Lung preparations containing cannabinoids

Abstract

The present invention relates to a particular class of pharmaceutical formulations and compositions containing cannabinoids for use in the treatment of various disorders.

Description

[Technical Field]

[0001] This invention relates to a specific type of pharmaceutical formulation and composition containing cannabinoids used in the treatment of various disorders. [Background technology]

[0002] Research over the past few years has revealed various application areas for the use of cannabinoids. Therefore, the manufacture of cannabinoid pharmaceuticals is attracting increasing attention. While there is considerable available evidence regarding the therapeutic effects of cannabinoids, more research and clinical trials are crucial to meeting the demand for safe and effective pharmaceutical formulations containing cannabinoids. More specifically, in the field of neurodegenerative diseases, antioxidant, anti-glutamate, and anti-inflammatory effects are just some of the characteristics that make cannabinoids potential candidates in developing novel therapeutic strategies. Furthermore, in the field of post-traumatic stress disorder (PTSS), cannabinoids may form potential candidates in developing new therapeutic strategies due to their role in regulating fear memories. There is some evidence suggesting that cannabinoids may be beneficial for a variety of other conditions, including blisters, blister-related pain, and acute and chronic pain such as neuropathic pain and headaches.

[0003] The selection of an appropriate pharmaceutical formulation largely depends on factors such as drug absorption (rate), metabolism, and bioavailability. Therefore, pharmaceutical formulations should be selected with the properties of the active substance and the desired drug release in mind. For example, when rapid uptake of the active substance is required, a formulation for pulmonary delivery may be a suitable candidate. These formulations provide rapid absorption of the active substance into the systemic circulation through the large surface area of ​​the alveolar region, the thin blood-air barrier, and avoidance of the first-pass effect, thereby increasing the overall bioavailability of the active substance. Formulations for pulmonary delivery are particularly useful for increasing the bioavailability of active substances that are largely inactivated by the liver (e.g., many cannabinoids). Formulations for pulmonary delivery have proven to be a valuable alternative to conventional oral drug therapies such as capsules or tablets. Certain dosage forms, such as liquid formulations, suspensions, powders (including micro- and nanometer-sized particles), or aerosols, can be used to provide uptake of the active substance via the lungs (e.g., delivery by inhalation).

[0004] Lung-delivered formulations are particularly well-suited for use in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD-related disorders, essential tremor, multiple system atrophy, Huntington's disease, or motor neuron disease (MND). Currently, there are no cures for these various types of neurodegenerative disorders. This is one reason why there is a strong need for treatments that can at least improve symptoms, reduce pain, and / or improve mobility, ultimately improving overall quality of life.

[0005] In cases of PTSS, there is a high need for treatment that can at least provide symptom relief and ultimately improve the overall quality of life of the person suffering from it. To achieve such improvement, many symptoms can be addressed, such as flashbacks, nightmares, avoidance, altered physical and emotional responses, uncontrollable thoughts about past events, and severe anxiety.

[0006] The present invention satisfies the need for a highly bioavailable cannabinoid pharmaceutical formulation by providing a novel pulmonary delivery formulation containing one or more cannabinoids suitable for use in the treatment of disorders such as neurodegenerative disorders, vesicles, post-traumatic stress syndrome, and pain, as well as secondary symptoms caused by these disorders. [Overview of the Initiative]

[0007] The present invention relates to a combination comprising tetrahydrocannabinol (THC) and cannabidiol (CBD) used for the treatment of a disorder selected from the list including pain, neurodegenerative disorders, blisters, or post-traumatic stress syndrome, characterized in that the combination is formulated in a pulmonary delivery formulation comprising at least one excipient, more particularly a sugar.

[0008] In the following embodiments, the formulations specified herein are selected from a list including liquid formulations, suspensions, powders, or aerosols.

[0009] In another embodiment, the present invention provides combinations in which the concentration of the excipient is about 5% to 10% (by weight / by weight).

[0010] In yet another embodiment, the present invention provides combinations of the excipients having a ratio of approximately 1 / 1 to approximately 1 / 20 (weight / weight), preferably approximately 1 / 12 (weight / weight), of CBD / excipient, THC / excipient, or CBD-THC / excipient.

[0011] In the following embodiments, the formulations specified herein are powder formulations comprising particles having an average particle size of about 0.1 μm to about 100 μm, preferably about 0.1 μm to about 10 μm, and more preferably about 0.1 μm to about 5 μm.

[0012] In yet another embodiment, the present invention provides a powder formulation comprising particles produced by electrospray.

[0013] In yet another embodiment, the aerosol specified herein is an aerosol that does not contain a propellant.

[0014] In the following embodiments, the formulations specified herein are formulated for administration by inhalation.

[0015] In the following embodiment, the formulation is administered to the subject using an inhalation device.

[0016] In further embodiments, the pain is selected from a list that includes headache, migraine, physiological pain, or physical ailment.

[0017] In the following embodiments, the present invention discloses combinations specified herein for use in the treatment of pain, neurodegenerative disorders, post-traumatic stress syndrome, or blisters, wherein the skin blisters are caused by burns or other related trauma, or by disorders selected from the list including skin allergies, various forms of eczema, bullous pemphigoid, bullous impetigo, herpetiform dermatitis, pemphigus vulgaris, mucous membrane pemphigoid, pemphigoid of pregnancy, epidermolysis bullosa, pemphigus foliaceus, or toxic epidermal necrolysis.

[0018] In further embodiments, the neurodegenerative disorder is selected from a list including Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD-related disorders, essential tremor, multiple system atrophy, Huntington's disease, or motor neuron disease (MND).

[0019] In the following embodiments, the present invention provides combinations specified herein for use in the treatment of a disorder selected from the list including pain, neurodegenerative disorders, post-traumatic stress syndrome, or blisters, the use of which includes relief of secondary symptoms caused by the disorder, such as (secondary) pain, itching, secondary impetigo, swelling, inflammation, or bacterial infection.

[0020] In another embodiment, the present invention is a combination comprising tetrahydrocannabinol (THC) and cannabidiol (CBD) for use in the treatment of a disorder selected from the list including pain, neurodegenerative disorders, blisters, or post-traumatic stress disorder, wherein the combination is formulated into a formulation for pulmonary delivery, and the use includes a reduction in opioid consumption / dependence in the treatment of the disorder.

[0021] In another embodiment, the combination for use as defined herein may include one or more additional pharmaceutically active agents suitable for use in the treatment of the disorder.

[0022] Referring now specifically to the drawings, it is emphasized that the details shown are for purposes of example only, illustrative descriptions of various embodiments of the present invention. These drawings are presented to provide what is considered to be the most useful and easy description of the principles and conceptual aspects of the present invention. In this regard, no attempt is made to show the structural details of the present invention in more detail than is necessary for a fundamental understanding of the present invention. This description is to make clear to those skilled in the art how some forms of the present invention can actually be embodied together with the drawings.

Brief Description of the Drawings

[0023] [Figure 1A] It is a diagram showing modulated differential scanning calorimetry of a formulation containing CBD. Pure CBD and selected SD samples were analyzed by modulated differential scanning calorimetry (mDSC) to evaluate the solid state of CBD in the spray-dried powder. The mDSC graph (Figure 1B) of the formulation containing lactose or random methyl-β-CD as excipients (i.e., without leucine) did not show a melting peak of CBD (i.e., 67°C, Figure 1A). [Figure 1B] Same as above

Modes for Carrying Out the Invention

[0024] The present invention is described with reference to certain drawings with respect to specific embodiments, but the present invention is not limited thereto. The drawings are only schematic and non-limiting as further shown.

[0025] Furthermore, the terms first, second, and the like in this specification and the claims are used to distinguish between similar elements and are not necessarily for the purpose of describing an order in terms of time, space, ranking, or any other arbitrary method. The terms used in this way are interchangeable under appropriate circumstances, and it should be understood that the embodiments of the present invention described herein can operate in a direction different from those described or illustrated herein.

[0026] It should be noted that the term "comprising" used in the claims should not be construed as being limited to the means recited thereafter. This does not exclude other elements or steps. Therefore, it should be construed as indicating the presence of the features, wholes, steps, or components described as such, and does not exclude the presence or addition of one or more other features, wholes, steps, or components, or groups thereof. Therefore, the scope of the expression "a product comprising A and B" shall not be limited to a product consisting only of components A and B. This means that, with respect to the present invention, the related elements of the product are A and B, and there may also be further components such as C.

[0027] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or property described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the use of the expressions "in one embodiment" or "in an embodiment" in various places in this specification does not necessarily refer to the same embodiment. Furthermore, the particular features, structures, or properties can be combined in any suitable manner that will be apparent to those skilled in the art in one or more embodiments.

[0028] Similarly, in describing exemplary embodiments of the Invention, it should be understood that, for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects, various features of the Invention may be summarized in a single embodiment, figure, or description of the Invention. However, this method of disclosure should not be interpreted as reflecting an intention that the claimed Invention requires more features than those expressed in each claim. Rather, as reflected in the appended claims, the inventive aspects are fewer than all the features of a single above-described embodiment of the disclosure. Therefore, the claims following the detailed description are hereby explicitly incorporated into this detailed description, and each claim stands alone as a distinct embodiment of the Invention.

[0029] Furthermore, while some embodiments described herein include some features but do not include other features included in other embodiments, as will be understood by those skilled in the art, combinations of features from different embodiments are intended to fall within the scope of the invention and form different embodiments. For example, any of the claimed embodiments can be used in any combination within the appended claims.

[0030] Numerous specific details are described in the description provided herein. However, it will be understood that embodiments of the present invention can be carried out without these specific details. In other examples, well-known methods, structures, and techniques are not described in detail so as not to obscure the understanding of this specification.

[0031] As already described in detail herein, in a first embodiment, the present invention provides a combination comprising tetrahydrocannabinol (THC) and cannabidiol (CBD) for use in the treatment of a disorder selected from the list including pain, neurodegenerative disorders, post-traumatic stress syndrome, or blisters, characterized in that the combination is formulated into a formulation for pulmonary delivery.

[0032] In a more specific embodiment, the present invention provides a combination comprising tetrahydrocannabinol (THC) and cannabidiol (CBD) for use in the treatment of a disorder selected from the list including pain, neurodegenerative disorders, post-traumatic stress syndrome, or blisters, characterized in that the combination is formulated into a formulation for pulmonary delivery.

[0033] Alternatively, the present invention relates to a combination of one or more cannabinoids or derivatives thereof used for the treatment of a disorder selected from the list including pain, neurodegenerative disorders, post-traumatic stress syndrome, or blisters, wherein the combination is formulated into a formulation for pulmonary delivery.

[0034] In some embodiments, the present invention relates to a formulation for lung delivery containing THC.

[0035] In some embodiments, the present invention relates to a formulation for lung delivery containing CBD.

[0036] In some embodiments, the combination of CBD and THC may have a synergistic effect (for example, in terms of anti-inflammatory activity) on the treatment of at least one of the disorders.

[0037] In some embodiments, CBD can reduce at least one of the potential side effects caused by THC, and vice versa. For example, CBD can counteract side effects caused by THC, such as tachycardia and sedation.

[0038] In some embodiments, at least one of the cannabinoids in the combination may have an immunomodulatory effect or, if not, may affect the immune system to support the treatment of one of the above disorders.

[0039] As used herein, unless otherwise specified, the term "cannabinoid" is understood to refer to activity-generating compounds, including those of the endocannabinoid system.

[0040] As used herein, unless otherwise specified, the term “endocannabinoid system” is understood to be a cellular signaling system comprising endocannabinoids, such as endogenous ligands for cannabinoid receptors (CB1 and CB2), and cannabinoid receptor proteins expressed at levels in the central and peripheral nervous systems of vertebrates.

[0041] In some embodiments, cannabinoids, including THC and CBD, may be produced synthetically and / or derived from plants.

[0042] In some embodiments, the cannabinoids may be derived from cannabis plants belonging to the species Cannabis sativa L. The subspecies may include the subspecies Cannabis sativa Sativa and subspecies Indica.

[0043] In some embodiments, the combination may include at least one cannabis plant metabolite, particularly cannabinoids, terpenes, terpenoids, triglycerides, sterols, alkanes, squalenes, tocopherols, alkaloids, or carotenoids.

[0044] Where used herein, unless otherwise specified, the term “cannabis plant” is understood to refer to the genus of flowering plants in the Cannabaceae family. Three main species can be identified: Cannabis sativa, Cannabis indica, and Cannabis ruderalis.

[0045] In some embodiments, combinations containing THC and CBD may include THC and CBD in THC:CBD ratios of approximately 1:1000, 1:500, 1:250 to approximately 1000:1, 500:1, 250:1, preferably approximately 1:100, 1:50, 1:25 to approximately 100:1, 50:1, 25:1, and more preferably approximately 1:10 to approximately 10:1.

[0046] In some embodiments, the combination containing THC and CBD may contain THC and CBD in a ratio of approximately 2:1 to approximately 1:2.

[0047] In some embodiments, the combination of THC and CBD may contain THC and CBD in a ratio of approximately 1:1 to approximately 1:1.

[0048] In some embodiments, combinations containing THC and CBD may contain THC amounts ranging from approximately 0.0625 mg, 0.125 mg, 0.25 mg, 0.50 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, and 100 mg of THC to a maximum of approximately 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, and 1000 mg of THC, preferably approximately 0.0625 mg to 100 mg of THC.

[0049] In some embodiments, combinations containing THC and CBD may contain CBD amounts ranging from approximately 0.0625 mg, 0.125 mg, 0.25 mg, 0.50 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, and 100 mg to a maximum of approximately 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, and 1000 mg of CBD.

[0050] In some embodiments, the combination may include at least one from a list containing THC, CBD, or other cannabinoids.

[0051] In some embodiments, these “other cannabinoids” may be selected from a list including the following types of cannabinoids: delta-9-trans-tetrahydrocannabinol (Δ 9 -THC) type, delta-8-trans-tetrahydrocannabinol (Δ 8 -THC type, cannabigerol (CBG) type, cannabichromene (CBC) type, cannabidiol (CBD) type, cannabinodiol (CBND) type, cannabiersoin (CBE) type, cannabicyclol (CBL) type, cannabinol (CBN) type, cannabitriol (CBT) type, or other types of cannabinoids.

[0052] Delta-9-trans-tetrahydrocannabinol (Δ 9-THC) types include delta-9-tetrahydrocannabinol (THC), delta-9-tetrahydrocannabinolate A (THCA-A), delta-9-tetrahydrocannabinolate B (THCA-B), delta-9-tetrahydrocannabivarin (THCV), delta-9-tetrahydrocannabivaric acid (THCVA), delta-9-tetrahydrocannabiorcol (THCO), and delta-9-trans-tetrahydrocannabiorcholic acid (THCOA). Molecules from the list include cannabidol, delta-9-tetrahydrocannabinol-C4 (THC-C4), delta-9-trans-tetrahydrocannabinolic acid-C4 (THCA-C4), β-phentyl-delta-9-tetrahydrocannabinolate, α-phentyl-delta-9-tetrahydrocannabinolate, epi-bornyl-delta-9-tetrahydrocannabinolate, bornyl-delta-9-tetrahydrocannabinolate, α-terpenyl-delta-9-tetrahydrocannabinolate, 4-terpenyl-delta-9-tetrahydrocannabinolate, α-cadinyl-delta-9-tetrahydrocannabinolate, γ-eudesmyl-delta-9-tetrahydrocannabinolate, or cannabidol.

[0053] Delta-8-trans-tetrahydrocannabinol (Δ 8 Examples of -THC) type molecules include those from the list containing delta-8-trans-tetrahydrocannabinol (Δ8-THC) or delta-8-trans-tetrahydrocannabinolic acid (Δ8-THCA).

[0054] Cannabigerol (CBG) types include molecules from the list containing cannabigerol (CBG), cannabigerol acid (CBGA), cannabigerol monomethyl ether (CBGM), cannabigerol acid monomethyl ether (CBGAM), cannabigevalin (CBGV), cannabigerovalic acid (CBGVA), cannabinerol acid ((Z)-CBGA), γ-eudesmyl-cannabigerolate, α-cadinyl-cannabigerolate, 5-acetyl-4-hydroxycannabigerol, 4-acetoxy-2-geranyl-5-hydroxy-3-n-pentylphenol, (±)-6,7-trans-epoxycannabigerol acid, (±)-6,7-cis-epoxycannabigerol acid, (±)-6,7-cis-epoxycannabigerol, (±)-6,7-trans-epoxycannabigerol, carmagerol-dihydroxy-CBG, or sesquicannabigerol.

[0055] Cannabichromene (CBC) types include molecules from the list containing cannabichromene (CBC), cannabichromenic acid (CBCA), cannabiclomevalin (CBCV), cannabiclomevalic acid (CBCVA), cannabichromene C3 (CBC-C3), (±)-4-acetoxycannabichromene, (±)-3''-hydroxy-Δ4''-cannabichromene, or (-)-7-hydroxycannabichromene.

[0056] Cannabidiol (CBD) types include molecules from the list containing cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivaric acid (CBDVA), cannabidiol monomethyl ether (CBDM), cannabidiolcol (CBD-C1), cannabidiol-C4 (CBD-C4), or cannabimovone.

[0057] Cannabinodiolic (CBND) types include the molecules listed, which contain cannabinodiolic (CBND-C5) or cannabinodivaline (CBND-C3).

[0058] Cannabiersoin (CBE) types include molecules from the list containing cannabiersoin (CBE), cannabiersoic acid A (CBEA-A), cannabiersoic acid B (CBEA-B), cannabiersoin-C3 (CBE-C3), cannabiersoin-C3 acid B (CBEA-C3 B), cannabiglendol-C3-OH-iso-HHCV-C3, dehydrocannabifuran (DCBF), or cannabifuran (CBF).

[0059] Cannabicyclol (CBL) types include molecules from the list containing cannabicyclol (CBL), cannabicycloalic acid (CBLA), or cannabicyclovaline-CBLV (CBL-C3).

[0060] Cannabinol (CBN) types include molecules from the list containing cannabinol (CBN), cannabinolic acid (CBNA), cannabivarin-CBV (CBN-C3), cannabinol-C4 (CBN-C4), cannabinol-C2 (CBN-C2), cannabiolchol (CBN-C1), cannabinol methyl ether (CBNM), 4-terpenyl-cannabinolate, 8-hydroxycannabidiol (8-OH-CBN), or 8-hydroxycannabidiolic acid (8-OH-CBNA).

[0061] Cannabitriol (CBT) types include (-)-trans-cannabitriol ((-)-trans-CBT-C5), (+)-trans-cannabitriol ((+)-trans-CBT-C5), cis-cannabitriol ((±)-CBT-C5), (-)-trans-10-ethoxy-9-hydroxy-Δ6a(10a)-tetrahydrocannabinol ((-)-trans-CBT-OEt-C5), and trans Molecules from the list include -cannabitriol-C3((±)-trans-CBT-C3), CBT-C3 homolog, trans-10-ethoxy-9-hydroxy-Δ6a(10a)-tetrahydrocannabivarin-C3((-)-trans-CBT-OEt-C3), 8,9-dihydroxy-Δ6a(10a)-tetrahydrocannabinol(8,9-di-OH-CBT-C5), cannabidiolic acid A cannabitriol ester (CBDA-C5 9-OH-CBT-C5 ester), cannabitriol valine (CBTV), or ethoxycannabitriol valine (CBTVE).

[0062] Other types of cannabinoids include cannabifuran (CBF), dehydrocannabifuran (DCBF), cannabitetrol (CBTT), cannabilipzole (CBR), cannabicitran (CBR-C3), cannabioxepane (CBX), cannabicoumaronone (CBCON), cannabicoumaronate, cannabiglendol-C3 (OH-iso-HHCV-C3), 10-oxo-Δ6a(10a)-tetrahydrocannabinol (OTHC), (-)-Δ9-cis-(6aS,10aR)-tetrahydrocannabinol (cis-Δ9-THC), 4-acetoxy-2-geranyl-5-hydroxy-3-n-pentylphenol, 2-geranyl-5-hydroxy-3-n-pentyl-1,4-benzoquinone, 5-acetoxy-6-geranyl-3-n-pentyl-1,4-benzoquinone, Molecules from the list containing 8α-hydroxy-Δ9-tetrahydrocannabinol, 8β-hydroxy-Δ9-tetrahydrocannabinol, 10α-hydroxy-Δ8-tetrahydrocannabinol, 10β-hydroxy-Δ8-tetrahydrocannabinol, 10α-hydroxy-Δ9,11-hexahydrocannabinol, 9β,10β-epoxyhexahydrocannabinol, or 11-acetoxy-Δ9-tetrahydrocannabinolic acid A are examples.

[0063] The use of formulations for pulmonary delivery can increase the bioavailability of at least one active substance compared to other formulations. For example, when using oral drug delivery, the drug undergoes hepatic drug metabolism (also known as the first-pass effect) before reaching the systemic circulation. Cannabinoids, in particular, are substantially inactivated by this first-pass effect. Therefore, using formulations that avoid this first-pass effect, such as those for pulmonary delivery, increases the overall bioavailability of cannabinoids, resulting in a more appropriate pharmaceutical formulation. Compared to oral delivery, inhalation of the above formulations provides a faster onset of pharmacological action and peak plasma levels.

[0064] Formulations for pulmonary delivery are designed for the uptake of active substances via the lungs. This pulmonary pathway of drug delivery specifically includes the bronchi, bronchioles, and alveoli, which are the main absorption zones, thereby bypassing the first-pass effect. This is an advantage compared to, for example, oral drug delivery. Furthermore, the pulmonary pathway can provide active or passive transport of molecules (e.g., active substances) through the alveolar epithelium, capillary epithelium, and the lymphatic clefts between these two cell layers. Generally, it is said that the smaller the molecule, the faster this transport.

[0065] In some embodiments, at least 0.1%, 0.2%, 0.5%, 1%, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 95% of the active substance of the lung-delivery formulation can reach the lung region, more specifically the alveolar region.

[0066] In some embodiments, the formulation for lung delivery may be an aqueous formulation or a non-aqueous formulation.

[0067] In some embodiments, the formulation for lung delivery may include at least one propellant. Examples of such propellants can be selected from a list including fluorochlorohydrocarbons, compressed gases, propane, n-butane, isobutane, dimethyl ether, methyl ethyl ether, nitrous oxide, hydrofluoroalkanes (HFAs), and carbon dioxide.

[0068] In some embodiments, the formulation for lung delivery may contain a solvent selected from a list including inorganic solvents and organic solvents.

[0069] The amount of solvent can affect the droplet size contained in at least a portion of the formulation for lung delivery.

[0070] Examples of solvents include molecules from the list, which include ethanol, propanol, propylene glycol, glycerol, polyethylene glycol, and submicron liposome dispersions (microemulsions and micelle solutions). In some embodiments, at least a portion of the cannabinoids in the lung delivery formulation can be dissolved in the solvent.

[0071] In some embodiments, the lung delivery formulation may contain oligosaccharides or polysaccharides selected from a list including water-soluble complex hydrocarbons such as starch, polyols or sugar alcohols, maltodextrin, (2-hydroxypropyl)-beta-cyclodextrin (HPBCD) or random methyl-beta-cyclodextrin (RMBCD), cellulose or cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl methylcellulose (HEMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sodium alginate or calcium alginate, acacia gum, xanthan gum, guar gum, or combinations thereof.

[0072] In some embodiments, the polysaccharide may include cellulose or a cellulose derivative.

[0073] In some embodiments, the formulation for lung delivery may include an emulsifier selected from a list including, for example, lecithin, Acconon mixture, Capmul MCG, propylene glycol ester, Caprol polyglycerol ester, Captex medium-chain ester, Kolliphor EL, Kolliphor RH40, poloxamer, polysorbate, and Tween 80.

[0074] In some embodiments, the formulation for lung delivery may contain a monosaccharide or disaccharide selected from a list including glucose, dextrose, fructose, sucrose, lactose, trehalose, mannitol, maltose, or isomaltose.

[0075] In some embodiments, a delivery device can be used to deliver a formulation for lung delivery to a target. Such delivery devices may include nebulizers, medium-dose inhalers (MDIs), dry powder inhalers (DPIs), and soft mist inhalers (SMIs).

[0076] Where used herein, unless otherwise specified, the term “nebulizer” is understood to mean a drug delivery device used to administer an active substance to the lungs in the form of a mist. Generally, oxygen, compressed air, or ultrasonic power is used to convert a liquid solution or suspension into aerosol droplets that can be directly inhaled. In some embodiments, the liquid solution or suspension may be sprayed under high pressure through a small nozzle to form aerosol droplets that can be inhaled using the nebulizer.

[0077] A nebulizer that does not contain a propellant is a type of nebulizer that has the main advantage of eliminating the use of propellant gases such as fluorochlorohydrocarbons.

[0078] In some embodiments, the aspirable aerosol droplets may have an average droplet size of less than 100 μm, 90 μm, 80 μm, 70 μm, 60 μm, 50 μm, 40 μm, 30 μm, 20 μm, 15 μm, 10 μm, 9 μm, 8 μm, 7 μm, 6 μm, 5 μm, 4 μm, 3 μm, 2 μm, 1 μm, 0.5 μm, or 0.1 μm.

[0079] Where used herein, unless otherwise specified, the term “metered-dose inhaler (MDI)” is understood to mean a drug delivery device used to administer an active substance to the lungs in aerosol form, wherein a propellant (e.g., a hydrofluorocarbon) and optionally at least one stabilizing excipient are added to the formulation to accommodate drug delivery.

[0080] Where used herein, unless otherwise specified, the term “dry powder inhaler (DPI)” is understood to mean a drug delivery device used to administer an active substance to the lungs in the form of a dry powder, the powder generally comprising micrometer-sized or nanometer-sized particles and optionally at least one stabilizing excipient to facilitate drug delivery. Generally, inhalation by the subject is required for the drug to enter the lungs. An example disclosed herein (Example 1) illustrates how a formulation for a dry powder inhaler may be constructed.

[0081] Where used herein, unless otherwise specified, the term “soft mist inhaler (SMI)” is understood to refer to a drug delivery device used to administer an active substance to the lungs in the form of a fine mist (aerosol). Generally, inhalation by the subject is required for the drug to enter the lungs. Generally, aerosols without propellants are used in SMI devices. An example disclosed herein (Example 2) illustrates how a formulation for a soft mist inhaler may be constructed.

[0082] In some embodiments, at least one of the cannabinoids in a formulation for pulmonary delivery may cause bronchodilation. More specifically, this occurs when the formulation for pulmonary delivery is delivered to the target by inhalation (e.g., by a delivery device).

[0083] In some embodiments, the combination may be administered multiple times a day, more specifically at least once, twice, three times, four times, five times, six times, seven times, eight times, nine times, or ten times a day.

[0084] In another embodiment, the combination may be administered 3, 4, 5, 6, 7, 8, 9, 10 times or less per day.

[0085] In some embodiments, the combination may be administered by the subject. Formulations for pulmonary delivery are generally suitable for administration by the subject without any additional assistance. However, if the subject's condition does not allow for self-administration, the formulation may be administered by another person (e.g., a nurse).

[0086] In some embodiments, it may be necessary to dilute the combination. Dilution can be performed, for example, using a certain amount of physiological serum (e.g., a 0.9% NaCl solution).

[0087] In some embodiments, at least one of the substances in the lung-delivery formulation is absorbed at least partially throughout the body.

[0088] In some embodiments, at least one of the substances in a formulation for pulmonary delivery may have local effects when inhaled. These local effects may include effects on the bronchi (e.g., bronchodilation).

[0089] In some embodiments, the lung delivery formulation may contain at least a minimum amount of THC of about 0.01% by weight, 0.02% by weight, 0.03% by weight, 0.04% by weight, 0.05% by weight, 0.1% by weight, 0.0, 0.5% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 40% by weight, and 50% by weight.

[0090] In some embodiments, the lung delivery formulation may contain at least a minimum amount of CBD of about 0.01% by weight, 0.02% by weight, 0.03% by weight, 0.04% by weight, 0.05% by weight, 0.1% by weight, 0.2% by weight, 0.5% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 40% by weight, and 50% by weight.

[0091] In some embodiments, the lung-delivery formulation may contain up to a maximum amount of THC of about 60% by weight, 70% by weight, 80% by weight, 90% by weight, and 95% by weight.

[0092] In some embodiments, the lung-delivery formulation may contain up to a maximum amount of CBD of about 60% by weight, 70% by weight, 80% by weight, 90% by weight, and 95% by weight.

[0093] Where used herein, unless otherwise specified, the term "weight %" is also understood as weight percentage, and is obtained by dividing the mass of the component by the total mass of the mixture and multiplying the result by 100.

[0094] In the following embodiments, the formulations specified herein are selected from a list including liquid formulations, suspensions, powders, or aerosols.

[0095] In some embodiments, the powder formulation may contain particles of micrometer size or nanometer size.

[0096] In some embodiments, the formulations specified herein may be formulated in a semi-solid or crystalline form.

[0097] As used herein, unless otherwise specified, the term “liquid formulation” is understood to mean all types of formulations comprising a liquid component and at least one active substance. Examples include, for example, at least one active substance dissolved or suspended in the liquid.

[0098] As used herein, unless otherwise specified, the term “suspension” is understood to refer to all types of formulations that are heterogeneous systems comprising two phases, more specifically, to include a first substance (i.e., a dispersed phase) uniformly distributed throughout a second substance (i.e., a continuous phase) and insoluble in the continuous phase. Generally, suspensions relate to a fluid continuous phase and a solid dispersed phase.

[0099] Where used herein, unless otherwise specified, the term “powder” is understood to mean a dry bulk solid consisting of a plurality of very fine particles having the ability to flow.

[0100] Where used herein, unless otherwise specified, the term "aerosol" is understood as a suspension system of particles (i.e., solid or liquid) in a gas (e.g., air).

[0101] In yet another embodiment, the aerosol specified herein is an aerosol that does not contain a propellant.

[0102] In the following embodiments, the formulations specified herein are formulated for administration by inhalation. The inhalable formulations can be selected from a list including, for example, powders, vapors, suspensions, and aerosols.

[0103] In some embodiments, the powder for inhalation may contain particles of micrometer size or nanometer size.

[0104] To avoid any ambiguity, the components, concentrations, ratios, etc., specified below in this specification with respect to “formulations” may also apply to dry powder formulations, liquid formulations, suspensions, or aerosol formulations, and to starting materials (or liquid feeds) for manufacturing such formulations.

[0105] As used herein, the term “liquid feed” is understood to mean a starting material or starting liquid that is converted into a liquid formulation, suspension, powder, or aerosol, containing a medicinal active ingredient (API) such as CBD, THC, or CBD / THC and optionally one or more other excipients.

[0106] Furthermore, the concentration of the components in the liquid supply does not necessarily have to be the same as the final concentration of the formulation of the present invention.

[0107] Where used herein, unless otherwise specified, the term “excipient” is understood to mean a substance formulated with an API, which may be used for long-term stabilization, to increase the volume of formulations containing small amounts of potent active ingredients (and thus often referred to as “extenders,” “fillers,” or “diluents”), or to impart therapeutic enhancement to the active ingredient in the final dosage form, such as promoting drug absorption, reducing viscosity, or increasing solubility. Excipients may also be used in the manufacturing process to assist in addressing concerns of the active substance, such as promoting powder flowability and non-stickiness, in addition to assisting in vitro stability, such as preventing denaturation or aggregation over the expected shelf life.

[0108] Furthermore, as used herein, excipients may be any substrate used in the drug delivery process that helps improve the selectivity, efficacy, and / or safety of drug administration. Various methods have been employed to bind drugs to excipients, including adsorption, integration into bulk structures, encapsulation, and covalent bonding.

[0109] In further embodiments, the combination of the present invention may further comprise one or more excipients. In the context of the present invention, examples of excipients include nanoemulsions, dendrimers, micelles, liposomes, solid lipid nanoparticles, and biodegradable polymer nanoparticles.

[0110] In some embodiments, the above formulation for lung delivery may further contain excipients such as lipid carriers, polymer carriers, microsphere carriers, preferably polymer carriers.

[0111] In a preferred embodiment, the formulation for lung delivery may comprise at least one excipient, which is a sugar.

[0112] In another embodiment, the formulation for lung delivery includes sugars and polysaccharides such as ethanol, lactose, glucose, dextrose, fructose, mannose, sucrose, mannitol, trehalose, maltose, or isomaltose; water-soluble complex carbohydrates, such as starch, polyols, or sugar alcohols; maltodextrin, (2-hydroxypropyl)-beta-cyclodextrin (HPBCD), or random methyl-beta-cyclodextrin (RMBCD); cellulose, or hydroxypropyl methylcellulose (HPMC); hydroxyethyl methylcellulose It may further contain at least one excipient selected from a list including cellulose derivatives such as cellulose (HEMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sodium alginate or calcium alginate, acacia gum, xanthan gum, guar gum; amino acids such as citrate, glycine, L-leucine, isoleucine, and trileucine; tartrate, methionine, vitamin A, vitamin E, zinc citrate, trisodium citrate, zinc chloride, polyvinylpyrrolidone, polysorbate 80, phospholipids including diphosphotidylcholine; and surfactants such as lecithin.

[0113] In some embodiments, the polysaccharide may include cellulose or a cellulose derivative.

[0114] In some embodiments, the formulation for lung delivery may contain at least one excipient at concentrations of about 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%.

[0115] For example, Examples 3 (CBD formulation) and 4 (THC formulation and CBD / THC formulation) provide methods for producing inhalation-ready dry powder using lactose or RMBCD as an excipient. These methods merely indicate the components and concentrations, and therefore the examples are not limited to those specific components and concentrations used.

[0116] In some embodiments, the above-mentioned formulation for inhalation may contain a medicinal active ingredient (API) (such as CBD, THC, or CBD / THC) and excipients in an API / excipient ratio of about 1 / 1, 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 13, 1 / 14, 1 / 15, 1 / 16, 1 / 17, 1 / 18, 1 / 19, 1 / 20 (weight / weight) to about 2 / 1, 3 / 1, 4 / 1, 5 / 1, 6 / 1, 7 / 1, 8 / 1, 9 / 1, 10 / 1, 11 / 1, 12 / 1, 13 / 1, 14 / 1, 15 / 1, 16 / 1, 17 / 1, 18 / 1, 19 / 1, 20 / 1 (weight / weight), preferably about 1 / 12 (weight / weight).

[0117] For example, in Example 3, a specific liquid feed containing CBD and lactose in a 1 / 12 (weight / weight) ratio is provided, meaning that the liquid feed has a concentration of approximately 7.3% CBD and approximately 87.9% lactose. The final concentrations of CBD and lactose in the formulation may be less than or equal to the initial feed concentrations.

[0118] Depending on the excipient, increasing the amount of the excipient, for example from about 1 / 12 (weight / weight) to about 1 / 15 (weight / weight), may reduce the stickiness of the powder, resulting in better API encapsulation and therefore a better particle yield.

[0119] In a preferred embodiment, the formulation for lung delivery may contain at least one sugar.

[0120] In some embodiments, the formulation for lung delivery may contain at least one sugar at concentrations of about 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%.

[0121] In some embodiments, the formulation for pulmonary delivery may contain mannitol at concentrations of approximately 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%.

[0122] In some embodiments, the formulation for pulmonary delivery may contain maltodextrin at concentrations of approximately 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%.

[0123] In some embodiments, the formulation for lung delivery may contain trehalose at concentrations of approximately 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%.

[0124] In some embodiments, the formulation for lung delivery may contain lactose at concentrations of approximately 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%.

[0125] In some embodiments, formulations for pulmonary delivery may contain (2-hydroxypropyl)-beta-cyclodextrin (HPBCD) at concentrations of approximately 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%.

[0126] In some embodiments, formulations for pulmonary delivery may contain random methyl-beta-cyclodextrin (RMBCD) at concentrations of approximately 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%.

[0127] In some embodiments, the formulation for lung delivery may contain leucine at concentrations of approximately 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%.

[0128] In some embodiments, the formulation for lung delivery may contain lecithin at concentrations of approximately 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%.

[0129] In a preferred embodiment, the formulation for lung delivery may contain lactose and leucine.

[0130] In another preferred embodiment, the formulation for pulmonary delivery may contain about 7% (by weight / weight) lactose and about 5% (by weight / weight) leucine.

[0131] In another preferred embodiment, the formulation for pulmonary delivery may contain about 7% (by weight / weight) lactose and about 10% (by weight / weight) leucine.

[0132] In yet another preferred embodiment, the formulation for lung delivery may contain about 7% (by weight / by weight) of RMBCD.

[0133] In some embodiments, the inhalation formulations are obtained by converting a liquid feedstock into the formulation using freeze-drying or atomization technologies, particularly biopharmaceutical conversion processes such as electrospraying, spray drying, or freeze-drying. Atomization technologies are suitable for the production of drug-encapsulated nanoparticles and dried nanoparticle powders.

[0134] As used herein, unless otherwise specified, the term “electrospray” is understood to mean an electrohydrodynamic atomization (EHDA) method that uses an electric field to break down a conductive liquid jet flowing through a capillary nozzle into fine droplets with high monodispersity. Electrospray is a widely used and inexpensive method for producing nanoparticles and nanosuspensions.

[0135] Where used herein, unless otherwise specified, the term “spray drying” is understood as a process in which a liquid feed is converted into a dry powder in a single step. This process is typically carried out by first atomizing the solution into fine droplets, and then rapidly drying them in a large chamber using a warm gas to form nanostructured particles. The resulting dry particles are collected in a cyclone. Process parameters such as liquid feed rate, atomization pressure, nozzle air rate, inlet airflow, outlet temperature, cyclone gas, and / or spray rate are process conditions that can be adapted to adjust particle size and morphology, thereby obtaining a suitable formulation. Further details of these parameters can be found in the Examples section. These nanostructured particles are readily formulated, for example, into tablets and can be redispersed in water as nanoparticles.

[0136] The examples disclosed herein include a dry powder formulation obtained by electrospraying (Example 1) and a dry powder formulation obtained by spray drying (Examples 3 and 4).

[0137] In some embodiments, the above-mentioned formulation for inhalation may include particles produced by liquid atomization technology, particularly electrospray or spray drying.

[0138] In another embodiment, the inhalation formulation may include particles produced by electrospray. In a further embodiment, the inhalation formulation may include particles produced by spray drying.

[0139] In some embodiments, the above-mentioned formulation for inhalation may contain micrometer-sized or nanometer-sized particles.

[0140] As used herein, the terms “micrometer-sized particles” (particles in the μm scale) and “nanometer-sized particles” (particles in the nm scale) refer to “inhalable particles” that can be inhaled into the nose or mouth. Therefore, both terms can be used interchangeably in relation to inhalable particles. For example, micrometer-sized particles for lung delivery with a diameter of approximately 0.5 μm (i.e., 500 nm) to approximately 10 μm (10,000 nm) can reach the lungs and enter the systemic circulation to deliver the activator. A diameter of less than approximately 10 μm is desirable for passing through the throat, and a diameter of approximately 0.5 μm or larger is desirable to avoid exhalation. Generally, micrometer-sized particles with a diameter greater than 10 μm or greater than 20 μm are useful for local delivery to the airways and lungs. Micrometer-sized particles with a diameter of approximately 0.5 microns to approximately 10 microns can reach the lungs and successfully pass through most natural barriers.

[0141] In some embodiments, the formulation for lung delivery comprises micrometer or nanometer-sized particles having an average particle size of less than approximately 100 μm, 90 μm, 80 μm, 70 μm, 60 μm, 50 μm, 40 μm, 30 μm, 20 μm, 15 μm, 10 μm, 9 μm, 8 μm, 7 μm, 6 μm, 5 μm, 4 μm, 3 μm, 2 μm, 1 μm, 0.5 μm, or 0.1 μm.

[0142] In a preferred embodiment, the above formulation for lung delivery comprises micrometer or nanometer-sized particles having an average particle size of about 0.1 μm to about 100 μm, preferably about 0.1 μm to about 50 μm, more preferably about 0.1 μm to about 10 μm, and most preferably 0.1 μm to 5 μm. The examples disclosed herein (Examples 3 and 4) show a dry powder formulation having micrometer particles in the range of about 0 μm to 5 μm, containing an active ingredient such as CBD or THC.

[0143] In some embodiments, the above formulations for pulmonary delivery may contain wrinkled particles. As used herein, the term “wrinkled particle” is understood to mean particles having a wrinkled morphology, i.e., particles without a smooth surface, which significantly increases the surface area and improves the aerodynamics of the aerosol in dry powder inhalation. For example, wrinkled particles spray-dried in the presence of leucine may have increased dispersibility and a higher fraction of fine particles. In particular, as illustrated in Example 3, using formulations containing HPBCD or random methyl-BCD may result in more wrinkled particles due to the lower diffusion rate of these larger molecules (i.e., cyclodextrins), which may result in formulations with better inhalation characteristics.

[0144] In some embodiments, the morphology and structure of the above-mentioned formulation for lung delivery are characterized using X-ray diffraction.

[0145] In the following embodiment, the formulations specified herein are administered to a subject using an inhalation device.

[0146] Where used herein, unless otherwise specified, the term “inhalation device” is understood to mean a device for delivering a formulation to the target, more specifically to the respiratory system such as the lungs, for pulmonary delivery. Examples of inhalation devices include, for example, nebulizers, metered-dose inhalers, dry powder inhalers, and soft mist inhalers.

[0147] In some embodiments, the inhalation device can provide a dosage form selected from a list including single-dose or multi-dose forms.

[0148] In the following embodiments, the present invention discloses combinations specified herein used for the treatment of pain, neurodegenerative disorders, post-traumatic stress syndrome, or disorders selected from the list, the skin blisters being caused by burns or other related trauma, or disorders selected from the list, including skin allergies, various forms of eczema, bullous pemphigoid, bullous impetigo, herpetiform dermatitis, pemphigus vulgaris, mucous membrane pemphigoid, pemphigoid of pregnancy, epidermolysis bullosa, pemphigus foliaceus, or toxic epidermal necrolysis.

[0149] As used herein, unless otherwise specified, the term “blister” is understood to mean a swelling of the upper layer of skin filled with bodily fluids such as serum or plasma, generally caused by, for example, infection, burns or friction or other related trauma, or a disorder selected from the list including skin allergies, various forms of eczema, bullous pemphigoid, bullous impetigo, herpetiform dermatitis, pemphigus vulgaris, mucous membrane pemphigoid, pemphigoid of pregnancy, epidermolysis bullosa, pemphigus foliaceus or toxic epidermal necrolysis.

[0150] Where used herein, unless otherwise specified, the term “skin allergy” is understood as a reaction to an allergen or irritant, which may result in symptoms such as itching, redness of the skin, rash, and blisters. Treatment includes treatment of the underlying disease causing the skin allergy and treatment of the symptoms.

[0151] As used herein, unless otherwise specified, the term “eczema” (sometimes also referred to as dermatitis) is understood to be a group of conditions that are partially related, resulting in inflammation of the skin and characterized by itching, redness of the skin, rash, thickening of the skin and small blisters.

[0152] In some embodiments, various forms of eczema may be selected from a list including atopic dermatitis, contact dermatitis, dyshidrotic eczema, nummular eczema, seborrheic dermatitis, or stasis dermatitis.

[0153] As used herein, unless otherwise specified, the term “bullous pemphigoid” is understood to mean an autoimmune pruritic skin disease. This is a type of pemphigoid, which is a group of autoimmune bullous skin diseases. Bullous pemphigoid may be characterized by the formation of blisters in the (epithelial) dermal layer and the formation of anti-hemidesmosome antibodies.

[0154] As used herein, unless otherwise specified, the term “bullous impetigo” is understood to be a bacterial skin infection that produces large blisters, primarily in the folds of the skin (e.g., the groin, armpits). The blisters are caused by exfoliative toxins produced by Staphylococcus aureus, which disrupt the intercellular connections of the epidermis.

[0155] Where used herein, unless otherwise specified, the term “herpetiform dermatitis” is understood to mean a chronic autoimmune skin condition characterized by fluid-filled blisters, chronic papular vesicular rashes, and intense itching. Herpetiform dermatitis is a skin manifestation of celiac disease, and its symptoms are chronic and related to the amount of gluten consumed.

[0156] Where used herein, unless otherwise specified, the term “pemphigus vulgaris” is understood as a chronic skin disease characterized by the formation of vesicles on the skin. This is a type II hypersensitivity reaction involving the formation of antibodies against desmosomes. Attack of these desmosomes by antibodies causes separation of skin layers, which resembles blisters.

[0157] As used herein, unless otherwise specified, the term “mucosal pemphigoid” (sometimes referred to as MMP) is understood to refer to a group of chronic autoimmune subepithelial bullous diseases that primarily affect mucous membranes and sometimes skin.

[0158] Where used herein, unless otherwise specified, the term “pregnancy pemphigoid” is understood to mean pregnancy-related autoimmune skin disease. In many cases, itchy rashes develop into blisters. This is sometimes called pregnancy herpes.

[0159] Where used herein, unless otherwise specified, the term “epidermolysis bullosa” is understood as a group of genetic skin conditions characterized by the formation of blisters on mucous membranes and skin. Wound care and pain relief are often applied, but the condition cannot be cured.

[0160] As used herein, unless otherwise specified, the term “pemphigus foliaceus” is understood to mean an autoimmune vesicular disease of the skin. The skin lesions are often crusted erosions with an erythematous base.

[0161] Where used herein, unless otherwise specified, the term “toxic epidermal necrolysis” is understood to mean a potentially life-threatening skin disorder that results in blister formation and affects mucous membranes.

[0162] In some embodiments, at least one of the cannabinoids in the combinations specified herein, or in the combinations thereof, may alleviate at least one of the symptoms of the above-mentioned disorders.

[0163] Examples of symptoms associated with these blisters include itching, redness, rash, thickening, hypersensitivity, bleeding, and pain of the skin or oral mucosa.

[0164] Where used herein, unless otherwise specified, the term “neurodegenerative disorders” is understood to be a general term for a number of conditions that primarily affect brain neurons. These are often incurable, debilitating conditions that frequently result in progressive degeneration and / or nerve cell death.

[0165] In further embodiments, the neurodegenerative disorder is selected from a list including Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD-related disorders, essential tremor, multiple system atrophy, Huntington's disease, or motor neuron disease (MND).

[0166] Where used herein, unless otherwise specified, the term “Alzheimer’s disease (AD)” is understood to mean a chronic neurodegenerative disease. This disease is often characterized, among other things, by disorientation, mood swings, and behavioral problems. In addition, AD is the most common cause of dementia.

[0167] As used herein, unless otherwise specified, the term “Parkinson’s disease (PD)” is understood to be a neurodegenerative disease of the central nervous system that affects the motor system. Symptoms include rigidity, difficulty walking, and tremors.

[0168] Where used herein, unless otherwise specified, the term “PD-related disorders” is understood to refer to a group of disorders associated with the pharmacological management of PD itself and / or disorders including dopamine deficiency syndrome, dopamine-dependent syndrome, impulse control disorder, and dopamine dysregulation syndrome.

[0169] Where used herein, unless otherwise specified, the term “essential tremor” is understood as a progressive neurological disorder that can affect any part of the body. Essential tremor causes involuntary, rhythmic contractions and relaxations of certain muscle groups. Furthermore, it is the most common movement disorder.

[0170] As used herein, unless otherwise specified, the term “multiple system atrophy” is understood as a progressive neurodegenerative disorder caused by progressive degeneration of neurons in several parts of the brain (e.g., the cerebellum and basal ganglia). Multiple system atrophy is characterized in particular by slow movement, tremor, and autonomic dysfunction.

[0171] Where used herein, unless otherwise specified, the term “Huntington’s disease” is understood as a genetic disorder that causes progressive degeneration of brain nerve cells, resulting in cognitive, physical, and psychiatric impairments. Signs and symptoms tend to develop between the ages of 30 and 40.

[0172] As used herein, unless otherwise specified, the term “motor neuron disease (MND)” is understood to mean a group of neurodegenerative diseases that affect motor neurons and cause motor-related symptoms (e.g., muscle weakness). This group includes progressive bulbar palsy, amyotrophic lateral sclerosis (ALS), progressive muscular atrophy, unilateral muscular atrophy, and primary lateral sclerosis.

[0173] In some embodiments, at least one of the cannabinoids in a combination may delay or interfere with the progression of the above-mentioned disorder (or at least one of its symptoms).

[0174] Examples of symptoms associated with neurodegenerative diseases include memory impairment, difficulty with muscle coordination, (painful) muscle spasms, convulsions, mobility, tremors, rigidity, aphasia, dysarthria, aggression, sleep disturbances, weakness, paralysis, loss of appetite, depression, salivation, hallucinations, urinary dysfunction, glaucoma, bronchial asthma, vomiting, and agitation.

[0175] In some embodiments, at least one of the cannabinoids in a combination may improve functional recovery.

[0176] In some embodiments, at least one of the cannabinoids in a combination may reduce demyelination and / or induce remyelination.

[0177] In some embodiments, at least one of a combination of cannabinoids can be used to achieve significantly better control of intracranial pressure / cerebral perfusion pressure.

[0178] In some embodiments, at least one of the cannabinoids in a combination may have neuroprotective effects.

[0179] In some embodiments, at least one of the cannabinoids in a combination may reduce the secretion of inflammatory cytokines.

[0180] As used herein, unless otherwise specified, the term “Post-Traumatic Stress Disorder (also known as PTSS)” is understood to be a mental health condition often triggered by the experience or witnessing of a traumatic event. Symptoms of PTSS include intrusive memories, negative changes in thoughts and mood, changes in physical and emotional responses, and avoidance.

[0181] In some embodiments, at least one of the cannabinoid combinations can at least mitigate or interfere with the above-mentioned disorder (or at least one of its symptoms).

[0182] Examples of PTSS-related symptoms include intrusive memories (e.g., recurring, unwanted, or distressing memories of the traumatic event, flashbacks of the traumatic event, disturbing dreams or nightmares, and profound emotional distress or physical reactions to elements that remind someone of the traumatic event), avoidance (e.g., avoiding thoughts or conversations related to the traumatic event, avoiding activities, places or people that remind someone of the traumatic event), negative changes in thoughts and mood (e.g., negative thoughts about oneself or others, feelings of despair about the future, memory problems, difficulty maintaining close relationships, feelings of alienation from family and friends, lack of interest in certain activities, difficulty experiencing positive emotions, and feelings of apathy), and altered physical and emotional responses (e.g., easily startled / frightened, persistent urges to be on alert for danger, self-destructive behaviors (e.g., heavy drinking, driving too fast), sleep problems, difficulty concentrating, irritability, outbursts of anger, aggression, overwhelming feelings of guilt or shame).

[0183] In some embodiments, the combinations specified herein, or at least one of the cannabinoids in such combinations, may reduce anxiety.

[0184] In some embodiments, the combinations specified herein, or at least one of the cannabinoids in such combinations, may alleviate depression.

[0185] In some embodiments, the combinations specified herein, or at least one of the cannabinoids in such combinations, may contribute to reducing amygdala hyperactivity.

[0186] In some embodiments, the combinations specified herein, or at least one of the cannabinoids in such combinations, may have neuroprotective effects.

[0187] In some embodiments, the combinations specified herein, or at least one of the cannabinoids in such combinations, may reduce suicidal tendencies.

[0188] In some embodiments, the combinations specified herein, or at least one of the cannabinoids in such combinations, may alleviate severe stress.

[0189] To clarify, when referring to pain, it can be understood as primary pain or secondary pain. In the context of this invention, the terms “primary pain” or simply “pain” are understood as pain associated with significant emotional distress or functional impairment that does not have an underlying disease that adequately explains the pain or its effects. Examples of primary pain conditions include fibromyalgia, complex regional pain syndrome, headache, migraine, irritable bowel syndrome, or nonspecific low back pain.

[0190] In the context of this invention, the term "secondary pain" is understood as pain that may initially be considered a symptom of another underlying disease. Examples of secondary pain include cancer-related pain, blister-related pain, surgery, injury, internal disease, muscle, bone or joint disease, headache, or nerve injury. Primary and secondary pain can coexist.

[0191] Where used herein, unless otherwise specified, the terms “pain” or “soreness” are understood as a distressing sensation or an unpleasant sensory or emotional experience related to, or similar to, actual or potential tissue damage. Pain can be viewed, for example, as a physiological response of the human body to tissue damage and infection. Two response phases can be distinguished: acute and chronic. The acute phase is an initial, nonspecific phase characterized by local vasodilation and increased capillary permeability, accumulation of fluids and proteins in the interstitial space, migration of neutrophils from capillaries, and release of inflammatory mediators such as cytokines. The release of these pro-inflammatory mediators leads to the perception by the human body, which is defined, in particular, as “pain.”

[0192] Chronic pathological pain persists beyond the resolution of the pain source and can even profoundly impact the quality of life of those who suffer from it.

[0193] In some embodiments, the pain may be neuropathic pain. Such neuropathic pain is understood as pain resulting from damage to the peripheral or central nervous system, and pain sensitization is generally induced by sensory stimuli in the absence of harmful stimuli.

[0194] In some embodiments, primary pain is selected from a list that includes headache, migraine, physiological pain, or physical ailment.

[0195] Where used herein, unless otherwise specified, the term “headache” is understood to mean a symptom of pain in the face, head, or neck. It may occur as tension headache (the usual headache causing pain in the head, face, or neck), cluster headache, sinus headache, or migraine. Cluster headache is a severe, painful headache that occurs on one side of the head and occurs in clusters, i.e., in cycles of headache attacks followed by periods without headache. Sinus headache is often accompanied by symptoms of sinus infection, such as fever, nasal congestion, cough, congestion, and facial pressure. Migraine is a severe, intense headache that, in addition to head pain, often has other symptoms such as nausea, pain in one eye or behind one ear, pain in the temples, seeing spots or flashing lights, hypersensitivity to light and / or sound, temporary vision loss, and vomiting.

[0196] Cancer-related pain is one of the most severe forms of pain. Such pain can be further exacerbated by cancer treatments, including radiation therapy and chemotherapy. The formulations of the present invention can be used to treat cancer-related pain in muscles, bones, and joints. The formulations of the present invention can also be used in combination with currently available treatments for such pain to provide enhanced and / or additive relief.

[0197] In the following embodiments, the present invention provides combinations specified herein for use in the treatment of disorders selected from the list, including pain, neurodegenerative disorders, post-traumatic stress syndrome, or blisters, the use of which includes the alleviation of secondary symptoms caused by the disorders.

[0198] In some embodiments, long-term treatment may be necessary to alleviate the secondary symptoms described above. Some of the disorders that can be treated with the above combinations require long-term treatment to adequately alleviate the secondary symptoms associated with those disorders.

[0199] In some embodiments, this may involve lifelong treatment. In other embodiments, it may be treatment until the complete disappearance of secondary symptoms caused by the disorder.

[0200] In some embodiments, the above secondary symptoms may be chronic or recurrent symptoms.

[0201] In further embodiments, the present invention provides combinations specified herein for use in the treatment of disorders selected from the list including pain, neurodegenerative disorders, post-traumatic stress syndrome, or blisters, the use of which includes relief of secondary symptoms caused by the disorders, such as secondary pain, itching, secondary impetigo, swelling, inflammation, or bacterial infection.

[0202] In some embodiments, the secondary pain is selected from a list including pain associated with blisters, cancer, surgery, injury, internal diseases, muscle, bone or joint diseases, or nerve damage; in particular, muscle sprains, muscle pain, bruises, arthritis, cancer-related pain, joint pain such as shoulder, knee, elbow, or hip pain; surgical pain, pre- and post-operative pain.

[0203] Where used herein, unless otherwise specified, the term “anti-inflammatory properties” is understood to mean properties designated for, for example, substances / compounds / treatments / drugs that reduce inflammation or swelling.

[0204] Where used herein, unless otherwise specified, the term “analgesic properties” is understood to mean properties designated for a substance / compound / treatment / drug that reduces pain, for example, by interacting with the peripheral and central nervous systems in various ways.

[0205] Where used herein, unless otherwise specified, the term “antipruritic properties” is understood to refer to properties designated for substances / compounds / treatments / drugs that inhibit itching (also known as pruritus).

[0206] Where used herein, unless otherwise specified, the term “antifungal properties” is understood to mean properties designated for, for example, substances / compounds / treatments / drugs that prevent or treat various fungal conditions.

[0207] Where used herein, unless otherwise specified, the term “antibacterial properties” is understood to mean properties designated for a substance / compound / treatment / drug that inhibits the growth or reproductive capacity of bacteria, or completely eliminates bacteria.

[0208] The analgesic effect of THC is related to the agonism of cannabinoid receptors CB1 and CB2. Other effects include muscle relaxation and antiemetic effects. On the other hand, CBD is related to 5-HT 1A CBD exhibits activity including receptor agonism, GPR55 antagonistism, negative allosteric modulation of CB1, TRPV1 activation, PPARγ activation, and reuptake inhibition. CBD also appears to indirectly activate endogenous cannabinoid signaling, while showing activity at both CB1 and CB2 receptors. All of this is thought to contribute to CBD's anxiolytic, neuroprotective, anti-inflammatory, and immunomodulatory properties.

[0209] Furthermore, studies have shown that the activity of CBD against Gram-positive bacteria (e.g., Staphylococcus aureus and Streptococcus pneumoniae) is similar to that of conventional antibiotics (e.g., vancomycin), further illustrating the role of CBD in bacterial infections.

[0210] Furthermore, specific combinations of THC and CBD used in combination therapy have been shown to possess synergistic properties, such as suppressing neuroinflammation and reducing muscle spasms. Additionally, CBD alone, THC, and combinations of THC have been shown to have anti-inflammatory and anti-algesic effects. Moreover, studies suggest that either CBD alone or CBD combined with THC may alter fear memories and may have a positive effect on anxiety in cases of post-traumatic stress disorder (PTSD).

[0211] The combination of THC and CBD has been shown to be effective in treating neuropathic pain, such as allodynia. In this case, CBD has been shown to enhance the pain-relieving effects of THC.

[0212] Where used herein, unless otherwise specified, the term “allodynia” is understood as central pain sensitization resulting from stimuli that are not normally painful. In many cases, these stimuli are repetitive.

[0213] In some embodiments, the pain may be neuropathic pain.

[0214] In some embodiments, the combination may have at least one property selected from a list that includes anti-inflammatory, analgesic, antipruritic, antifungal, or antibacterial properties.

[0215] In another embodiment, the present invention provides combinations specified herein for use in the treatment of disorders selected from a list including pain, blisters, neurodegenerative disorders, or post-traumatic stress syndrome, wherein such use includes reducing opioid consumption / dependence in the treatment of such disorders.

[0216] The combination of the present invention provides a suitable alternative to pharmaceuticals containing, for example, opioid substances. Since these opioid substances have been shown to carry a significant risk of addiction and can lead to fatal overdoses, the combination of the present invention provides a more specifically alternative to meet long-term needs in this therapeutic area. The combination of the present invention reduces the risk of drug addiction (e.g., opioid addiction), particularly when long-term treatment is required. The longer the duration of drug use, such as morphine, oxycodone, or other potent analgesics, the higher the risk of addiction. Furthermore, the longer these analgesics are used, the higher the dose due to substantial tolerance. This can contribute to the risk of fatal overdose. Therefore, the use of the combination of the present invention provides a suitable alternative with the positive effect of reducing the risk of drug addiction compared to the use of conventional drugs (e.g., opioids).

[0217] Finally, the anti-algesic effects demonstrated by the combination of THC and CBD may offer a valuable treatment for opioid-induced hyperalgesia associated with long-term use of opioids such as morphine, oxycodone, and methadone.

[0218] In another embodiment, the combinations of use specified herein may include one or more additional pharmaceutically active agents suitable for use in the treatment of the above-mentioned disorders.

[0219] In some embodiments, additional pharmaceutically active agents may act as ligands for bodily cannabinoid receptors (e.g., cannabinoid receptor type 1 (CB1), cannabinoid receptor type 2 (CB2)) and other cannabinoid receptors.

[0220] In some embodiments, combination uptake may occur via the pulmonary pathway.

[0221] In other embodiments, additional pharmaceutically active agents may be a class of drugs that contribute to the alleviation of secondary symptoms such as pain and inflammation. [Examples]

[0222] The following disclosures are exemplary embodiments. Those skilled in the art will understand that the apparatus, techniques, and methods disclosed herein illustrate representative embodiments that function well in practice. However, those skilled in the art should understand that many modifications can be made in light of the disclosed specific embodiments to obtain similar or equivalent results without departing from the spirit and scope of the invention.

[0223] Example 1: Lung preparation used in a dry powder inhaler In this embodiment, the formulation is treated with electrospray to produce drug nanoparticles.

[0224] Table 1: 1% weight / weight Δ used in dry powder inhalers 9 - Composition of THC (10 mg / mL) lung preparation. [Table A]

[0225] The formulations were processed by electrospray using a Fluidnatek™ LE10 lab line at Bioinicia SL (Valencia, Spain) equipped with a variable high-voltage power supply from 0 kV to 30 kV. The formulations were supplied to 5 mL syringes, and each solution was pumped through a stainless steel needle injector. Samples were collected on a grounded metal plate. The applied voltage, flow rate, and distance from the tip to the collector were optimized based on visual observation of Taylor cone formation and the absence of droplet deposition on the collector. Different biopolymers of different origins, such as whey protein concentrate (WPC) with 80% protein content, the polysaccharide maltodextrin, the plant protein zein, or the plastic-derived polymer polyvinylpyrrolidone (PVP), were evaluated as potential matrices. To improve the sprayability as previously described by the authors, surfactants were added to all solutions at a concentration of 6% by weight relative to the polymer weight.

[0226] Example 2: Lung preparation used in a soft mist inhalation device Each single dose (sometimes referred to as a "puff") of this formulation from a soft mist inhaler (15 microliters) can deliver an effective dose of 150 μg to the person in need.

[0227] Table 2: 1% weight / weight Δ used in soft mist inhalation devices 9 - Composition of THC (10 mg / mL) lung preparation. [Table B]

[0228] Example 3: Spray drying of CBD for inhalation particles for lung delivery Equipment setup Spray drying was performed using a spray dryer (ProCepT spray dryer) equipped with a small cyclone. The liquid feed was atomized using a two-fluid nozzle with a 0.4 mm orifice. The nozzle air velocity was adjusted to obtain a particle size close to the desired range (e.g., 1 μm to 5 μm). The following parameters are examples of parameters that can be used during spray drying: inlet airflow (0.30 m 3 ( / min), cyclone gas (100 L / min), inlet temperature (120°C), and spray rate (4 g / min).

[0229] Preparation of liquid feed Liquid feeds were prepared by mixing a CBD solution in a solvent such as ethanol with another excipient in water (e.g., mannitol, maltodextrin, trehalose, lactose, (2-hydroxypropyl)-beta-cyclodextrin (HPBCD), random methyl-beta-cyclodextrin). Adding a surfactant such as lecithin to the suspension resulted in less sedimentation after 48 hours of storage, leading to a more stable system.

[0230] While the ethanol / water ratio was 1 / 2 (volume / volume), changing the solvent ratio from 1 / 2 to 1.5 / 1 (volume / volume) or 1 / 1 (volume / volume) water / ethanol can result in a more stable (i.e., no phase separation, no precipitation) liquid feed for formulations containing 1 / 12 (weight / weight) CBD / excipient.

[0231] Evaluation of various pharmaceutical excipients When the CBD / excipient ratio was kept constant at 1 / 12 (weight / weight), a suspension containing cyclodextrin as an excipient was spray-dried, and a higher yield was obtained compared to suspensions containing other excipients such as lactose, mannitol, maltodextrin, and trehalose (51% or less) (i.e., 62% and 76% for HPBCD and random methyl-BCD, respectively) (Table 3).

[0232] In the case of maltodextrin, trehalose, or lactose, the addition of a surface-active amino acid (i.e., leucine) equivalent to 10% (weight / weight) of the total weight of CBD and excipients significantly increased the yield (Table 3). In the case of lactose, HPBCD, and RMBCD, the same increase in yield was observed after adding leucine equivalent to 5% (weight / weight) of the combined weight of CBD and other excipients (Table 3). In particular, formulations containing 5% or 10% (weight / weight) of leucine increased the yield to 73% and 74%, respectively, compared to formulations containing 0% leucine (yield 47%). The positive effect of leucine on yield does not necessarily further increase the yield of cyclodextrin-based formulations (Table 3). Leucine typically migrates to the surface of droplets during the drying stage in a spray dryer, resulting in an increased leucine concentration in the outer crust that reduces particle cohesiveness. Leucine has the ability to improve the fluidity of inhaled powders.

[0233] Table 3: Yield, average particle size, and size fraction (0 μm to 5 μm). [Table C]

[0234] Scanning electron microscopy Scanning electron microscope (SEM) images show that spherical particles can be obtained from a powder containing trehalose and lactose as excipients (data not shown). When leucine was added to the formulation, particles with a rougher surface were obtained compared to smooth particles without leucine, confirming by SEM images that leucine migrated to the outer crust during the drying stage (data not shown).

[0235] When HPBCD and random methyl-BCD were used as excipients, the diffusion rate of these larger molecules (i.e., cyclodextrins) was lower, resulting in more wrinkled particles (which provided better inhalation characteristics) (SEM images not shown). The surfaces of the leucine-containing and leucine-free particles were similar, confirming that leucine did not migrate outside the droplets. This observation supported the previously made hypothesis that leucine is trapped within the cyclodextrins. Some of the resulting particles appeared to break during the drying process, and the broken shells were visible in the SEM images.

[0236] Modulated differential scanning calorimetry Pure CBD and selected SD samples were analyzed by modulated differential scanning calorimetry (mDSC) to evaluate the solid state of CBD in spray-dried powder. For example, the mDSC graph (Figure 1B) of formulations containing lactose or random methyl-BCD as excipients (i.e., leucine-free) did not show a CBD melting peak (i.e., 67°C, Figure 1A).

[0237] Optimization of processes using RMBCD as an excipient Formulations containing random methyl beta-cyclodextrin (RMBCD) and leucine-free may yield the highest yield (i.e., 76%) among all evaluated formulations, but may contain a certain amount of broken particles in the powder that could affect the inhalation properties of the product.

[0238] Furthermore, a formulation with 5% (weight / weight) RMBCD excipient and a 2 / 1 (volume / volume) water / ethanol ratio using an inlet temperature of 120°C yielded 76%, but the preparation resulted in precipitation / phase separation just 5 minutes after preparation, and therefore this is a liquid feed with low stability (Table 5).

[0239] Changing the water / ethanol solvent ratio from 2 / 1 to 1 / 1 (volume / volume) can result in a more stable (i.e., no phase separation, no precipitation) liquid feed for a clear 1 / 12 (weight / weight) CBD / RMBCD formulation. However, increasing the ethanol can lead to a higher abundance of broken particles (Table 5, Sample 2), so the solvent ratio can vary to avoid broken particles while still maintaining a stable solution (e.g., 1.5 / 1 (volume / volume) water / ethanol).

[0240] Reducing the solids content may slow down crust formation and potentially avoid particle fracture. The solids content can be reduced from 5% (weight / weight) to 2.5% (weight / weight), but this does not necessarily improve the yield (Table 5, Sample 3).

[0241] Lowering the inlet temperature (e.g., from 120°C to 100°C) may reduce the amount of broken particles in the spray-dried powder (as exemplified by high yield (71%) and high liquid feed stability (Table 5, Sample 4)).

[0242] Table 5: Yield and stability of liquid feeds of CBD formulations containing RMBCD as an excipient. [Table D]

[0243] conclusion In summary, liquid supplies containing CBD solution, ethanol, water, and excipient solutions (e.g., mannitol, maltodextrin, trehalose, lactose, (2-hydroxypropyl)-beta-cyclodextrin (HPBCD), randommethyl-beta-cyclodextrin (RMBCD)) may be suitable for preparing spray-dried formulations for inhalation applications.

[0244] Specifically, formulations containing lactose and 5% (weight / weight) leucine (a surface-active compound) at a CBD / lactose ratio of 1 / 12 (weight / weight), and formulations containing randomly methylated beta-cyclodextrin (RMBCD) at a CBD / RMBCD ratio of 1 / 12 (weight / weight) and no leucine, exhibit high yields and stability at the end of the spray drying process. More specifically, formulations containing randomly methylated beta-cyclodextrin may have superior stability compared to suspensions containing lactose and do not require leucine for high yields.

[0245] Example 4: Spray Drying of THC or CBD / THC for Inhalable Particles for Lung Delivery Equipment Setup Spray drying is carried out using a spray dryer (ProCepT spray dryer) equipped with a small cyclone. A two-fluid nozzle with a 0.4 mm orifice was used to atomize the liquid feed. The air velocity of the nozzle was adapted to obtain particle sizes close to the desired range (e.g., 1 μm to 5 μm). The following parameters are examples that can be used during spray drying: inlet air flow (0.30 m 3 / min), cyclone gas (100 L / min), inlet temperature (100 °C or 120 °C), and spray rate (4 g / min).

[0246] Preparation of Liquid Feed The liquid feed was prepared by mixing a solution of THC or CBD / THC in ethanol with another excipient such as lactose in water or randomly methylated beta-cyclodextrin (RMBCD) (a THC or CBD / THC - 1 / 12 (weight / weight) excipient ratio).

[0247] THC Formulation Containing Lactose as an Excipient At a THC / lactose ratio of 1 / 12 (weight / weight), an ethanol / water ratio of 1 / 2 (volume / volume), and an inlet temperature of 120°C, a leucine-free THC and lactose-containing formulation (Table 6) may result in a very low yield (i.e., 5%) compared to a lactose-containing, 0% leucine CBD formulation (47%). The addition of 5% leucine can increase the yield of the THC formulation to 76%, as can the CBD formulation containing lactose and 5% leucine (see Example 3 and Table 6; i.e., 73%). Similar particle sizes can also be obtained.

[0248] Formulations containing the active compounds CBD and THC in a 1 / 1 (weight / weight) ratio with 5% leucine may have similar yields (74%) and particle sizes (Table 6). Scanning electron microscopy analysis of three leucine-containing powders can confirm identical morphology (data not shown).

[0249] Table 6: Comparison of CBD and THC preparations containing lactose. [Table E]

[0250] THC preparations containing RMBCD as an excipient At a THC / RMBCD ratio of 1 / 12 (weight / weight), an ethanol / water ratio of 1 / 1 (volume / volume), and an inlet temperature of 120°C, the leucine-free formulation containing THC and RMBCD (Table 6) remained stable for 24 hours without mixing, demonstrating that this formulation is reliably suitable for spray drying.

[0251] However, compared to CBD formulations containing RMBCD (71%), this formulation yielded a slightly lower yield (i.e., 65%), which is likely due to a slightly smaller average particle size in the product (i.e., 1.99 μm instead of 2.55 μm) (Table 7).

[0252] Formulations containing CBD and THC in a 1 / 1 (weight / weight) ratio may have similar yields (64%) and particle sizes compared to similar formulations containing only CBD or only THC (Table 7). Scanning electron microscopy analysis of the three powders may confirm identical morphology, however, the powder containing THC may be more cohesive than the formulation containing CBD, as exemplified by the formation of larger aggregates (data not shown).

[0253] Table 7: Comparison of CBD and THC preparations, including RMBCD. [Table F]

[0254] conclusion Formulations containing lactose and leucine, the active compound CBD, THC, or a combination of CBD / THC, may not affect various parameters of the formulation, as they may yield similar yields and acceptable fluidity in all powders.

[0255] Formulations containing RMBCD, the active compound THC, or a CBD / THC combination may have slightly lower yields and higher cohesiveness / stickiness compared to formulations containing RMBCD with CBD as the active compound.

[0256] summary For obtaining CBD, THC, or CBD / THC-based formulations for inhalation use, lactose (an approved inhalation carrier) is a potentially most promising excipient, as it yields high yields (i.e., approximately 73%) when 5% leucine is added to the formulation. Alternatively, promising results have been obtained using random-methyl-BCD (i.e., cyclodextrin) as an excipient without the addition of leucine. [Explanation of Symbols]

[0257] Figure 1A Rev Heat Flow (W / g) Reversible heat flow (W / g) Temperature (℃) Temperature (℃) Figure 1B Rev Heat Flow (W / g) Reversible heat flow (W / g) Temperature (℃) Temperature (℃) Upper two lines Lower two lines Lactose Lactose + leucine Ran Methyl-BCD Ran Methyl-BCD + Leucine

Claims

1. A pulmonary delivery agent comprising tetrahydrocannabinol (THC) and cannabidiol (CBD) for use in the treatment of a disorder selected from the list including pain, neurodegenerative disorders, post-traumatic stress syndrome, or blisters, wherein the agent comprises at least one excipient which is a substituted beta-cyclodextrin selected from hydroxyalkylated and / or alkylated beta-cyclodextrins.

2. The agent according to claim 1, wherein the substituted beta-cyclodextrin is (2-hydroxypropyl)-beta-cyclodextrin (HPBCD) or random methyl-beta-cyclodextrin (RMBCD).

3. The agent according to claim 1, wherein the substituted beta-cyclodextrin is (2-hydroxypropyl)-beta-cyclodextrin (HPBCD).

4. The agent according to claim 1, wherein the agent does not contain terpenes.

5. The drug according to any one of claims 1 to 4, wherein the drug is selected from a list including liquid formulations, suspensions, powders, or aerosols.

6. The agent according to any one of claims 1 to 5, wherein the excipient has a CBD-THC / excipient ratio of 1 / 1 to 1 / 20 (weight / weight) or 1 / 12 (weight / weight).

7. The agent according to any one of claims 1 to 6, wherein the agent further comprises leucine, or at least 5% (by weight / by weight) of leucine.

8. The drug according to any one of claims 1 to 7, wherein the drug is a powder formulation.

9. The drug according to claim 8, wherein the powder formulation contains particles having an average particle size of 0.1 μm to 100 μm, or 0.1 μm to 10 μm, or 0.1 μm to 5 μm.

10. The agent according to claim 5, wherein the aerosol is an aerosol that does not contain a propellant.

11. The drug according to any one of claims 1 to 10, wherein the drug is formulated for administration by inhalation.

12. The drug according to any one of claims 1 to 11, wherein the drug is administered to a subject using an inhalation device.

13. The drug according to any one of claims 1 to 12, wherein the pain is selected from a list including headache, migraine, physiological pain, or physical ailment.

14. A drug according to any one of claims 1 to 13, for use in the treatment of blisters.

15. The agent according to claim 14, wherein the blisters are caused by burns or other related injuries, or by a disorder selected from the list including skin allergies, various forms of eczema, bullous pemphigoid, bullous impetigo, herpetiform dermatitis, pemphigus vulgaris, mucous membrane pemphigoid, pemphigoid of pregnancy, epidermolysis bullosa, pemphigus foliaceus, or toxic epidermal necrolysis.

16. The agent according to any one of claims 1 to 13, wherein the neurodegenerative disorder is selected from the list including Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD-related disorders, essential tremor, multiple system atrophy, Huntington's disease, or motor neuron disease (MND).

17. The agent according to any one of claims 1 to 16, wherein the use includes the alleviation of secondary symptoms caused by the disorder.

18. The agent according to claim 17, wherein the aforementioned secondary symptoms are selected from a list including secondary pain, itching, secondary impetigo, swelling, inflammation, or bacterial infection.

19. The agent according to any one of claims 1 to 18, wherein the use comprises a reduction in opioid consumption / dependence in the treatment of at least one of the disorders.

20. The agent according to any one of claims 1 to 19, further comprising one or more additional pharmaceutically active agents suitable for use in the treatment of the said disorder.

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