonary administration comprises intranasal or oral inhalation.

[00111] In some embodiments, the composition is administered as an aerosol.

[00112] In certain embodiments, the migraine treated by the composition is selected from vestibular migraine, abdominal migraine, chronic migraine, migraine with brainstem aura, hemiplegic migraine, and menstrual migraine.

[00113] In various embodiments, administration of the composition reduces one or more symptoms of migraine including pain, photophobia, phonophobia, osmophobia, olfactory hallucination, nausea, vomiting, aura, vertigo, unilateral cephalalgia, and mechanical allodynia. [00114] In some embodiments, the administration of the composition reduces migraine symptoms within 1 minute of administration.

[00115] In some embodiments, the administration of the composition reduces migraine symptoms within 5 minutes of administration.

[00116] In some embodiments, the administration of the composition reduces migraine symptoms within 15 minutes of administration.

[00117] In some embodiments, the administration of the composition reduces migraine symptoms within 30 minutes of administration.

[00118] In some embodiments, the administration of the composition reduces migraine symptoms within 1 hour of administration. In other embodiments, the administration of the composition reduces migraine symptoms within 2 hours of administration.

[00119] In some embodiments, the administration of the composition reduces migraine symptoms for at least 4 hours after administration.

[00120] In some embodiments, the administration of the composition reduces migraine symptoms for at least 6 hours after administration.

[00121] In some embodiments, the administration of the composition reduces migraine symptoms for at least 8 hours after administration.

[00122] In some embodiments, the administration of the composition reduces migraine symptoms for at least 12 hours after administration.

[00123] In some embodiments, the administration of the composition reduces migraine symptoms for at least 24 hours after administration.

[00124] In some embodiments, the administration of the composition reduces migraine symptoms for at least 48 hours after administration.

[00125] In some embodiments, the dosage of THC ranges from about 1 pg to about 1000 mg, about 1 pg to about 10 pg, about 10 pg to about 50 pg, about 50 pg to about 100 pg, about 100 pg to about 250 pg, about 250 pg to about 500 gg, about 500 gg to about 1 mg, about 1 mg to about 2.5 mg, about 2.5 mg to about 5 mg, about 5 mg to about 7.5 mg, about 7.5 mg to about 10 mg, about 10 mg to about 12.5 mg, about 12.5 mg to about 15 mg, about 15 mg to about 17.5 mg, about 17.5 mg to about 20 mg, about 20 mg to about 22.5 mg, about 22.5 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 750 mg, and about 750 mg to about 1000 mg.

[00126] In some embodiments, the dosage of CBD ranges from about 1 gg to about 1000 mg, about 1 gg to about 10 gg, about 10 gg to about 50 gg, about 50 gg to about 100 gg, about 100 gg to about 250 gg, about 250 gg to about 500 gg, about 500 gg to about 1 mg, about 1 mg to about 2.5 mg, about 2.5 mg to about 5 mg, about 5 mg to about 7.5 mg, about 7.5 mg to about 10 mg, about 10 mg to about 12.5 mg, about 12.5 mg to about 15 mg, about 15 mg to about 17.5 mg, about 17.5 mg to about 20 mg, about 20 mg to about 22.5 mg, about 22.5 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 750 mg, and about 750 mg to about 1000 mg.

[00127] In some embodiments, the dosage of THC ranges from about 1 gg/kg/day to about 15 mg/kg/day, about 1 gg/kg/day to about 10 gg/kg/day, about 10 gg/kg/day to about 50 gg/kg/day, about 50 gg/kg/day to about 100 gg/kg/day, about 100 gg/kg/day to about 200 gg/kg/day, about 200 gg/kg/day to about 300 gg/kg/day, about 300 gg/kg/day to about 400 gg/kg/day, about 400 gg/kg/day to about 500 gg/kg/day, about 500 gg/kg/day to about 1 mg/kg/day, about 1 mg/kg/day to about 5 mg/kg/day, about 5 mg/kg/day to about 10 mg/kg/day, and about 10 mg/kg/day to about 15 mg/kg/day.

[00128] In some embodiments, the dosage of CBD ranges from about 1 gg/kg/day to about 15 mg/kg/day, about 1 gg/kg/day to about 10 gg/kg/day, about 10 gg/kg/day to about 50 gg/kg/day, about 50 gg/kg/day to about 100 gg/kg/day, about 100 gg/kg/day to about 500 gg/kg/day, about 500 gg/kg/day to about 1 mg/kg/day, about 1 mg/kg/day to about 5 mg/kg/day, about 5 mg/kg/day to about 10 mg/kg/day, and about 10 mg/kg/day to about 15 mg/kg/day.

[00129] In some embodiments, CBD is encapsulated within microparticles composed of biocompatible polymers. The microparticles contain from about 1 pg to about 10 gg, about 10 gg to about 50 gg, about 50 pg to about 100 gg; about 100 gg to about 250 gg, about 250 gg to about 500 gg, about 500 gg to about 1 mg, about 1 mg to about 2.5 mg, about 2.5 mg to about 5 mg, about 5 mg to about 7.5 mg, about 7.5 mg to about 10 mg, about 10 mg to about 12.5 mg, about 12.5 mg to about 15 mg, about 15 mg to about

17.5 mg, about 17.5 mg to about 20 mg, about 20 mg to about 22.5 mg, about

22.5 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, or about 35 mg to about 40 mg of CBD per dose.

[00130] In other embodiments, CBD is incorporated into nanoparticles. The nanoparticles contain fromabout 1 gg to about 10 gg, about 10 gg to about 50 gg, about 50 gg to about 100 gg; about 100 gg to about 250 gg, about 250 gg to about 500 gg, about 500 gg to about 1 mg, about 1 mg to about 2.5 mg, about 2.5 mg to about 5 mg, about 5 mg to about 7.5 mg, about 7.5 mg to about 10 mg, about 10 mg to about 12.5 mg, about 12.5 mg to about 15 mg, about 15 mg to about 17.5 mg, about 17.5 mg to about 20 mg, about 20 mg to about

22.5 mg, about 22.5 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, or about 35 mg to about 40 mg of CBD per dose.

[00131] In some embodiments, CBD is encapsulated in liposomes. The liposomes may contain from about 1 gg to about 10 gg, about 10 gg to about 50 gg, about 50 gg to about 100 gg; about 100 gg to about 250 gg, about 250 pg to about 500 pg, about 500 pg to about 1 mg, about 1 mg to about 2.5 mg, about 2.5 mg to about 5 mg, about 5 mg to about 7.5 mg, about 7.5 mg to about 10 mg, about 10 mg to about 12.5 mg, about 12.5 mg to about 15 mg, about 15 mg to about 17.5 mg, about 17.5 mg to about 20 mg, about 20 mg to about

22.5 mg, about 22.5 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, or about 35 mg to about 40 mg of CBD per dose.

[00132] In some embodiments, CBD is incorporated into a hydrogel matrix. The hydrogel matrimay contain about 1 pg to about 10 pg, about 10 pg to about 50 pg, about 50 pg to about 100 pg; about 100 pg to about 250 pg, about 250 pg to about 500 pg, about 500 pg to about 1 mg, about 1 mg to about 2.5 mg, about 2.5 mg to about 5 mg, about 5 mg to about 7.5 mg, about

7.5 mg to about 10 mg, about 10 mg to about 12.5 mg, about 12.5 mg to about 15 mg, about 15 mg to about 17.5 mg, about 17.5 mg to about 20 mg, about 20 mg to about 22.5 mg, about 22.5 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, or about 35 mg to about 40 mg of CBD per dose.

[00133] In some embodiments, the sustained delivery vehicle releases CBD over a period of about 2 to about 48 hours after administration, with each formulation delivering a dose of about 1 pg to about 40 mg of CBD.

[00134] In some embodiments, CBD is encapsulated within microparticles composed of biocompatible polymers. In other embodiments, the microparticles release CBD over a period of 2 to 48 hours after administration, with each microparticle formulation delivering about 1 pg to about 40 mg of CBD per dose.

[00135] In some embodiments, the microparticles encapsulating CBD have a particle size ranging from about 1 pm to about 10 pm, which enables efficient deposition in the respiratory tract and sustained release of CBD over time. [00136] In some embodiments, the microparticles release CBD in a biphasic manner, with an initial burst release followed by a prolonged release phase, delivering a total of about 1 pg to about 40 mg of CBD per dose.

[00137] In some embodiments, CBD is incorporated into nanoparticles composed of biodegradable polymers with a particle size ranging from about 50 nm to about 500 nm. In other embodiments, these nanoparticles release CBD gradually over a period of 2 to 48 hours, delivering about 1 pg to about 40 mg of CBD per dose.

[00138] In some embodiments, the nanoparticles have a surface coating that enhances their stability and prolongs the release of CBD within the lungs, providing sustained therapeutic effects.

[00139] In some embodiments, the nanoparticles achieve a controlled release profile, where CBD is released in a linear manner over 4-24 hours, with each dose delivering about 1 pg to about 40 mg of CBD.

[00140] In some embodiments, CBD is encapsulated within liposomes formed from phospholipids. For example, phosphatidylcholine is used to form the liposomes, which provide a sustained release of CBD over 2 to 48 hours, with each dose delivering about 1 pg to about 40 mg of CBD.

[00141] In some embodiments, the liposomes have a size range of about 50 nm to about 200 nm.

[00142] In certain embodiments, the administration of the composition does not induce a psychoactive effect in the subject.

[00143] In some embodiments, the administration of the inventive composition via inhalation comprises generating an inhalable aerosol upon heating the inventive composition in an electronic vaporizer.

[00144] In some embodiments, the at least one cannabinoid compound is extracted from a plant material, wherein the plant is of cannabis genus. [00145] In some embodiments, the inventive composition further comprises at least one additive selected from the group consisting of a propellant and a pharmaceutically acceptable excipient.

[00146] In some embodiments, the inventive composition further comprises at least one carrier acceptable for pulmonary administration. In some embodiments, the inventive composition further comprises at least one pharmaceutically acceptable carrier, which is acceptable for pulmonary administration.

[00147] In some embodiments, the inventive composition further comprises at least one stabilizer.

[00148] In some embodiments, the inventive composition further comprises at least one additive selected from the group consisting of a propellant and a pharmaceutically acceptable excipient.

[00149] In some embodiments, the inventive composition further comprises at least one additive at a concentration of 0.1-1% w/w. In some embodiments, the composition further comprises at least one additive at a concentration of 0.1-0.5% w/w. In some embodiments, the cannabinoid composition further comprises at least one additive at a concentration of 0.1- 0.3% w/w.

[00150] In some embodiments, the inventive composition further comprises at least one preservative. In some embodiments, the preservative is selected from the group consisting of ascorbic acid, sodium ascorbate, benzyl alcohol, propylparaben, methylparaben, benzalkonium chloride, phenylethyl alcohol, chlorobutanol, potassium sorbate, phenol, m-cresol, o-cresol, p- cresol, chlorocresol, butylated hydroxytoluene (BHT) and combinations thereof.

[00151] In some embodiments, the aerosol generating device is selected from the group consisting of an electronic vaporizer, a nebulizer and an inhaler. In some embodiments, the aerosol generating device is an electronic vaporizer. In some embodiments, the aerosol generating device is a nebulizer. In some embodiments, the aerosol generating device is an inhaler. In some embodiments, the aerosol generating device is an inhaler or a nebulizer.

[00152] In some embodiments, delivery of the inventive composition to a subject comprises delivering the inventive composition to the respiratory system of the subject.

[00153] In some embodiments, there is provided an aerosol generating device cartridge comprising a liquid container, wherein the liquid container contains the inventive composition as disclosed herein. In some embodiments, there is provided an aerosol generating device cartridge comprising a liquid container, wherein the liquid container contains the inventive composition comprising a solution, mixture, or suspension comprising at least one cannabinoid.

[00154] The present disclosure is premised, in part, on the discovery that the multilayer dosage form described herein facilitates the superior early antimigraine effects of THC alone in combination with the superior later and sustained benefits of the THC/CBD mix. The dosage form is particularly effective in view of the knowledge that cannabis generally is known for pain management: the effects and dosage of THC and CBD are not the same for pain management generally and treatment of migraine specifically.

[00155] Multilayer Dosage Form

[00156] The present disclosure relates to multilayer dosage form comprising: a) a delayed-release core comprising a therapeutically effective amount of cannabidiol (CBD) and a pharmaceutically acceptable excipient;

(b) an immediate release layer disposed upon and fully enveloping the entirety of the core, comprising a therapeutically effective amount of A⁹- tetrahydrocannabinol (THC) and a pharmaceutically acceptable excipient. [00157] The multilayer dosage form surprisingly facilitates superior early anti-migraine effects of THC alone as well as the superior later and sustained benefits of a THC/CBD mixture.

[00158] In some embodiments, the multilayer dosage form comprises a delayed release layer disposed between (a) the delayed-release core and (b) the immediate release layer. In an embodiment, the delayed release layer comprises an enteric coating that is useful, for example, in oral administration.

[00159] In additional embodiments, the multilayer dosage form comprises an immediate release coating disposed on the immediate release layer. The immediate release coating can be a sugar coating or any other substance known to those skilled the art for dissolving or disintegrating rapidly upon contact with a physiological environment, such as the stomach, lung, or nasal passage.

[00160] In various embodiments, the dosage form is a tablet or particle. In some embodiments, a dosage form is a population of particles contained within a capsule. A particle can be a microparticle, wherein the mean diameter can be about 1 to about 100 pm. In other embodiments, the particle can be a nanoparticle, wherein the mean diameter is less than about 1 pm. Particles are suitable, for example, in nebulized or dry inhaler formulations.

[00161] The dosage form of the present disclosure can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

[00162] Suitable oral compositions as described herein include without limitation tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, syrups or elixirs.

[00163] The dosage form of the present disclosure that is suitable for oral use may be prepared according to any method known to the art for the manufacture of multilayer compositions known to those skilled in the formulation arts, including jet milling and fluidized bed technologies.

[00164] Examples of excipients useful in the dosage form include without limitation inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. Coating layers are applied by coating techniques to delay disintegration and absorption in the gastrointestinal tract and thereby to provide a sustained therapeutic action over a desired time period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

[00165] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

[00166] For aqueous suspensions, a compound of the present disclosure is admixed with excipients suitable for maintaining a stable suspension. Examples of such excipients include without limitation are sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia.

[00167] Oral suspensions can also contain dispersing or wetting agents, such as naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[00168] Oily suspensions may be formulated by suspending a compound of the present disclosure in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.

[00169] Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[00170] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water can be comprised of the dosage form of present disclosure in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[00171] The dosage form of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation reaction products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. [00172] Oral unit dosage forms, such as tablets and capsules, may independently contain from about 0.1 mg to about 1000 mg of THC and CBD. In another embodiment, such dosage forms independently contain from about 50 mg to about 500 mg of THC and CBD. In yet another embodiment, such dosage forms independently contain from about 25 mg to about 200 mg of THC and CBD. In still another embodiment, such dosage forms independently contain from about 10 mg to about 100 mg of THC and CBD. In a further embodiment, such dosage forms independently contain from about 5 mg to about 50 mg of THC and CBD. In any of the foregoing embodiments the dosage form can be administered once a day or twice per day. The mass ratio of CBD to THC can range, in some embodiments, from about 30: 1 to about 1: 1. In some embodiments, the ratio is about 20: 1. In other embodiments, the ratio is about 2: 1.

[00173] Various embodiments of the present disclosure also contemplate pharmaceutical compositions comprising one or more compounds of the various embodiments of the present disclosure and one or more pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof.

[00174] In many cases, the composition includes isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, the compounds described herein can be formulated in a time release formulation, for example in a composition that includes a slow release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are known to those skilled in the art. [00175] Oral forms of administration are also contemplated herein. The pharmaceutical compositions of the present disclosure may be orally administered as a capsule (hard or soft), tablet (film coated, enteric coated or uncoated), powder or granules (coated or uncoated) or liquid (solution or suspension). The formulations may be conveniently prepared by any of the methods well-known in the art. The pharmaceutical compositions of the present disclosure may include one or more suitable production aids or excipients including fillers, binders, disintegrants, lubricants, diluents, flow agents, buffering agents, moistening agents, preservatives, colorants, sweeteners, flavors, and pharmaceutically compatible carriers.

[00176] For each of the recited embodiments, the compounds can be administered by a variety of dosage forms as known in the art. Any biologically acceptable dosage form known to persons of ordinary skill in the art, and combinations thereof, are contemplated. Examples of such dosage forms include, without limitation, chewable tablets, quick dissolve tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, gum, granules, particles, microparticles, dispersible granules, cachets, douches, suppositories, creams, topicals, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, ingestibles, injectables (including subcutaneous, intramuscular, intravenous, and intradermal), infusions, and combinations thereof.

[00177] Other compounds which can be included by admixture are, for example, medically inert ingredients (e.g., solid and liquid diluent), such as lactose, dextrose-saccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; gelling agents such as colloidal clays; thickening agents such as gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin, polysorbates or lauryl sulfates; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffers and antioxidants, which are known additives for such formulations.

[00178] Liquid dispersions for oral administration can be syrups, emulsions, solutions, or suspensions. The syrups can contain as a carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol. The suspensions and the emulsions can contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

[00179] The amount of active compound in a therapeutic composition according to various embodiments of the present disclosure may vary according to factors such as the disease state, age, gender, weight, patient history, risk factors, predisposition to disease, administration route, preexisting treatment regime (e.g., possible interactions with other medications), and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of therapeutic situation.

[00180] In some embodiments, the present disclosure contemplates compositions comprising a therapeutically effective amount of one or more compounds of the various embodiments of the present disclosure

[00181] Although the disclosure is described in conjunction with specific embodiments thereof, it is evident that numerous alternatives, modifications and variations that are apparent to those skilled in the art may exist. It is to be understood that the disclosure is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth herein. Other embodiments may be practiced, and an embodiment may be carried out in various ways. Accordingly, the disclosure embraces all such alternatives, modifications and variations that fall within the scope of the appended claims.

[00182] Certain embodiments of the present disclosure may include some, all, or none of the above advantages. One or more technical advantages may be readily apparent to those skilled in the art from the figures, descriptions, and claims included herein. Moreover, while specific advantages have been enumerated above, various embodiments may include all, some, or none of the enumerated advantages. The features and aspects of the various embodiments described herein may be applied, in whole or in part, to other embodiments, and that each embodiment may be considered individually or in combination with other embodiments as appropriate, as would be understood by one skilled in the art. Thus, all combinations of the various elements described herein are within the scope of the disclosure.

[00183] This disclosure can be additionally understood by reference to the Example which follows, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the disclosure as described more fully in the claims which follow thereafter.

[00184] Example: A randomized, double-blind, placebo-controlled crossover study treats 92 human patients suffering from acute migraine attacks, wherein up to 4 migraine attacks in each patient are treated by administration to the patient as follows:

Migraine 1 : delta-9-tetrahydrocannabinol (THC) alone;

Migraine 2: cannabidiol (CBD) alone;

Migraine 3 : dosage form of THC and CBD according to the present disclosure; and

Migraine 4: placebo.

[00185] Results: THC without CBD exerts the best early results at 1 hour but a THC/CBD dosage form as described herein has the best results at 2 hours, 24 hours and 48 hours. Placebo has the least effect, followed by CBD alone.

[00186] Without being bound to any particular theory, it is believed that THC without CBD is more effective than the THC/CBD mix at 1 hour because CBD acts as a negative allosteric modulator of the CB1 receptor, thereby competing with THC and decreasing its efficacy (Laprairie et al., 2015 and Zou, 2018). CBD exerts its biological effect via numerous mechanisms including by inhibiting the degradation of anandamide (AEA) by Fatty Acid Amide Hydrolase, decreasing AEA reuptake (Di Marzo et al., 2001), decreasing inflammation by activation of peroxisome proliferator-activated receptor gamma (PPAR-gamma), activating and desensitizing transient receptor potential vanilloid 1 (TRPV1) and via agonism or allosteric modulation of serotonin-l-A (5HT1A) (Di Marzo et al., 2001). The present results surprisingly show that the THC/CBD mix is more effective than THC alone or CBD alone at 2 hours, 24 hours, and 48 hours (Pertwee, 2008).

[00187] The following are additional embodiments of the present disclosure:

[00188] Embodiment l is a method of treating a migraine or reducing one or more symptoms thereof in a subject afflicted with migraine, comprising pulmonary administration to the subject of a composition comprising: i) an immediate release formulation comprising A⁹ -tetrahydrocannabinol (THC) and ii) a sustained release formulation comprising cannabidiol (CBD).

[00189] Embodiment 2 relates to embodiment 1, wherein the THC to CBD ratio is between 1 : 1 and 1:5 on a molar basis.

[00190] Embodiment 3 relates to embodiment 2, wherein the ratio of THC to the CBD is 1 : 1.8 on a molar basis. [00191] Embodiment 4 relates to embodiment 1, wherein the THC to CBD ratio is between 1: 1 and 1:5 w/w%,

[00192] Embodiment 5 relates to embodiment 3, wherein the THC to CBD ratio is 1: 1.8 w/w%.

[00193] Embodiment 6 relates to any of embodiments 1 - 5, wherein the composition is a solution, liquid suspension, or dry powder.

[00194] Embodiment 7 relates to any of embodiments 1 - 6, wherein the composition further comprises a pharmaceutically acceptable solvent.

[00195] Embodiment 8 relates to any of embodiments 1 - 7, wherein the sustained release formulation comprises cannabidiol (CBD) and a sustained delivery vehicle.

[00196] Embodiment 9 relates to embodiment 8, wherein the sustained delivery vehicle is selected from hydrogel, microparticle, nanoparticle, micelle, and liposome.

[00197] Embodiment 10 relates to embodiment 8, wherein the liposome is a cationic liposome or a liposome-polymer hybrid nanoparticle.

[00198] Embodiment 11 relates to any of embodiments 1 - 10, wherein the sustained release formulation comprises one or more pharmaceutically acceptable excipients.

[00199] Embodiment 12 relates to embodiment 11, wherein the excipients are selected from hydroxypropyl-P-cyclodextrin, lactose, mannitol, glucose, sorbitol, sucrose, and trehalose.

[00200] Embodiment 13 relates to any of embodiments 1 - 12, wherein the pulmonary administration is intranasal administration or oral inhalation.

[00201] Embodiment 14 relates to any of embodiments 1 - 13, wherein the composition is administered as an aerosol.

[00202] [00203] Embodiment 15 relates to embodiment 14, wherein the aerosol is administered by a nebulizer, pressurized metered dose inhaler, dry powder inhaler, or nasal atomizer.

[00204] Embodiment 16 relates to any of embodiments 1 - 15, wherein the migraine is selected from vestibular migraine, abdominal migraine, chronic migraine, migraine with brainstem aura, hemiplegic migraine, and menstrual migraine.

[00205] Embodiment 17 relates to any of embodiments 1 - 16, wherein administration of the composition is for reducing one or more symptoms of migraine in the subj ect.

[00206] Embodiment 18 relates to any of embodiments 1 - 17, wherein the symptoms are selected from pain, photophobia, phonophobia, osmophobia, olfactory hallucination, nausea, vomiting, aura, vertigo, unilateral cephalalgia, and mechanical allodynia.

[00207] Embodiment 19 relates to any of embodiments 1 - 18, wherein administration of the composition reduces the migraine symptoms within 2 hours of administration to the subject.

[00208] Embodiment 20 relates to any of embodiments 1 - 19, wherein administration of the composition reduces migraine symptoms for at least 24 hours after administration.

[00209] Embodiment 21 relates to any of embodiments 1 - 20, wherein administration of the composition reduces migraine symptoms for at least 48 hours after administration.

[00210] Embodiment 22 relates to any of embodiments 1 - 21, wherein administration of the composition does not induce a psychoactive effect in the subject

[00211] Embodiment 23 is a multilayer dosage form comprising:

(a) a delayed-release core comprising a therapeutically effective amount of cannabidiol (CBD) and a pharmaceutically acceptable excipient;

(b)an immediate release layer disposed upon and fully enveloping the entirety of the core, comprising a therapeutically effective amount of A⁹- tetrahydrocannabinol (THC) and a pharmaceutically acceptable excipient.

[00212] Embodiment 24 relates to embodiment 23, further comprising a delayed release layer disposed between (a) the delayed-release core and (b) the immediate release layer.

[00213] Embodiment 25 relates to embodiment 24, wherein the delayed release layer comprises an enteric coating.

[00214] Embodiment 26 relates to any of embodiments 23 to 25, further comprising an immediate release coating disposed on the immediate release layer.

[00215] Embodiment 27 relates to any of embodiments 23 to 26, wherein the dosage form is a tablet or particle.

[00216] Embodiment 28 relates to embodiment 27, wherein the particle is a microparticle or nanoparticle.

[00217] Embodiment 29 is a method for treating a subject suffering from migraine, comprising administering to the subject the multilayer dosage form according to any of embodiments 23 to 28.

[00218] Embodiment 30 relates to embodiment 29, wherein the migraine is chronic migraine with or without aura.

[00219] Embodiment 31 relates to embodiment 29, wherein the migraine is episodic migraine with or without aura.

[00220] Embodiment 32 relates to embodiment 29, wherein the method comprises acute migraine treatment. [00221] Embodiment 33 relates to embodiment 29, wherein the method comprises migraine prevention.

[00222] Embodiment is a method for treating a subject suffering from a painful condition, the method comprising administering to the subject the multilayer dosage form according to any of embodiments 23 to 29.

[00223] Embodiment 35 relates to embodiment 34, wherein the painful condition includes acute pain, post- operative pain, or chronic pain condition.

[00224] References

[00225] Throughout this disclosure, the following publications are referenced in parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to describe more fully the state of the art to which this disclosure pertains.

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Claims

I CLAIM:

1. A method of treating a migraine or reducing one or more symptoms thereof in a subject afflicted with migraine, comprising pulmonary administration to the subject of a composition comprising: i) an immediate release formulation comprising A⁹- tetrahydrocannabinol (THC) and ii) a sustained release formulation comprising cannabidiol (CBD).

2. The method according to claim 1, wherein the THC to CBD ratio is between 1 : 1 and 1 :5 on a molar basis,

3. The method of claim 2, wherein the ratio of THC to the CBD is 1 : 1.8 on a molar basis.

4. The method according to claim 1, wherein the THC to CBD ratio is between 1:1 and 1:5 w/w%,

5. The method according to claim 3, wherein the THC to CBD ratio is 1:1.8 w/w%.

6. The method according to any of claims 1 - 5, wherein the composition is a solution, liquid suspension, or dry powder.

7. The method according to claim 1, wherein the composition further comprises a pharmaceutically acceptable solvent.

8. The method according to claim 1, wherein the sustained release formulation comprises cannabidiol (CBD) and a sustained delivery vehicle.

9. The method according to claim 8, wherein the sustained delivery vehicle is selected from hydrogel, microparticle, nanoparticle, micelle, and liposome.

10. The method according to claim 9, wherein the liposome is a cationic liposome or a liposome-polymer hybrid nanoparticle.

11. The method according to claim 1, wherein the sustained release formulation comprises one or more pharmaceutically acceptable excipients.

12. The method according to claim 11, wherein the excipients are selected from hydroxypropyl-P-cyclodextrin, lactose, mannitol, glucose, sorbitol, sucrose, and trehalose.

13. The method according to claim 1, wherein the pulmonary administration is intranasal administration or oral inhalation.

14. The method according to claim 1, wherein the composition is administered as an aerosol.

15. The method according to claim 14, wherein the aerosol is administered by a nebulizer, pressurized metered dose inhaler, dry powder inhaler, or nasal atomizer.

16. The method according to claim 1, wherein the migraine is selected from vestibular migraine, abdominal migraine, chronic migraine, migraine with brainstem aura, hemiplegic migraine, and menstrual migraine.

17. The method according to claim 1, wherein administration of the composition is for reducing one or more symptoms of migraine in the subject.

18. The method according to claim 17, wherein the symptoms are selected from pain, photophobia, phonophobia, osmophobia, olfactory hallucination, nausea, vomiting, aura, vertigo, unilateral cephalalgia, and mechanical allodynia.

19. The method according to claim 1, wherein administration of the composition reduces the migraine symptoms within 2 hours of administration to the subject.

20. The method according to claim 1, wherein administration of the composition reduces migraine symptoms for at least 24 hours after administration.

21. The method according to claim 20, wherein administration of the composition reduces migraine symptoms for at least 48 hours after administration.

22. The method according to claim 1, wherein administration of the composition does not induce a psychoactive effect in the subject

23. A multilayer dosage form comprising:

(a) a delayed-release core comprising a therapeutically effective amount of cannabidiol (CBD) and a pharmaceutically acceptable excipient;

(b) an immediate release layer disposed upon and fully enveloping the entirety of the core, comprising a therapeutically effective amount of A⁹-tetrahydrocannabinol (THC) and a pharmaceutically acceptable excipient.

24. The multilayer dosage form according to claim 23, further comprising a delayed release layer disposed between (a) the delayed-release core and (b) the immediate release layer.

25. The multilayer dosage form according to claim 24, wherein the delayed release layer comprises an enteric coating.

26. The multilayer dosage form according to any of claims 23 to 25, further comprising an immediate release coating disposed on the immediate release layer.

27. The multilayer dosage form according to claim 23, wherein the dosage form is a tablet or particle.

28. The multilayer dosage form according to claim 27, wherein the particle is a microparticle or nanoparticle.

29. A method for treating a subject suffering from migraine, comprising administering to the subject the multilayer dosage form according to claim 23.

30. The method according to claim 29, wherein the migraine is chronic migraine with or without aura.

31. The method according to claim 29, wherein the migraine is episodic migraine with or without aura.

32. The method according to claim 29, wherein the method comprises acute migraine treatment.

33. The method according to claim 29, wherein the method comprises migraine prevention.

34. A method for treating a subject suffering from a painful condition, the method comprising administering to the subject the multilayer dosage form according to claim 23.

35. The method according to claim 34, wherein the painful condition includes acute pain, post- operative pain, or chronic pain condition.