Intranasal delivery of cannabinoids

Abstract

The present invention relates to a method of treatment in which a composition comprising a cannabinoid and an amphipathic carbohydrate compound, such as GCPQ, is administered intranasally. The method of treatment is particularly suitable for use in central nervous system disorders. The invention further relates to the composition formulated with other ingredients into a pharmaceutical composition for use in treatment.

Description

[Technical Field]

[0001] The present invention relates to compositions and methods of treatment in which compositions comprising an amphiphilic carbohydrate compound and a cannabinoid are delivered intranasally to the human or animal body. [Background technology]

[0002] Phytocannabinoids found in the Cannabis sativa plant are known to exhibit therapeutic potential. Many of these compounds can bind to a wide variety of biological targets in the body's endocannabinoid system, which regulates cognition, pain sensation, appetite, memory, sleep, immune function, and mood. These effects are primarily mediated by two members of the G protein-coupled receptor family, cannabinoid receptors 1 and 2 (CB1 and CB2). As reported by [1], the CB1 receptor regulates the central and peripheral nervous systems. In particular, cannabidiol (CBD), one of the main active phytocannabinoids, is a promising candidate due to its favorable safety profile and lack of psychotropic effects that could lead to substance abuse. CBD has demonstrated promise as an analgesic, anticonvulsant, muscle relaxant, anxiolytic, and antipsychotic, among other uses currently being investigated, and exhibits neuroprotective, anti-inflammatory, and antioxidant activities. Beneficial therapeutic effects have been reported in patients with inflammatory, neurodegenerative, and autoimmune diseases, as well as in patients with epilepsy and cancer. (2018) reported that a Phase 3 clinical trial of the Epidiolex® CBD product demonstrated clinically significant improvements in epilepsy due to Lennox-Gastaut syndrome and Dravet syndrome, two of the most difficult-to-treat types of refractory epilepsy. In 2018, Epidiolex was approved by the FDA as the first CBD-based product available on the U.S. market for the treatment of these two rare forms of epilepsy.

[0003] However, the pharmaceutical industry's development of CBD as a therapeutic and effective drug has been hindered by its inherent characteristics, such as low bioavailability and water solubility. Cannabinoids generally have extremely low aqueous solubility (specifically, only 0.7 μg / mL for CBD) and are highly lipophilic. As a result, CBD is not readily absorbed orally, requiring large amounts to provide therapeutic benefit. Due to the high lipophilicity of CBD (LogP 6.3), it is most commonly supplied as an oil or alcohol formulation. Approved oil suspensions designed for oral and oromucosal administration routes, such as Epidilex® delivered orally in an oil solution and Sativex® as an oromucosal spray, have been approved. However, a limitation of oral CBD delivery is first-pass metabolism. One study showed that 7-hydroxy-cannabidiol (7-OH-CBD) metabolites account for 40% of orally delivered CBD. Therefore, first-pass metabolism is shown to be a significant barrier to increasing the bioavailability of CBD after oral administration (Non-Patent Document 1).

[0004] In recent years, nasal administration has been explored as a potential brain delivery route that bypasses the BBB (Non-Patent Document 2). Nasal administration of drugs prevents peripheral degradation, eliminating the drawbacks associated with oral administration and enabling targeted delivery to the site of action (brain) while reducing plasma exposure, potentially eliminating peripheral side effects. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Millar, SA et al. (“Towards Better Delivery of Cannabidiol (CBD)”, Pharmaceuticals, 2020) [Non-patent document 2] Wang et al “IF Nose-to-Brain Delivery.”, J Pharmacol Exp Ther, 370:593-601, 2019 Summary of the Invention [Problem to be solved by the invention]

[0006] There is a need for compositions and methods for the delivery of cannabinoids to humans other than by oral administration. The present invention provides cannabinoid compositions for nasal to brain delivery of cannabinoids. [Means for solving the problem]

[0007] In a first aspect of the present invention, there is provided a method of treatment in which a composition comprising a cannabinoid and an amphipathic carbohydrate compound is delivered intranasally to the human or animal body. More particularly, the present invention provides a method of treating a disease of the human central nervous system comprising administering to the human or animal a composition comprising a cannabinoid and an amphipathic carbohydrate compound, wherein the composition is administered intranasally to the human or animal body.

[0008] In a second aspect of the present invention, there is provided a pharmaceutical composition suitable for intranasal administration comprising an amphipathic carbohydrate compound and a cannabinoid and one or more pharmaceutically acceptable excipients.

[0009] By methods of treatment in accordance with the present invention, the present invention is also intended to encompass compositions comprising an amphipathic carbohydrate compound and a cannabinoid for use in those methods or treatments. Thus, for example, the present invention provides compositions comprising an amphipathic carbohydrate compound and a cannabinoid for use in methods of treatment that are delivered intranasally to the human or animal body. More specifically, the present invention provides a composition comprising a cannabinoid and an amphipathic carbohydrate compound for use in a method for treating a disease of the central nervous system in a human by intranasal administration. Typically, the disease is epilepsy. Alternatively, in embodiments, the treatment may be treatment of pain, anxiety, and / or an autoimmune disease. There is also provided the use of the composition in the manufacture of a medicament for use in therapy.

[0010] The present treatment method solves some of the problems experienced in the art by delivering higher concentrations of therapeutic cannabinoids to the brain than traditional oral administration methods, while reducing dose dumping to the lungs or stomach. The treatment involves administering a therapeutically effective amount of a cannabinoid via the nose to the brain. The formulation can effectively treat a variety of central nervous system disorders, including epilepsy and pain disorders. Advantageously, the intranasal administration method of the present invention is largely free of disadvantages such as peripheral degradation. The composition can be formulated to be advantageously compatible with nasal sprays, facilitating easy and effective intranasal delivery via the olfactory nerve directly to the brain. Major side effects of oral cannabidiol include diarrhea, vomiting, and elevated liver enzymes, which can be mitigated by using a delivery method that bypasses the gastrointestinal tract. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows a schematic workflow for preparing a GCPQ-CBD formulation in water. [Figure 2] Graphs showing a calibration curve (3-100 μg / mL) and peak overlay (A) demonstrating the linearity and quantification range of CBD, and a representative integration (B) for a MET-CBD formulation sample showing detection at a retention time of approximately 4 minutes. Chromatograms of peaks obtained from CBD solutions of increasing concentrations, as shown in the inset calibration curve graph, are overlaid. [Figure 3] Graphs of the colloidal properties of CBD-GCPQ formulations prepared at CBD-to-GCPQ ratios of 1:10 g / g (A) and 1:5 g / g (B) and resuspended in water at concentrations of 1 mg / mL or 5 mg / mL (CBD equivalents), showing the size distribution according to strength and size (Z-average), polydispersity (PDI), and zeta potential (ZP) parameters. Data are presented as the mean ± SEM of triplicate measurements. Each line corresponds to a different batch of formulation. [Figure 4]Graphs showing colloidal parameters of freshly prepared CBD-GCPQ (1:5 g / g) formulations (n=3) in water at a concentration of approximately 5 mg / mL (CBD equivalent) before spray drying ("pre-SD"), including size distribution according to strength, size (Z-average), and polydispersity (PDI) parameters, compared to rehydration of the powder at the same concentration of approximately 5 mg / mL. Data are presented as the mean ± SEM of three replicate batches (each measured three times). Each line corresponds to a different batch of formulation. [Figure 5] Figure 5A is a graph showing the size distribution D50 of spray-dried CBD-GCPQ microparticles at 0, 7, 14, and 30 days when stored at RT and 4°C. Figure 5B is a graph showing the % of spray-dried CBD-GCPQ particles less than 10 μm at 0, 7, 14, and 30 days when stored at RT and 4°C. [Figure 6] Figure 6A is a graph showing the mean zeta potential values ​​of spray-dried CBD-GCPQ particles upon reconstitution in water at 0, 7, 14, and 30 days when stored at RT and 4° C. Figure 6B is a graph showing the polydispersity of spray-dried CBD-GCPQ particles upon reconstitution in water at 0, 7, 14, and 30 days when stored at RT and 4° C. Figure 6C is a graph showing the CBD concentration in mg / mL of spray-dried CBD-GCPQ particles upon reconstitution in water at 0, 7, 14, and 30 days when stored at RT and 4° C. [Figure 7] Graphs showing the calibration curve (1-500 ng / mL) and peak overlay (A) demonstrating the linearity and quantification range of spiked CBD in the mobile phase to validate the MRM method in non-biological samples, and representative integrations (B) showing the area under the peak (AUP) and signal-to-noise ratio (SNR) for the lowest concentration of 1 ng / mL. Chromatograms of peaks obtained from CBD solutions of increasing concentrations, as shown in the inset calibration curve graph, are overlaid. [Figure 8] Figure 8A shows a calibration curve of AUC ratio versus CBD concentration in brain (1-100 ng / mL), and Figure 8B shows a calibration curve of AUC ratio versus CBD concentration in plasma (3-200 ng / mL). [Figure 9]Figure 1 shows colloidal stability and pH measurements of a CBD-GCPQ (1:5) formulation prepared for in vivo administration and rehydrated at a concentration of 5 mg / mL (CBD equivalents). The size distribution, measured by strength, size (Z-average), and polydispersity (PDI) parameters, is shown for initial pH (4.5-4.8) and after pH adjustment with NaOH to pH 5.5-5.6. Each curve represents a different batch (n=3). [Figure 10] Figure 10A shows a graph of CBD concentration versus time from an in vivo pharmacokinetic study in rats (top left), showing CBD levels in the brain over a 2-hour period. Figure 10B shows a graph of CBD concentration versus time from an in vivo pharmacokinetic study in rats (top right), showing CBD levels in the olfactory bulb over a 2-hour period. Figure 10C shows a graph of CBD concentration versus time from an in vivo pharmacokinetic study in rats (bottom), showing CBD levels in plasma over a 2-hour period. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention relates to compositions and methods of treatment in which compositions comprising an amphiphilic carbohydrate compound and a cannabinoid are delivered intranasally to the human or animal body. The amphiphilic carbohydrate compounds in the compositions and methods of the present invention may form particulate aggregates. These may be formed by aggregation of individual amphiphilic molecules and have an average particle size of 10 nm to 50 μm. The average particle size can be easily determined using microscopy or photon correlation spectroscopy, and is conveniently determined in aqueous dispersion before filtration. The minimum average particle size of the polymeric micellar aggregates may be at least 10 nm, more preferably at least 30 nm, and the maximum average particle size may preferably be 10 μm or less. The average particle size may be 10 nm to 50 μm, or 10 nm to 20 μm, or 10 nm to 5 μm, or 10 nm to 1 μm, or 10 nm to 500 nm, or 10 nm to 100 nm, or 20 nm to 50 μm, or 20 nm to 20 μm, or 20 nm to 5 μm, or 20 nm to 1 μm, or 20 nm to 500 nm, or 20 nm to 100 nm, or 50 nm to 50 μm, or 50 nm to 20 μm, or 50 nm to 5 μm, or 50 nm to 1 μm, or 50 nm to 500 nm, or 10 nm to 100 nm.

[0013] In the present invention, an amphiphilic carbohydrate compound is formulated with a cannabinoid drug. The amphiphilic carbohydrate compound can self-assemble into nanoparticles. The pharmaceutical composition of the present invention may comprise a nanodispersion of nanoparticles of an amphiphilic carbohydrate compound and a drug. The compositions used in the methods of the present invention are preferably in the form of nanoparticles, which can be further processed to form nano-in-microparticle compositions by various methods, including spray drying (described in detail below), by adding to a powder to create granules, or by freeze-drying. The nano-in-microparticle compositions may be in the form of a dry powder and are preferably colloidally stable upon reconstitution in an aqueous medium. Preferably, the nano-in-microparticles are spherical in shape. The nano-in-microparticles may also be hollow or ellipsoidal or irregular in shape. Preferably, the average size of the nanoparticles in the nano-in-micro composition is less than 1000 nm, and even more preferably, the average size of the nanoparticles is less than 500 nm. The average particle size may be 10 nm to 1 μm, or 10 nm to 750 nm, or 10 nm to 500 nm, or 10 nm to 250 nm, or 20 nm to 1 μm, or 20 nm to 750 nm, or 20 nm to 500 nm, or 20 nm to 250 nm, or 50 nm to 1 μm, or 50 nm to 750 nm, or 50 nm to 500 nm, or 50 nm to 250 nm.

[0014] The size distribution of the microparticles in the nanoparticle composition is D 10 , D 50 and D 90 It can be measured by D 10 represents the point on the distribution curve below which 10% of the particles fall, and D 50 is the median particle size (or volume) distribution, representing the point on the distribution curve below which 50% of the particles fall, and D 90 represents the point on the distribution curve below which 90% of the particles fall. Size distribution according to this parameter may also be calculated by microscopy, such as laser scattering and / or scanning electron microscopy. The median volume distribution D of the microparticles according to the present invention 50The diameter of the fine particles is preferably 5 to 30 μm, more preferably 10 to 25 μm. 10 The size distribution may be less than 15 μm. 10 The size distribution is preferably greater than 10 μm to avoid lung deposition. Median volume distribution D of the fine particles in the nanoparticle composition 50 is usually 5 to 30 μm, preferably 10 to 25 μm. Generally, less than 10% of the particles are less than 10 μm. In a more preferred embodiment, the polydispersity of the nanoparticles constituting the nano-in-microparticles is less than 0.5, preferably less than 0.2, and more preferably less than 0.1. The polydispersity may be 0.01 to 0.5, 0.01 to 0.3, 0.01 to 0.1, 0.05 to 0.5, 0.05 to 0.3, 0.05 to 0.1, 0.1 to 0.3, or 0.1 to 0.2.

[0015] The amphiphilic carbohydrate compound of the composition is preferably a chitosan derivative, more preferably represented by the following general formula (I):

[0016] [ka] (In the formula, a+b+c+d=1.000 a is 0.01 to 0.970 b is 0.01 to 0.990 c is 0.0001 to 0.970 d is between 0.01 and 0.990; where X is a hydrophobic group; R1, R2, and R3 are independently selected from substituted or unsubstituted alkyl groups; R4, R5, R6 and R 10 are independently selected from hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group; R7 may be present or absent, and if present is an unsubstituted or substituted alkyl group, an unsubstituted or substituted amine group, or a substituted or unsubstituted amide group; R8 and R9 are independently selected from hydrogen and any of a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group. The compound represented by the formula (I) or a salt thereof is included. Alternatively, in one embodiment, in the above general formula I: a is 0.00 to 0.970 b is 0.01 to 0.990 c is 0.000 to 0.970 d is 0.01 to 0.990, and a+b+c+d=1.000. In the above general formula, the units a, b, c, and d may be arranged in any order, and may be arranged in that order, partially in that order, or randomly. There may be more than one each of units a, b, c, and d containing different R groups. An asterisk (*) in the formula is used to indicate a continuous polymer chain.

[0017] In preferred embodiments, the molar ratio of units d is greater than 0.01, more preferably at least 0.110, more preferably at least 0.120, more preferably at least 0.150, or in some embodiments at least 0.18. The molar ratio of units d is typically not greater than 0.500, more preferably not greater than 0.350. The molar ratio of the unit b is preferably 0.010 to 0.800, more preferably 0.050 to 0.600. The molar ratio of c units is preferably 0.0200 to 0.850, more preferably 0.05 to 0.550. Preferably, the molar ratio of units a is 0.05 to 0.85, more preferably 0.10 to 0.75. Units d provide a first portion of the monomer units and are derivatized with hydrophobic groups, and units b provide a second portion of the monomer units and are derivatized with quaternary nitrogen groups. Units a provide a third group of monomer units in which the amine group is derivatized in a manner different from the first or second groups. More than one "a" group may be present (e.g., different "a" groups may be present in the R8 and R9 groups attached to the N atom). The c units provide a fourth group of monomer units in which the amine group is not derivatized.

[0018] In the present invention, the hydrophobic group X is preferably C 4-30 Alkyl groups such as alkyl groups, C 4-30 Alkenyl groups such as alkenyl groups, C 4-30 Alkynyl groups such as alkynyl groups, C 5-20 The X group is selected from substituted or unsubstituted groups that are aryl groups such as aryl groups, polycyclic hydrophobic groups having more than one C4-C8 ring structure such as sterols (e.g., cholesterol), polyoxaC1-C4 alkylene groups such as polyoxabutylene polymers, or hydrophobic polymer substituents such as poly(lactic acid), poly(lactide-co-glycolide), or poly(glycolic acid) groups. The X group may be a linear, branched, or cyclo group. Any of the X groups may be linked to unit d directly (i.e., at C2 of the monomer unit) or through a functional group such as an amine, acyl, or amide group, thereby forming a linkage that may be represented as an X' ring, X'-NH-, X'-CO- ring, or X'CONH- ring, where X' is a hydrophobic group as defined above. Preferred examples of X groups include those represented by the formula CH3(CH2)n-CO-NH or CH3(CH2)n-NH or alkenoic acids CH3(CH2)p-CH=CH-(CH2)q-CO-NH-, where n is 4-30, more preferably 6-20, and p and q, which may be the same or different, are 4-16, more preferably 4-14. A particularly preferred class of X substituents are those attached to chitosan monomer units via amide groups, for example, as represented by the formula CH3(CH2)nCO-NH-, where n is 2-28. Examples of amide groups include those produced by coupling of carboxylic acids to the amine groups of chitosan. Preferred examples include fatty acid derivatives CH3(CH2)nCOOH, such as those based on capric acid (n=8), lauric acid (n=10), myristic acid (n=12), palmitic acid (n=14), stearic acid (n=16) or arachidic acid (n=18).

[0019] In the above formula, R1, R2, and R3 are preferably independently substituted or unsubstituted alkyl groups (e.g., C 1-10 R1, R2 and / or R3 may be straight or branched chain. Preferably, R1, R2 and R3 are independently selected from methyl, ethyl or propyl groups. In the above formula, R and R are preferably independently hydrogen and a substituted or unsubstituted alkyl group (e.g., C 1-10 alkyl groups). R8 and / or R9 may be linear or branched. Preferably, R8 and R9 are independently selected from methyl, ethyl or propyl groups. In the above formula, R4, R5, R6 and R on C6 or the sugar unit 10 are independently selected from hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group. 10 The R, R, R and R groups are substituted with one or more hydroxyl groups or other non-ionic hydrophilic substituents. 10 Examples of groups are represented by the formula -(CH2)p-OH (wherein p is 1 to 10, preferably 2 to 4) or (CH2)p-CH(CH2-OH)2 (wherein p is 1 to 10) or (CH2)pC(CH2-OH)r (wherein p is 1 to 10 and r is 3) or (CH2CH2OH)p (wherein p is 1 to 300). The R7 group may or may not be present in the general formula. If it is absent, it provides a quaternary ammonium functional group directly attached to the monomer unit of the chitosan backbone. If the R7 group is present, it may be an unsubstituted or substituted alkyl group (e.g., C 1-10 R7N may be an alkyl group, an amine group as represented by the formula -NH-(CH2)n-, or an amide group as represented by the formula -NH-CO-(CH2)n-, where n is 1 to 10, preferably 1 to 4. +A preferred example of an R1R2R3 substituent is coupling a betaine (-OOC-CH2-N-(CH3)3) to the amine substituent of unit b to form -NH-CO-CH2-N + By providing an amide group such as R1R2R3.

[0020] As noted above, some of the substituents described herein may be unsubstituted or substituted with one or more additional substituents known to those skilled in the art. Examples of common substituents include halo; hydroxyl; ether (e.g., C 1-7 alkoxy); formyl; acyl (e.g., C 1-7 Alkyl acyl, C 5-20 aryl acyl; acyl halide; carboxy; ester; acyloxy; amide; acylamido; thioamide; tetrazolyl; amino; nitro; nitroso; azido; cyano; isocyano; cyanato; isocyanato; thiocyano; isothiocyano; sulfhydryl; thioether (e.g., C 1-7 Alkylthio);Sulfonic acid;Sulfonate;Sulfone;Sulfonyloxy;Sulfinyloxy;Sulfamino;Sulfonamino;Sulfinamino;Sulfamyl;Sulfonamide;C 1-7 Alkyl (e.g., unsubstituted C 1-7 Alkyl, C 1-7 Haloalkyl, C 1-7 Hydroxyalkyl, C 1-7 Carboxyalkyl, C 1-7 Aminoalkyl, C 5-20 Aryl-C 1-7 containing alkyl);C 3-20 Heterocyclyl; and C 5-20 Aryl (e.g., C 5-20 Carboaryl, C 5-20 Heteroaryl, C 1-7 Alkyl-C 5-20 Aryl and C 5-20 haloaryl) groups.

[0021] The term "ring structure" as used herein refers to a closed ring of 3 to 10 covalently bonded atoms, even more preferably 3 to 8 covalently bonded atoms, and even more preferably 5 to 6 covalently bonded atoms. The ring may be an alicyclic ring or an aromatic ring. The term "alicyclic ring" as used herein refers to a ring that is not an aromatic ring. As used herein, the term "carbocyclic ring" refers to a ring in which all of the ring atoms are carbon atoms. The term "carboaromatic ring" as used herein refers to an aromatic ring in which all of the ring atoms are carbon atoms. As used herein, the term "heterocycle" refers to a ring in which at least one of the ring atoms is a polyvalent ring heteroatom, such as nitrogen, phosphorus, silicon, oxygen, or sulfur, but more commonly nitrogen, oxygen, or sulfur. Preferably, there are 1 to 4 heteroatoms in the heterocyclic ring. The above rings may be part of a "polycyclic group."

[0022] In one embodiment, the amphiphilic carbohydrate compound may contain an additional group, an acyl group A:

[0023] [ka] may include: The group A may be present in an amount of 0.5% to 30 mol %, and in that case, the amounts of the remaining units may be appropriately adjusted so that the units a are in the range of 0.05 to 40 mol %, the units b are in the range of 5 to 20 mol %, the units c are in the range of 0.05 to 20 mol %, and the units d are in the range of 5 to 30 mol %.

[0024] The amphiphilic carbohydrate compounds of the present invention preferably have the following formula:

[0025] [ka] (In the formula, Unit a' corresponds to unit c in formula I; Units b' and e' together correspond to unit a in formula I; Unit c' corresponds to unit b in formula I; Unit d' corresponds to unit d in formula I; The unit f' corresponds to the unit A above. (the ratio of units a'+b'+c'+d'+e'+f')=1, and the preferred amount of each unit is as described above) or a salt thereof. Preferably, the amphiphilic carbohydrate compound is quaternary ammonium palmitoyl glycol chitosan (GCPQ). Preferably, the amphiphilic carbohydrate compound is N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycol chitosan, also known as quaternary ammonium palmitoyl glycol chitosan (GCPQ).

[0026] In this case, the palmitoylation level of GCPQ (corresponding to group d) is preferably 5-50% per monomer, for example, 10-25% per monomer. In one embodiment, the d level is 31% or less per monomer, preferably in the range of 11-31%, and even more preferably in the range of 11-20%. The quaternization level (b) is preferably 3-40% per monomer, preferably 10-30% per monomer. In one embodiment, the b level is 17% or less per monomer, preferably in the range of 8-17%. Percentage levels are mole percent. The molecular weight of the amphiphilic carbohydrate compound, typically GCPQ, may be in the range of 1 to 40 kDa or 1 to 30 kDa, for example 5 to 30 kDa, 10 to 30 kDa or 8 to 20 kDa, and even more preferably is about 10 to 15 kDa.

[0027] The methods according to the present invention can be used to treat central nervous system infections and autoimmune diseases.

[0028] The cannabinoid is preferably a non-psychoactive cannabinoid. By non-psychoactive cannabinoid, we mean a compound derived from the Cannabis sativa plant that does not induce changes in perception, behavior, or mental processes. For example, a non-limiting list of non-psychoactive cannabinoids suitable for use in the present invention includes cannabidiol (CBD), cannabigerol (CBG), cannabidiolic acid (CBDA), cannabidivarin (CBDV), and cannabichromene (CBC). Preferably, the non-psychoactive cannabinoid according to the present invention is cannabidiol. Cannabinoids can be used as analgesics, anticonvulsants, muscle relaxants, anxiolytics or antipsychotics, and may also have neuroprotective, anti-inflammatory and antioxidant activities. Thus, the present invention can be applied to any of these uses.

[0029] The present invention is particularly useful for the delivery of non-psychoactive cannabinoids to the brain. The non-psychoactive cannabinoids delivered by the present invention may exert a therapeutic effect in the brain. Cannabinoids have been shown to be particularly useful for treating diseases of the central nervous system, particularly infectious and autoimmune diseases of the central nervous system (CNS). The compositions according to the invention can be used to treat several disorders, including epilepsy, Dravet syndrome, Bell's palsy, cerebral palsy, Alzheimer's disease, dementia, motor neuron disease, multiple sclerosis, Parkinson's disease, long covid, neurofibromatosis, shingles, sciatica, pain and sleep disorders such as migraine, Lennox-Gastaut syndrome, psychiatric disorders, neurodegenerative conditions and brain tumors. Preferred conditions for treatment according to the present invention are epilepsy, pain, anxiety and autoimmune diseases.

[0030] The therapeutic method according to the present invention involves intranasal delivery of a composition comprising a cannabinoid and an amphipathic carbohydrate compound to the animal or human body. Intranasal administration of a drug enhances targeted delivery to the brain while eliminating undesirable side effects that may be common with other forms of administration, such as oral routes. Targeted delivery to the brain is achieved by bypassing the blood-brain barrier (BBB) ​​and delivering the drug to the upper nose for transport along the olfactory nerves.

[0031] Cannabinoid compositions can be developed using amphiphilic carbohydrate compounds and appropriately formulated into nanoparticles or, preferably, nano-in-microparticles for compatibility with nasal drug delivery devices that administer the compounds intranasally. Preferably, the drug is cannabidiol and the amphiphilic carbohydrate compound is GCPQ. The composition may be suitable for nasal spraying. This particular approach significantly reduces dose discharge to the lungs or stomach during intranasal administration.

[0032] The device may operate as described below. The formulations of the present invention may be dispensed from a dispenser of fluid, particularly gas-borne solid or liquid particles, comprising a container for the fluid, a chamber for containing particles that is in fluid communication with the container in use, means for transferring fluid from the container into the chamber, and optionally means for engaging the fluid with the particles contained in the chamber to produce a transfer fluid containing the particles that de-agglomerates the particles if agglomerated and agitates the particles to cause turbulence, an outlet that may be arranged to be in fluid communication with the chamber, and discharge means for discharging the transfer fluid from the dispenser through the outlet.

[0033] As used herein, the term "turbulent flow" includes cyclonic or vortex flow, which are preferred forms. The dispenser can be used and operated in any orientation, including upright, inverted, or horizontal. Another advantage is that it solves the problem of deagglomerating and / or fluidizing fine particles using relatively uncomplicated and potentially inexpensive technology. The particles are generally solid particles, particularly those that tend to agglomerate fairly easily during storage and / or transportation, and are useful for dispensing particulate compositions containing pharmaceuticals in metered doses. The properties of any particle, such as its density, particle size, specific surface area, desired dosage, etc., can be anywhere within a wide variety of ranges that are compatible with the function of the device. Preferably, the size distribution of the particles is narrow and the shapes are similar.

[0034] The fluid in the container may be any fluid that is sufficiently fluid to agitate the particles turbulently, is stable during storage, and is inert to the particles and the object being dispensed. The fluid may be a gas such as air, or if the particles are not inert to air for long periods, a conventional, optionally fluorinated, lower hydrocarbon propellant such as nitrogen, a hydrofluorocarbon (HFC), or carbon dioxide; a liquid such as water, or if the particles are not inert to water for long periods, a (usually pressurized) conventional, optionally fluorinated, lower hydrocarbon propellant such as butane or an HFC, a hydrofluoroalkane (HFA) propellant, or any compatible combination thereof.

[0035] Fluid communication between the container and the chamber often includes at least one channel, preferably at least a pair of channels, extending between the container and the chamber. Any channel extending between the container and the chamber may be in the form of a conduit, duct, or tube. The shape and size of any channel for mixing particles with a fluid may be any within a wide variety of ranges compatible with its function. They may have a circular cross section and / or any other regularly curved cross section, for example, a substantially elliptical, semicircular, or semi-elliptical cross section, depending on the specific characteristics of the particles, such as their density, particle size, specific surface area, desired dose, etc. However, in many cases, each has a straight cross section, such as a slot, a triangular, square, or elliptical cross-sectional duct, etc. In cases where the amount of drug-containing composition provided in a fully filled dispenser of the present invention is 0.5 to 35 mg, the cross-sectional area of ​​each channel is typically 0.03 to 3.0 mm. 2 , especially 1.0~1.5mm 2 The channel is usually straight, although it may have widely varying shapes along its length, for example curved. Where there is at least one pair of channels, all channels will typically be of similar, and often identical, size and configuration, although channels within a pair may, of course, be reverse wound where appropriate.

[0036] The container may be a pressurized fluid container, and upon actuation of the release means, pressurized fluid is forced from the container into the chamber under its own pressure head. In such cases, the release means may be the same entity as the means for moving the pressurized fluid into the chamber to engage the particles. A pressurized fluid container has the advantage in dispensers according to the invention of potentially releasing fluid more quickly and / or forcefully into the chamber. This may be desirable, particularly where particulates contained in the chamber tend to agglomerate rather easily during storage and / or transport, in order to de-agglomerate and turbulently agitate the particulate-laden moving fluid. Amphiphilic carbohydrate compounds such as GCPQ are biocompatible polymers that can form a protective molecular envelope around incorporated drugs, and drugs such as the preferred non-psychoactive cannabinoids of the present invention can be efficiently loaded into the resulting stable nanoparticles.

[0037] Nanoparticle compositions can be synthesized by common nanoparticle synthesis methods known in the art, including sol-gel processes, chemical vapor deposition (CVD), atomic layer deposition (ALD), molecular layer deposition (MLD), high-pressure homogenization and other microfluidization techniques, probe sonication, simple shaking of the drug in the presence of an amphiphilic carbohydrate in an aqueous medium, milling, thin film formation, and subsequent hydration. Preferably, the method involves dissolving the cannabinoid in a solution of the amphiphilic carbohydrate, followed by evaporation to form a thin film and subsequent rehydration. The ratio of non-psychoactive cannabinoid to amphiphilic carbohydrate compound is typically 0.5:10 to 5:10 g / g. The ratio of cannabinoid to amphipathic carbohydrate compound may be 0.5:10 to 5:10 g / g or 0.5:10 to 4:10 g / g or 0.5:10 to 3:10 g / g or 0.5:10 to 2:10 g / g or 0.5:10 to 1:10 g / g or 1:10 to 5:10 g / g or 1:10 to 4:10 g / g or 1:10 to 3:10 g / g or 1:10 to 2:10 g / g, the ratio may be 1:1 or 1:2 or 1:3 or 1:4 or 1:5 or 1:6 or 1:7 or 1:8 or 1:9 or 1:10 g / g, even more preferably the ratio is 1:5 g / g. In a preferred embodiment, the mass ratio of the cannabinoid to the amphipathic carbohydrate compound is greater than 1:0.5, preferably 1:1 to 1:10, and even more preferably 1:5 to 1:3. Such a ratio is typically used with GCPQ as the amphipathic carbohydrate compound, which has the preferred palmitoylation and quaternization levels as defined above. Accordingly, a further aspect of the present invention provides a composition comprising GCPQ and a cannabinoid, wherein the GCPQ has a palmitoylation level in the range of 11 to 31 mol% and a quaternization level in the range of 8 to 17 mol%, and the GCPQ:cannabinoid mass ratio is 1:1 to 1:10. Preferably, the composition is a pharmaceutical composition comprising GCPQ, a non-psychoactive cannabinoid, and one or more pharmaceutically acceptable excipients.

[0038] The resulting nanoparticle composition can be converted into a nano-in-micro composition by further processing. For example, a nano-in-micro composition can be formed by spray drying or freeze drying the nanoparticle composition. A nano-in-micro composition can also be formed by adding a nanoparticle composition to a powder to form granules. The nano-in-micro particle composition can be in the form of a dry powder. Nano-in-microparticle compositions are particularly suitable for reliable and selective delivery of large microparticles to the upper nose, where the microparticles can disintegrate into smaller particles that can effectively penetrate the mucus and promote mucosal uptake.

[0039] The nanoparticles and nano-in-micro compositions of the present invention can also be stored for at least 30 days without significant degradation of their stability and properties (e.g., size and morphology). The formulations of the present invention should also be stable over long periods of time, as measured by the stability of the API, particularly cannabinoids, over time. After 4 weeks of storage at 4°C or 25°C, the API recovery of the formulations of the present invention is at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 99%. After 4 weeks of storage, the formulations of the present invention are at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 99%. The API recovery rate of the formulation of the present invention after storage at 25°C for 4 weeks is about 50% to about 99%, or about 50% to 90%, or about 50% to about 80%, or about 50% to about 70%, or about 50% to 60%, or about 60% to about 99%, or about 60% to 90%, or about 60% to about 80%, or about 60% to about 70%, or about 70% to about 99%, or about 70% to 90%, or about 70% to about 80%, or about 80% to about 99%, or about 80% to about 90%, or about 90% to about 99%. The API recovery rate of the formulation of the present invention after storage at 40°C for 4 weeks is about 50% to about 99%, or about 50% to 90%, or about 50% to about 80%, or about 50% to about 70%, or about 50% to 60%, or about 60% to about 99%, or about 60% to 90%, or about 60% to about 80%, or about 60% to about 70%, or about 70% to about 99%, or about 70% to 90%, or about 70% to about 80%, or about 80% to about 99%, or about 80% to about 90%, or about 90% to about 99%.

[0040] The compositions of the present invention can be further formulated to form pharmaceutical compositions particularly suitable for intranasal delivery. Additional components that may be included in the pharmaceutical composition include tonicity enhancing agents, preservatives, solubilizers, non-toxic excipients, demulcents, sequestering agents, pH adjusters, co-solvents and viscosity increasing agents. The pharmaceutical composition may be formulated as a powder or liquid dispersion. Nasal spray delivery may be achieved by a spray device. The dosage can be determined based on age, body weight, administration time, administration method, drug combination, the severity of the clinical or actual condition of the patient being treated, and other factors. The daily dosage may vary depending on the patient's condition and body weight, species or active ingredient, and administration route. For oral use, the daily dosage is approximately 0.1 mg to 10.0 g / person / day, 0.1 mg to 5.0 g / person / day, 0.1 mg to 1.0 g / person / day, 0.1 mg to 2.5 g / person / day, 0.1 mg to 1.0 g / person / day, 0.1 mg to 500 mg / person / day, 0.5 mg to 2.5 g / person / day, 0.5 mg to 1.0 g / person / day, 0.5 mg to 100 mg / person / day, or 1 mg to It may be 2.5g / person / day, or 1mg to 1.0g / person / day, or 1mg to 0.5g / person / day, or 1mg to 1.0g / person / day, or 1mg to 500mg / person / day, or 10mg to 2.5g / person / day, or 10mg to 1.0g / person / day, or 10mg to 0.5g / person / day, or 10mg to 0.1g / person / day, or 10mg to 50mg / person / day, or 0.5 to 5000mg / person / day, or 5 to 500mg / person / day, or 10 to 250mg / person / day, or 25 to 200mg / person / day. [Example] The invention is illustrated by the following examples. [Example]

[0041] Synthesis of GCPQ-CBD nanoparticles Materials and Methods CBD-GCPQ nanoparticles were synthesized at two different concentration ratios of CBD:GCPQ: 1:5 and 1:10. Cannabidiol (CBD>99%; THC Pharm) was dissolved in methanol at 1 mg / mL for both ratios. 17.5 P 18 Q 13The CBD-GCPQ formulation was dissolved in methanol at 5 mg / mL and 10 mg / mL. The CBD solution was then added dropwise to the GCPQ solution while swirling for a few seconds and vortexing to mix the solutions together. The mixture was incubated at room temperature for 1 hour with shaking at 150 rpm. The CBD-GCPQ formulation was then evaporated using a high-speed vacuum concentrator at 45°C for 2 hours, and the resulting thin film was rehydrated in Milli-Q water at 5 mg / mL (1:5 ratio) and 10 mg / mL (1:10 ratio). A schematic diagram of this method is shown in Figure 1.

[0042] Characterization Method The synthesized CBD-GCPQ nanoparticles were then characterized for colloidal stability and CBD content quantification. Colloidal Stability: Characterization was performed using dynamic light scattering (DLS). Samples were diluted 30-fold with Milli-Q water, and particle size, polydispersity, and zeta potential parameters were measured on a Malvern Zetasizer Nano S / N using a folded capillary zeta cell cuvette. The protocol for size and zeta potential measurements included a 30-second equilibration period before data acquisition for each sample, and measurements were performed in triplicate. CBD quantification: A high-performance liquid chromatography (HPLC) method for the detection and quantification of CBD in non-biological samples of MET-CBD formulations was performed on an Agilent HPLC-UV System 1220 Infinity LC using a mobile phase of 85:15% v / v methanol:water. All samples submitted to HPLC were diluted 100-fold with methanol. Data analysis was performed via Agilent Chemstation software.

[0043] result HPLC analysis of CBD quantification yielded a linear calibration curve within the range of 3–100 μg / mL based on spiked concentrations of known CBD in methanol (Figure 2A). Furthermore, a clear single CBD peak was observed in the CBD-GCPQ formulation with a consistent retention time of approximately 4 min. At a CBD concentration equivalent of 1 mg / mL, the formulation exhibited favorable colloidal stability parameters, with a size of less than 200 nm, a low polydispersity of approximately 0.1, and a high positive surface charge of approximately +50 mV (Figure 3). Higher CBD concentrations were required for in vivo applications, and therefore, CBD equivalents of 5–10 mg / mL were tested in CBD-GCPQ nanoparticle formulations. The formulations could not be fully dispersed at these high concentrations, and despite prolonged and vigorous vortexing and bath sonication, high viscosity and residual solids prevented the attainment of 10 mg / mL. The GCPQ level in these formulations was higher, i.e., the solids content was higher, especially at a CBD:GCPQ ratio of 1:10 g / g. CBD-GCPQ formulations, successfully formulated in water with 5 mg / mL CBD for both CBD and GCPQ ratios (1:10 and 1:5 g / g), produced colloidally stable nanoparticles with a unimodal particle population distribution that showed no signs of settling or aggregation. The 1:5 g / g CBD-GCPQ formulation exhibited more favorable particle sizing parameters when compared with the 1:10 g / g CBD-GCPQ formulation. The resulting nanoparticles exhibited a size of approximately 412 nm (CBD-GCPQ = 1:5 g / g) versus 551 nm (CBD-GCPQ = 1:10 g / g) and a slightly lower polydispersity index (PDI) of 0.14 (CBD-GCPQ = 1:5 g / g) versus 0.2 (CBD-GCPQ = 1:10 g / g). [Example]

[0044] MET-CBD nanoparticle powder Materials and Methods CBD-GCPQ nanoparticles were prepared from CBD (60 mg) and GCPQ (300 mg) in a 1:5 ratio according to the method of Example 1 and then resuspended in 12 ml of Milli-Q water before spray drying. The nanoparticle dispersion was spray-dried to obtain CBD-GCPQ nano-in-microparticles (Buchi Nano Spray Dryer B290, Buchi Labortechnik AG, Switzerland) with the following settings: inlet temperature = 180 °C, outlet temperature = 120 °C, aspirator % = 85%, pump % = 5%, ultrasonic controller = 1.8 at <50 °C). Characterization Method The synthesized CBD-GCPQ nanoparticles were then characterized for microparticle morphology and size analysis, colloidal stability, and CBD content quantification in both non-biological and biological samples. A portion of the spray-dried CBD-GCPQ powder was stored at room temperature for 30 days, while another sample was stored at 4°C for 30 days. At various time points (0, 7, 14, and 30 days), aliquots were removed and characterized. Particle size: The microparticle size of the spray-dried MET-CBD nano-loaded microparticles was determined by laser scattering using a Malvern Mastersizer 3000. An aliquot of powder (approximately 10 mg) was applied to a sample feed tray. Air was used as the dispersion medium for the microparticles from the sample feed tray to the sample cell. The microparticle size distribution was determined by D 10 , D 50 and D 90 It was characterized using parameters. Particulate form: The morphology of the microparticles was determined by scanning electron microscope (SEM) imaging. A strip of double-sided carbon tape was placed on an SEM stub. CBD-GCPQ powder was spread over the entire surface of the tape, and compressed air was used to remove any loose microparticles. Prior to measurement, the samples were sputter-coated with 20 nm of gold. SEM images of the samples were generated using a Phenom Pro Benchtop SEM. Colloidal Stability: Samples were prepared and characterized for colloidal stability according to the method described in Example 1. CBD quantification: Samples were prepared and characterized for CBD quantification in non-biological samples according to the methods described in Example 1.

[0045] result SEM characterization showed that the spray-dried particles were predominantly spherical in morphology compared to the CBD powder alone, which had a more irregular morphology. The average particle sizes (including SEM error values) are shown in Table 1 below. Table 1: Average particle size of CBD-GCPQ nano-in-microparticles, D 10 , D 50 , D 90 and the ratio of particles less than 10 μm (%)

[0046] [Table 1] Rehydration of the spray-dried particles in water to 5.4 mg / mL CBD (analyzed by HPLC) produced nanoparticles approximately 500 nm in size, which had a unimodal particle size distribution with low polydispersity (PDI = <0.2). The size of the rehydrated nanoparticles appeared slightly higher compared to the nanoparticles before spray drying. However, this is most likely due to the difference in the actual measured CBD concentration, and therefore the amount of GCPQ, in both CBD-GCPQ formulations, i.e., 5.43 mg / mL in the spray-dried formulation compared to 4.93 mg / mL in the original, as shown in Figure 4. This is typical of concentrated formulations, and may have resulted in a slightly higher particle size. The polydispersity before and after spray drying remained approximately 0.19 (Figure 4). Upon storage at room temperature and 4°C for 30 days, the spray-dried CBD-GCPQ microparticles maintained their spherical morphology across the several time points measured: days 0, 7, 14, and 30. All size parameters for the spray-dried CBD-GCPQ powder stored at room temperature and 4°C for 0, 7, 14, and 30 days are provided in Tables 2 and 3 below. Table 2: Size distribution of nano-in-microparticles stored at room temperature on days 0, 7, 14, and 30.

[0047] [Table 2] Table 3: Size distribution of nano-in-microparticles at 0, 7, 14, and 30 days after storage at 4 °C.

[0048] [Table 3] Median diameter volume distribution (D 50 ) and the percentage of particles less than 10 mm showed no statistically significant differences over the 30-day storage period at either temperature. The spray-dried CBD-GCPQ powder was then rehydrated to 5 mg / mL CBD equivalent, and nanoparticle colloidal stability and CBD concentration were analyzed and compared with day 0 parameters. As shown in Figure 5, no statistically significant differences in particle size were observed over the time period. Similarly, no significant differences in polydispersity and zeta potential were observed up to 30 days at either room temperature of 4°C (Figures 6A and 6B). While no CBD degradation within the CBD-GCPQ nanoparticle formulations was observed up to 30 days at either temperature (Figure 6C), refrigerated powder surprisingly yielded significantly higher CBD concentrations over time (days 14 and 30). In contrast, Mazzetti et al. in Scientific Reports from Nature Research (2020) 10:3697 reported an average of 13% degradation in a commercially available CBD oil-based e-liquid over 30 days at room temperature when exposed to light. Thus, the present invention represents a clear stability advantage over the art by forming stable and effective non-psychoactive cannabinoid-amphiphilic carbohydrate compositions. [Example]

[0049] In vivo pharmacokinetic study of MET-CBD administered intranasally in rats Materials and Methods animal: Male Sprague Dawley rats (Charles River, UK) were housed five per cage in an air-conditioning unit (20-22°C, 50-60% relative humidity) and provided with standard rodent chow and water ad libitum. Lighting was controlled on a 12-hour cycle (on at 07:00 h, off at 19:00 h). Animals were acclimated for 7 days prior to experimentation and allowed to acclimate to the procedure room for 1 h before testing. Rats weighed 200-230 g before dosing and were stratified to match mean weight across study groups.

[0050] CBD-GCPQ formulations for in vivo application and intranasal administration Prior to dosing rats, the CBD-GCPQ formulation from Example 2 was dispersed in Milli-Q water at 5 mg / mL CBD. The pH of the formulation was measured and adjusted to pH 5.5-5.6 by adding NaOH. Rats were stratified into five test groups, each containing six animals. Four groups received CBD-GCPQ over four post-dose time points (10 minutes, 30 minutes, 1 hour, and 2 hours), and one group received no CBD. CBD-GCPQ was administered intranasally (at 2 mg / kg CBD equivalent) using Smiths Medical Portex narrow-bore polyethylene tubing (0.28 mm inner diameter / 0.61 mm outer diameter, 15 mm long) attached to a 0.3 mL insulin syringe with a 30G needle. Animals were anesthetized by inhalation of isoflurane (approximately 4%) for several minutes prior to administration.

[0051] Tissue extraction and blood collection: At 10 minutes, 30 minutes, 1 hour, and 2 hours after administration, rats were sacrificed by carbon dioxide asphyxiation and death was confirmed by cervical dislocation. Blood samples (from which plasma was later sourced) were taken immediately after termination via cardiac puncture and collected in K3EDTA anticoagulated microtubes. Plasma was separated from blood cells by centrifugation, aspirated into 1.5 mL Eppendorf microtubes, and stored frozen at −50° C. until LC-MS analysis was performed. Brains were extracted and flash-frozen in liquid nitrogen and then stored frozen at -80°C until LC-MS analysis was performed. Brain homogenates and plasma were then used as biological matrices for compound extraction and LC-MS analysis.

[0052] Characterization The synthesized CBD-GCPQ nanoparticles were then characterized for CBD content in biological samples (brain and plasma from rats). CBD quantification: CBD content in biological samples was quantified using liquid chromatography-mass spectrometry (LC-MS). CBD and its internal standard, deuterated CBD (CBD-d3, molecular weight = 318 Da), were measured in brain and plasma matrices using an Agilent 6400 Series Triple Quad instrument. First, non-biological samples containing known concentrations of spiked target compound CBD and internal standard CBD-d3 were analyzed by LC-MS scan. The process involved a three-step workflow: 1) a full tandem spectroscopy (MS2) scan to identify precursor ions of both compounds; 2) a product ion scan in which selected precursor ions were fragmented to form and identify product ions; and 3) a multiple reaction monitoring (MRM) scan mode was performed on the CBD target compound based on the selected product ions to quantify the target compound in the sample. The binary pump contained a mobile phase of 95:5% v / v water:methanol at 0 min, followed by 15:85% v / v water:methanol at 2 min. The source parameters were set to a gas temperature of 300 to 350°C. LC-MS methods typically lose sensitivity when analyte quantification in biological matrices is introduced, commonly known as "matrix effects." Therefore, prior to analyzing brain and plasma samples from in vivo studies, the MRM method was optimized by varying the mobile phase composition, i.e., by using different polar and organic solvents and isocratic versus gradient compositions.

[0053] result CBD quantification for in vivo preclinical studies: CBD quantification via an isocratic method for non-biological samples revealed a distinct peak for CBD at a retention time of 1 min. A distinct peak at 4.4 min was also observed via a gradient method for biological matrices.

[0054] The first MS2 scan identified the most abundant precursor CBD ion with a mass-to-charge (m / z) ratio of 315.2 and a CBD-d3 ion with an m / z of 318.2, consistent with that reported by McRae, G. et al. (Quantitative determination and validation of 17 cannabinoids in cannabis and hemp using liquid chromatography-tandem mass spectrometry. Analytical and Bioanalytical Chemistry, 412:7381-7393, 2020). This CBD precursor ion was then selected for fragmentation into product ions in the second step of the workflow. Product ion scans indicated that the CBD precursor ion had completely decomposed into product ions. The CBD product ion at m / z = 193 and the CBD-d3 product ion at m / z = 196.3 were also confirmed to be consistent with the McRae et al. report and were selected for the third step of the workflow. Based on the mass-to-charge ratios identified in the MS2 and product ion scans, an MRM method for CBD and CBD-d3 quantification was established, and a calibration curve was generated in non-biological samples with excellent linearity within the quantification range of 1 to 500 ng / mL, as shown in Figure 7. The clearly defined CBD peak in the MRM scan confirmed the accuracy of the LC-MS quantification method and the high sensitivity of the method, with a lower limit of quantification (LLOQ) of at least 1 ng / mL. As shown in Figure 8, calibration curves were constructed with good linearity within the quantification ranges of 1 to 100 ng / mL for brain with R2 = 0.999 and 3 to 200 ng / mL for plasma with R2 = 0.995 for brain tissue and plasma. The LC-MS method provided highly sensitive CBD quantification, with LLOQs of 1 ng / mL and 3 ng / mL for brain and plasma matrices, respectively.

[0055] Colloidal stability, pH and size distribution: Prior to dosing in rats, 5 mg / mL nanoparticles were characterized for colloidal stability and pH. The nanoparticles formed a monodisperse (PDI<0.1) nanoparticle population with a size of less than 300 nm at a pH of 4.5–4.8. This pH was determined according to the method described by UK et al. (Nasal pH measurement: a reliable and repeatable parameter). The pH of the nanoparticles was adjusted to this range before administration, as this could cause discomfort and unwanted reactions in the animals, such as sneezing. Increasing the pH had minimal effect on the colloidal stability of the nanoparticles, resulting in only a slight increase in nanoparticle size to approximately 320 nm, with a polydispersity index still around 0.1. Figure 9 compares the size distribution and polydispersity before and after pH adjustment.

[0056] Intranasal administration in vivo pharmacokinetic study: Overall, intranasal administration of CBD-GCPQ was very well tolerated by the animals. No sneezing, distress, or adverse reactions were reported, and the rats appeared calm and relaxed. As reported by Galaj et al. (Possible Receptor Mechanisms Underlying Cannabidiol Effects on Addictive-Like Behaviors in Experimental Animals. Int. J. Mol. Sci., 22(1), 134, 2021), CBD can bind to specific receptors in the brain that release serotonin, producing a feeling of euphoria, while THC induces psychostimulant effects and can induce addictive behavior. Therefore, the calm behavior observed in the rats after administration indicates that CBD reached the brain fairly quickly. Figure 10 shows CBD levels in the brain, olfactory bulb, and plasma of test rats administered 2 mg / kg of CBD at 0 minutes (untreated control), 10 minutes, 30 minutes, 60 minutes, and 120 minutes. These results confirm that significant levels of CBD were present in the brain, olfactory bulb, and plasma within 10 minutes of administration. Maximum concentrations were reached at 30 minutes for all profiles, with concentrations gradually decreasing after 60 minutes. Even 120 minutes after administration, some CBD levels were still present in the brain and olfactory bulb. The maximum CBD concentration in plasma was 40-fold lower than in the brain, suggesting extremely low systemic exposure after intranasal administration. These results are superior to CBD levels reported in the literature. For example, Hozek et al. (Pharmacokinetic and behavioral profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of in vivo conversion of CBD to THC. European Neuropsychopharmacology, 27, 1223-1237, 2017) reported that oral pulmonary administration of 10 mg / kg and 20 mg / kg, respectively, achieved brain CBD levels of approximately 200-300 ng / g, significantly lower than the 2,400 ng / g reported in this study (as shown in Figure 10A). Therefore, the intranasal method of the present invention achieved a CBD concentration 10-fold higher than that of the prior art, despite using a much lower dose of 2 mg / kg. Therefore, the present invention allows for the use of smaller clinical doses of amphiphilic carbohydrate-nonpsychoactive cannabinoid compositions. [Example]

[0057] Further composition generation and characterization The objective of this example was to generate compositions containing GCPQs with different amounts of palmitoylation (unit d in Formula I) and quaternization (unit b). Different ratios of cannabinoid to GCPQ were also tested. Materials and Methods CBD (THC Pharm UK) and GCPQ formulations were prepared by thin-film evaporation. Several GCPQ polymers with different molar percentages of palmitoylation (%P) and quaternary ammonium groups (%Q) were investigated, and the levels of palmitoylation and quaternary ammonium groups are indicated by the polymer identification labels: GCP11Q11; GCP19Q8; GCP20Q13; GCP20Q17; and GCP31Q13. In these figures, for example, GCP11Q11 refers to a polymer with 11 molar percentage of palmitoylation and 11 molar percentage of quaternary ammonium groups. CBD and MET were dissolved in MeOH in a round-bottom flask at CBD-to-MET ratios of 1:0.5, 1:1, 1:3, 1:5, and 1:10, resulting in a final CBD concentration of 1 mg / mL. The MeOH mixture was stirred at room temperature for 1 hour. A thin film was then obtained by rotary evaporation under vacuum in a 45°C water bath and rehydrated with milliQ water to a final CBD concentration of 5 mg / mL. The dispersion was then sonicated in a sonicator bath at 30°C for 10 minutes. Dynamic Light Scattering and Zeta Potential Dynamic light scattering (DLS) and zeta (ζ) potential measurements were performed using a Zeta-sizer Ultra (Malvern Instruments Ltd). Dispersions were diluted 30-fold with milliQ water and equilibrated at 25°C for 120 seconds before measurement. Measurements were collected in triplicate. The software derives the intensity distribution using CONTIN analysis and obtains the hydrodynamic diameter (DH) and polydispersity index (PI) using cumulant analysis. CBD content determination by high-pressure liquid chromatography (HPLC) The CBD content in the MET-CBD formulation was quantified by HPLC using the following settings:

[0058] [Table 4] A linear (R2 = 0.9996) calibration curve was constructed for CBD in methanol within the concentration range of 1–150 μg / mL. A clear single CBD peak was found in the MET-CBD formulation with the same retention time (approximately 4 min) as CBD alone. All samples subjected to HPLC were diluted 100-fold with methanol. Data analysis was performed using Agilent Chemstation software.

[0059] result The prepared formulations were characterized in terms of size, polydispersity index (PI), zeta potential, and CBD content (%). The stability of these formulations depended on the polymer type used, in terms of %P and %Q, and the CBD to polymer ratio. Stability was followed over a period of up to 8 hours or until the formation of a suspension / precipitation. Precipitation was observed after 24 hours in all cases. Table 4: Summary of CBD:GCP11Q11 results (Z-average; PI, zeta potential and CBD content) over time

[0060] [Table 5] Table 5: Summary of results (Z-average; PI, zeta potential and CBD content) over time for CBD:GCP19Q8 (MW 12 kDa)

[0061] [Table 6] Table 6: Summary of CBD:GCP20Q13 results (Z-average; PI, Zeta potential and CBD content) over time

[0062] [Table 7] 1. Multimodal size distribution Table 7: Summary of results (Z-average; PI, zeta potential and CBD content) for CBD:GCP20Q17 (MW=11.9 kDa) over time

[0063] [Table 8] Table 8: Summary of CBD:GCP31Q13 results (Z-average; PI, Zeta potential and CBD content) over time

[0064] [Table 9] As can be seen from the above results, GCPQ polymers with a molar % palmitoylation (%P) of 31% or less, typically 11-20%, are preferred. Furthermore, GCPQ polymers with a molar % quaternary ammonium group (%Q) of 17% or less, typically 8-17%, are preferred. The above results also demonstrate that the preferred CBD:GCPQ ratio is greater than 1:0.5, and ideally between 1:1 and 1:10.

Claims

1. A method of treatment comprising administering to a human or animal a composition comprising a cannabinoid and an amphipathic carbohydrate compound, wherein the composition is administered intranasally to the human or animal body.

2. A composition comprising a cannabinoid and an amphipathic carbohydrate compound for use in a method of treating humans or animals by intranasal administration.

3. 3. The method or composition of claim 1 or 2, wherein the treatment is treatment of a disease of the central nervous system or epilepsy.

4. 4. The method or composition of any one of claims 1 to 3, wherein the treatment is treatment of pain, anxiety or an autoimmune disease.

5. The method or composition of any one of claims 1 to 4, wherein the composition is in the form of nanoparticles.

6. 6. The method or composition of claim 5, wherein the nanoparticles are fabricated to form nano-in-microparticles.

7. 7. The method or composition of claim 6, wherein the composition is made by a process for forming nano-in-microparticles selected from spray drying, freeze drying, adding nanoparticles to a powder to form granules, preferably the process is spray drying.

8. 8. The method or composition of claim 6 or 7, wherein the average size of the nanoparticles in the nano-in-micro particle composition is less than 1000 nm or less than 500 nm.

9. The median volume distribution D of nanoparticles in the nano-in-micro particle composition ５０ The method or composition of any one of claims 6 to 8, wherein is 5 to 30 μm or 10 to 25 μm.

10. 10. The method or composition of claim 9, wherein less than 10% of the nanoparticles are less than 10 μm.

11. The method or composition of any one of claims 6 to 10, wherein the polydispersity of the nanoparticles within the nano-in-microparticles is less than 0.5, less than 0.2, or less than 0.

1.

12. The method or composition according to any one of claims 6 to 11, wherein the nanoparticles within the nano-in-microparticles are colloidally stable formulations.

13. The method or composition according to any one of claims 6 to 12, wherein the nano-in-micro particles are in the form of a dry powder.

14. 14. The method or composition of claim 13, wherein the nano-in-micro particles are compatible with an intranasal spray device.

15. The method or composition according to any one of claims 6 to 14, wherein the nano-in-micro particles have a spherical, hollow or irregular shape.

16. 16. A method or composition according to any preceding claim, wherein the ratio of cannabinoid to amphipathic carbohydrate compound is from 0.5:10 to 5:10 g / g.

17. 17. The method or composition of claim 16, wherein the ratio of cannabinoid to amphipathic carbohydrate compound is 1:10 to 3:10 g / g or about 1:5 g / g.

18. 18. The method or composition of any one of claims 1 to 17, wherein the cannabinoid is delivered to the brain of the human or animal body.

19. 19. The method or composition of any one of claims 1 to 18, wherein the cannabinoid is a non-psychoactive cannabinoid or cannabidiol.

20. 20. The method or composition of any one of claims 1 to 19, wherein the amphiphilic carbohydrate compound is a chitosan derivative.

21. The amphiphilic carbohydrate compound has the following general formula: 【Chemical 1】 (In the formula, a + b + c + d = 1.000 a is 0.01 to 0.970 b is 0.01 to 0.990 c is 0.0001 to 0.970 d is 0.01 to 0.990; X is a hydrophobic group; R １ , R ２ and R ３ are independently selected from substituted or unsubstituted alkyl groups; R ４ , R ５ , R ６ and R １０ are independently selected from hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group; R ７ may be present or absent and, if present, is an unsubstituted or substituted alkyl group, an unsubstituted or substituted amine group, or a substituted or unsubstituted amide group; R ８ and R ９ are independently selected from hydrogen and either a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group. A compound represented by the formula (I) or a salt thereof.

22. 22. The compound or salt thereof according to claim 21, wherein the amphiphilic carbohydrate compound is quaternary ammonium palmitoyl glycol chitosan (GCPQ).

23. A pharmaceutical composition suitable for intranasal administration comprising an amphipathic carbohydrate compound and a non-psychoactive cannabinoid and one or more pharmaceutically acceptable excipients.

24. 24. The pharmaceutical composition of claim 23, wherein the cannabinoid is selected from the group consisting of cannabidiol (CBD), cannabigerol (CBG), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabichromene (CBC), and combinations thereof.

25. 25. The pharmaceutical composition of claim 24, wherein the cannabinoid is cannabidiol (CBD).

26. 26. The pharmaceutical composition of any one of claims 23 to 25, wherein the excipient is selected from the group consisting of tonicity enhancing agents, preservatives, solubilizing agents, non-toxic excipients, demulcents, sequestrants, pH adjusting agents, co-solvents, viscosity increasing agents, and combinations thereof.

27. The pharmaceutical composition according to any one of claims 23 to 26, wherein the amphiphilic carbohydrate compound is GCPQ.

28. The pharmaceutical composition according to any one of claims 23 to 27, which is in the form of nanoparticles.

29. 29. The pharmaceutical composition of claim 28, wherein the nanoparticles are fabricated to form nano-in-microparticles.

30. 30. The pharmaceutical composition of claim 28 or 29, wherein the average size of the nanoparticles in the nano-in-micro particle composition is less than 1000 nm or less than 500 nm.

31. The median volume distribution D of nanoparticles in the nano-in-micro particle composition ５０ The pharmaceutical composition according to any one of claims 28 to 30, wherein the particle size is 5 to 30 μm or 10 to 25 μm.

32. 32. The pharmaceutical composition of claim 31, wherein less than 10% of the nanoparticles are less than 10 μm.

33. The pharmaceutical composition according to any one of claims 29 to 32, wherein the polydispersity of the nanoparticles within the nano-in-microparticles is less than 0.5, less than 0.2, or less than 0.

1.

34. The pharmaceutical composition according to any one of claims 29 to 33, wherein the nanoparticles within the nano-in-microparticles are in a colloidally stable formulation.

35. The pharmaceutical composition according to any one of claims 29 to 33, wherein the nano-in-micro particles are in the form of a dry powder.

36. 36. The pharmaceutical composition of claim 35, wherein the nano- or microparticles are compatible with an intranasal spray device.

37. The pharmaceutical composition according to any one of claims 29 to 36, wherein the nano- or microparticles are spherical in shape.

38. 38. A pharmaceutical composition according to any one of claims 23 to 37, wherein the ratio of cannabinoid to amphipathic carbohydrate compound is from 0.5:10 to 5:10 g / g.

39. 39. The pharmaceutical composition of claim 38, wherein the ratio of cannabinoid to amphipathic carbohydrate compound is 1:10 to 3:10 g / g or about 1:5 g / g.

40. 40. The pharmaceutical composition of any one of claims 23 to 39, wherein the cannabidiol is stable at 4°C for at least 4 weeks.

41. 41. The pharmaceutical composition of any one of claims 23 to 40, wherein the cannabidiol is stable at 25°C for at least 4 weeks.

42. 42. A pharmaceutical composition according to any one of claims 23 to 41, wherein the cannabidiol is recovered at least 99% after storage at 4°C for 4 weeks.

43. A pharmaceutical composition comprising GCPQ and a cannabinoid and one or more pharmaceutically acceptable excipients.

44. 44. The pharmaceutical composition of claim 43, wherein the palmitoylation level of GCPQ is in the range of 11 to 31 mol%.

45. 45. The pharmaceutical composition of claim 43 or 44, wherein the quaternization level of GCPQ is in the range of 8 to 17 mole %.

46. 46. ​​A pharmaceutical composition according to any one of claims 43 to 45, wherein the ratio of GCPQ:cannabinoid is from 1:1 to 1:

10.

47. 47. The pharmaceutical composition of claim 46, wherein the cannabinoid is selected from the group consisting of cannabidiol (CBD), cannabigerol (CBG), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabichromene (CBC), and combinations thereof.

48. 48. The pharmaceutical composition of claim 47, wherein the cannabinoid is cannabidiol (CBD).

49. A composition comprising GCPQ and a cannabinoid, wherein the palmitoylation level of the GCPQ is in the range of 11-31 mol %, and the quaternization level of the GCPQ is in the range of 8-17 mol %, and the ratio of GCPQ:cannabinoid is 1:1 to 1:10.

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