Cannabinoid compositions and dosage forms for intranasal or inhalational delivery

Abstract

This invention provides a pharmaceutical composition, its use, and a method of manufacturing the same. The pharmaceutical composition comprises a therapeutically effective amount of cannabinoid or a pharmaceutically acceptable salt or solvate thereof, and an amphiphilic copolymer comprising at least one hydrophilic component and at least one hydrophobic component. The cannabinoid is encapsulated in the amphiphilic copolymer, and the composition is suitable for intranasal or inhalation delivery.

Description

[Technical Field]

[0001] This invention relates to compositions and dosage forms for intranasal or inhaled delivery of cannabinoids. It also relates to methods of using and manufacturing dosage forms and compositions. More specifically, this invention relates to compositions and dosage forms comprising cannabinoids encapsulated in copolymers to form micelles. [Previous Technology]

[0002] Cannabinoids are a class of chemical compounds that act on cannabinoid receptors (CB1 or CB2) in cells to alter the release of neurotransmitters in the brain. Ligands of these receptor proteins include naturally occurring endocannabinoids in animals, phytocannabinoids found in cannabis (Cannabis sativa) and some other plants, and artificially produced synthetic cannabinoids. The most prominent cannabinoid is tetrahydrocannabinol (Δ9-THC), the main psychoactive compound in cannabis. Cannabidiol (CBD) is another major component of the plant and does not bind to CB1 or CB2 receptors.

[0003] Alzheimer's disease is a progressive neurological disorder in which brain cells atrophy (degenerate) and die. Alzheimer's disease is the most common cause of dementia (a persistent decline in thinking, behavior, and social skills that impairs a person's ability to function independently). There is currently no cure for Alzheimer's disease or a treatment to alter the disease process in the brain. In the later stages of the disease, complications caused by severe loss of brain function (such as dehydration, malnutrition, or infection) can lead to death. Plaques and tangles are considered the main causes of neurological damage in Alzheimer's patients. Plaques are deposits of β-amyloid protein that accumulate in the spaces between nerve cells, while tangles are twisted fibers of tau protein that accumulate within nerve cells.

[0004] The endocannabinoid system has emerged as a potential treatment for Alzheimer's disease (Aso and Ferrer, "Cannabinoids for treatment of Alzheimer's disease: moving toward the clinic", Front Pharmacol., 5:37 (2014); Cao et al., "The Potential Therapeutic Effects of THC on Alzheimer's Disease", Journal of Alzheimer's disease 42:973 (2014)). This system (also known as the endocannabinoid system) consists of various cannabinoid receptors (including the well-characterized CB1 and CB2 receptors) and their endogenous ligands, as well as enzymes associated with the synthesis and degradation of these endocannabinoid compounds (see above). Several findings suggest that, in experimental models of Alzheimer's disease, at non-psychoactive doses, the activation of CB1 and CB2 receptors by natural or synthetic agonists can have beneficial effects by reducing harmful β-amyloid action and tau phosphorylation, and by promoting the brain's innate repair mechanisms (Gemma Navarro et al., "Receptor-heteromer-mediated regulation of endocannabinoid signaling in activated microglia: Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia"; Belen G. Ramı'rez et al., "Prevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation").Therefore, studies have confirmed that cannabinoids remove Alzheimer's proteins (such as β-amyloid peptides) that form plaques from brain cells, thereby reducing cellular inflammation and the high neuronal mortality rate caused by Alzheimer's proteins (Bele et al., see above and Currais et al., "Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids", npj Aging and Mechanisms of Disease, doi:10.1038 / npjamd.2016.12 (2016)).

[0005] Drocannabinol or (-)-trans-Δ⁹-tetrahydrocannabinol (Δ9-THC) is a synthetically produced Δ9-THC. Drocannabinol is used as an appetite stimulant, antiemetic, and analgesic. It has the following structural formula:

[0006] Drin cannabinol is a transparent to amber resinous oil that is viscous at room temperature and hardens when refrigerated. It is insoluble in water but can be blended into oils (such as sesame oil).

[0007] Drolamide is marketed under the brand name Marinol® and is indicated for 1) anorexia associated with weight loss in patients with AIDS, and 2) nausea and vomiting associated with cancer chemotherapy in patients who have failed conventional antiemetic treatment. It is provided orally in soft gelatin capsule solutions at doses of 2.5 mg, 5 mg, or 10 mg. The formulation includes sesame oil, gelatin, glycerol, methylparaben, propylparaben, and titanium dioxide. This formulation is highly unstable at room temperature and requires refrigeration (2°C–8°C) or cooling conditions (8°C–15°C). It should be packaged in a light-protected, tightly sealed container and stored in a cool environment between 8°C and 15°C (46°F and 59°F). See the Marinol® package label, Physicians Desk Reference®, 2003 edition. Due to its first-pass metabolism in the liver, dronabinol has relatively low bioavailability in this formulation, which reduces the concentration of the drug that can circulate in the bloodstream.

[0008] These drawbacks are evident for the administration of dronabinol to treat Alzheimer's disease, as active cannabinoids must cross the blood-brain barrier in adequate amounts without excessive metabolism in order to reach the brain at an effective non-psychoactive dose and activate its cannabinoid receptors. The anti-inflammatory and self-repair benefits associated with cannabinoid therapy for Alzheimer's disease also involve mechanisms in the brain. There is a need for cannabinoid compositions and dosage forms that effectively target the brain, store stable substances, and resist rapid conversion into adverse (e.g., psychoactive) metabolites.

[0009] Currently, nabilone, dronabinol (e.g., Marinel®), cannabinol (e.g., Cemeset®), and cannabidiol (e.g., Epidolex, used for epilepsy) are the only cannabinoid drugs approved for commercial sale in the United States. In Europe and Canada, the sublingual spray Sativex®, containing a 52:48 ratio of dronabinol to cannabidiol, is also used to treat multiple sclerosis spasms. Sativex®, manufactured by GW Pharmaceuticals, is described in U.S. Patent No. 8,512,767. Like Marinel®, Sativex® must be refrigerated to maintain its chemical stability. Similar to Marinel®, limitations of Sativex® include poorer storage stability and pharmacokinetics.

[0010] Given the low stability, high viscosity, and low water solubility of cannabinoids, the stability, dosage accuracy, and uniformity of cannabinoid pharmaceutical compositions remain technical challenges. The manufacture of stable water-soluble cannabinoid formulations and dosage forms for intranasal administration is particularly challenging.

[0011] Therefore, there is an urgent need for modified water-soluble compositions and dosage forms containing cannabinoids for intranasal delivery. [Summary of the Invention]

[0013] The following describes several non-limiting forms and embodiments of the present invention.

[0014] This invention provides a pharmaceutical composition comprising a therapeutically effective amount of cannabinoid or a pharmaceutically acceptable salt or solvate thereof, and a combination of an amphiphilic copolymer comprising at least one hydrophilic component and at least one hydrophobic component. The cannabinoid is encapsulated in the amphiphilic copolymer. The composition is suitable for delivery by intranasal administration or inhalation. In some embodiments, the hydrophilic component is polyethylene glycol (PEG), and the hydrophobic component is selected from polycaprolactone (PCL), polylactic acid (PLA), and polylactide co-glycolic acid (PLGA). In some copolymer embodiments, the ratio of the hydrophilic component to the hydrophobic component is in the range of about 1:1 to about 1:5 (based on number average molecular weight). In one embodiment, the hydrophobic component is PLGA.

[0015] In some embodiments comprising PEG and PLGA components, the molecular weight (Mn) of PEG is about 2000 to about 5000 and the molecular weight (Mn) of PLGA is about 4500 to about 9000. In some embodiments, the PEG-PLGA polymers have the following general formula.

[0016] In this formula, m represents the number of repeating PLGA units, and n represents the number of repeating PEG units (in moles). Similarly, x and y represent the number of repeating units (in moles) of each PLGA component. Any suitable values ​​of x, y, m, and so on are within the scope of this invention. In some embodiments, each of x and y may be in the range of 1 to 3, and each of m and n may be in the range of 1 to 5. In a suitable PEG-PLGA embodiment, the PEG component has a molecular weight (Mn) of 2000 and the PLGA component has a molecular weight (Mn) of 4500. The PEG to PLGA ratio of this copolymer is 2000:4500 = 1:2.25 (in terms of number average molecular weight). In another suitable PEG-PLGA embodiment, the PEG component has a molecular weight (Mn) of 5000 and the PLGA component has a molecular weight (Mn) of 7000. The PEG to PLGA ratio of this copolymer is 5000:7000 = 1:1.4 (in terms of number average molecular weight). The better cannabinoids are Δ9-THC (dronabinol) or cannabidiol (CBD).

[0017] The compositions of the present invention provide an effective amount of cannabinoid suitable for treating neurological disorders such as Alzheimer's disease, Parkinson's disease, neuropathic pain, spasms, pain induced by spinal cord injury, migraine, multiple sclerosis, Tourette's syndrome, or post-traumatic stress disorder (PTSD). In some embodiments, an effective amount of the composition is administered to an individual to treat one of these disorders, such as Alzheimer's disease. The route of administration is intranasal or by inhalation. Therefore, the present invention also provides a method of administering a composition, comprising an encapsulation copolymer and an effective amount of cannabinoid, to an individual in need (including human patients) by intranasal or inhalation to treat neurological disorders (including pain).

[0018] In some embodiments, the suitable daily dose for human administration is from about 0.5 mg to about 7.5 mg, which may be administered in divided doses once daily, preferably twice daily. In some embodiments, the suitable human dose is 2.5 mg, which is administered throughout the day in one or more doses, such as once daily, twice daily, or three or more times daily. In some embodiments, the total daily dose is from about 2.5 mg to about 30 mg. For example, the daily dose may be about 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 20 mg, 25 mg, or 30 mg. In some embodiments, the total daily dose may be from about 10% to about 30% of each of these daily doses. In some embodiments, the total daily dose may be from about 30% to about 50% of each of these daily doses. In some embodiments, the total daily dose may be from about 50% to about 70% of each of these daily doses. In some embodiments, the delivery device (e.g., an intranasal spray or a metered-dose inhaler) may dispense a unit dose of about 2.5 mg of cannabinoids. In some embodiments, the unit dose may be less than about 2.5 mg, for example, from about 0.5 mg to less than about 2.5 mg, such as unit doses of 0.2 mg, 0.3 mg, 0.5 mg, 1.0 mg, and 2.0 mg. The composition may comprise one or more cannabinoids, such as a combination of Δ9-THC and CBD, which may be provided by weight in equal or unequal ratios. In embodiments containing more than one cannabinoid, the unit dose and daily dose of each cannabinoid may be provided individually or together. In some embodiments, the combined unit dose and / or daily dose of two or more cannabinoids may be within the ranges and amounts provided herein. In some embodiments, the combined unit dose and / or daily dose of two or more cannabinoids may be proportional to the ranges or amounts provided herein.

[0019] This invention advantageously provides improved, storage-stable cannabinoid compositions that effectively target the brain while bypassing unwanted first-pass metabolism. In vivo, primarily in the liver, cannabinoid Δ9-THC is hydrolyzed into the psychoactive compound 11-hydroxyΔ9-tetrahydrocannabinol (11-OH-THC), also known as OH-THC. Further oxidation produces inactive 11-nor-9-carboxy-Δ9-tetrahydrocannabinol, also known as THC-COOH. This invention advantageously reduces the amount of OH-THC reaching the brain. Improved solubility, particularly for intranasal or inhaled delivery, provides a more consistent cannabinoid targeting dose.

[0020] Those skilled in the art will understand these and other aspects of the invention after reading the following detailed description of the invention (including the appended claims).

Implementation Method

[0022] This document discloses detailed embodiments of the present invention; however, it should be understood that the disclosed embodiments are merely illustrative of the invention, which may be embodied in various forms. Furthermore, each example given in connection with the various embodiments of the invention is intended to be illustrative rather than restrictive. Therefore, the specific structural and functional details disclosed herein should not be construed as limiting, but are merely representative of teaching those skilled in the art to use the invention in different ways.

[0023] The pharmaceutical compositions of the present invention may be provided in any suitable dosage form, including, for example, powder, liquid, or liquid reconstituted from powder, the powder being or not a lyophilized powder. In various embodiments, devices suitable for intranasal delivery include spray pumps, metered-dose pumps or inhalers, pressurized nebulizers or inhalers, nebulizers, sprayers, aerosol devices, or any device suitable for intranasal or nasal inhalation delivery of liquid or powder compositions.

[0024] The pharmaceutical compositions and dosage forms of the present invention can be used to treat diseases, slow the progression of diseases, or alleviate the symptoms of diseases, including Alzheimer's disease, Parkinson's disease, neuropathic pain, spasms, pain induced by spinal cord injury, migraine, multiple sclerosis, Tourette syndrome, post-traumatic stress disorder (PTSD), and various combinations thereof. In various embodiments, the compositions and dosage forms of the present invention are particularly useful for treating Alzheimer's disease or slowing the progression of Alzheimer's disease. Some embodiments provide that the compositions and dosage forms of the present invention can be used for symptom relief of diseases including spasms (muscle stiffness / twitching) and / or neuropathic pain caused by multiple sclerosis (MS), as well as pain relief for cancer patients experiencing pain while undergoing opioid therapy.

[0025] In some embodiments, the compositions and dosage forms of the present invention may also be used to treat conditions in patients with cancer, including chemotherapy-induced vomiting, nausea and / or vomiting, to treat HIV / AIDS-related anorexia, and / or as appetite stimulants.

[0026] The compositions and dosage forms of the present invention can also be used to treat migraines.

[0027] As detailed below, the inventors have discovered that water-soluble compositions or formulations of cannabinoids can be prepared by encapsulating cannabinoids using polymeric micelles comprising a specific amphiphilic copolymer and employing a specific method. Surprisingly, when administered to mammals, cannabinoids encapsulated by polymeric micelles exhibit favorable metabolic and drug-targeting characteristics compared to alternative drug forms. Furthermore, cannabinoids encapsulated by polymeric micelles surprisingly exhibit clinical and metabolic characteristics very similar to naked cannabinoids (e.g., naked Δ9-THC), but without the psychoactive effects (e.g., "higher"). General Definition

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0029] Unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” used in this specification and the appended claims include a plurality of indicators. Thus, for example, a reference to “a method” includes one or more methods, and / or steps of the type described herein and / or methods that a person skilled in the art would understand upon reading this disclosure.

[0030] The terms “about” and “approximately” used in conjunction with the terms for quantity, amount, or range of a measurement refer to a normal measurement variation of a degree of care appropriate to the target being measured and consistent with the accuracy of the measuring device or method. For example, in some embodiments, the term “about” includes ±10%, such that “about 10” would include 9 to 11. Ranges and ratios herein may be expressed as “about” or “approximately” from one specific value to “about” or “approximately” another specific value. For example, unless otherwise stated, the range “about 1-5” is synonymous with the range “about 1 to about 5”.

[0031] As used herein, the term "composition" includes both a composition and the disclosure of a composition administered to it by the methods described herein. Additionally, in some embodiments, the compositions of the present invention may comprise a "formulation," which may alternatively be referred to as a dosage form.

[0032] As used herein with respect to dosage or amount (including therapeutic dose), “effective” means the amount of a compound or pharmaceutical composition sufficient to produce the desired activity when administered to an individual in need. It should be noted that when administered in combination of active ingredients, the effective amount of the combination may or may not include the amount of each ingredient that is effective when administered individually. The exact amount required will vary from individual to individual, depending on the individual’s species, age and general condition, the severity of the disease being treated, one or more specific drugs used, the mode of administration, and the like.

[0033] As used herein, the term "polymeric micelle" refers to a nanocarrier formed by the spontaneous arrangement of an amphiphilic component copolymer in an aqueous solution according to the method of this disclosure. The amphiphilic block copolymer is a copolymer comprising hydrophilic and hydrophobic blocks. The nanostructure has a hydrophobic core-hydrophilic shell architecture that facilitates the loading of cannabinoids or other hydrophobic drugs into the core. The polymeric micelle is a self-assembled core-shell nanostructure formed in an aqueous solution containing the amphiphilic block copolymer. When cannabinoids are arranged within the core of the polymeric micelle, the cannabinoids are encapsulated by the polymeric micelle. When the concentration of the block copolymer increases to a critical aggregation concentration or critical micelle concentration or above, resulting in the formation of vesicle-like or core-shell micelle structures, micelles are formed in the aqueous solution. The polymeric micelle is advantageously easy to manufacture.

[0034] As used herein, the terms "intranasal administration," "intranasal delivery," "nasal delivery," or "intranasal" refer to the administration of a drug into the nasal cavity, such that the drug comes into contact with and is initially placed on the mucosa or epithelial surface within the individual's nasolacrimal duct. When a drug is administered intranasally, it enters the individual via the epithelium (e.g., respiratory or olfactory epithelium) placed within the nasal cavity. In various embodiments, "intranasal dispensing" results in at least 100%, 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, or 20% of cannabinoids being administered to the individual via the olfactory epithelium or via the epithelium lining the nasal cavity (i.e., absorbed into the body via or through surface and cellular processes associated with the olfactory epithelium or surface of the nasal cavity, respectively). In various embodiments, intranasal dispensing is achieved by inhalation. In various embodiments, the individual does not inhale during intranasal dispensing.

[0035] Unless otherwise indicated, the phrases “administered intranasally by inhalation” or “inhalation” as used herein refer to the process by which a patient inhales air into the lungs during intranasal administration of a drug to create an airflow into the nasal cavity, thereby facilitating the effective delivery of the drug to the nasal cavity rather than to the lungs. The synonyms “administered intranasally by inhalation” or “inhalation” as used herein include “inhalation,” “nasal inhalation,” and “olfactory inhalation.” “Inhalation” and “administered intranasally by inhalation” are methods of intranasal administration and are therefore within the class of administration methods covered by the term “intranasal administration.”

[0036] The terms “level” and “concentration” used herein are interchangeable.

[0037] As used herein, the term "solvent" refers to an aggregate consisting of solute ions or molecules and one or more solvent molecules. As used herein, the term "solute" refers to a substance that is soluble in a solvent or is a minor component of a solution containing a solvent, and the term "solvent" refers to a substance that is capable of dissolving other substances (i.e., solutes) or is a major component of a solution. As used herein, the term "hydrate" refers to a solvate in which the solvent is water. Solvates and hydrates of a pharmaceutical ingredient are crystalline modifications of a pharmaceutical ingredient containing both the drug and solvent molecules. A solvate is formed when a compound (e.g., a drug) crystallizes and the solvent is trapped within the resulting crystalline structure. A solvent-free crystal is referred to as an "anhydrous substance" rather than a "solvent." A solvate contains stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, is formed during crystallization using pharmaceutically acceptable solvents (e.g., water, ethanol, and the like). When the solvent is an alcohol, an alcoholic compound is formed. Generally, for the purposes of the compositions, formulations and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0038] As used herein, the terms "treat," "treating," or "treatment," and other grammatically equivalent forms, include alleviating, suppressing, or reducing symptoms; reducing or suppressing the severity of symptoms of a disease or condition; reducing the incidence of symptoms of a disease or condition; reducing or suppressing the recurrence of symptoms of a disease or condition; delaying the onset of symptoms of a disease or condition; delaying the recurrence of symptoms of a disease or condition; weakening or improving symptoms of a disease or condition; improving the underlying cause of symptoms; suppressing a disease or condition, such as preventing its development; relieving a disease or condition; causing a disease or condition to subside; relieving symptoms caused by a disease or condition; or terminating the symptoms of a disease or condition. These terms further include achieving a therapeutic benefit. A therapeutic benefit means the eradication or improvement of the underlying condition being treated and / or the eradication or improvement of one or more physiological symptoms associated with the underlying condition, resulting in an observed improvement in the patient.

[0039] The terms "subject," "patient," or "individual" are used interchangeably herein and refer to, for example, a mammal or non-mammal suffering from the condition described herein. Examples of mammals include (but are not limited to) any member of the mammalian class: humans, non-human primates (e.g., chimpanzees and other ape and monkey species); farm animals, such as cattle, horses, sheep, goats, and pigs; domesticated animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-mammals include (but are not limited to) birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0040] As used herein, the terms “effective amount,” “pharmacologically effective amount,” “physiologically effective amount,” or “therapeuticly effective amount” refer to a sufficient amount of a therapeutic agent or compound administered to alleviate, to a certain extent, one or more symptoms of the disease or ailment being treated. The result is a reduction and / or alleviation of the signs, symptoms, or cause of the disease or any other desired change in the biological system. For example, an “effective amount” for therapeutic use includes the amount of the composition of the drugs described herein required to deliver a desired level of the drug (e.g., Δ9-THC) in the bloodstream or at the site of action (e.g., the brain) to the individual to be treated, thereby producing a clinically significant reduction in the symptoms of the disease. The precise amount will depend on a variety of factors, such as the specific therapeutic agent, the activity of the therapeutic agent, the delivery device used, the physical characteristics of the therapeutic agent, the individual’s intended use (i.e., the number of doses administered daily), individual considerations, and so on, and can be readily determined by someone skilled in the art. In some embodiments, the appropriate “effective” amount is determined in any individual case using techniques such as dose escalation studies. In some cases, an "effective amount" for therapeutic use comprises a composition of agents as described herein that provide clinically significant disease attenuation. An appropriate "effective" amount in any individual case is determined using any suitable technique, such as dose escalation studies.

[0041] As used herein, the terms “administer,” “administering,” “administration,” “delivery,” and the like refer to methods that enable the delivery of an agent or composition to a desired biological site of action. These methods include, but are not limited to, oral and nasal routes. Dosing techniques used in conjunction with the agents and methods described herein can be found, for example, in the following sources: Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In some embodiments, the agents and compositions described herein are administered intranasally.

[0042] As used herein, the term "acceptable" in relation to formulations, compositions or ingredients means that it has no lasting harmful effect on the general health of the individual being treated.

[0043] Polymers are composed of repeating units (monomers) in long chains of varying lengths, chemically bonded together. The “molecular weight” (also referred to as molecular mass) of a polymer as used herein is an average of the distribution of chain lengths and molecular weights, which may also be referred to by the polymer supplier as its publicly disclosed molecular weight or “grade.” The number average molecular weight (“Mn”) is the ordinary arithmetic mean (mean or average) of the molecular weights of individual polymer components; that is, the total weight of the polymer divided by the total number of molecules. The weight average molecular weight (“Mw”) of a polymer is its average molar mass, which depends on the fraction of the total weight represented by each polymer component.

[0044] Unless otherwise stated, references to the molecular weight of a particular polymer herein refer to the average molecular weight (“Mn”) or the disclosed molecular weight or grade of the polymer (if applicable), however the disclosed molecular weight is determined.

[0045] The phrase "medically acceptable" as used in connection with the compositions of the present invention means that, when administered to mammals (e.g., humans), the molecular entities and other components of such compositions are physiologically tolerable and typically do not produce adverse reactions. Preferably, as used herein, the term "medically acceptable" means approved by federal or state regulatory agencies or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in mammals, and more specifically in humans.

[0046] As used herein, the term "pharmaceutical composition" refers to a mixture of the therapeutic agent described herein (e.g., Δ9-THC) and one or more other components. In preferred embodiments of the invention, such other components include polymeric micelles, carriers, and / or excipients, such as fluidizing agents, lubricants, preservatives, surfactants, antistatic agents, antimicrobial agents, and the like. Pharmaceutical compositions can facilitate the delivery of therapeutic agents to a living organism, for example, via intranasal administration.

[0047] The term "medically acceptable salt" or "salt" includes (but is not limited to): (1) an acid addition salt formed by reacting a therapeutic agent in its free base form with a medically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid and the like; or formed by reacting with an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethylenediaminetetrafluoro ... Sulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4′-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucoconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid and the like; (2) salts formed when the acidic protons present in the parental therapeutic agent are replaced by metal ions (e.g., alkali metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (e.g., magnesium or calcium) or aluminum ions). In some cases, the therapeutic agent may be coordinated with an organic base such as (but not limited to) ethanolamine, diethanolamine, triethanolamine, glycerol, N-methylglucosamine, dicyclohexylamine, and hydroxymethyl methylamine. In other cases, the therapeutic agent forms a salt with an amino acid (such as, but not limited to, arginine, lysine, and the like). Acceptable inorganic bases for forming salts with compounds including acidic protons include (but are not limited to) aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0048] The compositions of the present invention may contain at least one propellant as a delivery medium. As used herein, the term "propellant" includes any volatile short-chain hydrocarbon, hydrofluorocarbon, or chlorofluorocarbon approved by the Food and Drug Administration for use in pressurized containers to move fluids in a dispenser.

[0049] As used herein, the term "biodegradable" refers to compounds that can be broken down and metabolized by an individual. Cannabinoids

[0050] The terms "cannabinoid" or "cannabinoid derivative" refer to any cannabinoid isolated from the cannabis plant or any compound synthesized from a cannabinoid analogue and / or derivative, including tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), and dodecyl-E,4E,8Z,10E / Z-tetraenoic acid-isobutylamide, cannabinol (CBG), cannabinoid, cannabicyclophenol (CBL), hypocannabinol (CBV), tetrahydrocannabinol (THCV), hypocannabinol (CBDV), hypocannacyclophenol (CBCV), cannabinone (CBGV), cannabinol monomethyl ether (CBGM), and cannabinone as non-limiting examples. Other examples of cannabinoids and cannabinoid derivatives include cannabinoid acid, Δ9-tetrahydrocannabinoid acid (COOH-THC), cannabidiol, cannabinoid-3-hydroxycannabinol, cannabidiol, cannabidiol, tetrahydrocannabinol, cannabidiol, dehydrocannabidiol, cannabicyclophenol, cannabicyclophenol, dihydroxycannabinol, cannabicyclophenol, or various combinations thereof. In various embodiments, the cannabinoid is selected from Δ9-THC (dronabinol), cannabinone, and cannabidiol (CBD).

[0051] In some embodiments, the active pharmaceutical ingredient in the composition is tetrahydrocannabinol (THC) or a pharmaceutically acceptable salt thereof. In various embodiments, the active pharmaceutical ingredient in the composition is cannabinol. THC exists in a variety of isomeric forms, including (+)-trans-Δ8-tetrahydrocannabinol, (-)-trans-Δ8-tetrahydrocannabinol, (+)-trans-Δ9-tetrahydrocannabinol, and (-)-trans-Δ9-tetrahydrocannabinol (or drocannabinol; trademark name Marinol®). The positions and stereoisomers of THC include the following: (+)-Δ8-THC (+)-Δ9-THC (-)-Δ8-THC (-)-Δ9-THC

[0052] (-)-trans-Δ9-THC (drocannabinol) is the main natural component of cannabis. Δ9-THC and its Δ8-THC isomers have similar pharmacological profiles, but Δ9-THC has higher potency than the Δ8-THC isomer, and their solubility is essentially the same. Although Δ8-THC is more stable, does not oxidize to cannabinol, and has a much longer shelf life than Δ9-THC, it is less potent in most pharmacological tests (see, for example, Ophthalmic Res. (1992) 24: 142-149). Therefore, there is a need for stable formulations containing Δ9-THC (drocannabinol) and other active cannabinoid compounds and derivatives.

[0053] OH-THC is the major active metabolite of Δ9-THC, and COOH-THC is the major inactive metabolite of Δ9-THC (Sharma et al., "Chemistry, Metabolism, and Toxicology of Cannabis: Clinical Implications", Iran J. Psychiatry, 7:149-156 (2012). Hydroxylation of Δ9-THC produces the psychoactive compound OH-THC. After ingestion of Δ9-THC, systemic absorption typically reaches its peak within 1-2 hours (see above). Pharmaceutical Compositions

[0054] In one embodiment, the present invention provides a pharmaceutical composition comprising cannabinoids or pharmaceutically acceptable salts or solvates thereof and an amphiphilic copolymer. The composition comprises a therapeutically effective amount of cannabinoids or pharmaceutically acceptable salts or solvates thereof. The amphiphilic copolymer comprises at least one hydrophilic component or block and at least one hydrophobic component or block. The cannabinoid is encapsulated in the amphiphilic copolymer, and the resulting composition is particularly stable at room temperature and suitable for intranasal, nasal, or inhalation delivery. It has previously been demonstrated that encapsulation with polymeric micelles increases the storage stability of otherwise unstable drugs and produces a sustained-release effect during drug administration (Hu et al., International Journal of Pharmaceutics, 450:331-337 (2013), the disclosure of which is incorporated herein by reference to illustrate the stabilizing and sustained-release effects of polymeric micelles on encapsulated drugs). Active cannabinoid component

[0055] In various embodiments, the pharmaceutical or active ingredient contained in the pharmaceutical composition or dosage form of the present invention is any of the cannabinoids and various mixtures thereof provided above. In various embodiments, the cannabinoid is Δ9-THC (dronabinol), its pharmaceutically acceptable salt or solvate, or various combinations thereof. In various embodiments, the pharmaceutical composition administered to the present invention does not include metabolites of Δ9-THC as an active ingredient. In various embodiments, the pharmaceutical or active ingredient is cannabinol, its pharmaceutically acceptable salt or solvate, or various combinations thereof. Another suitable active ingredient is cannabidiol (CBD). In some embodiments, Δ9-THC and CBD are used in combination with each other. Polymerized micelles

[0056] In various embodiments, the amphiphilic copolymer forms polymeric micelles encapsulating cannabinoids. In various embodiments, the average diameter of the polymeric micelles is about 10 nm to about 500 nm, about 50 nm to about 250 nm, about 50 nm to about 200 nm, about 10 nm to about 50 nm, 10 nm to about 100 nm, 10 nm to about 75 nm, or about 100 nm to about 150 nm. In various embodiments, the average diameter of the polymeric micelles is about or at least about 10 nm, 20 nm, 25 nm, 30 nm, 40 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, 200 nm, 225 nm, 250 nm, 275 nm, 300 nm, 325 nm, 350 nm, 375 nm, or 400 nm. In various embodiments, the average diameter of the polymeric micelles does not exceed about 20 nm, 25 nm, 30 nm, 40 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, 200 nm, 225 nm, 250 nm, 275 nm, 300 nm, 325 nm, 350 nm, 375 nm, 400 nm, or 450 nm.

[0057] In various embodiments, the polymeric micelles are coupled to a targeting ligand (e.g., a lectin or antibody). As a non-limiting example, a lectin may be covalently bound to the outer surface of the polymeric micelles to promote their embedding within the mucosal layer of the nasal cavity. Embedding of the polymeric micelles within the mucosal layer of the nasal cavity can increase the residence time of the polymeric micelles within the nasal cavity and thereby improve the efficacy of drug release within the nasal cavity. As another non-limiting example, an antibody may be covalently bound to the outer surface of the polymeric micelles to promote their targeting to the mucosal layer of the nasal cavity or the surface of cells disposed within the nasal cavity. In various embodiments, the antibody may bind to the surface proteins of epithelial cells disposed within the nasal cavity, or the antibody may bind to polysaccharide or peptide components of the mucosal layer within the nasal cavity. Amphiphilic copolymers

[0058] The polymeric micelles encapsulating cannabinoids are formed from amphiphilic copolymers. In various embodiments, the amphiphilic copolymer comprises a hydrophobic block component and a hydrophilic block component. In various embodiments, the amphiphilic copolymer is a diblock copolymer (AB type or BA type, where A represents a hydrophilic block and B represents a hydrophobic block), a triblock copolymer (ABA type or ABC type, where C represents a hydrophobic or hydrophilic block), a graft copolymer, or a charged copolymer. In some embodiments, the amphiphilic copolymer is a diblock copolymer comprising a single hydrophobic block and a single hydrophilic block. In various embodiments, the amphiphilic copolymer is biodegradable.

[0059] The molecular weight of the polymer or copolymer or polymeric component can be determined by any suitable method or as specified by any of its manufacturers or suppliers (e.g., polymer "grade"). Unless otherwise indicated, the molecular weight of the polymer or copolymer or polymeric component refers to the index-average molecular weight ("Mn"). In various embodiments, the amphiphilic copolymer comprises a hydrophilic block. In some embodiments, the hydrophilic block comprises or consists of poly(ethylene glycol) (PEG) or poly(ethylene oxide) (PEO) or various mixtures thereof. In various embodiments, the weight-average molecular weight or number-average molecular weight (expressed in Daltons) of the hydrophilic blocks, preferably the number-average molecular weight, is about or at least about 1,000 Da, 1,250 Da, 1,500 Da, 1,750 Da, 2,000 Da, 2,250 Da, 2,500 Da, 2,750 Da, 3,000 Da, 3,250 Da, 3,500 Da, 4,000 Da, 4,250 Da, 4,500 Da, 4,750 Da, 5,000 Da, 5,250 Da, 5,500 Da, 5,750 Da, or 6,000 Da. In various embodiments, the hydrophilic block has a molecular weight of no more than about 1,500 Da, 1,750 Da, 2,000 Da, 2,250 Da, 2,500 Da, 2,750 Da, 3,000 Da, 3,250 Da, 3,500 Da, 4,000 Da, 4,250 Da, 4,500 Da, 4,750 Da, 5,000 Da Da, 5,250 Da, 5,500 Da, 5,750 Da, 6,000 Da or 6,500 Da. In various embodiments, the weight-average molecular weight or number-average molecular weight of the hydrophilic blocks, preferably the number-average molecular weight, is about 500 Da to about 7,000 Da, about 750 Da to about 6,500 Da, about 900 Da to about 6,000 Da, about 1,500 to about 6,000 Da, about 1,750 to about 6,000 Da, or about 2,000 to about 5,000 Da.

[0060] In various embodiments, the amphiphilic copolymer comprises a hydrophobic block. In various embodiments, the hydrophobic block comprises or consists of poly(L-amino acid), biodegradable poly(ester), phospholipid / long-chain fatty acid, polyoxypropylene oxide, or various combinations thereof. In various embodiments, the hydrophobic block comprises or consists of poly(lactic-co-glycolic acid) (PLGA). Non-limiting examples of biodegradable poly(ester) include poly(glycolic acid), polylactic acid (PLA) (e.g., poly(D,L-lactic acid) or poly(D-lactic acid)), lactide / glycolic acid copolymers, and poly(ε-caprolactone) / polycaprolactone (PCL). In various embodiments, the hydrophobic block is selected to be compatible with cannabinoids so as not to interfere with or engage in harmful chemical interactions with cannabinoids, and to effectively promote the encapsulation of cannabinoids by polymeric micelles.

[0061] In various embodiments, the number-average molecular weight (in Daltons) of the hydrophobic blocks is about or at least about 3,000 Da, 3,250 Da, 3,500 Da, 4,000 Da, 4,250 Da, 4,500 Da, 4,750 Da, 5,000 Da, 5,250 Da, 5,500 Da, 5,750 Da, 6,000 Da, 6,250 Da, 6,500 Da, 6,750 Da, 7,000 Da, 7,250 Da, 7,500 Da, 7,750 Da, 8,000 Da, 8,250 Da, 8,500 Da, 8,750 Da, or 9,000 Da. In various embodiments, the number average molecular weight of the hydrophilic blocks does not exceed about 3,250 Da, 3,500 Da, 4,000 Da, 4,250 Da, 4,500 Da, 4,750 Da, 5,000 Da, 5,250 Da, 5,500 Da, 5,750 Da, 6,000 Da, 6,250 Da, 6,500 Da, 6,750 Da Da, 7,000 Da, 7,250 Da, 7,500 Da, 7,750 Da, 8,000 Da, 8,250 Da, 8,500 Da, 8,750 Da or 9,000 Da. In various embodiments, the molecular weight (Mn) of the hydrophilic block is about 1,000 Da to about 9,000 Da, about 1,500 Da to about 8,000 Da, about 3,000 Da to about 8,000 Da, about 4,000 Da to about 8,000 Da, about 4,000 Da to about 7,500 Da, about 4,000 Da to about 7,500 Da, about 4,500 Da to about 9,000 Da, or about 4,000 Da to about 10,000 Da.

[0062] In various embodiments, the amphiphilic copolymer comprises hydrophilic and hydrophobic blocks in a ratio, based on number average molecular weight, of about 1:10 to about 10:1, about 1:100 to about 100:1, about 1:5 to about 5:1, about 1:20 to about 20:1, about 30:1 to about 1:30, about 1:2 to about 2:1, about 3:1 to about 3:1, about 4:1 to about 1:4, about 6:1 to about 1:6, about 1:7 to about 7:1, about 8:1 to about 1:8, or about 9:1 to about 1:9. In various embodiments, the amphiphilic copolymer comprises hydrophilic and hydrophobic blocks in a ratio, based on number average molecular weight, of about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. Without being limited by any theory, hydrophobic polymers are preferred over hydrophilic polymers for more effectively encapsulating cannabinoids within suitable micelles, while hydrophilic polymers impart water solubility to the composition.

[0063] In various embodiments, the hydrophilic component of the amphiphilic copolymer is polyethylene glycol (PEG), and the hydrophobic component is selected from polycaprolactone, polylactic acid, and polylactide co-glycolic acid (PLGA). In some embodiments, the composition is prepared and dispensed as a liquid or powder and then lyophilized. In other embodiments, the powder and lyophilized formulation are reconstituted prior to dispensing.

[0064] It has been recognized in this art that drug delivery via olfactory mucosa or mucous membranes is a feasible route for delivering certain drugs. Formulations for intranasal delivery of cannabinoids offer several advantages over oral dosage forms, such as enabling direct absorption of the drug through a mucosal lining with a highly vascularized blood supply, resulting in faster onset of action and bypassing the blood-brain barrier (Ganger and Schindowski, "Tailoring Formulations for Intranasal Nose-to-Brain Delivery: A Review on Architecture, Physico-Chemical Characteristics and Mucociliary Clearance of the Nasal Olfactory Mucosa", Pharmaceutics, 10:116 (2018)). Furthermore, intranasal drug delivery avoids problems associated with first-pass metabolism. Therefore, intranasal delivery can be advantageous when rapid onset of action, better efficacy, and bypassing the blood-brain barrier are desired. For patients who have difficulty swallowing or suffer from vomiting and anorexia, intranasal delivery of medications can produce better compliance than oral forms (such as tablets or capsules).

[0065] In some embodiments of the present invention, the pharmaceutical composition is suitable for intranasal or nasal delivery, or delivery by inhalation.

[0066] In various embodiments, devices suitable for intranasal delivery include spray pumps, metered-dose pumps or inhalers, pressurized nebulizers or inhalers, nebulizers, sprayers, aerosol devices, or any device suitable for intranasal or nasal inhalation delivery of liquid or powder compositions. In a preferred embodiment, the pharmaceutical composition is a liquid that may or may not be reconstituted from a powder, and the powder may or may not be lyophilized. In another preferred embodiment, the liquid system is delivered by a device including a spray pump. Excipients

[0067] In various embodiments, excipients suitable for intranasal delivery may be added to the compositions or formulations of the present invention. Typically, excipients are used to improve the characteristics of the composition, such as by providing more efficient and reproducible therapeutic delivery, improving the handling characteristics of the powder (e.g., flowability and consistency), the stability of the formulation, and / or facilitating the manufacture and filling of unit dosage forms. In some embodiments, the excipient material is used to further improve the physical and chemical stability of cannabinoids, help the formulation adhere to or bind to the nasal mucosal layer and enhance cannabinoid uptake into mucosal cells, thereby increasing the potency of the cannabinoids. Excipients may further be used to minimize residual moisture content and / or prevent moisture uptake, minimize particle aggregation, alter particle surface properties (i.e., roughness), increase ease of delivery, and improve particle targeting to sinuses. In some embodiments, excipients are also used as build-up agents when it is desired to reduce the concentration of cannabinoids in the formulation. Additionally, excipients may be used as masking agents for unpleasant odors and / or tastes.

[0068] Useful excipients that can be added to the compositions and formulations of the present invention include (but are not limited to) mucosal adhesives (e.g., crosslinked polyacrylic acid, carboxymethyl cellulose, carboxymethyl cellulose, alginate, chitosan, polyacrylic acid, hyaluronic acid, carbomer, hydroxypropyl cellulose, methyl cellulose, polyelectrolytes and their derivatives), fluidizing agents, lubricants (e.g., magnesium stearate), adhesives, surfactants, acidifiers, alkalizing agents, pH adjusters, antimicrobial preservatives (e.g., lipophilic preservatives, chlorobutanol, hydroxybenzoates, methylparaben, propylparaben, chlorobutanol, phenylmercuric acetate, thimerosal, benzalkonium chloride). Excipients include chlorides, menthol, eucalyptolxylomethazoline, oxymethazoline and various combinations thereof, absorption enhancers (e.g., cyclodextrins, bile salts, lauryl ether-9 sulfate, fusidic acid derivatives, fatty acids, hydrophilic polymers, surfactants, β-cyclodextrins and the like), antioxidants, antistatic agents, buffers or pH adjusters, chelating agents, humectants, gelling agents or wetting agents. Excipients also include colorants, coating agents, sweeteners, flavoring agents and fragrances and other masking agents.

[0069] In some embodiments, the compositions and formulations of the present invention comprise formulations containing individual excipients or multiple excipients in any suitable combination. In some embodiments, a fluidizing agent is added to the composition to improve its flowability. Typically, fluidizing agents help prevent the composition from agglomerating or clumping and allow for improved powder handling. The use of fluidizing agents can increase capsule filling efficiency and consistency, and increase the dosing consistency and efficiency of nasal delivery devices. Examples of fluidizing agents include calcium phosphate, magnesium stearate, or anhydrous silicate disclosed in U.S. Patent No. 5,098,907. Fluidizing agents can be used alone or in combination. In some embodiments, calcium phosphate is used.

[0070] pH adjusters include, for example, disodium hydrogen phosphate, citric acid, and sodium citrate. Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​salt, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like, while examples of oil-soluble antioxidants include ascorbate palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like. Examples of preservatives include, for example, benzyl ammonium chloride.

[0071] Suitable antistatic agents may be selected from, for example, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, sodium dioctyl sulfosuccinate, and fatty amine salts of alkyl aryl sulfonic acids. Suitable antistatic agents are also disclosed in International Application WO 94 / 04133.

[0072] In some embodiments, the adhesive is a bioadhesion promoter and / or a mucosal adhesion promoter. In some embodiments, the adhesive is a carrier particle, while in other embodiments, the adhesive coats the carrier particle or a therapeutic agent. Alternatively, the adhesive may be added to the formulation in its free state, unbound to a carrier or drug. Bioadhesion promoters and / or mucosal adhesives enhance the adhesion of one or more therapeutic agents to the nasal mucosa. Typically, bioadhesion promoters and / or mucosal adhesion promoters swell and expand when placed in contact with water.

[0073] Typically, bioadhesion promoters and / or mucosal adhesion promoters are polymeric substances that can be hydrated to cause the polymer to swell. Generally, the faster the polymer swells, the faster the initiation of bioadhesion and / or mucosal adhesion. Exemplary bioadhesion promoters and / or mucosal adhesion promoters are disclosed in U.S. Patent Application No. 20060216352, the disclosure of which is incorporated herein by reference to provide examples of bioadhesion promoters and / or mucosal adhesion promoters. Examples of bio / mucosal adhesion promoters include polymers, such as cellulose (e.g., microcrystalline cellulose), cellulose derivatives, starch, starch derivatives, crosslinked polymers based on, for example, starch, cellulose, polyvinylpyrrolidone, and various combinations thereof. In addition, inorganic salts can be used as bio / mucosal adhesion promoters; for example, as calcium phosphate, dicalcium phosphate hydrate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium carbonate, barium sulfate, and various combinations thereof. Other specific, non-limiting examples of biological / mucosal adhesion promoters include cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), methylcellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, and sodium carboxymethyl cellulose (NaCMC); starch derivatives such as moderately cross-linked starch; acrylic polymers such as carbomer and its derivatives (polycarbophyl, Carbop®, etc.); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, pectin; stearin; xanthan gum; guar gum; poly-(methyl vinyl ether / maleic anhydride); and cross-linked carboxymethyl cellulose; and various combinations thereof.

[0074] Examples of pH adjusters include magnesium hydroxide and aluminum hydroxide. Examples of chelating agents include citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid. Useful surfactants include cholic acid surfactants or phosphatidylcholine (e.g., dipalmitoylphosphatidylcholine), diphosphatidylglycerol, cetyl alcohol, fatty alcohols (e.g., polyethylene glycol), polyoxyethylene-9-lauryl ether, surfactant fatty acids (e.g., palmitic acid or oleic acid), or other surfactants as disclosed in U.S. Patent No. 5,855,913.

[0075] In some embodiments of the present invention, a water-absorbing and gel-forming material is added to the composition to improve drug absorption. Typically, this gel-forming material is used as a carrier, alone or in combination with a water-absorbing but non-gel-forming substance. Exemplary gel-forming materials include, for example, cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose. Further disclosures of water-absorbing and gel-forming materials and their uses can be found in U.S. Patent No. 6,835,389.

[0076] Representative examples of wetting agents include, for example, gelatin, casein, lecithin (phospholipid), gum arabic, cholesterol, tragacanth gum, stearic acid, benzyl ammonium chloride, calcium stearate, glyceryl monostearate, cetearyl alcohol, polysitropyl emulsion wax, sorbitan ester, polyoxyethylene alkyl ether (e.g., polyethylene glycol ether, e.g., polysitropyl alcohol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., TWEEN™), polyethylene glycol, polyoxyethylene stearate, colloidal silica, phosphate ester, sodium lauryl sulfate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).

[0077] Useful sweeteners include, for example, D-sorbitol, licorice, saccharin and stevia.

[0078] Typically, the amount of pharmaceutical excipients (if present) ranges from about 0.01% by weight to about 95% by weight. More typically, the excipients range from about 0.5% by weight to about 80% by weight, about 1.0% by weight to about 50% by weight, or about 5% by weight to about 30% by weight of the composition.

[0079] Therapeutic agents, carriers, excipients, and other components may require grinding, milling, spray drying, or other processing steps before use. Typically, the required processing transforms the therapeutic agent into particles having a desired median size and / or a defined particle size distribution range. In some embodiments, natural or processed therapeutic agents, carriers, excipients, and other components are suitable for intranasal use as is. In other embodiments, these components require further processing, such as sieving, to achieve a desired or desired particle size distribution. Manufacturing Method

[0080] In one embodiment, the present invention provides a method for manufacturing cannabinoids encapsulated in polymeric micelles using a drying or solvent evaporation method. For a discussion of drying or solvent evaporation methods and alternative methods for encapsulating drugs using polymeric micelles, see Cholkar et al., Recent Patents on Nanomedicine, 2:82-95 (2012), the contents of which relating to methods and materials for encapsulating drugs using polymeric micelles are incorporated herein by reference. The solvent evaporation method involves dissolving an amphiphilic copolymer and cannabinoids in a solvent, and then evaporating the solvent to produce a film containing cannabinoids and the amphiphilic copolymer. The film is then rehydrated using a preheated aqueous solution or water, causing polymeric micelles encapsulating the cannabinoids to spontaneously form. The method may include, as appropriate, a sonication or filtration step to ensure uniform particle size and / or remove unencapsulated drug. Therefore, in various embodiments, the manufacturing method includes contacting cannabinoids with an amphiphilic copolymer in a solvent, then preparing a dried film containing cannabinoids and the amphiphilic copolymer, and finally contacting the dried film with water or an aqueous solution to prepare a rehydrated composition containing cannabinoids encapsulated by polymeric micelles.

[0081] In various embodiments, the manufacturing method further includes sonicating the rehydrated composition to produce a cannabinoid suspension encapsulated in polymeric micelles. In various embodiments, the manufacturing method further includes filtering the cannabinoid suspension encapsulated in polymeric micelles. In some embodiments, the filtration is carried out using a filter with an average pore size of about or at least about 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 350 nm, 400 nm, or 450 nm. In some embodiments, the filtration system uses a filter with an average pore size not exceeding about 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 350 nm, 400 nm, 450 nm, or 500 nm. In various embodiments, the filter has an average pore size of about 100 nm to about 500 nm, about 50 nm to about 500 nm, about 200 nm to about 300 nm, or about 120 nm to about 320 nm. In various embodiments, the filter is a nylon membrane filter.

[0082] In various embodiments, contacting the cannabinoid with the amphiphilic copolymer includes dissolving the cannabinoid and the amphiphilic copolymer together in a solvent. In various embodiments, the solvent is an organic or inorganic solvent. In various embodiments, the solvent is dichloromethane, acetonitrile, or methanol. In some embodiments, the manufacturing method further includes removing the solvent. The solvent may be removed by an evaporation process including evaporation under vacuum or partial vacuum. In various embodiments, the concentration of the amphiphilic copolymer in the solvent is about 8 mg / ml to about 16 mg / ml, about 1 mg / ml to about 20 mg / ml, about 1 mg / ml to about 100 mg / ml, about 0.8 mg / ml to about 160 mg / ml, about 5 mg / ml to about 20 mg / ml, or about 5 mg / ml to about 50 mg / ml.

[0083] In some embodiments, contacting the cannabinoid with the amphiphilic copolymer includes contacting the cannabinoid with the amphiphilic copolymer at a specific ratio (by weight) of cannabinoid to amphiphilic copolymer, C:A. In various embodiments, the C:A ratio is about 1:50 to about 50:1, about 1:40 to about 40:1, about 1:30 to about 30:1, about 1:20 to about 20:1, or about 1:10 to about 10:1. In various embodiments, the C:A ratio is about 1:20. In various embodiments, the C:A ratio is about 1:10 to about 1:30, about 1:5 to about 1:50, about 1:15 to about 1:30, about 1:15 to about 1:50, about 1:20 to about 1:40, about 1:20 to about 1:50, or about 1:20 to about 1:100. In various embodiments, the C:A ratio is selected to ensure maximum encapsulation of the cannabinoid by the amphiphilic copolymer.

[0084] In some embodiments, the manufacturing method includes freeze-drying a suspension of cannabinoids encapsulated in polymeric micelles. In various embodiments, freeze-drying produces a powder of cannabinoids encapsulated in polymeric micelles. The powder of cannabinoids encapsulated in polymeric micelles can be resuspended in a solution, aqueous solution, or water to produce a dosage form containing cannabinoids encapsulated in polymeric micelles.

[0085] In various embodiments, polymeric micelles encapsulating cannabinoids can be prepared according to the method provided in US 8,629,177, which includes the steps of: 1) dissolving the amphiphilic copolymer and Δ9THC in a supercritical, critical, or near-critical carbon dioxide fluid, and 2) injecting the carbon dioxide fluid mixture into a degassed solution containing a crosslinking agent (e.g., polyvinyl acetate (PVA)) in a buffer solution to form particles or spheres.

[0086] In various embodiments, the manufacturing method of the present invention is simplified by omitting the step of using supercritical fluids, compared to the method of US 8,629,177. Additionally, in various embodiments, the composition does not contain polyvinyl acetate (PVA), crosslinking agents, or curing agents. Furthermore, in various embodiments, the manufacturing method does not include curing or crosslinking steps.

[0087] In some embodiments, polymeric micelles are formed by simple dissolution, dialysis, oil-in-water emulsion, lyophilization or freeze-drying, solvent evaporation or various combinations thereof.

[0088] In various embodiments, the composition comprising cannabinoids encapsulated in polymeric micelles does not contain heptane or isopropanol.

[0089] In various embodiments, the method includes physically trapping cannabinoids within the core of polymeric micelles formed from amphiphilic copolymers. Dosage Form

[0090] In one embodiment, the present invention provides a dosage form comprising a therapeutically effective amount of cannabinoid encapsulated in polymeric micelles.

[0091] In various embodiments, the dosage form comprises about or at least about 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, or 15 mg of cannabinoids. In various embodiments, the dosage form comprises no more than about 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, or 15 mg of cannabinoids. In some embodiments, the dosage form comprises about 1 mg to about 15 mg of cannabinoids. In various embodiments, the dosage form is a liquid and contains cannabinoids at concentrations of about 0.1 mg / ml to about 16 mg / ml, about 1 mg / ml to about 5 mg / ml, about 1 mg / ml to about 10 mg / ml, or about 0.1 mg / ml to about 10 mg / ml.

[0092] In various embodiments, the dosage form is a liquid, a liquid suspension, or a powder. In various embodiments, the powder comprises lyophilized polymeric micelles encapsulating a therapeutically effective amount of cannabinoids.

[0093] In some embodiments, the dosage form is suitable for intranasal delivery. In certain embodiments, the dosage form is suitable for delivery by inhalation. In various embodiments, the dosage form comprises a suspension of polymeric micelles encapsulating cannabinoids in water, an aqueous solution, or a polar solvent.

[0094] In some embodiments, the dosage form is a liquid suspension, a suspension, an emulsion, or a multiphase composition. In various embodiments, the dosage form comprises an isotonic saline solution and a pharmaceutically acceptable buffer. In various embodiments, the dosage form is an aqueous liquid suspension comprising polymeric micelles encapsulating a therapeutically effective amount of cannabinoids.

[0095] Cannabinoid formulations encapsulated in polymeric micelles are advantageously less prone to abuse (e.g., heating or inhaling the formulation when inhaling cannabinoids). Advantageously, the use of intranasal formulations allows cannabinoids to reach the brain via an effective and rapid route, avoiding lung and stimulant or other forms of poisoning.

[0096] In various embodiments, the dosage form is formulated to penetrate nasal mucus and adhere to the local epithelium to minimize mucociliary clearance and promote maximum intranasal cannabinoid uptake. In various embodiments, the dosage form targets the nasal mucosa or olfactory mucosa.

[0097] In various embodiments, the dosage form is intended to deliver the powder to the nose via inhalation. The powder may be disposed in a container (e.g., a hard gelatin capsule or blister pack) or a multi-dose device. The capsule or blister may be broken or torn within the inhaler device (discussed further below), thereby enabling the inhalation of the powder.

[0098] In various embodiments, the dosage form comprises an inert carrier or excipient. In various embodiments, the dosage form comprises about 0.1% to about 2.0%, about 0.1% to about 99.9%, about 0.1% to about 95%, about 0.1% to about 90%, about 0.1% to about 50%, about 95% to about 99.99%, about 97% to about 99.9%, or about 75% to about 99.9% by weight of an inert carrier or excipient.

[0099] In various embodiments, the dosage form includes any of a variety of other pharmaceutically active compounds known in the art, which may have an additive or synergistic effect when administered in combination with cannabinoids. For example, in some embodiments, cannabinoids are delivered simultaneously with analgesics (e.g., opioids, in embodiments treating acute pain without causing respiratory depression). In other embodiments, cannabinoids are delivered simultaneously with melatonin, caffeine, or vitamin B12. Treatment methods and administration methods

[0100] In one embodiment, the present invention provides a method for treating pain and neurological disorders. In various embodiments, the neurological disorder is Alzheimer's disease. The method includes administering a composition to a patient in need, the composition comprising a therapeutically effective amount of cannabinoid or a pharmaceutically acceptable salt or solvate thereof, and an amphiphilic copolymer comprising at least one hydrophilic component and at least one hydrophobic component. The cannabinoid is encapsulated in polymeric micelles formed from the amphiphilic copolymer. The composition is suitable for nasal, intranasal, or inhalation delivery.

[0101] In various embodiments, the therapeutically effective amount of cannabinoid is an amount that can effectively treat Alzheimer's disease in an individual identified as needing it. In various embodiments, the therapeutically effective amount of cannabinoid produces an observable or quantifiable reduction in β-amyloid plaques in the individual administered the cannabinoid. In various embodiments, the therapeutically effective amount of cannabinoid reduces signs or symptoms of Alzheimer's disease in the individual administered the cannabinoid composition. For example, in some embodiments, there is a reduction in amyloid β-protein aggregation in the brain. In some embodiments, there are indications of improved memory in the individual. The individual may exhibit improved short-term memory, less anxiety, and relief of sleep symptoms.

[0102] In various embodiments, the therapeutically effective amount of cannabinoid is a daily dose of about or at least about 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, or 35 mg. In various embodiments, the therapeutically effective dose of cannabinoids is a daily dose of less than 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, or 35 mg. In various embodiments, the daily dose of cannabinoids is about 1 mg to about 35 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, or about 1 mg to about 2.5 mg. In various embodiments, cannabinoids are administered once daily (QD). In various embodiments, cannabinoids are administered twice daily (BID).

[0103] In various embodiments, the composition comprising cannabinoids is administered to treat any disease of an individual to whom the cannabinoids are applicable. In some embodiments, the composition may be administered to pediatric patients under the age of 18 or adults 18 years of age or older.

[0104] In various embodiments, administration of the composition can target cannabinoids to the brain. In some embodiments, administration of the composition can preferentially deliver cannabinoids to a specific brain region. In various embodiments, the specific brain region is the olfactory complex, entorhinal cortex, hippocampus, frontal cortex, or posterior cortex. In various embodiments, preferential delivery to the specific brain region is measured as a higher concentration of cannabinoids or their metabolites in the specific brain region than in an alternative brain region after 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 45 min, 1 hour, 2 hours, or combinations thereof. In various embodiments, administration of the composition results in a higher concentration of cannabinoids or their metabolites in the brain than in the blood after 5 min, 10 min, 20 min, 25 min, 30 min, 45 min, 1 hour, or 2 hours.

[0105] In various embodiments, administration of the composition to an individual can produce a controlled metabolic treatment of the cannabinoids over time. In some embodiments, the controlled metabolic treatment includes a slower rate of cannabinoid conversion to its metabolites relative to a composition not containing polymeric micelle encapsulated cannabinoids. In various embodiments, the controlled metabolic treatment is measured as a higher concentration of OH-THC in a specific brain region, in the brain, or in the blood than COOH-THC after 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 1 hour, or 2 hours.

[0106] In various embodiments, treatment outcomes, including relief of symptoms associated with any of the disorders listed above, were observed approximately 15 min, 20 min, 25 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 12 hours, or 24 hours after administration of the composition. In some embodiments, treatment outcomes included dissolution of β-amyloid plaques, improvement of memory, inhibition of β-amyloid synthesis, inhibition of plaque formation, or downregulation of GSK-3β and / or pGSK-3β, or relief of symptoms associated with any of the disorders listed above.

[0107] In various embodiments, the compositions of the present invention are delivered intranasally. Intranasal administration of cannabinoids advantageously allows them to bypass the blood-brain barrier. Intranasal administration of the composition maximizes the chances of cannabinoids reaching the brain.

[0108] In various embodiments, a device for intranasal delivery of the composition is used to deliver the composition to an individual. In various embodiments, the device for intranasal delivery is a nasal pump spray or a dropper. In some embodiments, the composition is delivered intranasally by inhalation of a liquid- or powder-based aerosol. In some embodiments, the device is an electro-nebulizer or a two-way respiratory-powered nasal delivery device. In some embodiments, the device is OPTIMIST (Djupesland et al., Laryngoscope, 116:466-72 (2006), the disclosure of which is incorporated herein by reference to provide examples of intranasal delivery devices) or VIANASE (Giroux et al., Drug Delivery Technology, 5:44-49 (2005), the disclosure of which is incorporated herein by reference to provide examples of intranasal delivery devices). In some embodiments, the device is a precision olfactory delivery (POD) device (Shrewsbury et al., Headache, 59:394-409 (2019)). In various embodiments, the device delivers the composition into the upper nasal cavity. In various embodiments, the device is a squeeze bottle or a manual or electric intranasal pump dispenser. In various embodiments, the delivery device includes a nebulizer or a pressurized aerosol generator. In various embodiments, the delivery device delivers liquid or powder to the nasal mucosa.

[0109] In various embodiments, the composition comprises a propellant. In some embodiments, the propellant is a hydrofluoroalkane (HFA). HFA propellants are volatile, non-toxic, non-flammable, and environmentally friendly, making them excellent delivery media for aerosol formulations. In some embodiments, the propellant is selected from hydrofluoroalkanes selected from 1,1,1,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) and combinations thereof.

[0110] In various embodiments, administering polymeric micelle-encapsulated cannabinoids to an individual does not induce poisoning or a stimulating experience. Kit

[0111] This invention provides a kit for treating pain and neurological disorders. The kit includes, as appropriate, one of the compositions or dosage forms described above, arranged within a suitable delivery device. The delivery device is a means for intranasal delivery, such as the device described above. In various embodiments, the kit includes a specification explaining the method and frequency of intranasal administration of the composition. In various embodiments, the kit includes information relating to the safety and composition of the composition arranged within the delivery device.

[0112] In various embodiments, the kit comprises a lyophilized powder containing cannabinoids encapsulated in polymeric micelles. In some embodiments, the kit comprises a solution of cannabinoids encapsulated in polymeric micelles suspended therein prior to dosing.

[0113] In some embodiments, the delivery device is a device for delivering lyophilized powder into the nose to an individual.

[0114] In some embodiments, the use of the kit includes suspending a lyophilized powder containing cannabinoids encapsulated in polymeric micelles in a solution or solvent, and, where appropriate, in a portion of the kit, to create a suspension, and then disposing of the suspension within a delivery device. Examples

[0115] The invention is also illustrated and demonstrated by the following examples. However, the use of such and other examples in any part of this specification is illustrative only and does not limit the scope or meaning of the invention or any of the illustrated terms. Similarly, the invention is not limited to any particular preferred embodiment described herein. Many modifications and variations of the invention will become apparent to those skilled in the art upon reading this specification, and such modifications can be made without departing from the spirit or scope of the invention. The invention is limited only to the appended claims, including the full scope of the equivalents granted by those claims.

[0116] Unless otherwise stated in a specific instance, the following materials and methods shall be used. Materials and Methods: Drug Administration

[0117] The cannabinoid Δ9-THC used as the active ingredient in these examples. In the following examples, a dose of 0.2 mg / kg was delivered to mice based on their body weight. (The appropriate dose for mice is typically about 0.2 mg / kg to about 0.3 mg / kg). The mice were selected from strains C57B6, SJL, and B6D2F1, or a mixture of these strains. Strain C57B6 is generally preferred, but any suitable mouse strain may be used. For example, 6.25 µL of one of the 1.6 mg / ml Δ9-THC formulations described below was administered to a 50 g mouse. If less than 3 μl of the 1.6 mg / ml liquid was administered to the mouse, the entire dose was delivered by aspirating into the left nostril within 1 second. If more than 3 μl was administered, the total volume of the 1.6 mg / ml Δ9-THC formulation was aspirated and then divided into two drops into the left nostril until the entire volume was dispensed. The Δ9-THC treatment dispensed from the straw tip is in a small volume, causing the liquid preparation to bubble at the straw tip and then enter the mouse's nasal cavity during inhalation. The straw tip never directly touches the mouse's nose.

[0118] To deliver a specific dose of drug, the mouse was gently grasped and stabilized by rubbing its neck, with its abdomen facing upwards. The mouse's nose was kept parallel to the horizontal plane. The preparation was then aspirated into a droplet at the end of a pipette tip. This droplet was then placed into the mouse's left nostril. The pipette tip itself never directly touched the mouse's nose. The mouse was held in place, with its nose kept parallel to the horizontal plane for 30 seconds. After 30 seconds, the mouse was returned to its cage. The same procedure described above was followed to administer a volume greater than 3 µl of the preparation, except that the preparation was aspirated into the nose as a single droplet until the entire volume greater than 3 µl had been administered. Liquid chromatography (LC) tandem mass spectrometry (MS / MS) (LC / MS / MS)

[0119] 5.0-5.5 mg of different brain tissue regions (anterior cortex (OFC), hippocampus (HPC), olfaction) were used for LC / MS / MS. 350-375 μL of whole blood was used for LC / MS / MS.

[0120] Samples were prepared for LC / MS / MS as follows. For brain tissue samples, the samples were thawed at 37°C and then milled in 200 µl of PBS for 30 s, followed by sonication at 60% power for 10 sec. The sonicated brain tissue samples were then diluted with approximately 600 µl of water to a final volume of 800 µl and transferred to a glass tube to produce a pre-sample. For whole blood samples, the samples were thawed at 37°C and then sonicated at 60% power for 10 s. The sonicated blood samples were transferred to a glass tube and diluted with water to a final volume of 800 µl to produce a pre-sample.

[0121] Then, 200 µl of 10% acetic acid was added to each pre-sample and vortexed. 2,000 µl of a 9:1 hexane:ethyl acetate solution was added to the resulting solution, and the mixture was then mixed on a vortex mixer for 45 min. The mixture was then centrifuged at 2,800 × g for 15 min at 15 °C. After centrifugation, the resulting upper (organic) layer was transferred to a 2 mL bottle and completely dried under nitrogen at 37 °C. The dried composition was then vortexed in 40 µl of a 50:50 acetonitrile:water solution to produce the prepared sample. The prepared sample was then analyzed by LC / MS / MS.

[0122] The prepared and calibrated samples were analyzed by LC / MS / MS at a flow rate of 0.45 ml / min and a final injection volume of 15 µl.

[0123] LC / MS / MS was performed using an Agilent Technologies 6460 triple quadrupole LC / MS (model G6460A). The following software was used: Agilent Technologies MassHunter workstation software LC / MS data acquisition 6400 series triple quadrupole version B.05.00, Build 5.0.5027.0 and Agilent Technologies MassHunter workstation software qualitative analysis version B.05.00, Build 5.0.519.0.

[0124] All LC / MS / MS results are based on concentrations in 40 µl of reconstituted sample and the mass or volume of brain tissue or blood used to prepare each sample. "Total drug" indicates the sum of Δ9-THC, OH-THC, and COOH-THC values ​​calculated for the sample. No Δ9-THC metabolites were detected in control mice at any time point evaluated in any experiment. Statistical Analysis

[0125] All statistical analyses were performed using Prism Graph Pad 8.0. The average size of the polymeric micelles was measured using dynamic light scattering (DLS).

[0126] DLS is used to measure the size distribution of polymeric micelles and nanoemulsion particles. The ZetaSizer nano series machine (nano-ZS90) is used in conjunction with ZetaSizer software to measure and calculate the size distribution.

[0127] The following protocol was followed to measure the size distribution of polymeric micelles using DLS. 100 µl of the polymeric micelle sample was diluted in 100 µl of distilled deionized water to produce a diluted sample. The diluted sample was loaded into a DLS colorimetric tube and inserted into the Zetasizer nanosystem. The Zetasizer application was then performed using the following parameters: Measurement = Manual; Measurement Type = Size; Dispersant Type = Water; Temperature = 25°C. A similar protocol was used to measure the size distribution of nanoemulsion particles.

[0128] Table 3 and Figure 1 below provide the results obtained by the above-described DLS method for representative samples of polymeric micelle-encapsulated Δ9-THC formulations prepared according to embodiments of the present invention. The average diameter of the polymeric micelles in the representative samples is approximately 142.6 nm. Table 3: Zetasizer application output of DLS measurements for representative samples of polymeric micelle-encapsulated Δ9-THC formulations prepared according to embodiments of the present invention. Dispersant name: Water Dispersant RI: 1.330 Material RI: 1.54 Viscosity (cP): 0.8872 Material absorption: 0.000 Temperature (°C): 25.0 Duration used (5): 150 Count rate (kcps): 40.9 Measurement location (mm): 4.65 Unit Description: Disposable quantitative colorimetric tube Attenuator: 11 Size (d.nm): strength%: St Dev (d.nm): Z-mean (d.nm): 129.9 Peak 1: 142.6 97.1 71.40 Pdl: 0.402 Peak 2: 5364 2.9 332.4 Intercept 0.972 Peak 3: 0.000 0.0 0.000 Result quality: Good Example 1 - Nanoemulsion formulation

[0129] In this example, Δ9-THC was added to the oil phase and then combined with the aqueous phase to form an emulsion. (THC is more soluble in oil than in water). The emulsion was sonicated to provide nano-sized particles. Table 1 provides compositions of oil-phase and aqueous-phase mixtures for preparing nano-emulsion formulations. Table 1 Element Approximate volume % (Total 20 ml) 20 ml batch size Δ 9 -THC 32 mg (0.219 ml) fish oil 10% 2.0 ml MCT 10% 2.0 ml Coconut oil 5% 1.0 ml Lecithin / Emulsifier 5% 1.0 g Methylparaben (pfaltz & Bause 5026-62-0) 1% 0.2 g Propylparaben (pfaltz & Bause 35285-69-9) 1% 0.2 g Pluronic F 68 (MP 2750016) 1% 0.2 g Glycerol (Fisher 56-81-5) 2.5% 0.5 ml PEG 400 (fisher p167-1) 5% 1.0 ml Purified water Approximately 66% Approximately 13.2 ml

[0130] To prepare the nanoemulsion formulation, an oil phase mixture was first prepared. Coconut oil (Carrington Farms, pure, unrefined, cold-pressed) was dissolved in a water bath at 37°C. 1.0 g of lecithin (Fisher, 03376-250, batch number 153621) was weighed out. 2 ml of MCT (Now Sports, 100% pure MCT oil) was added to the lecithin to produce the oil phase mixture. 2 ml of fish oil (Carlson the Finest Norwegian Fish oil, lemon flavor) was added to the oil phase mixture. Then, 1 ml of coconut oil was added to the oil phase mixture. The oil phase mixture was then stirred at 200 rpm in a 500 ml glass beaker at 37°C for 2 hours using a stirrer until all added components were dissolved. The beaker was covered with plastic wrap. Once the components of the oil phase mixture were dissolved, the mixture was immediately stirred at room temperature for approximately 12 hours (e.g., overnight). Then, 220 mg of Δ9-THC (1-7370-7554, 145.9 mg / ml stock solution) (corresponding to 32 mg Δ9-THC) was added to the oil phase mixture. The oil phase mixture was then stirred at 200 rpm at room temperature for 1 hour.

[0131] The aqueous phase mixture was then prepared by combining 1 ml of polyethylene glycol (PEG 400) (Sigma P-3265, lot number 81K0326), 0.5 ml of glycerol (Sigma G5516-1L, lot number SHBD3108V), 0.2 g of sodium methylparaben (Pfaltz and Bause, item number 506130, lot number 18552, catalog number 5026-62-0), 0.2 g of sodium propylparaben (Spectrum P1457, lot number 2EC0375), 0.2 g of Pluronic F68 (MP Biomedicals, A1288.0500, lot number 5X010736, CAS 9003-11-6), and enough water to bring the total volume of the aqueous phase mixture to 14 ml in a 50 ml conical tube. The aqueous phase mixture was shaken at room temperature for 30 minutes.

[0132] The oil-phase mixture and aqueous-phase mixture prepared as described above were then combined in a 50 ml conical tube to produce an emulsion composition. Water was added to the resulting emulsion composition to bring the total volume of the emulsion composition to 20 ml. The emulsion composition was then vortexed at maximum speed (VWR model: G560) for 20 minutes. The emulsion composition was then emulsified by three 11-minute sonication cycles in an ice bath, allowing the emulsion composition to cool between each 11-minute cycle. The sonication cycle produced a nano-emulsion formulation. The sonication scheme was a 54-second pulse on, a 6-second pulse off, and an amplitude of 90%. The sonic generator was a Fisher Scientific FB120 model: 120W, 120V, 50 / 60 Hz NOM, frequency: 20 kHz, full size: 3A SL0-BLD.

[0133] The final working concentration of Δ9-THC in the nanoemulsion formulation was 1.5 mg / ml in a 20 ml final volume. The nanoemulsion formulation was stored at 4°C. The average particle size of the nanoparticles was approximately 215.2 nm. Example 2 - Δ9-THC formulation encapsulated in polymeric micelles.

[0134] In this example, cannabinoids are encapsulated in an amphiphilic copolymer to form a "poly" composition. The polymeric micelle encapsulated Δ9-THC formulation was prepared using poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolic acid) (PEG-PLGA) (Sigma Aldrich. Catalogue No.: 764825-1G) with number-average molecular weights of PEG 2000 and PLGA 4500 (total average 6500).

[0135] The Δ9-THC formulation encapsulated in polymeric micelles was prepared as follows. The PEG-PLGA polymer, comprising PEG (Mn = 2000) and PLGA (Mn = 4500), was from Sigma-Aldrich, product number 764825. Δ9-THC (Sigma, catalog number: T4764-1ML) was dried at 37°C under nitrogen for 5 min or until completely dried (maximum 10 min). Then, 1 mg of Δ9-THC and 10 mg of the PEG-PLGA polymer were dissolved in dichloromethane (maximum 5-10 ml). The organic solvent was then removed by rotary evaporation under reduced pressure to form a dried film.

[0136] The dried membrane was hydrated with distilled water preheated to 50°C to produce a suspension. The suspension was then sonicated at 50% power for 10 min using a 10-second on-off cycle to produce encapsulated Δ9-THC polymeric micelles in solution form. The sonic generator used for sonication was a full-size 3A SL0-BLD Fisher Scientific FB120, 120W, 120V, 50 / 60 Hz NOM, 20 kHz sonic generator. Unincorporated reagents were separated by filtration through a 220 nm Nylon membrane (Novatech catalog number 371-2215-OEM), and the filtered micelle solution was characterized, freeze-dried, or both.

[0137] For freeze-drying, 0.5 ml of the filtered micelle solution was transferred to a 5 ml glass vial and frozen in a freeze dryer at -20°C. The frozen product was then freeze-dried at a negative pressure of 10 kPa for 2 hours to produce a freeze-dried product. After freeze-drying, the vial was stoppered and stored at 4°C.

[0138] A polymeric micelle-encapsulated Δ9-THC formulation was prepared by suspending the lyophilized product in water to a final concentration of 1.6 mg / ml Δ9-THC and then subjecting it to sonication using the sonication method and sonication generator described above until clarification. Example 3 - Water-based Δ9-THC formulation

[0139] A water-based liquid composition (50 ml batch) containing Δ9-THC was prepared by combining mixture I and mixture II as provided in Table 2. Table 2 Mixture I (90 vol% water-based formulation) Approximate volume % (total 20 ml) 45 ml stock solution batch quantity Polyethylene glycol 400 12% 6 ml Methylparaben 0.4% 0.2 g propylparaben 0.4% 0.2 g Sucralose 0.05% 25 mg Butylated hydroxyanisole 0.05% 25 mg Water(H2O) Approximately 87.1% Approximately 38.6 ml Mixture II (10 vol% water-based formulation) Approximate volume % (total 5 ml) 5 ml stock solution batch quantity Δ 9 -THC 550 ul 80 mg (550 μL) ETOH 1% 500 ul Propylene glycol 5.5% 2.75 ml H2O Approximately 93.5% Approximately 1.67 ml

[0140] To prepare a water-based Δ9-THC formulation, mixture I was prepared in a 50 ml conical tube by means of (a) 3.6 ml polyethylene glycol (PEG 400) (Sigma P-3265, lot number 81K0326), (b) 0.12 g sodium methylparaben (Pfaltz and Bause, item number 506130, lot number 18552, catalog number 5026-62-0), (c) 0.12 g sodium propylparaben (Spectrum P1457, lot number 2EC0375), (d) 15.0 mg 98% sucralose powder (Alpha Aesar J66736, lot number T21D050) and (e) 15.0 mg of butylated hydroxyanisole (MP catalog number 101159, batch number QR11576) was dissolved in water sufficient to bring the final volume of the resulting mixture I to 30 ml. This mixture was then mixed on a shaker at room temperature for 10 minutes.

[0141] Mixture II was prepared by combining (i) 54.8 µl of stock solution of Δ9-THC containing 145.9 mg / ml Δ9-THC in heptane / IPA (total 8.0 mg Δ9-THC) with (ii) 50 µl of ethanol, 275 µl of propylene glycol and (iii) 120.2 µl of water in a test tube. The resulting mixture II was then vortexed.

[0142] A water-based Δ9-THC formulation was then prepared by combining 4.5 ml of mixture I with approximately 0.5 ml of mixture II in a test tube to a final volume of 5 ml. The test tube was then inverted to mix and produce the water-based Δ9-THC formulation. The final concentration of Δ9-THC in the water-based Δ9-THC formulation was 1.6 mg / ml. Example 4 - Oil-based Δ9-THC formulation

[0143] In this example, an oil-based liquid Δ9-THC composition was prepared. The oil-based solution was obtained from Yunnan TIANFU Inc., China. This solution was a proprietary mixture of tea extract, walnut extract, lingzhi mushroom, and coffee extract. 5.5 µl of Δ9-THC stock solution containing 145.9 mg / ml Δ9-THC in heptane / IPA (total 800 µg Δ9-THC) was added to 494.5 µl of the proprietary mixture to produce an oil-based Δ9-THC formulation. The oil-based Δ9-THC formulation was inverted approximately 5 times to mix. Example 5 - Naked Δ9-THC Formulation

[0144] The "naked" Δ9-THC formulation was prepared as follows. The Δ9-THC solution in heptane / IPA was obtained from Rhodes Technologies (1-370-7554) at a concentration of 14.6%. The Δ9-THC solution in heptane / IPA was diluted in PBS to a final concentration of 1.5 mg / µl. Example 6 - Administration of the Δ9-THC formulation to mice

[0145] Experiments were conducted to compare the distribution of Δ9-THC and Δ9-THC metabolites in mice after administration of each of the four compositions (or, “treated with each of the four compositions”): (1) naked Δ9-THC formulation (naked), (2) oil-based Δ9-THC formulation (oil), (3) water-based Δ9-THC formulation (liquid), and (4) nanoemulsion formulation (nano). Mice were killed 15 min, 30 min, 45 min, and 2 hr after administration of each formulation. Blood samples (375 µl) were collected by endocardial puncture, and the brain was removed and dissected into different regions: the olfactory cortex (OFC), the anterior and posterior cortex (collectively referred to as CTX), and the hippocampus (HPC). Each brain tissue sample was 5.5–5.5 mg.

[0146] Six mice were administered each of the five formulations (n=6 for each formulation), and no formulation was administered to a control group (n=3). Each formulation was delivered intranasally. Measurements were taken 15 minutes after formulation administration.

[0147] All Δ9-THC formulations produced detectable drug levels 15 minutes after intranasal administration, see Figures 2A-2C. Liquid Δ9-THC formulations produced higher total drug levels than oil-based formulations; however, there were no significant differences between liquid formulations and any other formulation, or between any other formulation (n=6, p<0.05), see Figure 2A. There were also no significant differences in detectable drug levels in the brain among the formulations after 15 minutes (n=6, p<0.05), see Figure 2B. After 15 minutes, there were no significant differences among formulations in CTX or HPC, see Figure 2C. However, in OFC, the total drug level in the nanoemulsion group was significantly higher than that of naked Δ9-THC, liquid Δ9-THC, and oil-based Δ9-THC (p<0.05), see Figure 2C.

[0148] Compared with other formulations, liquid-THC formulations showed higher levels of Δ9-THC to OH-THC conversion in whole blood than naked Δ9-THC formulations, nanoemulsion Δ9-THC formulations (n=6, p<0.01), and oil-based Δ9-THC (see Figure 3A). The higher level of Δ9-THC to THC-OH conversion is a drawback of liquid formulations. There was no significant difference in the conversion of Δ9-THC to its metabolites in brain tissue between any of the formulations (see Figure 3B).

[0149] After 15 minutes, in all five compositions, most of Δ9-THC was converted to THC-OH, with trace amounts of THC-COOH and Δ9-THC remaining (n=6, p<0.001). See Figure 4. Measurements were performed 30 minutes after formulation administration.

[0150] All Δ9-THC formulations produced detectable total drug levels 30 min after intranasal administration. There were no significant differences in total drug levels detected in the blood, brain, or between brain regions among the formulations (n=6, p<0.05), as shown in Figures 5A-5C.

[0151] After 30 minutes, there was no significant difference in the conversion of Δ9-THC to its metabolites in whole blood between any two groups (see Figure 6A). Trace amounts of residual Δ9-THC, some THC-OH, and increased amounts of THC-COOH were present (see Figure 6A). In brain tissue, nano-THC treatment showed significantly higher levels of THC-COOH than naked Δ9-THC (p < 0.01) and oil-based Δ9-THC formulations (p < 0.05) (see Figure 6B).

[0152] The naked Δ9-THC formulation showed a significant conversion of Δ9-THC to THC-OH (p < 0.05), see Figure 7. After 30 minutes, treatment with the nanoemulsion formulation showed a significant conversion of Δ9-THC to THC-COOH. This is an observed drawback associated with the nanoemulsion formulation. Measurements were taken 45 minutes after formulation administration.

[0153] The total drug level was detectable 45 min after intranasal administration for all Δ9-THC formulations, see Figures 8A-8C. There was no significant difference in the measured total drug level among the formulations (n=6, p<0.05), see Figures 8A-8C.

[0154] Treatment with the naked Δ9-THC formulation showed significantly higher COOH-THC conversion than liquid and polymer-encapsulated Δ9-THC (n=6, p<0.01), see Figure 9A. Animals treated with the nano-emulsion formulation showed higher Δ9-THC-THC-OH conversion in brain tissue than animals treated with other formulations (n=6, p<0.05), see Figure 9B. Treatment with the nano-emulsion formulation in brain tissue also produced significantly higher Δ9-THC-THC-COOH conversion than naked treatment (n=6, p<0.05), see Figure 9B.

[0155] Nanotherapy produced a significant conversion between Δ9-THC and THC-OH and THC-COOH (n=6, p<0.05 and p<0.001, respectively), see Figure 10. Liquid therapy also produced a significant conversion between Δ9-THC and THC-OH and THC-COOH (n=6, p<0.05 and p<0.01, respectively), see Figure 10. Measurements were taken 2 hours after formulation administration.

[0156] All treatments produced detectable total drug levels 2 hours after intranasal administration, see Figures 11A-11C. 2 hours later, there was a significant difference in the total drug levels measured in the blood between liquid and oil treatments, with liquid treatment producing higher total drug levels (n=6, p<0.05), see Figure 11A.

[0157] In whole blood, the oil-based formulation produced significantly higher THC-COOH conversion than all other formulations, see Figure 12A. This is an observed drawback of the oil-based formulation. After 2 hours, the naked formulation produced significantly higher THC-OH conversion than the nano-formulation and liquid formulation (n=6, p<0.05), see Figure 12B.

[0158] Treatment with the naked formulation resulted in a significant conversion of Δ9-THC to OH-THC (n=6, p<0.001), see Figure 13. Treatment with the nano-formulation, liquid formulation, and oil formulation resulted in significant conversion of Δ9-THC to both THC-OH and THC-COOH. After 2 hours, the oil formulation treatment resulted in the least conversion of Δ9-THC to THC-OH, see Figures 14A and 14B. Example 7. Administration of Δ9-THC encapsulated in polymeric micelles to mice.

[0159] Experiments were conducted to compare the distribution of Δ9-THC and Δ9-THC metabolites in mice after administration of the following formulations (alternatively, "treatment with the formulations"): polymeric micelle-encapsulated Δ9-THC formulations (polymer-THC) and naked Δ9-THC formulations (naked THC). Mice were euthanized 30 min after administration of each formulation. Blood samples (350 µl) were collected by endocardial puncture, and the brain was removed and dissected into different regions (olfactory (OFC), anterior cortex, posterior cortex (collectively referred to as CTX), and hippocampus (HPC)). Each brain tissue sample was 5.0–6.0 mg. Mice administered the formulations were 5-month-old mice (strains C57B6, SJL, and B6D2F1) from a mixed background.

[0160] Four mice were given each of the two formulations (n=4 for each formulation), and no control mice (n=4) were given either of the two formulations. The formulations were each delivered intranasally.

[0161] After 30 minutes, the total drug levels in the blood measured by polymer-THC treatment were significantly higher than those measured by treatment with naked THC formulations (p < 0.01), see Figure 16A. The blood Δ9-THC level produced by polymer-THC treatment was also significantly higher than that produced by naked THC treatment (p < 0.001), see Figure 16A, and the brain Δ9-THC level was higher than that produced by naked THC treatment, see Figure 16B. Furthermore, after 30 minutes, the levels of Δ9-THC to OH-THC and COOH-THC conversion produced by polymer-THC treatment in both the blood and brain were lower than those produced by naked THC treatment, see Figures 16A and 16B.

[0162] After 30 minutes, both treatments resulted in very little Δ9-THC conversion to THC-COOH (p < 0.05), and OH-THC conversion was detectable. After 30 minutes, as a percentage of total drug, polymer-THC treatment produced significantly more Δ9-THC than OH-THC or COOH-THC (p < 0.01). Compared to naked THC treatment, polymer-Δ9-THC treatment produced less Δ9-THC to OH-THC or COOH-THC conversion.

[0163] Examples 2 and 7 demonstrate the successful production of stable copolymer micelles encapsulating Δ9-THC, using certain hydrophilic and hydrophobic polymers to form a water-soluble carrier of cannabinoids (Example 2), and the successful delivery of stable polymeric micelles encapsulating Δ9-THC to mammals (Example 7). The polymeric micelles encapsulating Δ9-THC were successfully delivered to the brain. The polymeric micelles facilitated drug delivery and increased drug bioavailability in the brain. Δ9-THC can often be difficult to process and is a viscous substance, which can lead to difficulties in drug dosing and dosage measurement. Therefore, water-soluble stable polymeric micelles encapsulating Δ9-THC are a more manageable drug delivery alternative to naked THC. Encapsulating Δ9-THC in polymeric micelles allows Δ9-THC to become water-soluble and delivered to patients in a manner consistent with naked THC. Based on Examples 6 and 7, compared with other formulations evaluated, polymeric micelle formulations encapsulating Δ9-THC achieve the best balance of minimal components, ease and simplicity of manufacturing, and clinically relevant outcomes (e.g., metabolite control and delivery rate).

[0164] The polymeric micelle encapsulated Δ9-THC formulation (Example 2) exhibits superior efficacy in several aspects. First, at 30 minutes, the polymeric formulation demonstrates higher metabolic stability of Δ9-THC than naked Δ9-THC, as evidenced by the slow conversion of Δ9-THC to its metabolites (Figures 16-17). See also Figures 5-6. Second, compared to naked Δ9-THC, the polymeric formulation delivers Δ9-THC more efficiently to the blood and brain (Figure 15A). See also Figures 4A-4B. Third, the polymeric formulation shows selective delivery of Δ9-THC to the olfactory cortex and / or hippocampus, while naked THC does not show selective delivery to any brain region or preferential delivery to the frontal cortex. See Figures 15C and 4C.

[0165] The scope of this invention is not limited to the specific embodiments described herein. In fact, various modifications to the invention will become apparent to those skilled in the art from the foregoing description and drawings, in addition to the modifications described herein. Such modifications are intended to fall within the scope of the appended claims. It should be further understood that all values ​​are approximate and provided for descriptive purposes.

[0166] Unless otherwise indicated herein, the enumeration of numerical ranges herein is intended only as a shorthand for individually referring to each individual value and each endpoint falling within the range, and each individual value and endpoint is included in this specification as if it were individually enumerated herein.

[0167] Throughout this application, patents, patent applications, publications, product descriptions and solutions are cited, and the full text of their disclosures is incorporated herein by reference for all purposes. [Simplified Explanation of the Diagram]

[0169] In the figures presented below, where applicable, bars represent mean ± SEM (standard error of mean); OFC = olfactory cortex; CTX = frontal cortex; HPC = hippocampus; naked = naked Δ9-THC formulation (Δ9-THC oil); nano = nanoemulsion formulation (water and oil nanoemulsions of Δ9-THC); liquid = water-based Δ9-THC formulation; oil = oil-based Δ9-THC formulation; polymer = Δ9-THC encapsulated in polymerized micelles.

[0170] Figure 1 provides a graph of dynamic light scattering (DLS) data. This graph shows the particle distribution of the intensity of polymeric micelles (PM) prepared according to embodiments of the present invention. d.nm = diameter, expressed in nanometers. Figures 2A-2C show the total Δ9-tetrahydrocannabinol (Δ9-THC) levels in blood and brain tissue and the total drug distribution in the brain 15 minutes after intranasal delivery of each indicated formulation. Figure 2A provides a bar graph showing the total drug in the blood after 15 minutes. Figure 2B provides a bar graph showing the total drug in the brain after 15 minutes. Figure 2C provides a bar graph showing the total drug distribution in the brain after 15 minutes. Figures 3A-3B show the conversion of Δ9-THC to its metabolites for each indicated formulation 15 minutes after intranasal delivery: 11-OH-THC (i.e., OH-THC or THC-OH; 11-hydroxy-Δ9-tetrahydrocannabinol) and 11-COOH-THC (i.e., COOH-THC or THC-COOH; 11-nor-9-hydroxy-Δ9-tetrahydrocannabinol). Figure 3A provides a bar graph showing the conversion of Δ9-THC to its metabolites in whole blood after 15 minutes. Figure 3B provides a bar graph showing the conversion of Δ9-THC to its metabolites in the brain after 15 minutes. Figure 4 provides a bar graph showing the percentage of total Δ9-THC converted to its metabolites for each indicated formulation 15 minutes after intranasal delivery. Figures 5A-5C show the levels of total drug (Δ9-THC and its metabolites) in the blood and brain tissue of each indicated formulation 30 minutes after intranasal delivery, and the drug distribution in the brain tissue. Figure 5A provides a bar graph showing the total drug in the blood after 30 minutes. Figure 5B provides a bar graph showing the total drug in the brain after 30 minutes. Figure 5C provides a bar graph showing the distribution of the total drug in the brain after 30 minutes. Figures 6A and 6B show the conversion of Δ9-THC to its metabolites OH-THC and COOH-THC for each indicated formulation 30 minutes after intranasal delivery. Figure 6A provides a bar graph showing the conversion of Δ9-THC to its metabolites in the blood after 30 minutes. Figure 6B provides a bar graph showing the conversion of Δ9-THC to its metabolites in the brain after 30 minutes. Figure 7 shows the percentage of total Δ9-THC converted to its metabolites for each indicated formulation 30 minutes after intranasal delivery. Figures 8A-8C show the levels of total drug (Δ9-THC and its metabolites) in the blood and brain tissue of each indicated formulation 45 minutes after intranasal delivery. Figure 8A provides a bar graph showing the total drug in the blood after 45 minutes. Figure 8B provides a bar graph showing the total drug in the brain after 45 minutes. Figure 8C provides a bar graph showing the distribution of total drug to different brain tissues. Figures 9A and 9B show the conversion of Δ9-THC to its metabolites in the blood and brain of each indicated formulation 45 minutes after intranasal delivery.Figure 9A provides a bar graph showing the conversion of Δ9-THC in the blood after 45 minutes. Figure 9B provides a bar graph showing the conversion of Δ9-THC in the brain after 45 minutes. Figure 10 provides a bar graph showing the percentage of total Δ9-THC converted to its metabolites by intranasal administration of each indicated formulation after 45 minutes. Figures 11A-11C show the levels of total drug (Δ9-THC and its metabolites) in the blood and brain tissue of each indicated formulation 2 hours after intranasal administration. Figure 11A provides a bar graph showing the total drug in the blood. Figure 11B provides a bar graph showing the total drug in the brain. Figure 11C provides a bar graph showing the distribution of drug in the brain. Figures 12A and 12B show the conversion of Δ9-THC to its metabolites OH-THC and COOH-THC for each indicated formulation 2 hours after intranasal administration. Figure 12A provides a bar graph showing the conversion of Δ9-THC in the blood. Figure 12B provides a bar graph showing the conversion of Δ9-THC in the brain. Figure 13 provides a bar graph showing the percentage of total Δ9-THC converted to its metabolites after 2 hours for each indicated formulation administered intranasally. Figures 14A-14D show the Δ9-THC and its metabolites detected over time for each indicated formulation after intranasal delivery. Figures 14A-14D provide distribution plots of Δ9-THC, THC-OH, THC-COOH, and total drug over time, respectively. Figures 15A-15F show the Δ9-THC and its metabolites detected over time in the blood and brain for each indicated formulation after intranasal delivery. Figures 15A-15C provide distribution plots of Δ9-THC, THC-OH, and THC-COOH in the blood over time, respectively. Figures 15D-15F provide distribution plots of Δ9-THC, THC-OH, and THC-COOH in the brain over time, respectively. Figures 16A-16C show the levels and conversion of total drug (Δ9-THC and its metabolites) in the blood and brain tissue of each indicated formulation 30 minutes after intranasal delivery, and the drug distribution in the brain. Figure 16A provides a bar graph showing the total drug in the blood. Figure 16B provides a bar graph showing the total drug (Δ9-THC and its metabolites) in the brain. Figure 16C provides a bar graph showing the drug distribution in the brain. Figures 17A and 17B show the Δ9-THC conversion in the blood and brain tissue of each indicated formulation 30 minutes after intranasal delivery. Figure 17A provides a bar graph showing the Δ9-THC conversion in the blood. Figure 17B provides a bar graph showing the Δ9-THC conversion in the brain. Figure 18 provides a bar graph showing the percentage of total drug converted to its metabolites after 30 minutes for each indicated formulation administered intranasally.

Claims

1. A pharmaceutical composition comprising: a therapeutically effective amount of cannabinoid or a pharmaceutically acceptable salt or solvate thereof; and an amphiphilic copolymer comprising at least one hydrophilic component and at least one hydrophobic component, wherein the ratio of the hydrophilic component to the hydrophobic component is from 1:1 to 1:5 in terms of number average molecular weight, and wherein the hydrophilic component is polyethylene glycol (PEG) having a number average molecular weight of about 2000, and the hydrophobic component is polylactide co-glycolic acid (PLGA) having a number average molecular weight of about 4500; wherein the cannabinoid is encapsulated in the amphiphilic copolymer; and the composition is provided in a dosage form for intranasal or inhalation delivery.

2. The composition of claim 1, wherein the ratio of cannabinoid to amphiphilic copolymer is less than 1:10 by weight.

3. The composition of claim 1, wherein the ratio of cannabinoid to amphiphilic copolymer is in the range of 1:20 to 1:10 by weight.

4. The composition of claim 1, wherein the ratio of cannabinoid to amphiphilic copolymer is about 1:20 by weight.

5. The composition of any one of claims 1 to 4, wherein the hydrophilic component is polyethylene glycol (PEG) and the hydrophobic component is selected from polycaprolactone (PCL), polylactic acid (PLA), polylactide co-glycolic acid (PLGA), and combinations thereof.

6. The composition of any one of claims 1 to 4, wherein the hydrophilic component is polyethylene glycol (PEG) and the hydrophobic component is polylactide co-glycolic acid (PLGA).

7. The composition of claim 1, wherein the dosage form is for intranasal delivery.

8. The composition of any one of claims 1 to 4 and 7, wherein the cannabinoid is drocannabinol (Δ9-THC) or cannabidiol (CBD) or a pharmaceutically acceptable salt or solvate thereof.

9. A pharmaceutical composition comprising: a therapeutically effective amount of a cannabinoid selected from Δ9-THC and cannabidiol (CBD) or their pharmaceutically acceptable salts or solvates; and an amphiphilic copolymer comprising: a hydrophilic component of polyethylene glycol (PEG) having a number average molecular weight of about 2000; and a hydrophobic component of polylactide co-glycolide (PLGA) having a number average molecular weight of about 4500; wherein the ratio of cannabinoid to amphiphilic copolymer is less than 1:10 by weight, the cannabinoid being encapsulated in the amphiphilic copolymer; and the composition is provided in a dosage form for intranasal or inhalation delivery.

10. The composition of claim 9, wherein the ratio of the hydrophilic component to the hydrophobic component is about 1:1 to 1:5 in terms of number average molecular weight.

11. The composition of any one of claims 1 to 4 and 7, wherein the therapeutically effective amount is about 0.5 mg to 7.5 mg of cannabinoid.

12. The composition of claim 9 or 10, wherein the therapeutically effective amount is effective in treating at least one of the following: Alzheimer's disease, Parkinson's disease, neuropathic pain, spasms, pain induced by spinal cord injury, migraine, multiple sclerosis, Tourette syndrome, and post-traumatic stress disorder (PTSD).

13. Use of a pharmaceutical composition for preparing a medicament for treating a neurological disorder in a patient in need, wherein the pharmaceutical composition comprises a therapeutically effective amount of a cannabinoid selected from Δ9-THC and cannabidiol (CBD) or their pharmaceutically acceptable salts or solvates; and an amphiphilic copolymer comprising: a hydrophilic component of polyethylene glycol (PEG) having a number average molecular weight of about 2000; and a hydrophobic component of polylactide co-glycolide (PLGA) having a molecular weight of about 4500; wherein the ratio of the cannabinoid to the amphiphilic copolymer is less than 1:10 by weight, and the cannabinoid is encapsulated in the amphiphilic copolymer, wherein the pharmaceutical composition is administered to the patient via nasal administration or inhalation.

14. As claimed in claim 13, wherein the ratio of the hydrophilic component to the hydrophobic component is about 1:1 to 1:5 in terms of number average molecular weight.

15. As claimed in paragraphs 13 or 14, wherein the therapeutically effective amount of cannabinoid is about 0.2 mg to 7.5 mg per dose.

16. For the purposes of claim 13 or 14, wherein the neurological disorder is at least one of the following: Alzheimer's disease, Parkinson's disease, neuropathic pain, spasm, spinal cord injury-induced pain, migraine, multiple sclerosis, Tourette syndrome, and post-traumatic stress disorder (PTSD).

17. As claimed in claim 13 or 14, wherein the pharmaceutical composition is administered to the patient once daily.

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