Nasal sleep preparations

Abstract

A composition for the treatment of sleep disorders is disclosed, the composition comprising, by weight, 5-30% cannabis oil, 0.1-5.0% cannabidiol (CBD) and / or cannabinol (CBN), 0.01-1.0% lavender oil, 30-95% (or up to 100%) sesame oil, and 0.1-5.0% vitamin E and / or tocopherol equivalents. Such compositions can be administered, for example, intranasally, using a nasal spray bottle or the like.

Description

[Technical field]

[0001] The present invention relates to compositions formulated for intranasal application, e.g., nasal sprays, for use in treating and / or alleviating sleep- or rest-related conditions or disorders in a subject. Treatment may include intranasal application of cannabinoid-containing compositions, e.g., cannabinol (CBN) and cannabidiol (CBD)-containing oil compositions. [Background technology]

[0002] WO2019106652 relates to CBD-containing compositions for treating neurological disorders, muscular disorders, mites, and insomnia.

[0003] WO18232448 relates to sleep disorder compositions and their treatment, and discloses a sleep treatment composition comprising THC and a further cannabinoid.

[0004] WO2019003163 relates to terpene-rich cannabinoid products for women's health.

[0005] US20190314326 discloses dilutable formulations of cannabinoids and methods for their preparation.

[0006] US20190183849 relates to compounds and methods for the treatment of diseases and disorders, and discloses compositions comprising tetrahydrocannabinol (THC) and further cannabinoids. Summary of the Invention [Problem to be solved by the invention]

[0007] Insomnia and other sleep disorders are common problems worldwide, with a significant proportion of the population suffering from sleep disorders and associated conditions and problems.Sleep disorders can interfere with a subject's normal physical, mental, social and emotional functioning, and are therefore serious.

[0008] Common treatments for sleep disorders include, for example, sleeping pills, melatonin supplements, allergy or cold medications, medications for any underlying health problems, breathing devices or surgery (usually for sleep apnea), and dental guards (usually for teeth grinding).

[0009] There is a need for compositions and / or treatments for insomnia and other sleep disorders. [Means for solving the problem]

[0010] As shown herein, from a wide range of potential ingredients and concentration ranges, the inventors have surprisingly and / or unexpectedly found that the following compositions are effective for treating and / or alleviating conditions and symptoms associated with sleep disorders in subjects. Moreover, such formulations and their administration methods are also believed to be useful for treating or ameliorating conditions associated with Parkinson's disease, multiple sclerosis (MS), muscle spasms, anxiety, depression, Alzheimer's disease, epilepsy, pain, and / or conditions or diseases requiring a neuroprotective effect, etc.

[0011] First aspectSo, the present invention relates to a composition comprising, by weight, 5-30% cannabis oil, 0.1-5.0% cannabidiol (CBD) and / or cannabinol (CBN), 0.01-1.0% lavender oil, 30-95% (or up to 100%) sesame oil, and 0.1-5.0% vitamin E and / or tocopherol equivalents. The composition can be formulated for nasal application, e.g., as a nasal spray. For example, compositions are disclosed that include 5-30%, 10-20%, or about 16% cannabis oil, 0.1-5.0%, 0.2-2.0%, or about 0.4% CBD and / or 0.1-5.0%, 0.2-2.0%, or about 0.8% cannabinol CBN, 0.01-1.0%, 0.02-0.5%, or about 0.03% lavender oil, 30-95%, 50-90%, or about 82% sesame oil, and / or 0.1-5.0%, 0.2-1.0%, or about 0.55% vitamin E and / or tocopherol equivalents.

[0012] In some embodiments, the CBD used to provide the composition is crystalline, such as "CBD type A" as disclosed herein. In some embodiments, the CBD is provided as or capable of forming needle-like crystals.

[0013] Second Aspect Thus, the present invention relates to a method of providing a composition, such as a composition for nasal application of the first aspect. Such a method may comprise the steps or acts of (i) providing cannabis oil comprising CBD and / or CBN, (ii) providing lavender oil, sesame oil, and vitamin E (e.g. vitamin E oil), and (iii) mixing the cannabis oil of step (i) with the ingredients of step (ii), and optionally (iv) aliquoting the composition of step (iii) into one or more containers, such as nasal pump spray bottles adapted to provide 50-350 μl, 100-250 μl, or about 160 μl per "puff" (=volume of (liquid) composition for nasal application dispensed upon one actuation of the pump spray).

[0014] Third aspect The invention now relates to a composition provided by the method of the second aspect.

[0015] Fourth aspect Thus, the present invention relates to a container, such as a nasal pump spray bottle, comprising a composition according to the first, third, seventh or eighth aspect.

[0016] Fifth aspect Thus, the invention relates to a kit comprising the container of the fourth aspect, and optionally including instructions for use.

[0017] Sixth Aspect Thus, the present invention relates to a method for the treatment of a subject comprising the intranasal application or administration of a composition of the first, third, seventh or eighth aspect.

[0018] Seventh aspect The present invention thus relates to the composition of the first, third or eighth aspect for use as a medicine and / or therapeutic agent.This may include the treatment of one or more sleep disorders, such as insomnia; snoring; obstructive sleep apnea; sleep hypoventilation; restless legs syndrome; teeth grinding; narcolepsy; sleep talking, sleepwalking and / or other involuntary behaviors; nightmares and / or night terrors; and / or rapid eye movement behavior disorder, and / or related to one or more of these.Further conditions and / or diseases are disclosed herein.

[0019] Eighth aspect Thus, the present invention relates to a pharmaceutical composition comprising or consisting essentially of a composition of the first, third or seventh aspect, optionally comprising one or more pharma- ceutically acceptable carriers and / or diluents.

[0020] Ninth aspectThus, the present invention relates to a CBD-containing composition, such as an intranasal composition, in which the CBD used in the formulation is crystalline and / or "type A CBD". In some embodiments, the composition is a composition disclosed in the first, third, seventh or eighth aspect. In some embodiments, the CBD is type A (e.g. needle-shaped crystals) and / or is capable of forming needle-shaped crystals, such as disclosed herein in the first aspect and / or examples.

[0021] Tenth aspect Thus, the present invention relates to a dosing regimen comprising administering a composition disclosed herein, such as the first, third, seventh, eighth or ninth aspect, e.g., CBD and / or a CBD-containing composition, e.g., an intranasal composition. In some embodiments, the CBD is "type A". [Brief description of the drawings]

[0022] [Figure 1] A micrograph of cannabinol (CBD) forming needle-like crystals. CBD crystals provided by www.enecta.com. [Diagram 2] A micrograph of cannabinol (CBD) forming cluster or cluster crystals. CBD crystals provided by www.pharma-hemp.com. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] definition In the context of the present invention, unless the context clearly indicates otherwise, the singular form of a word may include the plural and vice versa. Thus, "a", "an" and "the" generally include the plural of the respective term. For example, "an ingredient" or "a method" may include a plurality of that "ingredient" or "method".

[0024] Similarly, the words "comprise", "contain", and "contain" should be interpreted inclusively, not exclusively. The embodiments provided by the present disclosure may lack elements not specifically disclosed herein. Thus, the disclosure of an embodiment defined using the terms "comprise" and "contain" is also the disclosure of an embodiment "consisting of" and "consisting essentially of" the disclosed components. Thus, the terms "comprise" and "contain" should generally be interpreted as specifying the presence of a recited part, step, feature, or ingredient, but not excluding the presence of one or more additional parts, steps, features, or ingredients. Thus, for example, a composition containing a compound may contain additional compounds.

[0025] Generally, the compositions disclosed herein, particularly topical and / or orally ingestible compositions, may include one or more pharma- ceutically acceptable carriers, excipients, stabilizers, and the like.

[0026] As used herein, particularly when followed by a list of terms, terms such as "for example" or "such as" are exemplary and descriptive only and should not be considered exclusive or inclusive. Any embodiment disclosed herein may be combined with any other embodiment disclosed herein.

[0027] Unless otherwise specified, all percentages expressed herein are by weight based on the total weight of the composition. Thus, unless otherwise specified, "%" refers to "weight / weight (w / w) %", also known as "weight %" or "wt%".

[0028] In the context of the present invention, the terms "about", "approximately", "approximately", or the symbol "~" may be used interchangeably and are meant to include variations and / or uncertainties normally accepted in the art, such as analytical error. Thus, "about" may also refer to measurement uncertainties commonly experienced in the art, which may be on the order of, for example, + / - 1, 2, 5, 10, or even 20 percent (%). Furthermore, "about" may be understood to refer to numbers in a numerical range, such as a range of + / - 20, + / - 15, + / - 10, + / - 5, + / - 2, + / - 1, + / - 0.5, + / - 0.1% of the referenced number. Additionally, all numerical ranges herein should be understood to include all integers or fractions within the range.

[0029] As used herein, the term "in some embodiments" is meant to include "in one embodiment," "in some embodiments," and "in one or more embodiments."

[0030] In the context of the present invention, the term "subject" or "patient" can be used interchangeably and is meant to include humans, animals, and / or mammals.In particular, a human subject can be selected from, for example, one or more of a female, male, elderly, adult, adolescent, child, or infant.An animal subject can be selected from, for example, a pet, a farm animal, a mammal, a reptile, a bird, and / or a zoo animal.

[0031] In the context of the present invention, the term "treatment" is meant as an action aimed at alleviating, reducing, improving and / or curing any symptoms, condition or disease in a subject. The effectiveness or efficiency of treatment can be evaluated by a control, e.g., no treatment, treatment with a known composition, or treatment with a placebo. Usually, "treatment" in this context includes administration of a suitable amount of the composition to a subject. The compositions of the present invention are preferably administered intranasally, e.g., by nasal spray using a nasal pump spray device used to treat nasal congestion, e.g., Navision® or Otrivin®, which contain xylometazoline, e.g., xylometazoline hydrochloride. Alternatively, the compositions can be administered inside the nostrils by other means, e.g., by applying a suitable amount with a finger or applicator, and / or by "sniffing" or "sniffing".

[0032] In the context of the present invention, the terms "intranasal" and simply "nasal" can be used interchangeably. This also applies to "intrannasally" and simply "into the nasal cavity".

[0033] "Sleep disorder" or "somnipathy" can be described as a disturbance in a subject's sleep pattern. Sleep disorders are common in both children and adults. Disturbances in sleep can be caused by a variety of problems, including teeth grinding (bruxism) and night terrors. In general, when a subject suffers from difficulty falling asleep and / or staying asleep without obvious cause, it is called insomnia. Sleep disorders can be classified into, for example, sleep disorders, parasomnias, circadian rhythm sleep disorders that involve sleep timing, and other disorders, including those caused by medical or mental conditions.

[0034] The most common sleep disorder is insomnia. Other disorders are sleep apnea, narcolepsy and hypersomnia (excessive sleepiness at inappropriate times), sleeping sickness (interruption of the sleep cycle due to infection), sleepwalking, and night terrors.

[0035] Older adults are at increased risk for developing sleep disorders, particularly for sleep-disordered breathing, periodic limb movement, restless legs syndrome, REM sleep behavior disorder, insomnia, and circadian rhythm disorders.

[0036] Nasal sprays are used to deliver drugs locally or systemically to the nasal passages. They are used locally for conditions such as nasal congestion and allergic rhinitis. In some situations, the nasal delivery route is preferred for systemic treatments, as it offers a favorable alternative to injections or pills. Substances can be absorbed very quickly directly through the nose. Many pharmaceutical drugs exist as nasal sprays for systemic administration (e.g., sedative analgesics that treat migraines, osteoporosis, and nausea). Other applications include hormone replacement therapy, which is a treatment for Alzheimer's and Parkinson's disease. Nasal sprays are often considered a more efficient way to deliver drugs that may be used to cross the blood-brain barrier.

[0037] Apart from treating one or more sleep disorders, the composition is also considered suitable for providing rest to subjects who are particularly nervous or even fearful, particularly irrational fear. Examples can include situations of users such as in public transport, passengers on airplanes, trains, buses or cars, such as travel situations where subjects want to rest and / or sleep but are prevented from doing so by anxiety. Further conditions and / or examples can include jet lag, anxiety, and / or difficulty falling asleep in unusual circumstances, such as when traveling, such as when not sleeping at home, such as when traveling on a bus, car, train, airplane, ship, in a hotel, pension, prison, or in a hospital, hospice, etc., or during military service. In some embodiments, the composition provides positive effects and / or treatments in conditions related to Parkinson's disease, multiple sclerosis (MS), muscle spasms, anxiety, depression, Alzheimer's disease, epilepsy, pain relief, and / or neuroprotective effects.

[0038] First aspectSo, the present invention relates to a composition comprising, by weight, 5-30% cannabis oil, 0.1-5.0% cannabidiol (CBD) and / or cannabinol (CBN), 0.01-1.0% lavender oil, 30-95% (or up to 100%) sesame oil, and 0.1-5.0% vitamin E and / or tocopherol equivalents.

[0039] The composition can be formulated for nasal application, for example as a nasal spray.

[0040] "Hemp seed oil" or "cannabis oil" is obtained by pressing hemp seeds. It is rich in healthy oils and fatty acids and is popular as a treatment for various conditions, including skin problems and stress. It may also contain properties that contribute to reducing the risk of diseases such as Alzheimer's and cardiovascular disease. Hemp oil may also reduce inflammation in the body. Hemp oil contains high amounts of omega-6 and omega-3 lipids, as well as all nine essential amino acids. Hemp seeds also contain the following compounds: vitamin C, calcium, iron, omega-3 fatty acids, gamma-linolenic acid, arginine, magnesium, and vitamin B. Hemp oil may contain further compounds, among them cannabinoids, but only in very small or trace amounts.

[0041] "Cannabidiol" or "CBD" (CAS number 3956-29-1) is a common cannabinoid used to treat a variety of medical conditions, including insomnia. CBD is considered one of many non-psychoactive cannabinoids found in cannabis, in contrast to tetrahydrocarbinol (THC) and tetrahydrocannabivarin (THCV).

[0042] "Cannabinol" or "CBN" (CAS number 521-35-7) is a cannabinoid that has been shown to effectively serve as a sleep aid or sedative, to regulate the immune system, and to reduce pain and inflammation caused by several conditions, including insomnia, arthritis, and Crohn's disease. It is considered mildly psychoactive and is found in only trace amounts in cannabis.

[0043] "Lavender essential oil" or "lavender oil" is used, for example, in aromatherapy. Generally, lavender oil is produced by steam distillation of the flowers of Lavandula angustifolia. The oil is believed to promote rest and treat anxiety, fungal infections, allergies, depression, insomnia, dermatitis, nausea, and menstrual cramps.

[0044] "Sesame oil" is an edible oil obtained by pressing sesame seeds. Sesame oil can also be used for a variety of treatments and ailments. Sesame oil is believed to have antifungal, antiviral, and anti-inflammatory properties. Additionally, it contains antioxidants such as sesamol and sesaminol.

[0045] "Vitamin E" is a group of eight fat-soluble compounds, including four tocopherols and four tocotrienols. Both tocopherols and tocotrienols occur in alpha, beta, gamma, and delta forms, determined by the number and position of methyl groups on the chromanol ring. Vitamin E is the major fat-soluble antioxidant in the cellular antioxidant defense system and is obtained exclusively from the diet. Vitamin E has health-promoting properties due to its antioxidant activity and ability to stabilize cell membranes and promote restoration of skin barrier function. Generally, the vitamin E activity of the various vitamin E isomers is expressed as "alpha-tocopherol equivalents" or simply "tocopherol equivalents" ("TE") herein. 1 TE is the activity of 1 mg of RRR-alpha-tocopherol (d-alpha-tocopherol). According to the Food and Agriculture Organization of the United Nations, for example, β-tocopherol should be multiplied by 0.5, γ-gamma-tocopherol by 0.1, and α-tocotrienol by 0.3.

[0046] In some embodiments, the composition comprises 5-30%, 10-20%, or about 16% cannabis oil.

[0047] In some embodiments, the composition comprises 0.1-5.0%, 0.2-2.0%, or about 0.4% CBD.

[0048] In some embodiments, the composition comprises 0.1-5.0%, 0.2-2.0%, or about 0.8% CBN.

[0049] In some embodiments, the composition comprises 0.01-1.0%, 0.02-0.5%, or about 0.03% lavender oil.

[0050] In some embodiments, the composition comprises 30-95%, 50-90%, or about 82% sesame oil.

[0051] In some embodiments, the composition comprises 0.1-5.0%, 0.2-1.0%, or about 0.55% vitamin E and / or tocopherol equivalents.

[0052] Thus, in some embodiments, by weight: i. 5-30%, 10-20%, or about 16% cannabis oil; ii. 0.1-5.0%, 0.2-2.0%, or about 0.4% cannabidiol (CBD) and / or 0.1-5.0%, 0.2-2.0%, or about 0.8% cannabinol (CBN); iii. 0.01-1.0%, 0.02-0.5%, or about 0.03% lavender oil; iv. 30-95%, 50-90%, or about 82% sesame oil; and Compositions are provided that contain between 0.1 and 5.0%, between 0.2 and 1.0%, or about 0.55% vitamin E and / or tocopherol equivalents.

[0053] Such compositions containing CBD, CBN, or CBD and CBN may be or are formulated for nasal application, such as by spraying by suitable means, such as by using a nasal spray bottle, to administer a suitable, preferably defined amount. Typically, such compositions are often referred to herein as "nasal spray compositions" or simply "nasal compositions," and both terms can be used interchangeably.

[0054] In some embodiments, the nasal composition comprises both CBN and CBD. Surprisingly and unexpectedly, compositions containing more CBN than CBD have shown better efficacy. Thus, in some embodiments, the weight ratio of CBN:CBD is greater than 1.

[0055] In some embodiments, the ratio of CBN:CBD can range from 10:1 to 5:1, 5:1 to 4:1, 4:1 to 3:1, 3:1 to 2:1, or 2:1 to 1.1. In some embodiments, the ratio of CBN:CBD is about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3.5:1, about 3:1, about 2.5:1, about 2:1, about 1.5:1, about 1.25:1, about 1.2:1, about 1.15:1, or about 1.1:1. In some embodiments, the ratio of CBN:CBD is in the range of 2.5:1 to 1.5:1, 2.25:1.75, 2.2 to 1.8, 2.1 to 1.9, or about 2:1. In some embodiments, the ratio of CBN:CBD ranges from 5:1 to 1:1, 4:1 to 1.1:1, 3:1 to 1.1:1, 2.5:1 to 1.1:1, 2.2:1 to 1.1., 2:1.1, 1.75:1, 1.5:1, 1.25:1, or 1.15:1. In some embodiments, the ratio of CBN to CBD is about 3:1 to 1.5:1, 2.5:1.75, 2.2 to 1.8, 2.1:1:9, or about 2:1.

[0056] A ratio such as 3:1-1.5 is believed to provide a good balance of the two cannabinoids, for example in terms of treating sleep disorders and / or one or more other conditions disclosed herein.

[0057] In some embodiments, the nasal composition may comprise one or more additional cannabinoids, such as one or more psychoactive cannabinoids and / or one or more non-psychoactive cannabinoids in a physiologically active amount. Such additional cannabinoids may be selected, for example, from one or more of THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBDA (cannabidiolic acid), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), THCP (tetrahydrocannabiphorol), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), and CBT (cannabicitran), and any combination thereof. In some embodiments, the one or more cannabinoids are present in physiologically insignificant amounts, such as impurities in one or more of the cannabis oil, CBN, and / or CBD. Typically, impurities are present at less than 1.5, 1.0, 0.5, 0.2, or 0.1% of the one or more additional cannabinoids relative to the total composition, the cannabis oil, CBN, or CBD.

[0058] In some embodiments, the composition may thus comprise 0.1-5.0% CBN and / or CBD, wherein said composition, CBN, CBD, and / or cannabis oil (x) does not comprise, (y) does not comprise in a physiologically active amount, and / or (z) comprises less than 2.0, 1.5, 1.0, 0.5, 0.2 or 0.1% (w / w) of one or more further cannabinoids, such as one or more cannabinoids selected from THC, THCA, CBDA, CBG, CBC, CBL, CBV, THCV, THCP, CBDV, CBCV, CBGV, CBGM, CBE, and CBT.

[0059] Additionally, a low content of one or more of CBDV, CBDA, CBG, THC, and / or THCV may indicate CBD and / or CBN of sufficient purity for the compositions of the present invention.

[0060] Suitable cannabis oil, CBD and / or CBN of sufficient purity can be supplied, for example, from www.enecta.com.

[0061] In some embodiments, the CBD is "crystalline" or "pure" CBD, e.g., CBD in powder form, having a purity of at least 98% and containing less than 1.5% (w / w) CBDV, CBG, and / or CBN, and less than 0.05% THC.

[0062] In some embodiments, the CBN is "crystalline" or "pure" CBN, e.g., CBN in powder form, having a purity of at least 98% and containing less than 1.5% (w / w) CBDV, CBG, and / or CBD, and less than 0.05% THC.

[0063] In some embodiments, the composition and / or cannabis oil comprises ≦0.2% by weight or ≦0.05% by weight CBDV. Typically, a low content of CBDV and / or other cannabinoids is desirable.

[0064] In some embodiments, the composition and / or cannabis oil comprises ≦0.2% by weight or ≦0.05% by weight CBDA. Typically, a low content of CBDA and / or other cannabinoids is desirable.

[0065] In some embodiments, the composition and / or cannabis oil comprises ≦0.5% by weight or ≦0.025% by weight of CBG. Typically, a low content of CBG and / or other cannabinoids is desirable.

[0066] In some embodiments, the composition and / or cannabis oil comprises ≦0.05% by weight or ≦0.020% by weight THC. Typically, a low content of THC or THCV and / or other cannabinoids, particularly psychoactive cannabinoids, is desirable.

[0067] As disclosed above, the composition may or may not include an additional cannabinoid, in some embodiments, such additional cannabinoid is a psychoactive cannabinoid, such as THC and / or THCV, and / or a cannabinoid that binds to CB1 receptor. In some embodiments, the additional cannabinoid is a non-psychoactive cannabinoid, such as one or more cannabinoids selected from THCA, CBDA, CBG, CBC, CBL, CBV, THCP, CBDV, CBCV, CBGV, CBGM, CBE, and CBT, and / or a cannabinoid that does not bind to CB1 receptor. In some embodiments, the additional cannabinoid is selected from or is one or more of THC, THCA, CBDA, CBG, CBC, CBL, CBV, THCV, THCP, CBDV, CBCV, CBGV, CBGM, CBE, and CBT, and any combination thereof.

[0068] Conventional nasal sprays contain salt, such as saline, and / or about 0.9% NaCl, whereas in some embodiments the compositions do not contain sodium chloride (saline) and / or contain less than 0.1 or 0.05% (w / w) NaCl.

[0069] Similarly, conventional nasal sprays contain water, whereas in some embodiments the compositions contain no water, e.g., no added water, and / or less than 1.0, 0.5, or 0.1% (w / w) water.

[0070] Surprisingly and unexpectedly, the nasal sprays disclosed herein that do not contain NaCl and / or water not only provide good results, but are also comfortable to use.

[0071] In some embodiments, the cannabis oil comprises ≦0.2% or ≦0.05% CBDV by weight, ≦0.2% or ≦0.05% CBDA by weight, ≦0.5% or ≦0.025% CBG by weight, and ≦0.05% or ≦0.020% THC by weight.

[0072] In some embodiments, the lavender oil has CAS number 8000-28-0 and INCI name: LAVANDULA ANGUSTIFOLIA OIL. In some embodiments, the lavender oil comprises (by weight) about 0.05% coumarin (CAS number 91-64-5), about 0.40% geraniol (CAS number 106-21-1), about 0.5% D-limonene (CAS number 5989-27-5), about 30% linalool (CAS number 78-70-6), and about 1% VOC-CH content. In some embodiments, the lavender oil comprises one or more of about 0.05% coumarin (CAS No. 91-64-5), about 0.40% geraniol (CAS No. 106-21-1), about 0.5% D-limonene (CAS No. 5989-27-5), and / or about 30% linalool (CAS No. 78-70-6). www.voegele-ingredients.de More can be provided.

[0073] In some embodiments, the sesame oil is a refined oil with the following specifications: acid < 0.5, peroxide value < 10.0, non-saponifiable matter < 2% (w / w), alkaline matter < 0.1, water < 0.1%. With respect to triglyceride composition, in some embodiments, the refined sesame oil comprises (by weight) 7-19% LLL, 13-30% OLL, 5-9% PLL, 12-23% OOL, 6-14% POL, 5-16% OOO, 2-8% SOL, and 2-10% POO. The fatty acid groups are expressed as linoleic acid (L), oleic acid (O), palmitic acid (P), and stearic acid (S). The triglyceride abbreviations used are trilinolein (LLL), 1,2-dilinoleoyl-3-oleoyl-rac-glycerol (OLL), 1,2-dilinoleoyl-3-palmitoyl-rac-glycerol (PLL), 1,2-dioleoyl-3-linoleoyl-rac-glycerol (OOL), 1-palmitoyl-2-oleoyl-3-linoleoyl-rac-glycerol (POL), triolein (OOO), 1-linoleoyl-2-oleoyl-3-stearoyl-rac-glycerol (SOL), and 1,2-dioleoyl-3-palmitoyl-rac-glycerol (POO). A suitable sesame oil is e.g. www.oelmuehle-hartmann.de is available at

[0074] In some embodiments, the cannabis oil, lavender oil, and sesame oil are as defined above. The use of such compositions is believed to provide a product with satisfactory properties in the context of the present invention, i.e., when provided in appropriate amounts as defined herein.

[0075] In some embodiments, suitable compositions also have the following characteristics: (a) a higher concentration of CBD than CBN; low(e.g., a ratio of about 1:2); (b) a concentration of CBD dissolved in the cannabis oil of 1-10% or 2-5%*; (c) a concentration of CBN dissolved in the cannabis oil of 2-20% or 4-10%; (d) the absence of physiologically active amounts of other cannabinoids, particularly THC or other psychoactive components; and (d) the absence of saline and / or alcohol.

[0076] In some embodiments, CBD and / or CBN can be dissolved in one or more of sesame oil, hemp oil, and lavender oil, and thus not just in hemp oil.

[0077] Generally, non-hallucinogenic cannabinoids are preferred to avoid undesirable side effects during use or treatment with compositions containing such compounds, especially when they are present in physiologically active amounts.

[0078] Further suitable concentrations and / or concentration ranges may be disclosed herein.

[0079] With respect to the CBD used in preparing or formulating a CBD-containing composition, in some embodiments, the CBD used to provide said composition is crystalline. In some embodiments, the CBD is "A-type CBD." In many cases, the use and / or presence of "A-type CBD" is preferred over "B-type CBD."

[0080] In some embodiments, the CBD used to provide the compositions disclosed above is characterized by certain features, such as crystal structure, type and / or higher order structure. The inventors have surprisingly and unexpectedly observed that CBD with needle-like crystal structure (=crystal structure A, see FIG. 1) appears to be significantly more potent than CBD with a different crystal structure, a non-needle-like structure (also referred to herein as "tufted" or "clustered") (=crystal structure B, see FIG. 2) (see, e.g., Example 10).

[0081] In some embodiments, the CBD, when crystalline, has or is capable of forming a needle-like crystal structure, hi some embodiments, the CBD of crystal structure A (or capable of forming needle-like crystals) is at least 1.5, 2, 3, 4, 5, 7.5, 10, 15 or 20 times more potent on a weight / weight basis than the CBD of crystal structure B (or capable of forming clustered / tassel-like crystals).

[0082] A CBD of crystal structure A, or capable of forming needle-like crystals, is also referred to herein as "A-type CBD," while a CBD of crystal structure B, or capable of forming "tufted" or "clustered" crystals, is referred to as "B-type CBD." In some embodiments, the CBD is "A-type CBD." In many instances, "A-type CBD" is preferred over "B-type CBD."

[0083] It may be speculated whether CBD needs to be in one or more specific conformations in an active form in order to be active upon administration to a subject, such as in a topical formulation. Lack of activity or efficacy may also be caused by lower uptake rates and / or difficulty in penetrating the skin.

[0084] Without wishing to be bound by any theory, it is conceivable that the difference in crystal structure may be caused by different molecular structures, e.g., different conformations. This may be due, for example, to the subject's body being unable to recognize the "wrong" CBD conformation. It is conceivable that the difference in CBD crystal structure may be caused by different extraction methods. In particular, the CBD disclosed in FIG. 1 was provided by an extraction method including extraction with isopropanol, distillation with heptane, and crystallization (see, for example, Example 9), while the CBD disclosed in FIG. 2 was provided by supercritical CO2 extraction.

[0085] Generally, crystalline CBD may be provided by methods and techniques known in the art, such as those disclosed in US10413845 and / or US10414709.

[0086] In short, crystalline CBD: Hemp or cannabis is dissolved in isopropanol or other extraction to produce an extract rich in cannabinoids, THC, CBD, and terpenes; The solvent portion of the extract evaporation to produce a substantially solvent-free extract; Virtually solvent-free extract distillation and isolating the CBD; and Distilled and isolated CBD Crystallization to produce crystallized and isolated CBD, optionally followed by one or more recrystallizations using a suitable organic solvent, such as an alkane, e.g., heptane, typically By vacuum drying, etc. Solvent Removal to remove volatile residues. The method can be provided by a method consisting essentially of hemp or cannabis (Cannabis sativa).

[0087] Thus, in some embodiments, the CBD crystals used to formulate and / or provide a topical composition are needle-shaped crystals, such as the crystals shown in Figure 1. Similarly, in some embodiments, the CBD crystals used to formulate a topical composition are not clustered or bunched, such as crystals similar to those shown in Figure 2.

[0088] In some embodiments, the CBD crystals used to provide and / or formulate the topical composition are not provided by an extraction method that includes supercritical CO2 extraction.

[0089] In some embodiments, the CBD crystals used to provide and / or formulate the topical composition are provided by a method comprising extraction with a C3-C4 alcohol, e.g., isopropanol, and one or more crystallization steps with a C6-C8 alkane, e.g., heptane. In some embodiments, the C3-C4 alcohol is isopropanol. In some embodiments, the C6-C8 alkane is heptane. In some embodiments, the C3-C4 alcohol is isopropanol and the C6-C8 alkane is heptane. It is believed that this combination provides CBD crystals of satisfactory quality, such as the absence or reduction of inhibitors and / or the desired conformation of CBD.

[0090] In some embodiments, a suitable CBD composition or product can be obtained when CBD crystals are provided by a process comprising CO2 extraction, in particular critical CO2 extraction, and one or more crystallization steps with a C6-C8 alkane, such as heptane.

[0091] As shown in Table 1, it can be seen that the cannabinoid profiles of CBD-A and CBD-B can be quite similar.

[0092] [Table 1]

[0093] However, it is conceivable that differences in crystal structure may be related to and caused by different extraction methods. Different crystal structures may also exhibit different concentrations of "CBD inhibitors" and / or different concentrations of "CBD enhancers". In some embodiments, terpenes, such as naturally occurring terpenes, particularly those found in plants, such as Cannabis sativa, are undesirable because they act as CBD inhibitors.

[0094] Thus, in some embodiments, CBD of crystal structure B, also known as "CBD type B", can be converted to CBD of crystal structure A, also known as "CBD type A" (and / or CBD capable of forming crystal structure A) by an organic extraction and / or recrystallization step. In such embodiments, it is conceivable that the change in crystal structure is related to the presence of inhibitors, which are significantly reduced in an additional extraction and / or crystallization step. Alternatively, the organic extraction step can provide a conformational change in CBD, making it more active again. In some embodiments, recrystallization with heptane can transform CBD type B into CBD type A.

[0095] In some embodiments, the CBD of crystalline structure B was provided by supercritical CO2 extraction, e.g. www.pharma-hemp.com and / or according to extraction protocols similar to those of the manufacturer.

[0096] In some embodiments, the presence of terpenes and / or terpenoids, particularly Cannabis sativa terpenes, in the CBD-containing topical compositions disclosed herein provides one or more undesirable effects, such as reduced efficacy or potency, inability or reduced ability to recognize CBD, the need for higher concentrations of CBD formulations to achieve similar effects, and an increase in non-CBD cannabinoids in the formulation. In some embodiments, the composition comprises 0.0001% or less, 0.001% or less, 0.01% or less, or 0.1% or less of terpenes, particularly Cannabis sativa terpenes, by weight.

[0097] In some embodiments, the crystalline CBD does not contain significant amounts of terpenes, e.g., less than 0.1%, less than 0.05%, less than 0.02%, less than 0.01%, less than 0.005%, less than 0.002%, less than 0.001% terpenes by weight.

[0098] It is also conceivable that other plant components, such as terpenoids, may act as inhibitors. In some embodiments, the presence of terpenoids, such as Cannabis sativa terpenoids, may be undesirable. In some embodiments, the crystalline CBD does not contain significant amounts of terpenoids, for example, less than 0.1% by weight, less than 0.05% by weight, less than 0.02% by weight, less than 0.01% by weight, less than 0.005% by weight, less than 0.002% by weight, less than 0.001% by weight of terpenoids.

[0099] In some embodiments, the use of CBD having or capable of providing crystals of crystal structure A, such as those shown in FIG. 1, in the CBD-containing compositions disclosed herein provides one or more of positive effects, such as improved efficacy, the potential to reduce the total amount of CBD in the formulation, a subject needing less intranasal formulation to achieve the same effect, improved recognition and / or uptake of CBD by the subject's body, reduction in non-CBD cannabinoids and / or other impurities in the formulation.

[0100] Generally, the composition of the first aspect can be provided using methods and procedures known in the art. In some embodiments, the composition of the first aspect can be provided as shown in the second aspect and / or examples.

[0101] In some embodiments, the CBD is "Type A CBD." In many cases, the use of "Type A CBD" is preferred over "Type B CBD."

[0102] Further embodiments of various compositions of the present invention are also disclosed in the examples.

[0103] Second AspectThus, the present invention relates to a method of providing a composition for nasal application according to a first aspect. Such a method may comprise the steps or acts of (i) providing cannabis oil comprising CBD and / or CBN, (ii) providing lavender oil, sesame oil, and vitamin E (e.g. vitamin E oil), and (iii) mixing the cannabis oil of step (i) with the ingredients of step (ii), and optionally (iv) aliquoting the composition of step (iii) into one or more containers, for example a nasal pump spray bottle adapted to provide 50-350 μl, 100-250 μl, or about 160 μl per puff.

[0104] In some embodiments, the CBD is "Type A CBD." In many cases, the use of "Type A CBD" is preferred over "Type B CBD."

[0105] In some embodiments, there is provided a method of providing a composition for nasal application according to any one of the preceding claims, comprising: i. the process or act of providing cannabis oil containing CBD and / or CBN; ii. the step or act of providing lavender oil, sesame oil, and vitamin E (e.g., vitamin E oil); and iii. The step or act of mixing the cannabis oil of step (i) with the ingredients of step (ii), and optionally iv. The step or act of aliquoting the composition of step (iii) into one or more containers, e.g., a nasal pump spray bottle adapted to provide 50-350 μl, 100-250 μl, or about 160 μl per puff. A method is disclosed that includes:

[0106] In some embodiments, the aliquot size is comparable to conventional nasal sprays on the market, hi some embodiments, the aliquot size is 1-20, 2-15, 3-12, or 5-10 ml.

[0107] Alternatively, the CBD and / or CBN can be dissolved in one or more of cannabis oil, sesame oil, and / or lavender oil. In some embodiments, the CBD and / or CBN is dissolved in sesame oil or in an oil mixture comprising cannabis oil and / or sesame oil and optionally lavender oil.

[0108] Generally, the composition will be protected from electromagnetic radiation, such as UV or visible light, to enhance shelf life, such as when stored at room temperature. This can be provided by means known in the art, such as light-proof packaging. In some embodiments, the container provides protection from UV light and / or visible light.

[0109] Third aspect The invention now relates to a composition provided by the method of the second aspect, such as a composition for intranasal application.

[0110] Fourth aspect Thus, the present invention relates to a container comprising a composition of the first, third, seventh or eighth aspect, e.g., a composition for intranasal application. In some embodiments, such a container can be a nasal pump spray bottle, e.g., a commonly sold nasal spray bottle containing oxymetazoline hydrochloride (e.g., 10 ml), e.g., "Nasivin" or similar.

[0111] In some embodiments, the container provides light and / or UV protection to the composition.

[0112] In some embodiments, the container is a nasal pump spray bottle, for example a pump bottle for administering 50-350 μl, 100-250 μl, or about 160 μl per puff per nostril.

[0113] In some embodiments, the container is adapted to contain a volume of 1-20, 2-15, 3-12, or 5-10 ml of composition for nasal application.

[0114] Fifth aspect Thus, the invention relates to a kit comprising the container of the fourth aspect, and optionally including instructions for use.

[0115] In some embodiments, the kit comprises packaging, such as a carton, for the container and / or instructions for use.

[0116] To provide protection from light and / or UV, in some embodiments, the packaging may provide light protection and / or UV protection. Thus, in some embodiments, the container and / or packaging may provide protection from UV light and / or visible light.

[0117] Sixth Aspect Thus, the present invention relates to a method for the treatment of a subject comprising the intranasal application or administration of a composition disclosed herein, such as a composition of the first, third, seventh or eighth aspect.

[0118] In some embodiments, the composition can be administered as described in the instructions. The nasal spray delivers the target dose (e.g., 160 μl) per spray (or "puff") and is manually operated to deliver the contents by pushing the plunger base into the flange until it stops. To use the nasal spray: (1) Close the nostril that is not to receive the medication. This is done by slowly pushing that nostril. (2) Slowly insert the tip of the bottle into the other nostril. (3) While squeezing the bottle (pushing the plunger base into the flange until it stops), take a deep breath through that nostril and apply one spray into the nasal cavity. (4) Repeat steps 1-4 for the other nostril. In some embodiments, if a larger dose is required, more than one puff per nostril may be required. Typically, administration of the nasal composition is performed using both nostrils. Alternatively, the application can be performed using only one nostril.

[0119] In some embodiments, the subject is an animal or a human.

[0120] In some embodiments, the subject is an infant, child, adolescent, adult, or elderly.

[0121] In some embodiments, the dosage regimen is 50-350 μl, 100-250 μl, or about 160 μl in each nostril. The application is usually performed in both nostrils. Alternatively, the application can be performed using only one nostril. In that case, it may be desirable to double the dosage / volume.

[0122] In some embodiments, the dosing regimen is 0.5-5, 1.5-3.5, or about 2.8 mg of CBN total per application, typically involving both nostrils. The application is typically performed in both nostrils. Alternatively, the application can be performed using only one nostril.

[0123] In some embodiments, the dosing regimen is 0.5-4, 0.8-1.8, or about 1.4 mg of CBD per application, typically involving both nostrils. The application is typically performed in both nostrils. Alternatively, the application can be performed using only one nostril.

[0124] In some embodiments, the dosing regimen is 0.5-5, 1.5-3.5, or about 2.8 mg total CBN and 0.5-4, 0.8-1.8, or about 1.4 mg total CBD per application, typically involving both nostrils. The application is typically performed in both nostrils. Alternatively, the application can be performed using only one nostril.

[0125] In some embodiments, the subject suffers from a sleep disorder associated with insomnia, snoring, obstructive sleep apnea, sleep hypoventilation, restless legs syndrome, teeth grinding, narcolepsy, talking in one's sleep, sleepwalking and / or other involuntary behaviors, nightmares and / or night terrors, rapid eye movement behavior disorder.

[0126] In some embodiments, the treatment may be for conditions such as jet lag, anxiety, and / or difficulty falling asleep in unusual circumstances, e.g., when traveling, e.g., when not sleeping at home, e.g., while traveling by bus, car, train, plane, in a hotel, boarding house, boarding school, prison, or in a hospital, hospice, etc., or during military or similar duty. In some embodiments, the compositions provide positive effects and / or treatment in conditions associated with Parkinson's disease, multiple sclerosis (MS), muscle spasms, anxiety, depression, Alzheimer's disease, epilepsy, pain, pain relief, and / or neurological conditions requiring a neuroprotective effect.

[0127] With regard to the effects of the treatment of the present invention, which may include, but are not limited to, those related in particular to sleep disorders and / or anxiety, such effects may include: Positive effects within 10-15 minutes of administration, Increased sleep duration, Fewer awakenings during intended sleep times, Increased feeling of refreshment the next day, The subject does not feel dazed, Reduced drowsiness, Increased deep sleep, Improve quality of life, It doesn't make people's consciousness dizzy. One spray in each nostril 10 to 15 minutes before bedtime is sufficient. relaxes muscles, Calms the body and mind, Fewer nightmares, and any combination thereof. may include one or more of:

[0128] Further desirable effects may include one or more measurable patterns or behaviors detectable by means common in the art, such as polysomnography and / or activity measurement (see, eg, Example 8).

[0129] Seventh aspectIn this regard, the present invention relates to the composition of the first, third or eighth aspect for use as a medicine and / or therapeutic agent.This may include the treatment of one or more sleep disorders, such as insomnia, snoring, obstructive sleep apnea, sleep hypoventilation, restless legs syndrome, teeth grinding, narcolepsy, sleep talking, sleepwalking and / or other involuntary behavior, nightmares and / or night terrors, and / or rapid eye movement behavior disorder, and / or related to one or more of these.In some embodiments, this may relate to the conditions and / or effects described herein, such as the sixth aspect.

[0130] Eighth aspect Thus, the present invention relates to a pharmaceutical composition comprising or consisting essentially of a composition of the first, third or seventh aspect, optionally comprising one or more pharma- ceutically acceptable carriers and / or diluents.

[0131] Ninth aspect Thus, the present invention relates to a CBD-containing composition, such as an intranasal composition and / or a composition for intranasal application, in which the CBD used in the formulation is crystalline and / or "type A CBD". In some embodiments, the composition is a composition disclosed in the first, third, seventh or eighth aspect. In some embodiments, the CBD is type A (e.g. needle-shaped crystals) and / or is capable of forming needle-shaped crystals, as disclosed herein, such as in the first aspect and / or examples.

[0132] Tenth aspect In the present invention, the present invention relates to a dosing regimen comprising administering a composition disclosed herein, such as the first, third, seventh, eighth or ninth aspect, e.g. a CBD and / or CBD-containing composition, e.g. an intranasal composition. In some embodiments, the CBD is "Form A" (e.g. needle-shaped crystals) and / or is capable of forming needle-shaped crystals, as disclosed herein, such as in the first aspect and / or examples.

[0133] The present invention is further illustrated in the following sections, which examples should not be construed as limiting the invention, however. EXAMPLES

[0134] Example 1 - Providing a nasal sleep composition Generally, the compositions can be formulated using methods and equipment conventional in the art.

[0135] Unless otherwise stated, percentages are by weight.

[0136] Generally, crystalline CBD is supplied by Enecta unless otherwise stated.

[0137] Provide cannabis oil containing CBD and / or CBN, such as by adding a suitable amount of CBD and / or CBN to the cannabis oil. Provide lavender oil, sesame oil, and vitamin E (e.g., vitamin E oil) in desired amounts (by weight) and mix with cannabis oil containing CBD and / or CBN. Divide the composition into suitable containers, such as nasal pump spray bottles, and keep protected from light. Store the composition preferably in a UV and light-tight container. For long-term storage, store the composition at 10-25 degrees Celsius.

[0138] For the cannabis oil containing CBD and CBN used in composition A, the Certificate of Analysis contains the following details: Product: 2.5% CBD 5% CBN cannabis oil, analysis number 20072002, product lot number Q0720L-0; yellow-green oil; analysis date 23 July 2020; Test results and specified limits: Analysis (HPLC) CBD2.48% 2.5±0.50%; CBN5.07% 5.0±0.50%; Related substances(%): CBDV 0.03%≦0.20%; CBDA 0.02%≦0.20%; CBG 0.01%≦0.50%; THC 0.01%≦0.05%; Further analysis: KF 0.1%≦0.5%; color (420 nm) 0.108AU≦0.300AU; total ash 0.08%≦0.30%; density 0.932g / ml≦0.950g / ml; viscosity 52mPa≦150mPa; peroxide 9meq O2 / kg≦15meq O2 / kg; Heavy metals: Arsenic, ongoing ppm≦1.5ppm; Cadmium, ongoing ppm≦0.5ppm; Mercury, ongoing ppm≦3.0ppm; Lead, ongoing ppm≦0.5ppm Microbiology: Total bacteria 35cfu / g ≤ 1000cfu / g; Yeast and mold 30cfu / g ≤ 100cfu / g; Salmonella: None / 25g; Escherichia coli: None / 10g; Pseudomonas aeruginosa: None / 1g; Coagulase positive Staphylococci: None / 1g

[0139] Other CBD and / or CBN concentrations can be provided, for example, by dissolving the appropriate amount of CBD and / or CBN in a suitable oil, such as cannabis oil. CBD and CBD are provided as "crystalline" or "pure" CBD in powder form having a purity of at least 98% and containing less than 1.5% (w / w) CBDV, CBG, and / or CBN, and less than 0.05% THC.

[0140] [Table 2]

[0141] [Table 3]

[0142] [Table 4]

[0143] Example 2 - Application / Use of Nasal Sleep Composition The different formulations for intranasal administration via "nose spray" are administered according to the instructions provided to the test subjects.

[0144] The nasal spray delivers a target dose of 160 μl per spray and is manually operated to deliver contents by pushing the plunger base into the flange until it stops.

[0145] Using the nasal spray: 1. Close the nostril that is not receiving the medication by gently pressing on that side of the nose. 2. Gently insert the tip of the bottle into the other nostril. 3. While squeezing the bottle (pressing the plunger base into the flange until it stops), inhale deeply through that nostril and apply one spray into the nasal cavity. 4. Repeat steps 1-4 for the other nostril. If necessary, multiple doses can be provided by repeating step 3.

[0146] Example 3 - Inclusion and Exclusion Criteria for Sleep Studies Selection criteria: Men and women aged 18-60 Typically, healthy individuals have mild to moderate symptoms of one of the following sleep disorders (SD): (1) insomnia, (2) snoring, (3) obstructive sleep apnea, (4) sleep hypoventilation, (5) restless legs syndrome, (6) teeth grinding, (7) narcolepsy, (8) sleep talking, sleepwalking, and other involuntary behaviors, (9) nightmares and night terrors, and (10) rapid eye movement behavior disorder.

[0147] Subjects were sleep deprived for more than one month, defined by medical history and / or objective devices (wrist activity monitor and sleep log) as regularly sleeping less than about 6.5 hours per night.

[0148] Inclusion criteria: External comparators for the extension of the efficacy study must meet the above criteria.

[0149] Exclusion Criteria: Diagnosed sleep disorders included: (a) chronic insomnia; (b) untreated sleep-disordered breathing (sleep apnea of ​​a certain level of severity [using standardized metrics]) or diagnosed UARS [upper airway resistance syndrome] that would impair ability to extend sleep duration [intervention group] or maintain sleep duration [comparison group]; (c) central apnea; (d) unstable weight (voluntary loss of BMI >5% over the past 6 months); currently enrolled in a weight loss program; (e) untreated or uncontrolled diabetes; (f) severe uncontrolled hypertension; (g) Medications: chronic use of prescription or over-the-counter medications (e.g., systemic corticosteroids, NSAIDs) known to affect sleep; current anticonvulsant therapy; (h) chronic fatigue syndrome and fibromyalgia; (i) acromegaly, hypothyroidism (unless on stable thyroid hormone replacement doses), Cushing's disease, or other endocrine disorders known to affect sleep; (j) ) inadequately controlled major depression (subjects must have been on stable pharmacological antidepressant treatment for 3 months and in remission without significant weight gain are eligible); (k) other current DSM-IV diagnoses, including: eating disorders, e.g., bulimia nervosa and binge eating disorder; anxiety disorders, e.g., PTSD and panic attacks; mania; and schizophrenia; (l) medication and substance abuse, e.g., excessive alcohol use or drug abuse or dependence that may compromise adherence; (m) rotational or shift workers (working in the evening or at night), and (n) being a long-distance commuter (greater than approximately 90 minutes one way) or frequently traveling across time zones; having an occupation that may require special vigilance, such as driving a truck, bus, or taxi; operating heavy machinery; being a pilot or air traffic controller; (o) being prone to traveling to different geographic areas during the study; (p) having sleep partners that would make compliance with study requirements difficult; (o) pregnancy and breastfeeding; (q) chronic excessive caffeine use (habitual intake of >500 mg / day).

[0150] Example 4 - Test Results (Formulations A to C)

[0151] [Table 5]

[0152] [Table 6]

[0153] [Table 7]

[0154] Example 5 Further intranasal formulations having various ratios and concentrations of CBD and CBN were provided according to Example 1.

[0155] The appropriate amounts of CBD and CBN were dissolved in essentially cannabinoid-free cannabis oil.

[0156] The CBD and CBD are provided as "crystalline" or "pure" CBD in powder form having a purity of at least 98% and containing less than 1.5% (w / w) CBDV, CBG, and / or CBN, and less than 0.05% THC.

[0157] [Table 8]

[0158] [Table 9]

[0159] [Table 10]

[0160] [Table 11]

[0161] [Table 12]

[0162] Example 6 - Formulation containing water and NaCl

[0163] [Table 13]

[0164] Example 7 - Results of Formulations D to I

[0165] [Table 14]

[0166] Results of the study with formulation I The study was discontinued after all participants found Formulation I (0.9% NaCl) to be too irritating to the nasal passages and increased the time it took to fall asleep.

[0167] [Table 15]

[0168] Example 8 Polysomnography and / or activity measurement are commonly used tests in the field to analyze sleep patterns and / or behavior.They can be used in experiments to evaluate the efficacy of sleep preparations and / or delivery routes presented herein, such as by comparing the sleep patterns / behavior with or without treatment, or with different treatments, such as one or more compositions of the present invention, and conventional treatments, including optionally negative control and / or placebo.

[0169] Example 9 - CBD via alcohol extraction, distillation, and crystallization Offering Crystalline CBD may be provided by methods and techniques known in the art, such as those disclosed in US10413845 and / or US10414709.

[0170] In short, crystalline CBD: extracting hemp or cannabis with a solvent selected from the group consisting of propanol, isopropanol, butanol, pentanol, hexanol, heptanol, and octanol to produce an extracted hemp or cannabis extract consisting essentially of tetrahydrocannabinol, terpenes, or cannabidiol; evaporating the solvent portion of the extract to produce a substantially solvent-free extract containing CBD; distilling the substantially solvent-free extract to isolate the CBD; and crystallizing the distilled and isolated CBD to produce crystallized and isolated CBD. The method can be provided by a method essentially consisting of hemp or cannabis (Cannabis sativa).

[0171] Often, the crystallized and isolated CBD is subjected to vacuum drying to remove volatile residues, particularly the solvent used in crystallization or, if necessary, recrystallization.

[0172] In particular, a method involving extraction with isopropanol and crystallization using heptane (with one or more optional recrystallization steps), followed by vacuum drying, can provide CBD having crystalline structure A, i.e., needle-like crystals. Moreover, such CBD can be very low in undesirable compounds, such as terpenes.

[0173] GC chromatography or other analytical methods known in the art can be used to monitor the process, e.g., to ensure high yield and / or purity of the desired product.

[0174] Regarding the raw material, hemp containing, for example, 2-3% CBD is dried and ground, then extracted with isopropanol, for example food-grade isopropanol.

[0175] Guidance for selecting appropriate reactions based on the boiling points or boiling ranges of various compounds can be found, for example, here: www.nwsci.com / customer / docs / SKUDocs / RMR / Technical%20Data_Extractions_03.28.18.pdf.

[0176] CBD having crystal structure A can be provided, for example, from www.enecta.com and / or following similar extraction and / or purification protocols from the manufacturer.

[0177] Example 10 - Comparison of intranasal sleep compositions formulated with various crystalline CBD Two intranasal sleep compositions are prepared as disclosed herein, such as according to Examples 1, 5 and / or 7, with the only difference being that the crystalline CBD used in the formulation is either Type A (needle-shaped crystals, FIG. 1) or Type B (tufts / clusters, FIG. 2).

[0178] Crystalline CBD Form A is supplied by Enecta, while CBD Form B is supplied by Pharma Hemp. Further details can be found, for example, in the first aspect of the invention, for example in Table 1.

[0179] Having tested both intranasal sleep compositions, it can be surprisingly and unexpectedly found and / or concluded that CBD type A is significantly more active than CBD type B.

Claims

1. By weight, i. 5-30%, 10-20%, or about 16% cannabis oil; ii. 0.1-5.0%, 0.2-2.0%, or about 0.4% cannabidiol (CBD), and / or 0.1-5.0%, 0.2-2.0%, or about 0.8% cannabinol (CBN); iii. 0.01-1.0%, 0.02-0.5%, or about 0.03% lavender oil; iv. 30-95%, 50-90%, or about 82% sesame oil; and v. 0.1-5.0%, 0.2-1.0%, or about 0.55% vitamin E and / or tocopherol equivalents A composition comprising: Optionally the composition is formulated for nasal application, such as a nasal spray.

2. 2. The composition of claim 1 comprising CBN and CBD, wherein the weight ratio of CBN:CBD is greater than 1, for example the ratio of CBN:CBD is in the range of 5:1 to 1:1, 4:1 to 1:1, 3:1 to 1:1, 2.5:1 to 1:1, or about 2:

1.

3. the composition comprises one or more further cannabinoids, such as one or more psychoactive cannabinoids and / or one or more non-psychoactive cannabinoids in a physiologically active amount, 3. The composition of claim 1 or 2, optionally wherein the one or more further cannabinoids are selected from one or more of THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBDA (cannabidiol acid), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), THCP (tetrahydrocannabiphorol), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), and CBT (cannabicitran), and any combination thereof.

4. The composition, CBN, CBD and / or hemp oil may further comprise one or more further cannabinoids, such as the cannabinoids of claim 3. Not included, does not contain a physiologically active amount; and / or containing less than 1.5, 1.0, 0.5, 0.2 or 0.1% (w / w); 4. The composition of claim 3, comprising 0.1 to 5.0% CBN and / or CBD.

5. The composition and / or cannabis oil ≦0.2% by weight or ≦0.05% by weight of CBDV, ≦0.2 wt.% or ≦0.05 wt.% CBDA, ≦0.5 wt.% or ≦0.025 wt.% CBG, and / or ≦0.05% by weight or ≦0.020% by weight THC The composition of claim 1 or 2, comprising one or more of:

6. The further cannabinoids are psychoactive cannabinoids, such as THC and / or THCV, and / or cannabinoids that bind to the CB1 receptor; and / or a non-psychoactive cannabinoid, such as a non-psychoactive cannabinoid selected from THCA, CBDA, CBG, CBC, CBL, CBV, THCP, CBDV, CBCV, CBGV, CBGM, CBE, and CBT, and / or a cannabinoid that does not bind to the CB1 receptor; and / or 4. The composition of claim 3, wherein the additional cannabinoid is selected from or is one or more of THC, THCA, CBDA, CBG, CBC, CBL, CBV, THCV, THCP, CBDV, CBCV, CBGV, CBGM, CBE, and CBT, and any combination thereof.

7. The composition, does not contain sodium chloride (saline) and / or contains less than 0.1 or 0.05% (w / w) NaCl; and / or 3. A composition according to claim 1 or 2, which does not contain added water and / or contains less than 1.0, 0.5 or 0.1% (w / w) water.

8. the cannabis oil comprises ≦0.2% or ≦0.05% by weight CBDV, ≦0.2% or ≦0.05% by weight CBDA, ≦0.5% or ≦0.025% by weight CBG, and ≦0.05% or ≦0.020% by weight THC; the lavender oil is produced by steam distillation of the flowers of Lavandula angustifolia (CAS No. 8000-28-0) and has a VOC-CH content of about 1% (by weight), and optionally contains one or more of about 0.05% coumarin (CAS No. 91-64-5), about 0.40% geraniol (CAS No. 106-21-1), about 0.5% D-limonene (CAS No. 5989-27-5), about 30% linalool (CAS No. 78-70-6); and / or 3. The composition of claim 1 or 2, wherein the sesame oil is a refined oil having the following specifications: acid≦0.5, peroxide value≦10.0, non-saponifiable matter≦2% (w / w), alkaline matter≦0.1, water≦0.1% and / or the following triglyceride composition by weight: 7-19% LLL, 13-30% OLL, 5-9% PLL, 12-23% OOL, 6-14% POL, 5-16% OOO, 2-8% SOL, and 2-10% POO, the fatty acid groups being expressed as linoleic acid (L), oleic acid (O), palmitic acid (P), and stearic acid (S).

9. the CBD used to provide the CBD-containing composition is crystalline; Optionally, the CBD crystals further comprise: It is a needle-shaped crystal, and / or is not provided by an extraction method that involves supercritical CO2 extraction; 3. The composition of claim 1 or 2, provided by a process comprising extraction with a C3-C4 alcohol, such as isopropanol, and one or more crystallization steps with a C6-C8 alcohol, such as heptane.

10. 13. A method for providing a composition for nasal application according to claim 1, comprising: i. the process or act of providing cannabis oil containing CBD and / or CBN; ii. the step or act of providing lavender oil, sesame oil, and vitamin E (e.g., vitamin E oil); and iii. The step or act of mixing the cannabis oil of step (i) with the ingredients of step (ii), and optionally iv. The step or act of aliquoting the composition of step (iii) into one or more containers, e.g., a nasal pump spray bottle adapted to provide 50-350 μl, 100-250 μl, or about 160 μl per puff. and optionally the aliquot size is 1-20, 2-15, 3-12 or 5-10 ml; and / or A method wherein said container provides protection from UV and / or visible light.

11. 11. A composition for intranasal application provided by the method of claim 10.

12. A container containing a composition for intranasal application according to any one of claims 1, 2 or 11, optionally comprising the container provides light and / or UV protection to the composition; the container is a nasal pump spray bottle, for example a pump bottle for administering 50-350 μl, 100-250 μl, or about 160 μl per puff per nostril; and / or The container is adapted to contain a volume of 1-20, 2-15, 3-12 or 5-10 ml of the composition for nasal application.

13. 13. A container according to claim 12, optionally Instructions for use, A kit comprising packaging, such as a carton, for the container and / or instructions for use, Optionally, the packaging provides light and / or UV protection.

14. 12. A composition according to any one of claims 1, 2 or 11 for use as a medicine and / or therapeutic agent.

15. i. insomnia, ii. Snoring; iii. obstructive sleep apnea, iv. sleep hypoventilation, v. Restless legs syndrome, vi. Teeth grinding, vii. narcolepsy, viii. Sleep talking, sleepwalking, and / or other involuntary behavior; ix. nightmares and / or night terrors, x. Rapid Eye Movement Disorder, and / or Jet lag, anxiety, difficulty falling asleep in unusual circumstances, such as when traveling (e.g. not sleeping at home, traveling by bus, car, train or plane, in a hotel, guesthouse, boarding school, prison, or hospital or hospice, or during military or similar duties, and / or Parkinson's disease, multiple sclerosis (MS), muscle spasms, anxiety, depression, Alzheimer's disease, epilepsy, pain, and / or neurological conditions requiring a protective effect. One or more conditions related to one or more of The composition according to claim 14 for use in the treatment of one or more of the following:

16. The method of claim 1, wherein the use comprises intranasal application of the composition to an animal or human subject, such as an infant, child, adolescent, adult, or elderly person; Optionally, the dosing regimen comprises: 50-350 μl, 100-250 μl, or about 160 μl in each nostril; a total of 0.5-5 mg, 1.5-3.5 mg or about 2.8 mg of CBN per application, usually including both nostrils; and / or 15. The composition of claim 14, typically comprising 0.5-4 mg, 0.8-1.8 mg or about 1.4 mg of CBD per application including both nostrils.

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