Preparation and use of cannabis nano-formulation

Abstract

To provide a formulation comprising natural cannabis material which may be safely applied, and which shows a pharmacological effect at a lower dose.SOLUTION: The present application relates to a formulation comprising at least one natural cannabis material, at least one solvent, and at least one stabilizer, wherein the formulation is a liquid suspension having a particle size (D90) of below 500 nm.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present application relates to a formulation comprising at least one natural cannabis material, at least one solvent, and at least one stabilizer, the formulation comprising cannabis particles having a particle size (D 90 ), and its use in the treatment of disease. [Background technology]

[0002] The use of cannabis as a natural material in the fields of medicine and pharmacology has a long history, dating back 2500 years. However, the use of cannabis products is also associated with fears of possible side effects or addiction. Nevertheless, cannabis has been identified as a natural product that can be used as a medicine with beneficial effects. An overview is given in Non-Patent Document 1. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Bridgeman et al., Pharmacy & Therapeutics, vol. 42, 3 (2017), pages 180-188 Summary of the Invention

[0004] In light of the controversial debate regarding the use of cannabis products and the inability of currently available products to address the need, there remains a need for products containing natural cannabis materials that can be safely applied, that have a constant delivery of active agents to patients in need thereof, and that exhibit pharmacological effects at lower doses compared to available products.

[0005] The present disclosure addresses these needs. In a first aspect, a formulation comprising at least one natural cannabis material, at least one solvent, and at least one stabilizer, the formulation comprising cannabis particles having a particle size (D 90A formulation is provided which is a liquid suspension having

[0006] A second aspect relates to formulations for use in palliative care and / or in the treatment or alleviation of disease.

[0007] Further details and preferred embodiments are disclosed below. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 shows a comparison of CBD plasma concentrations after a single dose of the formulation of Example 1 and Sativex™. [Diagram 2] FIG. 1 shows a comparison of THC plasma concentrations after a single dose of the formulation of Example 2 vs. Sativex™. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] In a first aspect, the disclosure provides a formulation comprising at least one natural cannabis material, at least one solvent, and at least one stabilizer, the formulation comprising cannabis particles having a particle size (D 90 ).

[0010] The formulations of the present disclosure relate to stable suspensions of natural cannabis material in a solvent. Based on the small particle size of the natural cannabis material, the formulations are particularly suitable for application to mammals, particularly humans.

[0011] In a second aspect, the present disclosure provides a method for the treatment or alleviation of a disease, comprising administering to said patient a therapeutically effective amount of ... medicament for use in palliative care and / or in the treatment or alleviation of a disease. The present invention relates to a formulation for use in treating a chronic condition, preferably selected from the group consisting of pain, in particular acute or chronic pain, somatic pain, visceral pain, neuropathic pain, cancer pain, chronic low back pain, chronic central pain; neuropathy, neurodegenerative diseases, insomnia, psychiatric disorders, nausea, anorexia, vomiting and nausea caused by chemotherapy, diabetic polyneuropathy, fibromyalgia, Tourette's syndrome, multiple sclerosis, convulsions in multiple sclerosis, anxiety disorders, schizophrenia, social phobia, sleep disorders, skin-related diseases such as psoriasis and neurodermatitis, glaucoma, restless legs syndrome, epilepsy, movement disorders such as Alzheimer's disease, dystonia, Huntington's disease, Parkinson's disease, bipolar disorders, and other medical indications affected by the endocannabinoid system and by any other receptors affected by cannabinoids (e.g. GPR18, GPR119, GPR55).

[0012] As described in more detail below, based on the use of natural cannabis material in the formulations of the present disclosure, the formulations may be used as medicines, particularly in palliative care and / or for the treatment or alleviation of disease.

[0013] In the following, preferred embodiments of the first and second aspects of the present disclosure are outlined in detail. It is understood that the embodiments are independent of each other and can be freely combined even if not explicitly stated or if it is obvious to those skilled in the art. As an example, the preferred embodiment for natural cannabis material is generally independent of the preferred embodiment for solvent or stabilizer, and therefore these embodiments can be freely combined.

[0014] formulation The present disclosure provides a formulation comprising at least one natural cannabis material, at least one solvent, and at least one stabilizer, the formulation comprising cannabis particles having a particle size (D 90The formulation is present as a liquid suspension and may therefore also be referred to as a suspension or nanosuspension. Nanosuspensions are so named because they contain particles with a size on the order of nanometers. The particles present in the suspension have a diameter (D) of less than 500 nm. 90 ).

[0015] In a preferred embodiment of the present disclosure, the particle size of these suspensions (D 90 ) is less than 450 nm, even more preferably less than 400 nm, even more preferably less than 300 nm, even more preferably less than 250 nm, even more preferably less than 220 nm. Because of the smaller particle size of the natural cannabis material in the formulations of the present disclosure, the natural cannabis material can be more easily absorbed and therefore more readily available in the body, especially in the plasma.

[0016] In preferred embodiments, the formulations of the present disclosure do not include cyclodextrin(s).

[0017] Natural cannabis materials Natural cannabis material is present in the formulations of the present disclosure. The natural cannabis material present in the formulation is natural material, i.e., material that is cultivated in nature. The material is obtained from plants in the Cannabaceae family, and is classified as Aphananthe, Cannabis, Sesame, or the like. Preferably, the material is obtained from a plant of a genera selected from the group consisting of Celtis, Chaetachme, Gironniera, Humulus, Lozanella, Parasponia, Pteroceltis, and Trema. In a particularly preferred embodiment, the material is obtained from a plant of the Cannabis genus.

[0018] In a particularly preferred embodiment, the at least one natural cannabis material is a material of the Cannabis genus, Cannabis being Cannabis sativa, Cannabis indica, Cannabis sativa ... From Cannabis indica and Cannabis ruderalis In other words, according to the above embodiment, the plant providing the natural cannabis material is a plant of the above species Cannabis sativa, Cannabis indica, or Cannabis ruderalis. It is particularly preferred that the at least one natural cannabis material is material obtained from a plant of the Cannabis sativa species.

[0019] As outlined above, at least one natural cannabis material is taken from a plant of the Cannabaceae family. In this context, the natural cannabis material can be the whole plant, i.e. the whole plant, or other parts. Any part of the plant, in particular the whole physiological part of the cannabis plant, may be used as the natural cannabis material. The plant parts may be selected according to preferred embodiments from the group consisting of leaves, stems, seeds, flowers, roots, and mixtures thereof. It is preferred to use parts of the plant that have a high CBD and / or THC content. In a particularly preferred embodiment, the plant parts are the flowers of the natural cannabis material.

[0020] In a preferred embodiment, the at least one natural cannabis material is a mixture of at least two natural cannabis materials. In other words, various parts of the plant, especially physiological parts such as flowers or leaves, may be used as natural cannabis material, or whole or parts of different plants may also be used as natural cannabis material. The two different plants or parts thereof then together form a natural cannabis material, expressed herein as two natural cannabis materials. The at least two cannabis materials are independently selected from the genera or species defined above. In a particularly preferred embodiment, the natural cannabis material is a mixture of Cannabis sativa and Cannabis indica or Cannabis ruderalis. A mixture of Cannabis indica and Cannabis ruderalis is less preferred. The content of CBD and / or THC is particularly high in Cannabis sativa, which makes this species particularly preferred as a natural cannabis material according to the present disclosure.

[0021] Natural cannabis material may have a particularly high CBD or THC content and is also referred to as cannabidiol-rich material (CBD-rich material) or tetrahydrocannabinol-rich material (THC-rich material). Natural cannabis material is also understood to refer to material derived directly from the plant, for example by drying and / or decarboxylation.

[0022] The natural cannabidiol-rich material preferably has a cannabidiol concentration in the range of 5% to 40% (weight / weight), preferably 10% to 30% (weight / weight), relative to the total mass of cannabinoids in the natural cannabis material.

[0023] The natural tetrahydrocannabinol-rich material preferably has a tetrahydrocannabinol concentration in the range of 5% to 40% (wt / wt), preferably 10% to 30% (wt / wt), relative to the total mass of cannabinoids in the natural cannabis material. In another preferred embodiment, the natural tetrahydrocannabinol-rich material preferably has a tetrahydrocannabinol concentration in the range of 5% to 40% (wt / wt), preferably 10% to 30% (wt / wt), relative to the total dry mass of cannabis flowers.

[0024] The amount of cannabinoids in natural cannabis material can vary. When Cannabis sativa is harvested, there is already variation in the amount of cannabinoids in different parts of the plant. The amount of cannabinoids in Cannabis sativa flowers can range, for example, from 10% to 30% by weight relative to the total dry mass of the natural cannabis material. Alternatively, the amount of cannabinoids in Cannabis sativa flowers can range, for example, from 10% to 30% by weight relative to the total dry mass of the cannabis flower.

[0025] Natural cannabis material is not merely an extract, i.e. a liquid or soluble fraction of natural cannabis material, but is cannabis material that is naturally present in the natural composition of the whole or part of the cannabis plant and has a molecular weight of less than 500 nm. The natural cannabis material is milled or ground to a particle size of less than 10 ...

[0026] A suspension is a heterogeneous mixture in which solid particles do not dissolve but are suspended throughout the bulk of the solvent and remain freely suspended in the medium. The nanoparticles present in the suspension of the present disclosure are encapsulated in complex nanocarriers having a hydrophilic coating.

[0027] However, in a preferred embodiment of the present disclosure, the formulation does not exclude also containing an extract, in particular an extract of natural cannabis material. Such an extract may be used to further increase the amount of cannabinoids in the formulation, in particular the amount of THC or CBD. It is understood that such an extract is present in addition to the presence of natural cannabis material as outlined above.

[0028] In a preferred embodiment, the natural cannabis material is present in the formulations of the present disclosure in an amount of 0.1% to 20% (wt / wt), relative to the total mass of the formulation, preferably 0.1% to 10% (wt / wt), preferably 0.2% to 5% (wt / wt), preferably 0.3% to 4% (wt / wt), preferably 0.5% to 3% (wt / wt), more preferably 0.5% to 1% (wt / wt), 1% to 2% (wt / wt), or 2% to 4% (wt / wt), relative to the total mass of the formulation.

[0029] Particles of natural cannabis material In the formulations according to the present disclosure, particles of at least one natural cannabis material are present. For the preparation of the nanosuspensions of the present disclosure, some or all of the at least one natural cannabis material is used.

[0030] The formulation is a stable suspension of at least one natural cannabis material in a solvent through the use of at least one stabilizer. Thus, the formulation is a heterogeneous mixture of a liquid solvent and a solid natural cannabis material. The natural cannabis material is in the form of nanoparticles having a particle size of less than 500 nm and is stabilized in the solvent by at least one stabilizer.

[0031] The formulations of the present disclosure may be prepared according to the methods disclosed in WO 2015 / 114164 or WO 2017 / 021491.

[0032] As also outlined below in the experimental section, the natural cannabis material was prepared using a particle size distribution (D 100 The natural cannabis material, i.e., particles, may be provided in dry form, fresh form (i.e., as it occurs in nature), or with a particular moisture content. The powder or particles of the natural cannabis material may be added to the solvent in any form specified in the preparation method.

[0033] In another preferred embodiment, the natural cannabis material used in the preparation of the nanosuspension may be dried, preferably lyophilized (freeze-dried) and / or heat-dried.

[0034] The particles of natural cannabis material used to prepare the nanosuspension preferably have a low moisture content. The term "moisture content" or "residual moisture" as used in this disclosure is defined using the formula: The mass of the moist or wet material m 湿潤 and the mass of dry material without moisture m 乾燥 and the mass of the material with residual moisture m 残留 This refers to the moisture content, w, of a material such as natural cannabis material, calculated from: Residual moisture content [%]w=(m 残留 -m乾燥 ) / (m 湿潤 -m 乾燥 )×100%

[0035] In another preferred embodiment, the natural cannabis material used for the preparation of the nanosuspension has a water content w of less than 15% (w<15%), preferably less than 10% (w<10%), more preferably less than 5% (w<5%) and most preferably less than 3% (w<3%).

[0036] Such low water content can be advantageous when preparing nanosuspensions. Furthermore, the natural cannabis material can be dispersed in a nanoparticle size (D 100 ). There are various methods known in the art to reduce the moisture content of natural cannabis material, any of which may be used in conjunction with the present disclosure. By way of example, the natural cannabis material may be lyophilized (i.e., freeze-dried) or heat-dried. Depending on the type of natural cannabis material prior to the drying step, it may be advantageous to wash, peel and / or core the natural cannabis material.

[0037] The natural cannabis material can also be dried in air or in an oven, for example at a temperature between 30°C and 140°C, until the residual moisture content w is as low as 5% or even 3%. Preferably, the drying step is combined with a step of decarboxylating the active agents in the natural cannabis material, in particular THC and CBD. This can be achieved in an oven, preferably at a temperature between 110°C and 150°C, preferably between 120°C and 140°C. The natural cannabis material can be kept at the elevated temperature for a period ranging from 30 minutes to 5 hours, preferably between 40 minutes and 1 hour, more preferably between 45 and 55 minutes.

[0038] In another preferred embodiment, the at least one natural cannabis material used for the preparation of the nanosuspension is pre-ground, preferably in a knife mill, before and / or after drying, and optionally to a particle size (D 100) to a particle size of less than 320 μm. Such comminution of the natural cannabis material can be done with the natural cannabis material as is, i.e., without prior cutting or drying, or the natural cannabis material may be cut into pieces and / or dried as described above. Further, the natural cannabis material may be sieved to a particle size of less than 320 μm (D 100 ) may be sieved to provide a powder of natural cannabis material.

[0039] The "total amount of natural cannabis material" contained in the formulation refers to the amount of dry mass, i.e. the mass of dry natural cannabis material without any solvent or stabilizer. Thus, the dry mass of the formulation is the sum of the dry mass of the particles of at least one natural cannabis material. This is also referred to as the solids of the formulation.

[0040] solvent The formulations of the present disclosure include, apart from at least one natural cannabis material, at least one solvent, and at least one stabilizer.

[0041] In a preferred embodiment, the solvent is selected from the group consisting of water, ethanol, lipid, non-polar organic solvent, and mixtures thereof, and preferably the solvent is a mixture of water and lipid, such as an emulsion.Preferably, the formulation of the present disclosure is a pharmaceutical formulation, and therefore the solvent used is preferably a pharma-ceutically acceptable solvent.In this respect, particularly preferred solvents are water, ethanol, and mixtures of water and lipid, preferably such mixtures of water and lipid.As used herein, the term "lipid" refers to a single lipid or a mixture of lipids.

[0042] In a further preferred embodiment, the lipid is a solid lipid, a liquid lipid, a wax, and the like. and even more preferably, the lipid is a mixture of liquid and solid lipids, especially in combination with water as the solvent.

[0043] The resulting formulation may therefore be an aqueous nanolipid formulation or a nanolipid formulation based on a mixture of solvents (e.g., water, lipid, ethanol). As used herein, the term "solvent" refers to a single solvent or a mixture of solvents.

[0044] In another preferred embodiment, the solvent is water, preferably distilled water, or a mixture of water and lipid, or a mixture of water and ethanol, or a mixture of water, lipid and ethanol.The water used as solvent can be any kind of water, for example, normal water, purified water, distilled water, double distilled water or triple distilled water, or demineralized water.Preferably, purified water or any type of distilled water that meets the standard of sterile solvent is used.

[0045] Similarly, the lipids used may be pure lipids or nanolipid formulations based on mixtures of lipids with water, lipids mixed with water, or lipids mixed with water and ethanol. Nanolipid formulations may therefore contain liquid lipids, solid lipids, or mixtures of solid and liquid lipids in various proportions.

[0046] Most preferably, the nano smart-lipid formulation is based on a mixture of water and lipids.

[0047] Such lipids may be selected from the subcategories of saturated and unsaturated fatty acids, fatty alcohols, waxes, fat-soluble vitamins, monoglycerides, diglycerides, triglycerides, sterol and steryl esters, phospholipids and their derivatives, or any other suitable organic compounds that are insoluble or not readily soluble in polar solvents.

[0048] From the group of triglycerides, liquid lipids, solid lipids, synthetic or semi-synthetic derivatives of glycerol and saturated or unsaturated fatty acids, or mixtures thereof can be preferably selected.Liquid lipids, also known as oils, are typically liquid at room temperature.Solid lipids, also known as fats, are usually solid at room temperature and have a high proportion of unsaturated fatty acids.

[0049] In a preferred embodiment, the lipid is selected from the group consisting of a glyceride, preferably a monoglyceride, a diglyceride, or a triglyceride, preferably the lipid is a triglyceride, more preferably the glyceride is a medium chain triglyceride and a saturated C 12 ~C 18 It is a mixture of glycerol esters of fatty acids (Gelucire™ 39 / 01).

[0050] In certain preferred embodiments, the liquid lipid comprises a medium chain triglyceride. Other liquid lipids may also be selected, such as tricaprylin, caprylic / capric / linoleic triglyceride, and acetylated monoglycerides.

[0051] In another preferred embodiment, the liquid lipids include natural oils selected from the group consisting of sesame oil, hemp oil, sunflower oil, soybean oil, safflower oil, rapeseed oil (including canola oil), linseed oil, nut oils (e.g., almond oil, cashew oil, walnut oil, peanut oil), cottonseed oil, rice bran oil, corn oil, palm oil (including coconut oil), palm kernel oil, marine oils (such as fish oils), and other edible oils.

[0052] Solid glycerides include, for example, hard fats (adeps solidus), gel ucire 43 / 01 (Gatefosse, France), tricaprin, trilauri Examples of suitable glyceryl tristearate include glyceryl tristearate, trimyristin, tripalmitin, glyceryl tristearate, and most preferably Gelucire® 39 / 01 (Gatefosse, France). However, other solid lipids such as Compritol™, Softisan™ 378, and cetyl palmitate may also be selected.

[0053] It is particularly preferred that the lipids are selected from the group of triglycerides. Thus, in a particular preferred embodiment, the mixture of lipids for the preparation of the nanolipid formulation comprises or consists of medium-chain triglyceride oils (Lipoid GmbH, Germany) and Gelucire® 39 / 01 (Gatefosse, France). It is particularly preferred to add medium-chain triglycerides at a concentration of 0.1% to 30% (w / w), preferably 0.5% to 10% (w / w), more preferably 0.1% to 8% (w / w), and Gelucire® 39 / 01 at a concentration of 3% to 20% (w / w), preferably 5% to 15% (w / w), relative to the total mass of the (final) formulation. All other mono-, di- and triglycerides, their mixtures, as well as other suitable lipids, may also be selected for the preparation of the formulation.

[0054] Partial glycerides (eg, glyceryl monostearate, glyceryl monocaprylate, glyceryl monomyristate) and derivatives of oleic acid may also be selected for preparing formulations according to the present disclosure.

[0055] From the category of phospholipids, which includes phosphatidylcholine, phosphatidylserine and glycerophosphocholine, it is most preferred to use soy lecithin, and it is preferred to use Lipoid™ P45 (Lipoid GmbH, Germany). These may include lipid derivatives, phospholipids derived from synthetic routes, and naturally occurring food sources (e.g., selected from poultry eggs, soybeans, rapeseed, sunflower, milk, fish eggs, and any combination thereof).

[0056] In certain preferred embodiments, the formulations of the present disclosure comprise a phospholipid, preferably Lipoid™ P45, in a concentration of 1% to 15% (w / w), preferably 2% to 9% (w / w), based on the total mass of the (final) formulation. In certain preferred embodiments, the phospholipid is 40% to 100% (w / w) phosphatidylcholine, such as Lipoid™ H100, Lipoid™ P75, Lipo from Lipoid GmbH, Germany. id™ P100, and most preferably Lipoid™ P45. Other proportions of phosphatidylcholine are possible.

[0057] Stabilizers The formulations of the present disclosure include, apart from at least one natural cannabis material, at least one stabilizer, and at least one solvent.

[0058] Stabilizers include phospholipids; polysorbates; polymers including homopolymers, block copolymers and graft copolymers, including hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and polyvinylpyrrolidone (PVP); non-ionic triblock copolymers including poloxamers; copolyvinylpyrrolidone; Labrasol™; gelatin; lecithin (phosphatides); gum acacia; xanthan gum; gum arabic; cholesterol; tragacanth; polyoxyethylene alkyl ethers; polyoxyethylene castor oil derivatives. ;Polyoxyethylene sorbitan fatty acid esters;Sorbitan fatty acid esters;Polyethylene glycol;Polyoxyethylene stearate;Colloidal silicon dioxide;Sodium dodecyl sulfate;Mono- and diglycerides;Magnesium aluminum silicate;Triethanolamine;Stearic acid;Calcium stearate;Glycerol monostearate;Cetostearyl alcohol;Cetomacrogol emulsifying wax;Short and medium chain alcohols;Labrafil(TM);Purol-oleique;Propane-1,2,3-triol (glycerin) ; polyvinyl alcohol; dioctyl sodium sulfosuccinate (DOSS); carmellose sodium; carrageenan; carbomer; hypromellose; and mixtures thereof.

[0059] In a preferred embodiment, the stabilizer is selected from the group consisting of phospholipids, surfactants, and polymers, preferably the stabilizer is a polymer selected from the group consisting of polysorbates, polysaccharides, and poloxamers.

[0060] In another preferred embodiment, the stabilizer is selected from the group consisting of phospholipids, polysorbates, propane 1,2,3-triol electrostatic or steric stabilizers, nonionic surfactants (including polyol esters, polyoxyethylene esters, poloxamers), anionic surfactants (e.g., carboxylates, alkyl sulfates, alkyl ethoxylates, sulfates and sulfate ions), cationic surfactants (e.g., quaternary ammonium compounds), and zwitterionic surfactants.

[0061] It is preferred to add some stabilizers to the formulation, such as phospholipids, surfactants and emulsifiers (e.g. polysorbates). In a preferred embodiment, the stabilizers are phospholipids; polysorbates; polymers, such as homopolymers, block copolymers and graft copolymers (e.g. hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP)); non-ionic triblock copolymers, such as poloxamers (e.g. Kolliphor® P407 or poloxamer 188); copolyvinylpyrrolidone; Labrasol®; gelatin; lecithin (phosphatide); gum acacia (gum acacia); xanthan gum; gum arabic; cholesterol, tragacanth; polyoxyethylene sorbitan fatty acid esters; sorbitan fatty acid esters; polyethylene glycols; polyoxyethylene stearates; mono- and diglycerides; magnesium aluminium silicates; short and medium chain alcohols; Labrafil™ (Gattefosse, France), Labrafil™ (Gattefosse, France), propane-1,2,3-triol and polyvinyl alcohol.

[0062] In a preferred embodiment, the formulation comprises polysorbate as stabilizer in an amount of up to 10% (w / w), preferably in an amount of 0.5% to 4.5% (w / w), in an amount of 1% to 4.5% (w / w), or in an amount of 1.5% to 4% (w / w), more preferably in an amount of 2% to 3% (w / w), or in an amount of 3% to 4% (w / w), most preferably in an amount of 2.5% to 4% (w / w), relative to the total mass of the formulation, and / or the formulation comprises a polysorbate selected as Polysorbate 80 (Tween™ 80) or Polysorbate 20 (Tween™ 20), preferably Polysorbate 80 (Tween™ 80), as stabilizer.

[0063] In another preferred embodiment, the formulation comprises a surfactant as stabilizer in an amount of up to 10% (w / w), preferably in an amount of 0.5% to 4.5% (w / w), in an amount of 1% to 4.5% (w / w), or in an amount of 1.5% to 4% (w / w), more preferably in an amount of 2% to 3% (w / w), or in an amount of 3% to 4% (w / w), most preferably in an amount of 2.5% to 4% (w / w), relative to the total mass of the formulation, and / or the formulation comprises a surfactant selected as sorbitan monooleate (Span™ 80) as stabilizer.

[0064] In yet another preferred embodiment, the formulation comprises poloxamer as a stabilizer in an amount of up to 10% (w / w), preferably in an amount of 0.2% to 1.5% (w / w), more preferably in an amount of 0.5% to 1% (w / w), relative to the total mass of the formulation; and / or The formulation contains a poloxamer selected as poloxamer 407 (Kolliphor® P407) or poloxamer 188 as a stabilizer.

[0065] In a further preferred embodiment, the formulation comprises a polysaccharide as stabilizer in an amount of up to 5% (w / w), preferably in an amount of 0.02% to 0.5% (w / w), in an amount of 0.04% to 0.1% (w / w), more preferably in an amount of 0.05% to 0.08% (w / w) relative to the total mass of the formulation, and / or the formulation comprises a polysaccharide as stabilizer selected as xanthan gum.

[0066] In a further preferred embodiment, the formulation comprises a phospholipid as stabilizer in an amount of 0.5% to 10% (w / w), preferably in an amount of 1% to 3% (w / w), relative to the total mass of the formulation, and / or the phospholipid contains 40% to 100% (w / w) of phosphatidylcholine, relative to the total mass of the phospholipid, and / or the formulation comprises a phospholipid selected as Lecithin® P45 as stabilizer.

[0067] The formulation may contain at least one stabilizer, preferably a mixture of at least two stabilizers. A particularly preferred stabilizer mixture for the formulation is a mixture of Polysorbate 80 (Tween® 80), Kolliphor® P407 and Lipoid® P45.

[0068] When selecting a non-ionic stabilizer, it is preferably selected from the group consisting of non-ionic surfactants such as polysorbates, including polyoxyethylene sorbitan monolaurate; monopalmitate, monostearate, monooleate, tristearate, trioleate, preferably monooleate.Thus, a particularly preferred example for the preparation of the formulation is polyoxyethylene sorbitan monooleate (Tween® 80).

[0069] Other particularly preferred non-ionic surfactants may be selected from sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan trioleate, and most preferably sorbitan monooleate (Span™ 80).

[0070] Non-ionic surfactants such as polysorbate 80 (Tween™ 80) or sorbitan monooleate (Span™ 80) are preferably added individually in an amount of up to 10% (w / w), more preferably in the range of 2% to 8% (w / w), and most preferably in the range of 2% to 6% (w / w), based on the total mass of the formulation.

[0071] When steric stabilizers are used as stabilizers, they adsorb or attach to the surface of nanoparticles, providing large and dense steric barriers. The purpose of the steric stabilizer is to overcome the attractive van der Waals forces, thus reducing particle aggregation, agglomeration or fusion. The steric stabilizer may be selected from polymers such as homopolymers, block copolymers and graft copolymers, e.g., hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP).

[0072] A particularly preferred steric stabilizer is Kolliphor® P407, a non-ionic triblock copolymer, preferably in an amount of up to 4% (w / w), more preferably in an amount of 0.5% to 3% (w / w), based on the total weight (mass) of the formulation.

[0073] Another particularly preferred stabilizer that may be used in the formulations of the present disclosure is glycerin (propane-1,2,3-triol). Glycerin is preferably present in an amount of about 100% by weight based on the total weight of the formulation. It is added in an amount of 10% to 30% (weight / weight), preferably 10% to 20% (weight / weight) or 15% to 25% (weight / weight).

[0074] In addition to, or as an alternative to, glycerin, thickeners and stabilizers such as xanthan gum, gum arabic, sodium carmellose, carrageenan, carbomer, hydroxyethylcellulose, hypromellose, methylcellulose, tragacanth may be used.

[0075] In certain preferred embodiments, xanthan gum is used as a stabilizer. The thickening agent xanthan gum is preferably added to the formulation at a concentration of 0.05% to 1% (w / w), based on the total mass of the formulation.

[0076] As can be gleaned from the examples below, it is particularly preferred that formulations of the present disclosure contain a combination of stabilizers, i.e., two or more stabilizers.

[0077] Additives Apart from the three essential components of at least one natural cannabis material, at least one solvent, and at least one stabilizer, the formulations of the present disclosure may also contain one or more additives as preferred embodiments, which may further add to the long-term stability of the formulation.

[0078] In a preferred embodiment, the additive is selected from the group consisting of preservatives, antioxidants, and penetrating agents.

[0079] To protect the formulation from microbial contamination, the formulation may additionally contain a preservative, or a mixture of preservatives.

[0080] In a preferred embodiment, the additive is a preservative, which is present in the formulation in an amount of 0.1% to 1% (w / w), preferably in an amount of 0.10% to 0.15% (w / w), relative to the total mass of the formulation, and / or the formulation comprises as additive a preservative selected as potassium sorbate and / or sodium benzoate.

[0081] Particularly preferred preservatives are sorbates, such as potassium sorbate, and benzoates, such as sodium benzoate. Most preferably, the formulation may contain the preservatives potassium sorbate and / or sodium benzoate, each individually, in an amount ranging from 0.1% to 2%, preferably from 0.5% to 1% (w / w), based on the total weight of the formulation.

[0082] Preferred preservatives include benzalkonium chloride, cetylpyridinium chloride, thiomersal, benzoic acid, and propylene glycol. Less preferred preservatives include biguanides (e.g., chlorhexidine), phenol, benzyl alcohol, methylparaben, ethylparaben, and propylparaben.

[0083] The formulations of the present disclosure contain cannabinoids that are sensitive to oxidation, therefore, it may be preferable to further include an antioxidant, or preferably a mixture of at least two or more antioxidants, in the formulations of the present disclosure.

[0084] In a preferred embodiment, the additive is an antioxidant, which is present in the formulation in an amount of 0.001% to 3% (w / w), preferably in an amount of 0.001% to 0.1% (w / w), in an amount of 0.005% to 0.1% (w / w), in an amount of 0.001% to 0.1% (w / w), in an amount of 0.1% to 1% (w / w) or in an amount of up to 0.02% (w / w) based on the total mass of the formulation, and / or the formulation comprises an antioxidant selected from the group consisting of EDTA, tocopherol, citric acid, and ascorbyl palmitate as an additive. In another preferred embodiment, the additive is an antioxidant, which is present in the formulation in an amount of 0.01% to 3% (w / w), relative to the total mass of the formulation.

[0085] The most preferred antioxidants include tocopherols, including various types of tocopherols differing in the number and position of methyl groups on the benzene ring (e.g., α-tocopherol (E307), γ-tocopherol (E308)), and particularly preferred mixtures thereof (e.g., available from Gustav Parmentier GmbH, Germany).

[0086] Further, particularly preferred antioxidants include ascorbic acid and its derivatives, including L-ascorbate salts (e.g., L-ascorbyl palmitate, L-ascorbyl stearate, sodium ascorbate, calcium ascorbate). From the group of ascorbate salts, L-ascorbyl palmitate is particularly preferred.

[0087] Further preferred antioxidants are ethylenediaminetetraacetic acid and derivatives of ethylenediaminetetraacetic acid, such as calcium disodium ethylenediaminetetraacetate. When ethylenediaminetetraacetic acid is used, it is most preferably added in combination with ascorbyl palmitate or its derivatives.

[0088] Ethylenediaminetetraacetic acid is preferably added in an amount ranging from 0.01% to 1% (weight / weight), preferably from 0.05% to 0.6% (weight / weight), based on the total amount of the formulation, and ascorbyl palmitate is added in an amount of 0.01% to 0.3% (weight / weight).

[0089] In particularly preferred embodiments, the formulation contains a mixture of antioxidants to achieve a synergistic antioxidant effect.

[0090] In another preferred embodiment, the formulation contains a mixture of antioxidants: tocopherol, ascorbyl palmitate, and ethylenediaminetetraacetic acid.

[0091] Alternatively, coenzyme Q10, gallates (eg, propyl gallate), and less preferred derivatives of phenols such as butylated hydroxyanisole, butylated hydroxyltoluene, and t-butylhydroquinone may also be added to the formulation.

[0092] The formulation of the present disclosure may also contain an additive to adjust its pH. Such a pH adjusting agent may be any known buffer, and in a preferred embodiment, citric acid is used. In another preferred embodiment, the formulation may contain a compound selected from the group consisting of lactic acid and lactate salts, phosphoric acid and phosphate salts, hydrochloric acid, and hydroxide salts. When citric acid is used, it may be added to the formulation in an amount of 0.1% to 3% (weight / weight), preferably 0.2% to 1.5% (weight / weight), based on the total amount of the formulation.

[0093] The formulations of the present disclosure may further comprise an osmotic agent, preferably selected from the group consisting of glycerin, glucose, sucrose, sorbitol, sodium phosphate, and any combination thereof.

[0094] disease The formulations of the present application may be used for the treatment or alleviation of a disease or condition in an animal, preferably a mammal, and more preferably a human. The diseases that can be treated with the formulations according to the present disclosure are cannabinoid-related diseases or conditions based on the presence of natural cannabis material in the formulation.

[0095] Cannabis induces a complex set of experiences in humans, including euphoria, heightened sensitivity to external experiences, and relaxation. The pharmacological effects of currently used medical cannabis are: This is mainly due to the two main components of the hemp plant, the phytocannabinoid tetrahydrocannabinol (THC) and the main non-euphoric and non-intoxicating compound cannabidiol (CBD). Until now, cannabis research has mainly focused on these two components. The content of THC and CBD, and their ratio to each other, varies depending on the plant variant. For example, some cannabis plant species are available with THC at about 22%, while others have a THC content of less than 1% and CBD content of 20%. As THC and CBD have different pharmacological effects, these cannabis plant species are used in different treatment algorithms. Molecules such as THC and CBD may provide novel targets for the development of effective and durable treatments for many diseases. In addition to THC and CBD, cannabis flowers contain many additional pharmacologically active phytochemicals such as cannabichromene (CBC), cannabigerol (CBG), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), and cannabinol (CBN). The plant contains various terpenes with therapeutic potential, such as D-limonene, β-myrcene, α-pinene, D-linalool, and β-caryophyllene. Terpenes are a very heterogeneous group of substances. Terpenes may act synergistically with phytocannabinoids. The cannabis plant contains more than 200 terpenes and terpenoids with different pharmacological properties. Terpenes add a characteristic aroma and flavor to cannabis.

[0096] Cannabinoid receptors are activated by phytocannabinoids, synthetic cannabinoids, and endocannabinoids. Cannabinoids bind reversibly and stereoselectively to cannabinoid receptors. Cannabinoid receptors are located throughout the body and are part of the endocannabinoid system, which is involved in a wide variety of physiological processes. Cannabinoid receptors are G protein-coupled receptors that contain seven transmembrane domains. CB1 receptors are expressed primarily in the central nervous system, but also in the lungs, liver, and kidneys. CB2 receptors are expressed primarily in the immune system and hematopoietic cells. There is evidence that there are other (G protein-coupled) non-CB1 and non-CB2 cannabinoid receptors (GPR18, GPR119, and GPR55) that are involved in endocannabinoid system signaling. Endocannabinoids, such as anandamide (AEA) and arachidonoylethanolamide (2-AG), are produced and cleaved from neuronal membrane lipid precursors following depolarization of the postsynaptic membrane and / or activation of postsynaptic metabotropic receptors. Endocannabinoids diffuse retrogradely to their receptors located on afferent nerve fibers. Endocannabinoid signaling is terminated by a cellular uptake process that likely involves transporter proteins, followed by intracellular hydrolysis of 2-AG by presynaptic monoacylglycerol lipase (MGL) and AEA by postsynaptic fatty acid amide hydrolase (FAAH). It remains to be shown that the same process applies to all the different neuronal populations expressing CB1 receptors. Of note, AEA may further bind to the cytosolic domain of postsynaptically localized transient receptor potential vanilloid type 1 (TRPV1) channels, thereby promoting the activation of postsynaptic terminals. CBD and THC are multi-target ligands and behave as allosteric modulators of AEA and 2-AG. Recent studies have shown that CBD does not directly bind to CB1 and CB2. CBD enhances morphine antinociception, reduces NMDA-mediated seizures, and reduces stroke damage via sigma 1 receptors. In particular, sigma 1 receptor (σ1R) antagonists inhibit glutamate N-methyl-D-aspartate receptor (NMDAR) activity.The sigma-1 receptor (σ1R) acts as a chaperone protein in the endoplasmic reticulum regulating calcium signaling by IP3 receptors. The σ1-receptor is a transmembrane protein and is expressed in many different tissue types. The σ1-receptor is particularly concentrated in certain regions of the central nervous system. Neuroactive steroids such as dehydroepiandrosterone (DHEA) and pregnenolone, as well as synthetic amines, activate the receptor. In in vitro assays, CBD disrupts the regulatory association of σ1R with the NR1 subunit of the NMDAR, an effect shared by σ1R antagonists such as BD1063 and progesterone, and by σ1R agonists such as 4-IBP, PPCC, and PRE084. CBD exhibits antagonist-like activity against σ1R to reduce the adverse effects of NMDAR overactivity, CBD attenuates NMDA-induced seizure syndrome, reduces infarct size caused by permanent unilateral middle cerebral artery occlusion, and enhances morphine-induced supraspinal antinociception.

[0097] Pain pathophysiology involves peripheral and central neuronal changes and neuroimmune interactions that become more prominent during inflammatory responses. Nociception (acute pain) has lasting effects on the sensory and reward circuits of the brain. Chronic pain is an abnormal persistent memory of an aversive state (memory of pain), and autobiographical memories may be described as the ghosts of our past. Most importantly, chronic pain is not the same as the more long-lasting acute nociception. Chronic pain is a disease process with distinct mechanisms that are related to anxiety and depression.

[0098] Modification of dysfunctional cognition by cannabinoids is a novel therapeutic approach in the treatment of chronic pain conditions. Noxious stimuli engage central circuits operated by endocannabinoids. Brain regions that play a key role in higher cognitive processes and in regulating stress-induced activity contain a high density of various cannabinoid receptors. Human brain imaging studies indicate that cortical and subcortical fear conditioning pathways may be fundamental for chronic pain. Emotion-related limbic circuits play a key role in higher cognitive processes and in regulating stress-induced hypothalamic-pituitary-adrenal (HPA) activity. Excessive fear and anxiety are also hallmarks of disorders such as post-traumatic stress disorder (PTSD) and phobias. PTSD is characterized by persistence of fear memories and maladaptive stress responses. The potential therapeutic benefits of cannabinoid compounds have also increased interest in understanding the molecular mechanisms underlying the beneficial effects of exposure therapy in fear disorders. The addition of CBD to exposure therapy is expected to enhance the effects of the treatment.

[0099] Human brain imaging studies show that the brain is more plastic than previously believed, with the formation of new synapses and new dendrites of nerve cells, so-called spines, occurring continuously. Spines are the target structures of most excitatory synapses in the brain and are highly dynamic, functionally and structurally, not only during development but also in adulthood. The brain structures involved in social and physical pain are similar. Chronic pain induces a chronic stress response, such as dendrite retraction and loss of dendritic spines in brain neurons, with deficits in synaptic plasticity and memory. This may predispose patients to cognitive disorders.

[0100] The molecular composition of the cannabinoid type 1 (CB1) receptor complex beyond classical G protein signaling components is unknown. CB1 receptors assemble with multiple members of the WAVE1 complex and the RhoGTPase Rac1 and regulate their activity. CB1 receptor activation levels directly affect WAVE1-mediated actin polymerization and stability in the growth cones of developing neurons, leading to their collapse, as well as in the synaptic spines of mature neurons, leading to their retraction. In adult mice, CB1 receptor agonists attenuated activity-dependent remodeling of dendritic spines in spinal neurons in vivo and inhibited inflammatory pain by modulating the WAVE1 complex. This study reports a novel signaling mechanism for cannabinoidergic regulation of the nervous system and demonstrates a previously unreported role of the WAVE1 complex in the therapeutic application of cannabinoids. These recent advances in pain research demonstrate the analytical power of molecular and cell biological techniques in a field where previously only systems biology methods were available. Aberrant dendritic spine structure following disease or injury may represent a "molecular memory" for maintaining, for example, chronic pain conditions that are sensitive to cannabinoid modulation of spine function. At a conceptual level, memory mechanisms engaged in dendritic spine remodeling by cannabinoids may contribute to a wide range of intractable neurological conditions.

[0101] Long-term memory formation and storage is a complex and dynamic process. Molecular and cellular mechanisms underlie this complexity, e.g., their expression in diverse cell types, their temporal dynamics, their role in long-term memory formation and storage, and the changes induced by memory retrieval. Repeated exposure to a fearful stimulus in the absence of an aversive event gradually reduces the fear response (Extinction by Re-learning). GABAergic-mediated neurons Activation of CB1 specifically located in the amygdala inhibits LTD in the lateral amygdala. These findings suggest that CB1 receptors expressed on either glutamatergic or GABAergic neurons play different roles in controlling synaptic transmission and plasticity. The results indicate that AEA reduces the activity of inhibitory interneurons in the amygdala. This non-inhibition may increase the activity of common output neurons, providing a prerequisite for the formation of new memories and their "extinction."

[0102] Recent studies have detailed the brain's ability to reorganize its neural network architecture to adapt to environmental needs. A core set of brain networks is commonly disturbed in chronic pain. All strategies for the treatment of chronic pain conditions must take into account stress-related comorbid conditions such as altered hedonic states, cognitive impairment, and abnormal behaviors such as fear, anxiety, and depression. The emotional basis of chronic pain opens new horizons of opportunities to develop new therapeutic strategies, since cognitive factors such as beliefs, expectations, and previous experiences are important regulators of pain perception and can substantially modulate the efficacy and tolerability of therapeutic interventions. Accumulating evidence points to a reorganization of the brain (neuronal plasticity) with this negatively valenced affective state. Chronic pain appears as the dark side of neuronal plasticity. Pain memories can be more damaging than their initial experience.

[0103] Human studies and several animal pain models support the view that therapeutic interventions with cannabinoids should interrupt the chronification process as early as possible. The anxiolytic and anti-stress effects of cannabinoids, for example, provide an entry point for successful multimodal therapy, since the adaptation of experience-based expectations (pain memories) is best countered by superimposing them with positive new associations. They create new links in neuronal circuits and help in relearning context-specific safety signals. It is crucial to regain the ability to derive pleasure from mundane activities. Gradual fading of memories is an important part of memory processing. However, fear memories may be actively protected in various brain structures. Fear conditioning clearly induces memory traces that are more resilient to extinction, and conditioned fear responses are more likely to be reactivated to aversive stimuli. Spontaneous recovery is possible after exposure. The brain does not have a simple clearing function.

[0104] It can be concluded from the above that cannabis, i.e. natural cannabis material as present in the formulations of the present disclosure, is relevant for treating the following diseases: Somatic pain: the sensation most people imagine when they think of pain: messages sent by receptors throughout the body whenever an injury occurs. Somatic pain signals travel via peripheral nerves to the brain and are typically experienced as a constant, dull ache in the area of ​​injury. Visceral pain: occurs when tissues or organs in the abdominal cavity are stretched or disturbed by disease or injury. Pain signals originate from a specific class of receptors present in the intestine, resulting in a feeling of pressure deep in the abdomen. Visceral pain often appears to come from a different part of the body than the actual source, a phenomenon called referred pain. Neuropathic pain: occurs when the nerves themselves are damaged. It is often experienced as a burning sensation that may respond to even light touch. Neuropathic pain does not usually respond to the narcotic painkillers that relieve many other types of pain. Antidepressants or anticonvulsants, as well as certain surgical procedures, may improve some cases of neuropathy. cancer pain Chemotherapy-induced vomiting and nausea chronic lower back pain Diabetic polyneuropathy fibromyalgia Palliative care Tourette Syndrome Chronic central nervous pain Convulsions in multiple sclerosis Anxiety disorders Schizophrenia social phobia Sleep disorders Skin-related disorders such as psoriasis and neurodermatitis Glaucoma Restless legs syndrome epilepsy Alzheimer's Disease Movement disorders such as dystonia, Huntington's disease, and Parkinson's disease

[0105] Thus, the formulations of the present disclosure may be particularly useful in the treatment or amelioration of one of the diseases listed above.

[0106] In a preferred embodiment, the formulations of the present disclosure may be used for palliative care and / or treatment of diseases, preferably the diseases are selected from the group consisting of pain, especially acute or chronic pain, somatic pain, visceral pain, neuropathic pain, cancer pain, chronic back pain, chronic central pain; neuropathy, neurodegenerative diseases, insomnia, psychiatric disorders, nausea, anorexia, vomiting and nausea caused by chemotherapy, diabetic polyneuropathy, fibromyalgia, Tourette's syndrome, multiple sclerosis, convulsions in multiple sclerosis, anxiety disorders, schizophrenia, social phobia, sleep disorders, skin-related diseases such as psoriasis and neurodermatitis, glaucoma, restless legs syndrome, epilepsy, movement disorders such as Alzheimer's disease, dystonia, Huntington's disease, Parkinson's disease, and other medical indications affected by the endocannabinoid system and any other receptors affected by cannabinoids (e.g. GPR18, GPR119, GPR55).

[0107] Based on the small particle size of the natural cannabis material in the formulation, the present disclosure provides a formulation according to the first aspect for use in the preparation of a medicament, in particular for buccal, mucosal, buccal, topical or oral application to an animal, preferably a mammal, more preferably a human, or for use in the preparation of a medicament for parenteral, intrathecal, intravenous, transdermal or transmucosal application, preferably buccal, topical or oral application to an animal, preferably a human.

[0108] definition Below, definitions of several terms are provided as they are used in the context of this disclosure.

[0109] When the term "comprising" is used in the present description and claims, it does not exclude other elements. For purposes of the present invention, the term "consisting of" is used in the present specification and claims. )" is considered to be a preferred embodiment of the term "comprising." Hereinafter, when a group is defined as comprising at least a certain number of elements, it is also understood to disclose the group preferably consisting of only those elements.

[0110] Where an indefinite or definite article is used when referring to a singular noun such as "a", "an" or "the", this includes a plural of that noun unless something specifically stated otherwise.

[0111] The term "at least one" refers to one or more occurrences of some of the following terms, in particular natural cannabis material, solvent and stabilizer. Each occurrence of each material may be selected independently from each other within the definition of each material when it occurs more than once, i.e., two, three, four or more times. In particular, at least one refers to one, two, three, four or five independently selected occurrences of each material, with one or two occurrences being particularly preferred.

[0112] Terms such as "may be obtained" or "may be defined," and "obtained" or "defined" are used interchangeably. This means, for example, that unless the context clearly indicates otherwise, the term "obtained" means that an embodiment must be obtained, for example, by the sequence of steps described (following) preceding the term "obtained." It is not meant to imply that no particular limitation exists, but such a limiting understanding is always included in the terms "obtained" or "defined" as preferred embodiments.

[0113] "THC" refers to tetrahydrocannabinol and includes all isomers of tetrahydrocannabinol, especially Δ 9 -Refers to THC.

[0114] "CBD" stands for cannabidiol, one of the primary cannabinoids in cannabis and the active agent of most interest to the community.

[0115] D 90 refers to the particle size distribution of the formulation. It is the particle size distribution that is determined by ... V90) has a size smaller than the given number, and 10% of the volume is made up of particles with a size larger than the given number. In other words, if 90% of the total volume of the particle is D 90 The remaining 10% of the total volume of the particles is D 90 It is formed by particles with larger diameters. For example, D 90 is 500 nm, particles having a size of 500 nm or less constitute 90% of the total volume of the sample, and particles having a size larger than 500 nm constitute 10% of the total volume of the sample.

[0116] D 100 refers to the maximum size of a particle. In other words, 100% of the particles have a size equal to or less than a given particle size.

[0117] Tween™ 80 is the trade name for polysorbate 80, also known as polyoxyethylene (20)-sorbitan-monooleate.

[0118] Span™ 80 is a synonym for sorbitan monooleate, which is a sorbitan fatty acid ester of sorbitan or 1,4-sorbitol anhydride (sorbitan) with fatty acids such as stearic acid, lauric acid, oleic acid, or palmitic acid.

[0119] Kolliphor® P407 (poloxamer 407) and poloxamer 188 both belong to the poloxamer group and are reported in the Europaeisches Arzneibuch, Deutscher Apotheker Verlag Stuttgart, 6 th edition, 2008, pages 3713-3715. Loxamers are block copolymers of ethylene oxide and propylene oxide.

[0120] Lipoid™ P45 is a non-fat soy lecithin with a phosphatidylcholine content of 45% (w / w).

[0121] Labrafil™ is the trade name (Gattefosse) for oleoyl polyoxyl-6 glyceride.

[0122] Labrasol™ is the trade name (Gattefosse) for caprylocaproyl polyoxyl-8 glyceride.

[0123] Gelucire® 39 / 01 is a mixture of medium chain mono-, di- and triglycerides, i.e. saturated C 12 ~C 18 It is a glycerol ester of fatty acids. EXAMPLES

[0124] The present invention will be described in more detail below with reference to the following examples.The following examples are provided to aid in the understanding of the disclosure, and should not be used as specific limitations on the disclosure described and claimed herein.Such variations of the present disclosure, including the replacement of all currently known or later developed equivalents, are within the purview of those skilled in the art, and any changes in formulation or experimental design should be considered to fall within the scope of the disclosure incorporated herein.

[0125] Example 1: Stable formulation of Cannabidiol-rich Cannabis sativa (1% (w / w)) Cannabidiol-rich Cannabis sativa strain (A6FS10 flos, AI Fame , Switzerland, D 90 Pre-ground and steam sterilized flower plant material from <320 μm, residual moisture <10% was used as cannabis powder.

[0126] The cannabis powder was placed in an oven chamber preheated to 135° C. When the cannabis powder reached a core temperature of 120° C., the powder was subsequently heated at 135° C. for an additional 55 minutes to achieve decarboxylation of the active ingredients. This step further reduces the residual moisture in the cannabis powder.

[0127] The amounts of all components are given in % (wt / wt) with respect to the total amount (mass) of the final nanosuspension.

[0128] 10.5% (w / w) Gelucire™ 39 / 01 was preheated in a regulated water bath at 70° C. for 1 hour and 30 minutes.

[0129] Separately, 0.7% (wt / wt) sodium benzoate, 0.6% (wt / wt) potassium sorbate, 0.1% (wt / wt) ethylenediaminetetraacetic acid, and 0.5% (wt / wt) citric acid were dispersed and thoroughly mixed into 56.69% (wt / wt) double-distilled water, and then preheated at 70°C for 1 hour.

[0130] 1.2% (wt / wt) medium chain triglyceride oil, 2% (wt / wt) Kolliphor™ P407, 0.05% (wt / wt) ascorbyl palmitate, 0.06% (wt / wt) mixed tocopherols (Vitapherole™), 4.8% (wt / wt) polyoxyethylene sorbitan monooleate 80 (Tween™ 80), and 5.8% (wt / wt) Lipoid™ P45 were mixed in a separate container.

[0131] All the compounds listed above (except cannabis powder) were combined in a suitable vessel at a temperature of 70°C.

[0132] Subsequently, 1% (wt / wt) of decarboxylated and sterilized pre-milled Cannabis sativa powder material (D 90 <320 μm, residual moisture <3%) was carefully added to the degassed mixture and dispersed under continuous stirring. When the cannabis material was dispersed in the solvent, the cannabis material in the formulation had a concentration of 1% (w / w) relative to the total mass of the formulation.

[0133] Again, the vessel with all ingredients was degassed until an oxygen partial pressure of less than 1.5 hPa was achieved. The dispersion was then milled in a wet ball stirrer mill (type X1, Buehler AG, Switzerland; 1000 rpm-1200 rpm, 45 °C) using yttrium-stabilized zirconia balls of size 0.4 mm-0.5 mm. Milling was performed to a particle size of 0.4 μm (D 100 ) was achieved. Subsequently, 16% (w / w) glycerin was added to obtain a final particle size (D) of the formulation of less than 0.2 μm (200 nm) as measured by a Beckman-Coulter LS13320 laser diffraction instrument. 90 Milling was continued until the flour reached a mass of 1000g.

[0134] [Table 1]

[0135] Example 2: Stable formulation of tetrahydrocannabinol-rich Cannabis sativa (2% (w / w)) Tetrahydrocannabinol-rich Cannabis sativa strains (Bedrocan flos, Bedrocan, Netherlands, D 90 Pre-ground and steam-sterilized floral plant material from <320 μm, residual moisture <10% was used as cannabis powder.

[0136] The cannabis powder was placed in an oven chamber preheated to 135° C. When the cannabis powder reached a core temperature of 120° C., the powder was subsequently heated at 135° C. for an additional 55 minutes to achieve decarboxylation of the active ingredients. This step further reduces the residual moisture in the cannabis powder.

[0137] The amounts of all components are given in % (wt / wt) with respect to the total amount (mass) of the final nanosuspension.

[0138] 13.5% (w / w) Gelucire™ 39 / 01 was preheated in a regulated water bath at 70° C. for 1 hour and 30 minutes.

[0139] Separately, 0.7% (wt / wt) sodium benzoate, 0.6% (wt / wt) potassium sorbate, 0.15% (wt / wt) ethylenediaminetetraacetic acid, and 0.6% (wt / wt) citric acid were dispersed and thoroughly mixed in 48.42% (wt / wt) double-distilled water. It was further preheated at 70°C for 1 hour.

[0140] 1.6% (wt / wt) medium chain triglyceride oil, 2.3% (wt / wt) Kolliphor™ P407, 0.07% (wt / wt) ascorbyl palmitate, 0.06% (wt / wt) mixed tocopherols (Vitapherole™), 5.2% (wt / wt) polyoxyethylene sorbitan monooleate 80 (Tween™ 80), and 6.8% (wt / wt) Lipoid™ P45 were mixed in a separate container.

[0141] All the compounds listed above (except cannabis powder) were combined in a suitable vessel at a temperature of 70°C.

[0142] Subsequently, 2% (wt / wt) of decarboxylated and sterilized pre-milled Cannabis sativa powder material (D 90 <320 μm, residual moisture <3%) was carefully added to the degassed mixture and dispersed under continuous stirring. When the cannabis material was dispersed in the solvent, the cannabis material in the formulation had a concentration of 2% (w / w) relative to the total volume of the formulation.

[0143] Again, the vessel with all ingredients was degassed until an oxygen partial pressure of less than 1.5 hPa was achieved. The dispersion was then milled in a wet ball stirrer mill (type X1, Buehler AG, Switzerland; 1000 rpm-1200 rpm, 45 °C) using yttrium-stabilized zirconia balls of size 0.4 mm-0.5 mm. Milling was performed to a particle size of 0.4 μm (D 100 ) was achieved. Subsequently, 18% (w / w) glycerin was added to obtain a final particle size (D) of the formulation of less than 0.2 μm (200 nm) as measured by a Beckman-Coulter LS13320 laser diffraction instrument.90 Milling was continued until the flour reached a mass of 1000g.

[0144] [Table 2]

[0145] Example 3: Stable formulation of cannabidiol-rich and tetrahydrocannabinol-rich Cannabis sativa mixtures The main active substances in Cannabis sativa are CBD, THC or a combination of both. These cannabinoids can therefore be used as reference materials to compare the concentrations of different nanolipid formulations containing Cannabis sativa plant material. Strains rich in THC (e.g. Bedrocan flos, Bedrocan, Netherlands) or THC-rich strains (e.g. Bedrocan flos, Bedrocan, Netherlands), or any combination thereof, may be used in the preparation of the nanolipid formulations described above.

[0146] As an example, the CBD-rich Cannabis sativa strain A6FS10 flos (AI Fame A formulation containing a mixture of A6FS10 (A6FS10, Switzerland) and the THC-rich Cannabis sativa strain Bedrocan flos (Bedrocan, The Netherlands) in a 2:1 (w / w) ratio (meaning 1.33% (w / w) A6FS10 and 0.67% (w / w) Bedrocan for a total cannabis concentration of 2% (w / w) was therefore prepared. A 2% (w / w) decarboxylated and sterilized pre-milled Cannabis sativa powder (D6FS10, Switzerland) containing the aforementioned strain mixture was then added to the 2:1 (w / w) ratio. 90 <320 μm, residual moisture <3%). Apart from different types of Cannabis sativa materials, the disclosed nanolipid formulations were prepared similarly to Example 2, using mixed cannabis powder instead of pure cannabidiol-rich cannabis powder.

[0147] Example 4: Stable formulation of tetrahydrocannabinol-rich Cannabis sativa (1% (w / w)) Tetrahydrocannabinol-rich Cannabis sativa strains (Bedrocan flos, Bedrocan, Netherlands, D 90 Pre-ground and steam-sterilized floral plant material from <320 μm, residual moisture <10% was used as cannabis powder.

[0148] Apart from the different types of Cannabis sativa materials, the formulation of Example 4 was prepared similarly to Example 1.

[0149] Example 5: Stable formulation of Cannabis sativa (1% (w / w)) THC-rich Cannabis sativa strain Bedrocan flos (Bedrocan, Netherlands) (D 90 Pre-ground and steam-sterilized flower plant material from <320 μm, residual moisture <10% was used as cannabis powder. The cannabis powder was placed in an oven chamber preheated to 135° C. When the cannabis powder reached a core temperature of 128° C., the powder was subsequently heated at 135° C. for an additional 45 minutes to achieve decarboxylation of the active ingredients. This process further reduces the residual moisture in the cannabis powder.

[0150] The amounts of all components are given in % (wt / wt) with respect to the total amount (mass) of the final nanosuspension.

[0151] 7.8% (w / w) Gelucire™ 39 / 01 was preheated in a regulated water bath at 60° C. for 1 hour.

[0152] Separately, 0.9% (wt / wt) sodium benzoate, 0.6% (wt / wt) potassium sorbate, 0.45% (wt / wt) ethylenediaminetetraacetic acid, 0.75% (wt / wt) citric acid, and 0.1% (wt / wt) xanthan gum (Xanthural 11K, CP Kelko, USA) were dispersed and thoroughly mixed into 56.34% (wt / wt) double-distilled water, and then preheated at 60°C for 1 hour.

[0153] 6.5% (wt / wt) medium chain triglyceride oil, 0.1% (wt / wt) ascorbyl palmitate, 0.06% (wt / wt) mixed tocopherols (Vitapherole™), 5.1% (wt / wt) polyoxyethylene sorbitan monooleate 80 (Tween™ 80), and 4.3% (wt / wt) sorbitan monooleate (Span™ 80) were mixed in a separate container.

[0154] All the compounds listed above (except cannabis powder) were combined in a suitable vessel at a temperature of 70°C.

[0155] Subsequently, 1% (wt / wt) of decarboxylated and sterilized pre-milled Cannabis sativa powder material (D 90 <320 μm, residual moisture <3%) was carefully added to the degassed mixture and dispersed under continuous stirring. When the cannabis material was dispersed in the solvent, the cannabis material in the formulation had a concentration of 1% (w / w) relative to the total mass of the formulation.

[0156] The dispersion was subsequently milled in a wet ball stirrer mill (type X1, Buehler AG, Switzerland; 1500 rpm, 45 °C) using yttrium-stabilized zirconia balls of size 0.4 mm to 0.5 mm. 100 ) was achieved. Subsequently, 16% (w / w) glycerin was added to obtain a final particle size (D) of the formulation of less than 0.2 μm (200 nm) as measured by a Beckman-Coulter LS13320 laser diffraction instrument. 90 Milling was continued until the flour reached a mass of 1000g.

[0157] [Table 3]

[0158] Example 6: Determination of plasma concentrations of cannabinol in a pharmacokinetic study A clinical trial was carried out in three healthy male volunteers to determine the pharmacokinetic effects of a cannabis preparation rich in cannabidiol (Example 1).A single dose of the cannabis preparation containing 1.3 mg of CBD was administered by oral mucosal administration.Blood samples were taken immediately before dosing, and 10, 20, 30, 45, 60 and 90 minutes after administration of the cannabis preparation, as well as 2, 3, 4, 5, 6, 7, 8 and 24 hours after administration.The plasma concentration of CBD in the blood samples was measured by LC-MS / MS.

[0159] After administration of a cannabis formulation, CBD is rapidly absorbed and is present in plasma within 10 minutes after a single dose of oromucosal administration. max ) was 1.96 ng / ml, and the area under the curve from 0 to 24 hours (AUC0h~24h) was 9.31 ng / ml * h. The C of the formulation ma x and AUC levels were measured using Sativex™ Oromucosal Spray (GW Pharma Ltd) and Table 4 (Stott et al., Eur J Clin Pharmacol 69 (2013), pages The pharmacokinetic profiles of the cannabis formulations compared to a normalized single dose of Sativex™ can be seen in Figure 1. Compared to Sativex™, the CBD-rich formulation of Example 1 showed increased AUC levels (22.71-fold) and C max It shows an increase in concentration (19.60-fold).

[0160] [Table 4]

[0161] Example 7: Determination of plasma concentrations of tetrahydrocannabinol and major metabolites in a pharmacokinetic study A clinical trial in three healthy male volunteers was carried out to determine the pharmacokinetic effects of a cannabis formulation rich in tetrahydrocannabinol (Example 4). A single dose of the cannabis formulation containing 3.0 mg of tetrahydrocannabinol was administered oromucosally. Blood samples were taken immediately before dosing and 2, 5, 10, 15, 20, 30, 45, 60 and 90 minutes, as well as 2, 3, 4, 5, 6, 7 and 24 hours following administration of the cannabis formulation. The plasma concentration of THC in the blood samples was measured by LC-MS / MS.

[0162] Following administration of cannabis nanoformulations, THC is absorbed and appears rapidly in plasma within 15 minutes after a single oromucosal administration. max ) was 0.57ng / ml, and the area under the curve from 0 to 24 hours (AUC0h~24h) was 6.94ng / ml * h. Mean THC plasma concentrations and AUC levels were compared to a normalized dose of Sativex™ oromucosal spray (GW Pharma Ltd) and are listed in Table 5 (Stott et al., Eur J Clin Pharmacol 69 (2013), pages 1135-1147). The pharmacokinetic profile of the THC-rich cannabis formulation of Example 4 compared to a normalized single dose of Sativex™ can be seen in Figure 2.

[0163] Compared to the oral mucosal spray Sativex™, the THC-rich formulation of Example 4 shows an increase in AUC level (3.62-fold). THC is highly lipophilic and is rapidly absorbed and distributed in body fat. The blood concentration and maximum concentration produced after oral mucosal administration of the formulation may vary depending on the composition of the formulation. However, the AUC values ​​over 24 hours clearly demonstrate the enhanced bioavailability of the formulation of Example 4 compared to Sativex™.

[0164] [Table 5]

[0165] Example 8: Case study of a male patient suffering from chronic pain due to fibrotic dysplasia treated with the formulation of Example 4 A 54-year-old male patient suffering from chronic pain for 40 years due to fibrous dysplasia and multiple surgical bone corrections was given pain therapy with the strong opioid fentanyl at a daily dose of 36.000 μg intravenously. The usual dose for chronic pain patients is 100 μg to 300 μg of fentanyl as a patch, changed every 3 days, resulting in approximately 100 μg of fentanyl per day. The patient was highly addicted to opioids and was wheelchair-bound due to the high fentanyl dose. After opioid withdrawal, the patient was changed to a cannabis oil extract with a THC dose of 800 mg per day. Here the patient was able to reduce his pain level to 4 on a numerical rating scale (NRS) of 0 (meaning 0 pain) to 10 (maximum pain). A pain level of NRS=4 is referred to below as baseline. Without cannabinoid drug treatment, the patient was at a pain level of 9. However, the very high THC dose of 800 mg daily caused severe psychotropic side effects. In Germany, the maximum permitted prescribed amount of THC is 1000mg per month.

[0166] The patient switched to the formulation of Example 4 in exchange for the cannabinoid oil extract at a dose of 800 mg THC, taking a dose of 28 mg THC per day starting on day 1. Within 14 days, the patient reduced the dose of the formulation of Example 4 to 14.9 mg THC per day, reduced his pain level from 4 to 1 (75% reduction from baseline), and reduced his THC dose from 800 mg to 14.9 mg, representing a 98% reduction in THC dose. The patient was monitored for 12 months, and at the end of the 12 month period, he was at a pain level of 1 with the dosage of THC of the formulation of Example 4 at 14.9 mg.

[0167] Example 9: Case study of a male patient suffering from multiple sclerosis spasticity treated with the formulation of Example 4 A 36-year-old male patient with a confirmed diagnosis of multiple sclerosis, anxiety disorder for more than 12 months, depression for more than 12 months, social phobia for more than 12 months, and multiple nerve damage for more than 12 months was treated under the following drug scheme: pregabalin 2x300mg / day for neuropathic pain, venlafaxine 1x150mg / day for anxiety disorder, decrystol 2000IU (international units) twice a week for multiple sclerosis, and copaxan 20ml injections three times a week for multiple sclerosis. The patient had 5-9 seizures per day, the severity of the seizures was 4 on the NRS scale of 0-10 (10 being the most severe), and the pain level of the neuropathic pain was 3.

[0168] The patient was administered the formulation of Example 4 as a co-medication to the above-mentioned baseline medication, starting with a dose of 12.1 mg THC, which was reduced to 7.5 mg THC / day within 5 weeks. Within 5 weeks, the patient was able to reduce convulsive seizures from 0 to 2 seizures per day (75% reduction from baseline), convulsive seizure severity to 2 (50% reduction from baseline), pain level to 1 (67% reduction from baseline), and the patient's baseline medication, pregabalin, was reduced by 100% from 2 x 300 mg / day to 0 mg / day.

[0169] Example 10: Case study of a female patient suffering from fibromyalgia treated with the formulation of Example 4 A 51-year-old female patient with a confirmed diagnosis of fibromyalgia and comorbid anxiety and depression was taking 100 mg / day of droxetine and 24.3 mg of THC per day (Sativex™). The patient had a pain level of NRS=2. Without medication, the patient's pain level was NRS=8. The patient wanted to change Sativex™ due to oral mucosal ulceration. Oral mucosal ulceration is a well-known side effect of Sativex™ due to its high alcohol content. The patient took the formulation of Example 4 in exchange for Sativex™. The patient was started on a dose of 2.8 mg of THC with the formulation of Example 4 and maintained this dose for the duration of treatment. The patient was able to reduce the THC dose from 24.3 mg of Sativex™ to 2.8 mg of THC with the formulation of Example 4 (88% reduction) and reduce the pain level to NRS=1 (50% reduction from baseline).

[0170] Example 11: Case study of a female patient suffering from primary chronic polyarthritis treated with the formulation of Example 4 A 62-year-old female patient with a confirmed diagnosis of primary chronic polyarthritis since age 42, with comorbidities of anxiety and depression, with baseline medications: Celecoxib 200mg twice daily (for pain), Tramadol 100mg (for pain), 5 drops of Amitriptyline 40mg / ml (for anxiety and depression), Aerius 5mg once daily (for chronic urticaria). The patient had the following comorbidities: intestinal paresis for >12 months, left mastectomy after breast cancer, chronic bronchitis for >12 months, depression for >12 months, severe arthritis of both knee joints for >12 months. The patient had a pain level (baseline) of NRS=7. Without medication, the patient's pain level was NRS=10.

[0171] The patient received the formulation of Example 4 as a co-medication to the above base medication. The patient received 3.1 mg THC / day during a 2-week titration phase. Within 2 weeks, the patient was able to reduce his pain level from NRS=7 to NRS=4 (a 43% reduction from baseline, a 50% reduction in base medication celecoxib from 400 mg / day to 200 mg / day, and a 100% reduction in tramadol from 37.5 mg / day to 0 mg / day).

[0172] Example 12: Reduction of 11-OH THC levels with the formulation of Example 4 Hydroxylation of THC at C(9) by CYP450 in the liver leads to the production of the pharmacologically active metabolite 11-OH-THC. Originally, 11-OH-THC was known to be the major psychoactive substance (Huestis et al., 2007), but reliable data on its psychoactive effects in humans are scarce. In several pharmacological animal studies, 11-OH-THC was found to induce 3-7 times more psychotropic side effects than THC (Grotenhermen et al., 2003; Lemberger et al., 1973). Furthermore, 11-OH-THC has been shown to have a greater effect on the brain than THC (Grotenhermen et al., 2003). The penetration of 1OH-THC was faster and in higher amounts compared to THC (Perez-Reyes et al., 1976; Grotenhermen et al., 2003). The psychological and physiological effects of intravenously administered THC and 11-OH-THC in adults were examined. The study showed that tachycardia and a psychological "high" occurred within 3 to 5 minutes after administration of a single intravenous dose of 11-OH-THC (dose: 1 mg).

[0173] The ratio of THC and 11-OH-THC, as well as the onset of peak concentrations, can dramatically affect the effect and side effect profile of medical cannabis. After smoking, peak 11-OH-THC concentrations occurred approximately 13 minutes after application (Huestis et al., 1992). Following inhalation administration (e.g., smoking, vaporization), significantly smaller amounts of the active metabolite 11-OH-THC (23%) compared to 77% THC have been reported, due to the avoidance of the hepatic first-pass effect (Meyer et al., 201 8, Spindle et al., 2016, Eisenberg et al., 2014).

[0174] In the case of oral administration (dronabinol capsules and solution), a three-fold higher formation of 11-OH-THC was observed compared to THC (Parikh et al., 2016). This may be due to extensive hepatic first-pass metabolism after THC use. Hunt et al. reported very high mean plasma clearance rates of 36 L / h in regular users and 60 L / h in regular users, which is similar to the amount of hepatic blood flow. This indicates that the limiting step in the metabolic rate is controlled by hepatic blood flow. The high clearance rates explain the high degree of first-pass metabolism and the significantly higher concentrations of 11-OH-THC after oral administration compared to inhalation (Hunt et al, 1980; Grotenhermen et al., 2003). Following administration of Sativex™, similar to oral delivery, , we can see a three-fold higher formation of 11-OH-THC compared to THC.

[0175] A clinical trial in three healthy male volunteers was carried out to determine the pharmacokinetic effects of a cannabis formulation rich in tetrahydrocannabinol (Example 4). A single dose of the cannabis formulation containing 3.0 mg of tetrahydrocannabinol was administered oromucosally. Blood samples were taken immediately before dosing and 2, 5, 10, 15, 20, 30, 45, 60 and 90 minutes, as well as 2, 3, 4, 5, 6, 7 and 24 hours following administration of the cannabis formulation. The plasma concentration of THC in the blood samples was measured by LC-MS / MS.

[0176] Following administration of the cannabis nanoformulation of Example 4, 11-OH-THC levels were significantly lower compared to the Sativex™ or dronabinol formulations. Mean THC plasma concentrations and AUC levels were compared with normalized doses of Sativex™ oromucosal spray (GW Pharma Ltd.) (Stott et al., Eur J Clin Pharmacol 69 (2013), pages 1135-1147) and The results are compared with dronabinol (Parikh N, Kramer WG, Khurana V, Cognata Smith C, Vetticaden S (2016) Bioavailability study of dronabinol oral solution versus dronabinol capsules in healthy volunteers. Clin Pharmacol 8:155-162) and listed in Table 6.

[0177] Compared to the oromucosal sprays Sativex™ and dronabinol, the THC-rich formulation of Example 4 exhibits significantly lower 11-OH-THC AUC levels (2.48-fold and 3.37-fold, respectively). The significantly lower 11-OH-THC AUC values ​​over 24 hours clearly demonstrate that the formulation of Example 4 is absorbed through the oral mucosa and avoids the first-pass effect compared to Sativex™ and dronabinol.

[0178] [Table 6]

[0179] Embodiment The present disclosure also relates to the following numbered embodiments: 1. A formulation comprising at least one natural cannabis material, at least one solvent, and at least one stabilizer, said formulation comprising a particle size (D 90 ). 2. The formulation of embodiment 1, wherein the at least one natural cannabis material is a material from the family Cannabaceae, preferably the natural cannabis material is a material from a genus selected from the group consisting of Afanense, Cannabis, Certis, Caetacum, Dironniera, Humulus, Rosanella, Parasponia, Pterocertis, and Trema, preferably the natural cannabis material is a material from the genus Cannabis. 3. The formulation of embodiment 2, wherein the at least one natural cannabis material is a material of the Cannabis genus, the Cannabis being a species selected from the group consisting of Cannabis sativa, Cannabis indica, and Cannabis ruderalis, preferably the at least one natural cannabis material is a material of the Cannabis sativa species. 4. A formulation according to any one of the preceding embodiments, wherein the at least one natural cannabis material is a mixture of at least two natural cannabis materials, preferably two or three natural cannabis materials, preferably a mixture of Cannabis sativa and Cannabis indica or Cannabis ruderalis. 5. A formulation according to any one of the preceding embodiments, wherein said at least one natural cannabis material is part or all of said natural cannabis material, preferably said part of said natural cannabis material is selected from the group consisting of leaves, stems, seeds, flowers, roots, and mixtures thereof, preferably said natural cannabis material comprises said natural cannabis material or is a flower thereof. 6. A formulation according to any one of the preceding embodiments, wherein the at least one natural cannabis material is present in an amount of 0.1% to 20% (wt / wt), relative to the total mass of the formulation, preferably 0.1% to 10% (wt / wt), preferably 0.2% to 5% (wt / wt), preferably 0.3% to 4% (wt / wt), preferably 0.5% to 3% (wt / wt), even more preferably 0.5% to 1% (wt / wt), 1% to 2% (wt / wt), or 2% to 4% (wt / wt), relative to the total mass of the formulation. 7. A formulation described in any one of the above embodiments, wherein the solvent is selected from the group consisting of water, ethanol, lipids, non-polar organic solvents, and mixtures thereof, preferably the solvent is a mixture of water and lipids. 8. The formulation of embodiment 7, wherein the lipid is selected from the group consisting of a solid lipid, a liquid lipid, a wax, and mixtures thereof, preferably the lipid is a mixture of a liquid lipid and a solid lipid. 9. The lipid is a glyceride, preferably selected from the group consisting of a monoglyceride, a diglyceride, or a triglyceride, preferably the lipid is a triglyceride, more preferably the glyceride is a mixture of medium chain triglycerides and saturated C 12 ~C 18 The formulation of embodiment 7 or 8, which is a mixture with glycerol esters of fatty acids (Gelucire™ 39 / 01). 10. The stabilizer is selected from the group consisting of phospholipids; polysorbates; polymers including homopolymers, block copolymers and graft copolymers, including hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP); non-ionic triblock copolymers including poloxamers; copolyvinylpyrrolidone; Labrasol®; gelatin; lecithin (phosphatides); gum acacia; xanthan gum; gum arabic; cholesterol; tragacanth; polyoxyethylene alkyl ethers; polyoxyethylene castor oil derivatives; polyoxyethylene sorbitan fatty acid esters; sorbitan fatty acid esters; polyethylene glycols; polyoxyethylene The formulation of any one of the above embodiments, wherein the active ingredient is selected from the group consisting of: stearic acid; calcium stearate; glycerol monostearate; cetostearyl alcohol; cetomacrogol emulsifying wax; short and medium chain alcohols; Labrafil™; Purol-oleique; propane-1,2,3-triol (glycerin); polyvinyl alcohol; dioctyl sodium sulfosuccinate (DOSS); carmellose sodium; carrageenan; carbomer; hypromellose; and mixtures thereof. 11. A formulation described in any one of the above embodiments, wherein the stabilizer is selected from the group consisting of phospholipids, surfactants, and polymers, preferably the stabilizer is a polymer selected from the group consisting of polysorbates, polysaccharides, and poloxamers. 12. Formulation according to embodiment 10 or 11, wherein the formulation comprises polysorbate as stabilizer in an amount of up to 10% (w / w), preferably in an amount of 0.5% to 4.5% (w / w), in an amount of 1% to 4.5% (w / w), or in an amount of 1.5% to 4% (w / w), more preferably in an amount of 2% to 3% (w / w), or in an amount of 3% to 4% (w / w), most preferably in an amount of 2.5% to 4% (w / w), relative to the total mass of the formulation, and / or the formulation comprises a polysorbate selected as Polysorbate 80 (Tween® 80) or Polysorbate 20 (Tween® 20), preferably Polysorbate 80 (Tween® 80), as stabilizer. 13. Formulation according to any one of embodiments 10 to 12, wherein the formulation comprises a surfactant as stabilizer in an amount of up to 10% (w / w), preferably in an amount of 0.5% to 4.5% (w / w), in an amount of 1% to 4.5% (w / w), or in an amount of 1.5% to 4% (w / w), more preferably in an amount of 2% to 3% (w / w), or in an amount of 3% to 4% (w / w), most preferably in an amount of 2.5% to 4% (w / w), relative to the total mass of the formulation, and / or wherein the formulation comprises a surfactant selected as sorbitan monooleate (Span® 80) as stabilizer. 14. A formulation according to any one of embodiments 10 to 13, wherein the formulation comprises a poloxamer as a stabilizer in an amount of up to 10% (w / w), preferably in an amount of 0.2% to 1.5% (w / w), more preferably in an amount of 0.5% to 1% (w / w), relative to the total mass of the formulation, and / or the formulation comprises a poloxamer selected as poloxamer 407 (Kolliphor® P407), or poloxamer 188 as a stabilizer. 15. The formulation contains 0.04% to 0.1% (wt / wt) in an amount of up to 5% (wt / wt) based on the total mass of the formulation, preferably in an amount of 0.02% to 0.5% (wt / wt), more preferably in an amount of 0.04% to 0.1% (wt / wt) 15. The formulation according to any one of embodiments 10 to 14, wherein the formulation comprises a polysaccharide as a stabilizer in an amount of 0.05% to 0.08% (w / w), more preferably in an amount of 0.05% to 0.08% (w / w), and / or the formulation comprises a polysaccharide as a stabilizer selected as xanthan gum. 16. A formulation according to any one of embodiments 10 to 15, wherein the formulation comprises a phospholipid as a stabilizer in an amount of 0.5% to 10% (w / w), preferably in an amount of 1% to 4% (w / w), relative to the total mass of the formulation, and / or the phospholipid contains 40% to 100% (w / w) of phosphatidylcholine, relative to the total mass of the phospholipid, and / or the formulation comprises a phospholipid selected as Lipoid® P45 as a stabilizer. 17. A formulation described in any one of the above embodiments, wherein the formulation further comprises an additive, preferably the additive is selected from the group consisting of a preservative, an antioxidant, and a penetrating agent. 18. The formulation according to embodiment 17, wherein the additive is a preservative, which is present in the formulation in an amount of 0.1% to 1% (w / w), preferably in an amount of 0.10% to 0.15% (w / w), relative to the total mass of the formulation, and / or the formulation comprises as additive a preservative selected as potassium sorbate and / or sodium benzoate. 19. A formulation according to embodiment 17 or 18, wherein the additive is an antioxidant, which is present in the formulation in an amount of 0.01% to 3% (w / w), preferably in an amount of 0.001% to 0.1% (w / w), in an amount of 0.005% to 0.1% (w / w), in an amount of 0.001% to 0.1% (w / w), in an amount of 0.1% to 1% (w / w) or in an amount of up to 0.02% (w / w), relative to the total mass of the formulation, and / or the formulation comprises as additive an antioxidant selected from the group consisting of EDTA, tocopherol, citric acid and ascorbyl palmitate. 20. The formulation according to any one of the above mentioned embodiments for use in palliative care and / or in the treatment or alleviation of a disease, preferably wherein said disease is selected from the group consisting of pain, in particular acute or chronic pain, somatic pain, visceral pain, neuropathic pain, cancer pain, chronic low back pain, chronic central pain; neuropathy, neurodegenerative diseases, insomnia, psychiatric disorders, nausea, anorexia, vomiting and nausea induced by chemotherapy, diabetic polyneuropathy, fibromyalgia, Tourette's syndrome, multiple sclerosis, convulsions in multiple sclerosis, anxiety disorders, schizophrenia, social phobia, sleep disorders, skin related diseases such as psoriasis and neurodermatitis, glaucoma, restless legs syndrome, epilepsy, movement disorders such as Alzheimer's disease, dystonia, Huntington's disease, Parkinson's disease, bipolar disorder and other medical indications affected by the endocannabinoid system and by any other receptors affected by cannabinoids (e.g. GPR18, GPR119, GPR55).

Claims

1. A formulation comprising at least one natural cannabis material, at least one solvent, and at least one stabilizer, said formulation comprising a particle size (D ９０ ).

2. 2. The formulation of claim 1, wherein the at least one natural cannabis material is a material from the family Cannabaceae, preferably the natural cannabis material is a material from a genus selected from the group consisting of Afanense, Cannabis, Certis, Caetacum, Dironniella, Humulus, Rosanella, Parasponia, Pterocertis, and Trema, preferably the natural cannabis material is a material from the genus Cannabis.

3. 3. The formulation of claim 2, wherein the at least one natural cannabis material is a material of the genus Cannabis, the Cannabis being a species selected from the group consisting of Cannabis sativa, Cannabis indica, and Cannabis ruderalis, preferably the at least one natural cannabis material is a material of the Cannabis sativa species.

4. 4. A formulation according to any one of claims 1 to 3, wherein said at least one natural cannabis material is part or all of said natural cannabis material, preferably said part of the natural cannabis material is selected from the group consisting of leaves, stems, seeds, flowers, roots and mixtures thereof, preferably said natural cannabis material comprises or is the flower of said natural cannabis material.

5. 5. The formulation according to any one of claims 1 to 4, wherein the at least one natural cannabis material is dispersed in the formulation in an amount of between 0.1% and 20% (w / w), relative to the total mass of the formulation, preferably between 0.1% and 10% (w / w), preferably between 0.2% and 5% (w / w), preferably between 0.3% and 4% (w / w), preferably between 0.5% and 3% (w / w), more preferably between 0.5% and 1% (w / w), 1% and 2% (w / w), or 2% and 4% (w / w), relative to the total mass of the formulation.

6. 6. The formulation according to any one of claims 1 to 5, wherein the solvent is selected from the group consisting of water, ethanol, a lipid, a non-polar organic solvent, and mixtures thereof, preferably the solvent is a mixture of water and a lipid.

7. 7. The formulation of claim 6, wherein the lipid is selected from the group consisting of a solid lipid, a liquid lipid, a wax, and mixtures thereof, preferably the lipid is a mixture of a liquid lipid and a solid lipid.

8. The lipid is a glyceride, preferably selected from the group consisting of monoglycerides, diglycerides, or triglycerides, preferably the lipid is a triglyceride, more preferably the glyceride is a mixture of medium chain triglycerides and saturated C １２ ~C １８ 8. A formulation according to claim 6 or 7, which is a mixture with glycerol esters of fatty acids (Gelucire™ 39 / 01).

9. The stabilizers may be selected from the group consisting of phospholipids, polysorbates, polymers including homopolymers, block copolymers and graft copolymers, including hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP), non-ionic triblock copolymers including poloxamers, copolyvinylpyrrolidone, Labrasol™, gelatin, lecithin (phosphatides), gum acacia, xanthan gum, gum arabic, cholesterol, tragacanth, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acids.

9. The formulation of any one of claims 1 to 8, wherein the surfactant is selected from the group consisting of: esters; sorbitan fatty acid esters; polyethylene glycol; polyoxyethylene stearate; colloidal silicon dioxide; sodium dodecyl sulfate; mono- and diglycerides; magnesium aluminum silicate; triethanolamine; stearic acid; calcium stearate; glycerol monostearate; cetostearyl alcohol; cetomacrogol emulsifying wax; short and medium chain alcohols; Labrafil™; Purol-oleique; propane-1,2,3-triol (glycerin); polyvinyl alcohol; dioctyl sodium sulfosuccinate (DOSS); carmellose sodium; carrageen; carbomer; hypromellose; and mixtures thereof.

10. 10. The formulation of any one of claims 1 to 9, wherein the stabilizer is selected from the group consisting of phospholipids, surfactants, and polymers, preferably the stabilizer is a polymer selected from the group consisting of polysorbates, polysaccharides, and poloxamers.

11. 11. Formulation according to claim 9 or 10, wherein the formulation comprises polysorbate as stabilizer in an amount of up to 10% (w / w), preferably in an amount of 0.5% to 4.5% (w / w), in an amount of 1% to 4.5% (w / w), or in an amount of 1.5% to 4% (w / w), more preferably in an amount of 2-3% (w / w), or in an amount of 3% to 4% (w / w), most preferably in an amount of 2.5% to 4% (w / w), relative to the total mass of the formulation; and / or wherein the formulation comprises a polysorbate selected as Polysorbate 80 (Tween™ 80) or Polysorbate 20 (Tween™ 20), preferably Polysorbate 80 (Tween™ 80), as stabilizer.

12. Formulation according to any one of claims 9 to 11, wherein the formulation comprises a poloxamer as stabilizer in an amount of up to 10% (w / w), preferably in an amount of 0.2% to 1.5% (w / w), more preferably in an amount of 0.5% to 1% (w / w) relative to the total mass of the formulation, and / or the formulation comprises a poloxamer selected as poloxamer 407 (Kolliphor™ P407), or poloxamer 188 as stabilizer.

13. Formulation according to any one of claims 9 to 12, wherein the formulation comprises a phospholipid as stabilizer in an amount between 0.5% and 10% (w / w), preferably between 1% and 4% (w / w), relative to the total mass of the formulation, and / or the phospholipid contains between 40% and 100% (w / w) of phosphatidylcholine, relative to the total mass of the phospholipid, and / or the formulation comprises a phospholipid selected as Lipoid™ P45 as stabilizer.

14. The formulation according to any one of claims 1 to 13, wherein the formulation further comprises an additive, preferably the additive is selected from the group consisting of preservatives, antioxidants and penetrating agents.

15. A formulation according to any one of claims 1 to 14 for use in palliative care and / or in the treatment or alleviation of a disease, preferably wherein the disease is pain, in particular acute or chronic pain, somatic pain, visceral pain, neuropathic pain, cancer pain, chronic low back pain, chronic central pain; neuropathy, neurodegenerative diseases, insomnia, psychiatric disorders, nausea, anorexia, vomiting and nausea induced by chemotherapy, diabetic polyneuropathy, fibromyalgia, Tourette's syndrome, multiple sclerosis, multiple sclerosis. convulsions, anxiety disorders, schizophrenia, social phobia, sleep disorders, skin related disorders such as psoriasis and neurodermatitis, glaucoma, restless legs syndrome, epilepsy, movement disorders such as Alzheimer's disease, dystonia, Huntington's disease, Parkinson's disease, and other medical indications affected by the endocannabinoid system and any other receptors affected by cannabinoids (e.g. GPR18, GPR119, GPR55).

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