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    • 专利摘要:
    [0001] Vaporizable liquid formulation comprising at least one cannabinoid compound and at least one diol chosen from the diols of Formula (I): in which: R1 and R2 are identical or different, and are chosen from the group consisting of an atom of hydrogen (-H) or alkyl radical having 1 to 2 carbon atoms; m + n = 1 or m + n = 2; n = 0 or n = 1 or n = 2; - m = 0 or m = 1; the diol being in the form of a mixture of isomers and / or isolated isomer when it comprises one or more asymmetric carbon atoms.
    公开号:FR3062303A1
    申请号:FR1750853
    申请日:2017-02-01
    公开日:2018-08-03
    发明作者:Antoine Piccirilli
    申请人:Laboratoires Ceres；
    IPC主号:
    专利说明:

    Holder (s):
    PICCIRILLI ANTOINE.
    O Extension request (s):
    © Agent (s): CABINET TRIPOZ.
    © LIQUID VAPORIZABLE FORMULATION COMPRISING AT LEAST ONE DIOL AND AT LEAST ONE CANNABINOID COMPOUND.
    ©) [0001] Sprayable liquid formulation comprising at least one cannabinoid compound and at least one diol chosen from the diols of Formula (I):
    FR 3 062 303 - A1
    in which:
    R! and R 2 are the same or different, and are chosen from the group consisting of a hydrogen atom (-H) or an alkyl radical comprising from 1 to 2 carbon atoms; m + n = 1 or m + n = 2; n = 0 or n = 1 or n = 2;
    - m = 0 or m = 1;
    the diol being in the form of a mixture of isomers and / or of isolated isomer when it comprises one or more asymmetric carbon atoms.
    LIQUID VAPORIZABLE FORMULATION COMPRISING AT LEAST ONE DIOL AND AT LEAST ONE CANNABINOID COMPOUND The present invention relates to the field of administration of cannabinoid compound (s).
    More specifically, the present invention relates to the technical field of vaporizable liquid formulations comprising at least one cannabinoid compound, as well as to a method of detoxifying an oil comprising at least one cannabinoid compound.
    In the prior art, a certain number of requests relate to what is currently commonly called "electronic cigarettes", or even "e-cigarettes", this is particularly the case of the WO 2014/590079, the device disclosed is an electronic cigarette comprising nicotine and an "ion pairing agent".
    [0004] The electronic cigarette has, schematically, three main elements:
    a cartridge or a reservoir;
    an atomizer;
    a means of power supply.
    Regarding the power supply means, it can be a battery, rechargeable or not.
    With regard to the cartridge or the reservoir, he or she comprises a vaporizable liquid formulation commonly called “e-liquid”, or even “e-cigarette liquid”, “liquid for e-cigarette”.
    In the context of the present application, the term “vaporizable liquid formulation” is the most encompassing term with regard to the liquids which can be used in an electronic cigarette and includes e-liquids. E-liquids traditionally include one or more solvents, one or more flavor (s) and / or color (s) and / or other additives, and sometimes nicotine (generally from 0 to 20 mg / ml).
    In the context of the present application, the term "vapor" is a set of liquid particles suspended in a gaseous medium. For example, the mist or mist is a vapor because the water droplets are suspended in the air. Liquid particles fall less than 0.5 m / second when dealing with a "vapor", in the latter case the liquid which produces the vapor was therefore "vaporizable".
    Certain variants with regard to vaporizable liquid formulations have been proposed in the prior art.
    Thus, application WO 2015/101760 in the name of LABORATOIRES GERES discloses the use of 1,3-propanediol (PDO). In some embodiments, 1,3-propanediol (PDO) also eliminates the use of glycerol. In addition, application W02016005709 in the name of LABORATOIRES GERES discloses the use of other polyols.
    As regards the atomizer, the latter makes it possible to convert the liquid into mist / vapor simulating smoke, the latter can in particular consist of a heating resistor. It can be integrated into the e-liquid cartridge, in case a cartridge is used. A valve of small dimension sensitive to the depression caused by the inspiration or a contactor with manual release allow the supply by the battery of the atomizer.
    In addition to these three main elements, the electronic cigarette can include other elements: indicator light mimicking combustion, display screen (allowing information on the degree of charge of the battery, etc.), adjustment wheel vapor intensity, etc.
    Cannabinoids are a group of chemicals.
    In the context of the present application, the term “cannabinoid compound” refers to all the compounds capable of activating the cannabinoid receptors of mammals (including in particular humans). They can be of plant origin (the latter are sometimes called "phytoxannabinoids"), endogenous (the latter are sometimes called "endocannabinoids") or even synthetic.
    Cannabinoid receptors in humans include the CB1 and CB2 receptors.
    Certain cannabinoid compounds are of great interest in the scientific and medical field.
    The cannabinoid compounds can be of plant, endogenous or even synthetic origin.
    The cannabinoid compounds can, for example, be extracted from the cannabis sativa plant, the extracts of which mainly contain variable proportions depending on their origin (variety, geography, soil and climate conditions, etc.) and the process for obtaining them. , the following families of compounds: canabinoid compounds belonging to the classes of delta-9 tetrahydrocannabidiols (A9-THCs), cannabigérols (CBGs), cannabichromenes (CBCs), cannabidiols (CBDs), delta-9 cannabidiols (A9-CBDs) ), delta-8 cannabidiols (Δδ-CBDs), cannabicyclols (CBLs), cannabielsoines (CBEAs), cannabinols and cannabinodiols (CBNAs and CBNs), cannabitriols (CBTs). There are also various minority cannabinoids including a furan or chroman motif. The euphoric properties of cannabis are mainly induced by delta-9 tetrahydrocannabidiol (Û9-THC):
    Delta-9 tetrahydrocannabidiols (A9-THCs) are especially included in the specialties SATIVEX® (oro-mucosal spray) and MARINOL® (comprising "dronabinol", synonymous with "delta-9 tetrahydrocannabidiols").
    Although less potent, delta-8 tetrahydrocannabidiol (A8-THC) has similar properties than A9-THC.
    Among the delta-9 tetrahydrocannabidiols, there are also compounds comprising an acid function, called the delta-9 THCA (forms A and B):
    Finally, cannabidiol (CBD) is attributed to the anaesic, anxiolytic, anti-inflammatory, antispasmodic and antipsychotic activities of cannabis. These acidic compounds are thermosensitive and decarboxylate very easily to lead to A9-THC.
    THC and CBD alone or in combination constitute the cibial compounds of cannabis sativa extracts.
    Cannabis sativa is a dioecious species (there are, however, monoecious varieties), very polymorphic. The same plant produces, depending on the climatic conditions, fibers or resin. ; but there are subspecies providing, under determined environmental conditions, longer fibers, and others, a higher resin production.
    [00025] Tetrahydrocannabinols (THCs) and cannabidiols (CBDs) are cannabinoid compounds of particular interest.
    The extracts of the piante cannabis sativa also include non-cannabinoid compounds, among which there are:
    terpenes, mainly monoterpenes (47-92%) and sesquiterpenes (7-48%). The main compounds are β-myrcene, a pinene, β-pinene, limonene, trans-g-ocymene, terpinolene and βcariophyllene;
    - aliphatic hydrocarbons, the main one being nonacosane (nC29);
    ies lipids in the form of mono, di and triglycerides in C6-C24 and waxes in C6-C24;
    ies various minor compounds such as alkaloids, lignans, polyphenols, etc.
    In the context of the present application, the term “undesirable lipid compounds” in particular mono, di and triglycerides C6-C24 and waxes C6-C24. When reference is made to a “level of undesirable lipid compounds”, it is the sum of the levels of mono, di and triglycerides in C6-C24 and in waxes in C6-C24. The removal of unwanted lipid compounds is called "defatting".
    In the context of the present application, the term “terpene compound” is understood to mean any compound being β-myrcene, Ι'α-pinene, β-pinene, limonene, trans-B-ocymene, terpinolene and / or β-cariophyllene. The removal of terpene compounds is called “deterpenation”.
    Terpene compounds can be troublesome due to their toxicity. Myrcene, limonene, a and β-pinene, which are terpene compounds, are allergenic and highly sensitizing.
    One of the solutions proposed in US application 2004/0049059 in the name of MUELLER, is to design formulations from extracts obtained by extraction with supercritical CO2, which after thorough purification (deterpenation, dewaxing), contain few terpenes and sesquiterpenes. Once rid of terpene compounds, the extracts can thus be flavored to order.
    Lipid pneumonia is linked to an accumulation of lipids in the pulmonary alveoli. These lipids are mostly of exogenous origin. In the context of the use of an electronic cigarette, it is important to limit the presence of unwanted lipid compounds in the vaporizable liquid formulation, in order to prevent them from becoming lodged in the user's pulmonary alveoli, this is moreover one of the objectives of the present invention.
    The inclusion of cannabinoid compounds in e-liquid is known, for example from application US20140166028 in the name of FUISZ.
    [00032] The vaporizable liquid formulations comprising THC, CED or even a total plant extract of cannabis sativa, also include a solvent based on propyiene glycol (PG) and vegetable glycerin (VG) (the glycerin content being able to reach more than 50% of the formulation), natural or synthetic flavors mainly of food quality and a fluidifying and / or homogenizing agent such as water and ethanol.
    In addition, these formulations may also contain nicotine, flavor enhancers (such as diacetyl), co-solvents, allowing the solubilization of aromatic molecules insoluble in the solvent (such as triacetin , a vegetable oil), enhancers of "throat hit", otherwise called "throat scratching" (such as capsaicin extracts), antioxidants, hit enhancers, preservatives or agents allowing the formation of dense vapor such as polyglycerols or polyethylene glycols (PEGs), or activators of the bioavailability of cannabinoids.
    [00034] The vaporizable liquid formulations comprising THC and / or CBD of the prior art have numerous drawbacks.
    With regard to homogeneity, due to their very variable chemical formulation, the extracts and formulations based on extracts of the cannabis sativa plant are not always homogeneous because they contain compounds with very different solubilities. This makes the use of a fluidifying and / or homogenizing agent such as water or ethanol necessary, but these agents are likely to cause additional problems.
    The addition of water significantly increases the microbiological risk by promoting bacterial development in the event of microbial contamination during the manufacture and / or use of the formulation. Cannabinoids and terpene compounds are also insoluble in water. On the industrial level, the presence of water will therefore induce the use of food or pharmaceutical grade water, or even, sterilizing filtration before packaging as well as systematic microbiological control. This problem can be partly solved by the introduction into the formulation of biocidal preservatives. However, this solution is not at all suitable for formulations intended to be inhaled.
    [00037] If the use of ethanol as a fluidizing and / or homogenizing agent solves the microbial problem, it nevertheless induces a toxicity problem. Indeed, the bioavailability of ethanol by inhalation is significantly higher than that observed by the oral route and thereby its intrinsic toxicity is increased. Thus, the ethanol present in inhaled pharmaceutical specialties is at the origin of severe intoxications which invited health agencies to propose a reduction, even the replacement of alcohol in these formulations. In addition, for ethanol, the FDA has set the exposure limit (PDE, Permissible Daily Exposure) at 166 mg / day. Thus, by way of example, a conventional formulation of cannabinoids (title in cannabinoids: 70 mg / ml), whose daily consumption by inhalation, can be reasonably fixed at 3 g / day, respecting the PDE value of ethanol would imply a maximum ethanol content in said formulation of 5% by weight. However, at this content, ethanol cannot effectively play the role of fluidifying and / or homogenizing agent. Finally, a formulation containing ethanol is not desired for consumers in alcohol withdrawal or more simply those not wishing to ingest alcohol.
    One of the solutions proposed is described in application US 2015/0083146 in the name of VERSO PV, LLC, is the use of an emulsifying agent in order to fluidize and / or homogenize the vaporizable liquid formulations comprising cannabinoids. Said emulsifying agents are lipid compounds. This solution is not viable since inhalation of lipid compounds induces a significant risk of lipoid pneumonia.
    Regarding energy consumption, by their formulation often rich in low volatile compounds such as glycerin (50% by weight) and lipid compounds, the vaporizable liquid formulations of the prior art are not easily vaporizable.
    [00040] Glycerin is often used in formulations based on CBD and THC to mask the strong bitterness of cannabinoids and bring more roundness and sweetness to the mouth. Highly hygroscopic, glycerin produces very dense vapor.
    Regarding the toxicity problems of the solvent, glycerin and propylene glycol induce high heating power, the formation of toxic and irritant compounds such as formaldehyde, acetaldehyde and acrolein.
    With regard to the toxicity problems of the extract, the acid cannabinoids known to be heat-sensitive such as delta-9 THCA will undergo decarboxylation reactions, which makes it impossible to envisage standardized and secure inhalable formulations, that is to say delivering a known and constant amount of cannabinoids and compatible with equipment of the electronic cigarette or personal heating vaporizer type; safety and efficacy in terms of active ingredient delivery being two essential prerequisites when one wishes to develop aerosol therapy technologies and formulations.
    With regard to sensory characteristics, and in particular olfactory characteristics, the conjunction of several factors induces poor sensory properties of inhalable or ingestible formulations based on cannabinoid extracts due to:
    the strong intrinsic bitterness of total cannabinoid extracts which is difficult to manage in terms of taste and odor;
    the presence of volatile terpenes and sesquiterpenes in a large and variable amount in oleoresins and essential oils of cannabis, the formulation of which is subject to great variability according to geographical origin, variety, seasonality and pedoclimatic conditions;
    the high glycerin contents, which brings on the one hand, an often too sweet note to the formulations but imposes on the other hand, the incorporation of aromas in significant quantities. It is in fact known to those skilled in the art that glycerol significantly blurs the taste power of the aromas.
    Supercritical or subcritical extraction technologies are very expensive in terms of investment and operating cost (discontinuous extraction process). Productivity is also affected by the low cannabinoid content of the treated biomass (leaves, cannabis flowers): <4.2% by weight. In addition, the supercritical fluid extraction installations are of small capacity unlike the conventional extraction units with chemical solvents or even hydrodistillation.
    Regarding solubility issues, THC and CBD are insoluble in water and very soluble in vegetable oils, light alcohols such as ethanol and non-polar hydrocarbons such as hexane and xyenes . Also, they have a very low solubility in glycerin. In contrast, THC and CBD exhibit moderate solubility in propylene glycol, especially when this solvent is combined with ethanol. Furthermore, ethanol and vegetable oils (comprising lipid compounds) are to be strongly limited or prohibited but are nevertheless used.
    Another solution considered is to increase the bioavailability of THC in the formulations according to the solution proposed in application US 2014/0166028 in the name of FUISZ. It is recommended in this case to introduce into said formulation a buffer solution in order to maintain the pH of the formulation in the oral cavity between 7, 8 and 10 as well as a THC captive agent.
    The buffering agent is preferably a solution of sodium carbonate and / or hydrogencarbonate. While the captive agent is chosen from xanthan gum and modified celluloses (HPMC, HEMC).
    This type of formulation containing water requires on the one hand the presence of a biocide and on the other hand is not aerosolizable under heat as can be formulations based on propylene glycol and glycerin . These formulations must be free of solid substances (xanthan gum, modified celluloses) or crystallized substances (sodium carbonate) in order to avoid the deposition of micro or nanoparticles in the pulmonary alveoli.
    As regards the safety of the formulations, the current formulations contain compounds which can induce a significant toxicological risk:
    unwanted lipid compounds inducing the risk of lipoid pneumonia;
    ethanol in significant quantity;
    potentially hepatoxic and genotoxic coumarins.
    Finally, as regards the problems linked to industrial implementation, the current formulations rich in glycerin and in lipid compounds are difficult to aerosolize and require high aerosolization temperatures inducing:
    - thermal reactions with formation of carbonaceous residues on the wicks of electronic cigarettes, which must be changed regularly;
    an increased consumption of energy prejudicial to the autonomy of use. The cannabis sativa extracts present in cannabinoid-based e-liquids can be obtained from the leaves of cannabis sativa, by extraction using a liquid or gaseous solvent (obtaining an oleoresin), by hydro-distillation (obtaining an essential oil) or by a combination of mechanical extraction and hydro-distillation. Depending on the extraction process used, the nature of the solvent, the purification steps (wintering, filtration, treatment with absorbent supports, sterilization, etc.), these extracts have formulation characteristics and organoleptic characteristics (appearance, color, viscosity, odor, taste) very different. Indeed, extraction technology has a strong impact on their properties.
    The most commonly encountered extracts, obtained by supercritical CO2 extraction, can be very rich in cannabinoid compounds when applying so-called "subcritical" conditions. Oily in appearance, however, they are more sticky and include more plant waxes than those obtained under so-called "supercritical" conditions. Waxes, which belong to the family of lipids with high melting point, tend to precipitate at moderately cool temperature (15-20 ° C) are undesirable.
    Extracts comprising cannabinoid compounds can also be obtained by extraction using organic solvents, liquids or gases such as ethanol, isopropanol, hexane, butane, propylene glycol and glycerin. Also, the extraction step is often followed by a slow wintering step in order to get rid by precipitation of cold insoluble compounds (waxes, chlorophyll, saturated fatty acids, etc.). Obviously, the nature of the solvent will have a significant impact on the formulation of the final extracts as well as on their organoleptic properties. These properties are presented in Table 1 below:
    Extraction solvent Charactersorganoleptics Formulation Pronounced color Odour Cannabidoid compounds Terpenes andSesquiterpenes Chlorophylls Waxes and other lipids Ethanol ++++ ++ +++ ++ ++++ + Isopropanol +++ -h ++ ++ +++ + Butane ++++ +++ + +++ Hexane (or other hydrocarbon) ++ +++ +++ +++ + +++ Glycerol and propylene glycol ++ ++ ++ ++ ++ + CO 2 supercritical +++ ++++ ++++ ++++ + +++
    Table 1: Impact of the nature of the solvent and of the process on the formulation and the organoleptic properties of the extracts obtained after removal of the solvent [00055] In the prior art, a certain number of polyols have been included in eliquids.
    In application W02015101760 in the name of LABORATOIRES GERES, the use of 1,3-propanediol (PDO) is disclosed.
    In application W02016005709 in the name of LABORATOIRES GERES, the use of other diols is disclosed.
    In these two requests, certain diols are disclosed.
    Surprisingly, it has been demonstrated by the applicant that the use of a non-twin and non-vicinal diol as a solvent in a vaporizable liquid formulation has the effect:
    better solubilize cannabinoid compounds (compared to propylene glycol);
    - making the vaporizable liquid formulation capable of vaporizing at lower power, thus allowing less degradation;
    to exacerbate the aromas of cannabinoid compounds;
    - increase the amount of THC and / or CBD delivered per puff;
    - to ensure a constant delivery of cannabinoids;
    increase the life of the resistors (wicks) by limiting in particular their fouling;
    - limit toxicity ίο
    - to reduce the maceration time (steeping, step consisting of loosening the aromatic molecules) of the vaporizable liquid formulation.
    Surprisingly, it has been demonstrated by the applicant that the use of a polyol chosen from the group consisting of non-feminine and non-vicinal diols had the effect of deterpenising the oily extract of cannabis sativa by means a simple process involving heating and then centrifugation.
    In the context of the present application, the term "oil" means any lipophilic, nonionic compound, insoluble in water and liquid at room temperature (25 ° C) and under atmospheric pressure (760 mm Hg). By water insoluble is meant within the meaning of the present invention a compound whose solubility at spontaneous pH in water at 25 ° C and at atmospheric pressure is less than 1%.
    Surprisingly, the use of such a method makes it possible to reduce the duration of maceration (steeping, step consisting in loosening the aromatic molecules) during the manufacture of a vaporizable liquid formulation.
    The invention relates to a vaporizable liquid formulation comprising at least one cannabinoid compound and at least one diol chosen from the diols of Formula (I):

    OH
    Formula (I) in which:
    - RI and R2 are identical or different, and are chosen from the group consisting of a hydrogen atom (-H) or an alkyl radical comprising from 1 to 2 carbon atoms;
    m + n = 1 or m + n = 2;
    n = 0 or n = 1 or n = 2;
    - m = 0 or m = l;
    the diol being in the form of a mixture of isomers and or of isolated isomer when it comprises one or more asymmetric carbon atoms.
    In one embodiment, the formulation is characterized in that said at least one diol is chosen from the diols of formula I in which the alkyl radical is chosen from the group consisting of methyl (-CH3) and ethyl radicals ( -CH2CH3).
    In one embodiment, the formulation is characterized in that said at least one diol is chosen from the diols of formula I in which n = l.
    In one embodiment, the formulation is characterized in that said at least one diol is chosen from the diols of formula I in which n = 2.
    In one embodiment, the formulation is characterized in that said at least one diol is chosen from the diols of formula I in which n = 0 and m = l.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one diol of Formula (I) is chosen from the group consisting of 1,3-propanediol (R1 = R2 = H , n = l, m = 0), 1,3-butanediol (R1 = H, R2 = CHa, n = l, m = 0), 1,4-butanediol (R1 = R2 = H, n = 2 , m = 0), 2-methyl-1,3propanediol (R1 = H, R2 = CH3, n = 0, m = l) and their mixtures.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one diol of Formula (I) is chosen from the group consisting of 1,3-propanediol, 1,3- butanediol, and mixtures thereof.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one diol of Formula (I) is 1,3propanediol.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one diol of Formula (I) is 1,3butanediol.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one cannabinoid compound is chosen from the group consisting of tetrahydrocannabinols (THCs), and in particular delta-9 tetrahydrocannabidiols (A9 -THCs), and more particularly delta-9 tetrahydrocannabidiols form A (A9-THCA) and delta-9 tetrahydrocannabidiols form B (A9-THCB), and delta-8 tetrahydrocannabidiol (A8-THC), cannabidiols (CBDs) , and in particular delta-9 cannabidiols (A9-CBDs) and delta-8 cannabidiols (A8-CBDs), cannabigerols (CBGs), cannabichromenes (CBCs), cannabicyclols (CBLs), cannabielsoines (CBEAs), and cannabinodiols (CBNAs and CBNs), cannabitriols (CBTs), cannabinoids comprising a furan or chroman motif, and mixtures thereof.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one cannabinoid compound is chosen from the group consisting of tetrahydrocannabinols (THCs), and in particular delta-9 tetrahydrocannabidiols (A9 -THCs) and delta-8 tetrahydrocannabidiol (Δδ-THC), cannabidiols (CBDs), and in particular delta-9 cannabidiols (A9-CBDs) and delta-8 cannabidiols (Δδ-CBDs), and their mixtures .
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one cannabinoid compound is of plant and / or synthetic origin.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one cannabinoid compound is of plant origin.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one cannabinoid compound is provided by a plant extract, and in that the level of terpene compounds in said formulation is less than 5% by weight relative to the total weight of said vaporizable liquid formulation.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one cannabinoid compound is provided by a plant extract, and in that the level of undesirable lipid compounds in said formulation is less than 5% by weight relative to the total weight of said vaporizable liquid formulation.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one cannabinoid compound is provided by a plant extract, in that the level of terpene compounds in said formulation is less than 5 % by weight relative to the total weight of said vaporizable liquid formulation and in that the level of undesirable lipid compounds in said formulation is less than 10% by weight relative to the total weight of said liquid vaporizable formulation.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said vegetable extract is an extract of at least one vegetable oil.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said plant extract is an extract of at least one vegetable oil derived from cannabis sativa.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one cannabinoid compound is chosen from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), and their mixture .
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one cannabinoid compound is tetrahydrocannabinol (THC).
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said at least one cannabinoid compound is cannabidiol (CBD).
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it comprises between 0.5 mg / ml and 1000 mg / ml of said at least one cannabinoid compound.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it comprises at least 0.1 mg / ml of said at least one cannabinoid compound.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it comprises at least 0.1 mg / ml of said diol of Formula (I).
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said vaporization is carried out by a heat of between 10 ° C and 200 ° C.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said vaporization is carried out by a heat of between 30 ° C and 150 ° C.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that said vaporization is carried out by a heat of between 50 ° C and 90 ° C.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it further comprises at least one solvent chosen from the group consisting of glycerol, propylene glycol, ethanol, diglycerol , triglycerol, 1,2-butanediol (BDO), 1,2-pentanediol, 1,2-hexanediol, 1,2heptanediol, 1,2-octanediol and mixtures thereof.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it also comprises at least glycerol.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it also comprises at least glycerol at a content of between 1 and 40% by weight relative to the total weight of said formulation vaporizable liquid.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it also comprises at least glycerol at a content of between 15 and 25% by weight relative to the total weight of said formulation vaporizable liquid.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it comprises less than 5% by weight of terpene compounds relative to the total weight of said vaporizable liquid formulation.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it comprises less than 4% by weight of myrcene relative to the total weight of said liquid vaporizable formulation.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it comprises less than 4% by weight of carriophyllene relative to the total weight of said liquid vaporizable formulation.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it comprises less than 4% by weight of limonene relative to the total weight of said liquid vaporizable formulation.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it comprises less than 4% by weight of a-pinene relative to the total weight of said vaporizable liquid formulation.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it comprises less than 4% by weight of β-pinene relative to the total weight of said liquid vaporizable formulation.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that it comprises less than 10% by weight of undesirable lipid compounds relative to the total weight of said vaporizable liquid formulation.
    In one embodiment, the vaporizable liquid formulation according to the invention is characterized in that its saponification index (mg KOH / g) is less than 20.
    The invention also relates to the use of a vaporizable liquid formulation according to the invention in the field of medicine and / or pharmacy.
    The invention also relates to the use of a vaporizable liquid formulation according to the invention in the field of analgesia and pain.
    The invention also relates to the use of a vaporizable liquid formulation according to the invention in an e-cigarette.
    The invention also relates to a method for detoxifying an oil comprising at least one cannabinoid compound, comprising at least the following successive steps:
    step 1: bringing said oil into contact with at least one diol of formula (I); step 2: heating the mixture;
    step 3: phase separation;
    step 4: recovery of the heavy phase.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said at least one diol of Formula (I) is chosen from the group consisting of 1 , 3-propanediol, 2-methyl-1,3-propanediol, 1,3-butanediol, 1,4-butanediol, and mixtures thereof. In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said at least one diol of Formula (I) is chosen from the group consisting of 1 , 3-propanediol, 1,3-butanediol, and their mixtures.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said at least one diol of Formula (I) is 1,3-propanediol.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said at least one diol of Formula (I) is 1,3-butanediol.
    In one embodiment, the method for detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said at least one cannabinoid compound is chosen from the group consisting of tetrahydrocannabinols (THCs), and in particular delta-9 tetrahydrocannabidiols (Δ9THCs), and more particularly delta-9 tetrahydrocannabidiols form A (A9-THCA) and delta-9 tetrahydrocannabidiols form B (â9-THCB), and delta-δ tetrahydrocannabidiol ( THC), cannabidiols (CBDs), and in particular delta-9 cannabidiols (A9-CBDs) and delta-8 cannabidiols (Δδ-CBDs), cannabigérols (CBGs), cannabichromenes (CBCs), cannabicyclols (CBLs) ), cannabielsoines (CBEAs), and cannabinodiols (CBNAs and CBNs), cannabitriols (CBTs), cannabinoids comprising a furan or chroman motif, and mixtures thereof.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said at least one cannabinoid compound is chosen from the group consisting of tetrahydrocannabinols (THCs), and in particular delta-9 tetrahydrocannabidiols (Δ9THCs) and delta-8 tetrahydrocannabidiol (Δδ-THC), cannabidiols (CBDs), and in particular delta-9 cannabidiols (A9-CBDs) and delta-8 cannabidiols (Δδ -CBDs), and their mixtures.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said at least one cannabinoid compound is of plant and / or synthetic origin.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said at least one cannabinoid compound is of plant origin.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that the level of terpene compounds in said heavy phase is less than 5% by weight relative to the total weight of said heavy phase.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heavy phase comprises less than 4% by weight of myrcene relative to the total weight of said heavy phase.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heavy phase comprises less than 4% by weight of carriophyllene relative to the total weight of said heavy phase.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heavy phase comprises less than 4% by weight of limonene relative to the total weight of said heavy phase.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heavy phase comprises less than 4% by weight of a-pinene relative to the total weight of said heavy phase.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heavy phase comprises less than 4% by weight of β-pinene relative to the weight total of said heavy phase.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heavy phase comprises less than 10% by weight of undesirable lipid compounds relative to the weight total of said heavy phase.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that the level of undesirable lipid compounds, in said heavy phase is less than 5% by weight relative to the total weight of said heavy phase.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that the level of terpene compounds in said heavy phase is less than 5% by weight relative to the total weight of said heavy phase and in that the level of undesirable lipid compounds in said heavy phase is less than 10% by weight relative to the total weight of said heavy phase.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said oil is obtained from cannabis sativa.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said at least one cannabinoid compound is chosen from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), and their mixture.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said at least one cannabinoid compound is tetrahydrocannabinol (THC).
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said at least one cannabinoid compound is cannabidiol (CBD).
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heavy phase comprises between 0.5 mg / ml and 1000 mg / ml of said at minus a cannabinoid compound.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heavy phase comprises at least 0.1 mg / ml of said at least one cannabinoid compound .
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that the saponification index (mg KOH / g) of said heavy phase is less than 20.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heating step is carried out by heating at atmospheric pressure (760 mm Hg) of said mixing up to a temperature between 300 and 100 ° C and for a period of time between 10 and 600 minutes.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heating step is carried out by heating at atmospheric pressure (760 mm Hg) of said mixing up to a temperature between 300 and 100 ° C and for a period of time between 20 and 150 minutes.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heating step is carried out by heating at atmospheric pressure (760 mm Hg) of the mixing up to a temperature of 100 ° C. and for a period of time between 10 minutes and 600 minutes [000133] Method for detoxifying an oil according to the invention, characterized in that a step of cooling to room temperature is included between said steps 2 and 3.
    Method of detoxifying an oil according to the invention, characterized in that a step of cooling to room temperature (25 ° C) is included between said steps 2 and 3.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heating step is carried out by heating said mixture under vacuum to a temperature comprised between 300 and 100 ° C and for a period of time between 10 and 600 minutes.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heating step is carried out by heating under vacuum said mixture to a temperature of 100 ° C and for a period of time between 10 minutes and 600 minutes.
    In one embodiment, the method for detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heating step is carried out by heating said mixture under vacuum to a temperature of 100 ° C and for a period of time between 20 minutes and 150 minutes.
    Of course, the heating step, when carried out under vacuum, can be carried out at lower temperatures.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that the said phase separation step is carried out by means of centrifugation.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said centrifugation is carried out under the following conditions: between 60 and 60,000 revolutions per minute for a period of time between 1 minute and 120 minutes.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said centrifugation is carried out under the following conditions: 1000 revolutions per minute for 10 minutes.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said detoxification is a deterpenation and / or deiipidation.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said detoxification is a deterpenation.
    In one embodiment, ie the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said detoxification is deiipidation.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said oil is an oil derived from cannabis sativa.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that at least one of steps 1 or 2 is carried out with stirring and nitrogen flow constant.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heavy phase is a vaporizable liquid formulation.
    In one embodiment, the method of detoxifying an oil comprising at least one cannabinoid compound according to the invention is characterized in that said heavy phase is a vaporizable liquid formulation according to the invention.
    EXAMPLES
    Example 1: Preparation of a vaporizable liquid formulation according to the invention based on THC, CBD and 1,3-propanediol (PDO) [000149] In a glass mixer equipped with mechanical stirring, a refrigerant and a double heating jacket, we precisely mix:
    g 98% ethanol (supplied by the company Sigma-Aldrich);
    350 mg of Δ-9 THC (supplied by the company Sigma-Aldrich);
    350 mg of cannabidiol (supplied by the company Sigma-Aldrich).
    The mixture is brought to reflux with stirring for 30 minutes until the cannabinoids are completely dissolved. The solution obtained is then cooled to 35 ° C. 10 ml of 1,3-propanediol (PDO) (sold by the company DuPont Tate & Lyle under the reference Zemea®) are then added. The mixture is then brought to reflux for 30 minutes.
    The mixture is then cooled to a temperature of 40 ° C. The ethanol is then evaporated using a rotary evaporator at a temperature of 50 ° C. and under a vacuum of 120 mm of mercury. After complete elimination of the ethanol, the mixture is maintained at 40 ° C.
    0.1 g of menthol is then added with stirring (supplied by the company Sigma-Aldrich). This gives the vaporizable liquid formulation A.
    Example 2 Preparation of a vaporizable liquid formulation according to the invention based on a cannabis extract titrated in CBD, THC and 1,3-propanediol (PDO) [000152] In a glass mixer equipped with a mechanical agitation, of a refrigerant and of a double heating jacket, the following are precisely mixed:
    g 92% ethanoi (supplied by the company Sigma-Aldrich);
    ml of the Elixinol® extract (30 ml capacity, titrated to 100 mg of cannabidiol, sold by the company Elixinol);
    350 mg of Δ-9 THC (supplied by the company Sigma-Aldrich).
    The mixture is brought to reflux with stirring for 30 minutes until the cannabinoids are completely dissolved. The solution obtained is then cooled to 35 ° C. 10 ml of 1,3-propanediol (PDO) (sold by the company DuPont Tate & Lyle under the reference Zemea®) are then added. The mixture is then brought to reflux for 30 minutes.
    The mixture is then cooled to a temperature of 40 ° C. The ethanol is then evaporated using a rotary evaporator at a temperature of 50 ° C. and under a vacuum of 120 mm of mercury. After complete elimination of the ethanol, the mixture is maintained at 40 ° C. 0.1 g of menthol is then added with stirring (supplied by the company Sigma-Aldrich). This gives the vaporizable liquid formulation B.
    Example 3 Preparation of a vaporizable liquid formulation according to the invention based on THC, CBD, glycerol (VG) and 1,3-propanediol (PDO) [000154] The procedure is identical to Example 1 but replacing the 1,3propanediol (PDO) with a mixture of 1,3-propanediol (PDO) and glycerol (marketed by the company Oieon under the reference Glycerin 4810, grade Pharmacopoeias USP and PE), consisting of 80% by weight 1,3-propanediol (PDO) and 20% by weight of glycerol. This gives the vaporizable liquid formulation C.
    Example 4 Preparation of a vaporizable liquid formulation according to the invention based on THC, CBD and 1,3-butanediol (BDO) [000155] The procedure is identical to Example 1 but replacing ie 1, 3propanediol (PDO) with 1,3-butanediol (BDO) (sold by the company SigmaAldrich). This gives the vaporizable liquid formulation D.
    Example 5 Preparation of a vaporizable liquid formulation according to the invention based on a cannabis extract titrated in CBD, THC and 1,3-butanediol (BDO) [000156] The procedure is identical to the example 2 but by replacing 1,3propanediol (PDO) with 1,3-butanediol (BDO) (sold by the company SigmaAldrich). This gives the vaporizable liquid formulation E.
    Example 6 Preparation of a liquid vaporizable formulation according to the invention based on THC, CBD, glycerol (VG) and 1,3-butanediol (BDO) [000157] The procedure is identical to Example 3 but by replacing 1,3propanediol (PDO) with 1,3-butanediol (BDO) (glycerol marketed by the company Oléon under the reference Glycerine 4810, grade Pharmacopoeias USP and PE). Mixture consisting of 80% by weight of 1,3-butanediol (BDO) and 20% by weight of glycerol. This gives the vaporizable liquid formulation F.
    Example 7 Preparation of a vaporizable liquid formulation based on CBD, THC and propylene glycol (PG) (according to the prior art) [000158] The procedure is identical to Example 1 but replacing the 1, 3propanediol (PDO) with propylene glycol (sold by the company Sigma-Aldrich). This gives the vaporizable liquid formulation G.
    Example 8: Preparation of a vaporizable liquid formulation based on a cannabis extract titrated in CBD, THC and propylene glycol (PG) (according to the prior art) [000159] The procedure is identical to the example 2 but by replacing 1,3propanediol (PDO) with propylene glycol (marketed by the company Sigma-Aldrich). This gives the vaporizable liquid formulation H.
    Example 9: Preparation of a vaporizable liquid formulation based on THC, CBD, glycerol (VG) and propylene glycol (PG) (according to the prior art) [000160] The procedure is identical to Example 3 but by replacing 1,3propanediol (PDO) with a mixture of propylene glycol (glycerol marketed by the company Oléon under the reference Glycerin 4810, grade Pharmacopoeias USP and PE. PG / VG mixture consisting of 80% by weight of propylene glycol and 20% by weight of glycerol, thus obtaining the vaporizable liquid formulation I.
    The formulations are characterized in the following tables 2-4:
    Formulation AT B VS Solvent 1,3-propanediol(PDO) 1,3-propanediol(PDO) 1,3-propanediol(PDO) + VG * Solute CBD + THC CBD + THC extract CBD + THC Aspect** clear solution clear solution clear solution Viscosity cP ** 51.9 52.3 67.8 * 80% 1,3-PDO / 20% VG** at 20 ° C
    Table 2: Characterization of the vaporizable liquid formulations according to the invention A to C
    Formulation D E F Solvent 1,3-butanediol 1,3-butanediol 1,3-butanediol (BDO) (BDO) (BDO) + VG * Solute CBD + THC CBD + THC extract CBD + THC Aspect** clear solution clear solution clear solution Viscosity cP ** 132.1 132.3 148.1 * 80% 1,3-PDO / 20% VG ** at 20 ° C
    Table 3: Characterization of the vaporizable liquid formulations according to the invention D to F
    Formulation G H I Solvent PG PG PG + VG Solute CBD + THC CBD + THC extract CBD + THC Aspect** clear solution clear solution clear solution Viscosity cP ** 53.5 53.7 81.1 * 80% 1,3-PDO / 20% VG ** at 20 ° C
    Table 4: Characterization of the vaporizable liquid formulations according to the prior art G to I
    Example 10: Preparation of vaporizable liquid formulations based on a cannabis extract with a high CBD content (3% by weight) The procedure is as in the previous examples in order to prepare the formulations J, K, L, Μ, N and O (Tables 5 and 6). However, 0.52 g of a cannabis extract enriched with CBD (Elixinol® 3600 mg Hemp Oil Tincture Natural) is introduced. This extract consists of C8-C10 Triglycerides (MCT Oil, Medium Chain Triglycerides) is THC titrated at 3% by weight (3600 mg in 120 ml of MCT Oil).
    Formulation J K L Solvent PDO BDO PG Solute CBD extract Elixinol CBD extract Elixinol CBD extract Elixinol Aspect** clear solution clear solution clear solution Viscosity cP ** 52.7 134.1 54.1 * 80% 1,3-PDO / 20% VG ** at 20 ° C
    Table 5: Characterization of the formulations of the vaporizable liquid formulations according to the invention J to L
    Formulation M NOT O Solvent PDO + VG * BDO + VG * PG + VG * Solute CBD extract Elixinol CBD extract Elixinol CBD extract Elixinol Aspect** clear solution clear solution clear solution Viscosity cP ** 68.1 149.8 82.7 * 80% 1,3-PDO / 20% VG ** at 20 ° C
    Table 6: Characterization of the formulations of the vaporizable liquid formulations according to the invention M to O
    Example 11: Evaluation of the thermal stability and of the vaporization of the vaporizable liquid formulations comprising THC.
    The procedure is as in Example 1 in order to prepare vaporizable liquid formulations comprising THC at a concentration of 10 mg / ml.
    Said formulations are analyzed by thermogravimetric (ATG) and differential thermal (ATD) analyzes on a Q600 TA Instrument device.
    Thermogravimetric analysis is a method of thermal analysis in which changes in the physical and chemical properties of materials are measured as a function of temperature. ATG can provide information on physical phenomena, such as vaporization or combustion.
    Similarly, one can obtain information on chemical phenomena such as dehydration or decomposition. By differential thermal analysis (ATD), the study material and an inert reference undergo identical thermal cycles. During the analysis, the temperature difference between the sample and its reference is recorded. These temperature differences monitored as a function of time with respect to the inert reference, provide information on the thermal phenomena undergone by the sample, or exothermic or endothermic. ATD analysis gives by integration of the curve of
    Heat Flow the enthalpy values which are said to be endothermic when there is an absorption of energy, or exothermic when there is a release of energy in the form of heat. The endothermic character is linked to a change in state of the compound (eg vaporization) while the exothermic character is induced by decomposition reactions or intra and intermolecular chemical reactions.
    The Q600 thermogravimetric analyzer from TA INSTRUMENT was used to jointly determine the vaporization temperatures of the products, the enthalpy values and the rate of non-vaporized products at 350 ° C. The analysis conditions are as follows:
    - test portion: 50 mg
    - open crucible under air flow: 100 ml / min
    - heating ramp: 10 ° C / min
    - temperature range: 25 to 350 ° C (temperature conditions representative of normal use as well as measurement of an electronic cigarette).
    Between each analysis, the device is cleaned by heating to 600 ° C under air flow, to remove any trace of non-vaporized residue and deposited on the crucible, the balance arms or the walls of the oven.
    The results obtained are presented in Table 7 below:
    Formulation (3) ATDSpray temperature(° C) (1) ATD Processing temperature (° C) (2) ATG Residue not evaporated at 350 ° C (%) VG 260 ND 27.3 PG 174 ND ND 1,3-PDO 189 ND ND 1,3-BDO 171 ND ND THC 123 ND 0.02 PDO + THCIO mg / ml 109-115 ND ND BDO + THC 10 mg / ml 117-123 ND ND PG + THC 10 mg / ml 105-112 ND 0.31 20% GV + 80% PG + THC 10 mg / ml 162-209 301 0.71 20% GV + 80% PDO + THC 10 mg / ml 194 ND 0.01 20% GV + 80% BDO + THC 10 mg / ml 205 ND 0.02 (1) endothermic peak(2) exothermic peak (reaction and / or decomposition)(3) PG = propylene glycol (synthetic), GV = vegetable glycerol, PDO = 1,3-propanediol (PDO),BDO = 1,3-butanediol (BDO)
    Table 7: Analysis of the formulations by ATD-ATG [000170] The conclusions are presented below.
    Glycerol vaporizes at 260 ° C with 27.3% of formation of uncharacterized residues (which may be related to a thermal decomposition product).
    [000172] Propyiene glycol vaporizes at a temperature of 174 ° C without any thermal decomposition.
    1,3-Propanediol (PDO) vaporizes at a temperature of 189 ° C without any thermal decomposition.
    THC vaporizes at a temperature of 123 ° C, producing a residue after evaporation of 0.02%, possibly linked to the presence in THC of a non-vaporizable heavy impurity, present in very small quantities.
    In mixture, 1,3-propanediol (PDO) and THC vaporize simultaneously between 109 and 115 ° C (1 single vaporization peak observed in ATD) without giving rise to a decomposition and / or without reacting with each other .
    In mixture, the 1,3-butanediol (BDO) and THC vaporize simultaneously between 117 and 123 ° C (1 single vaporization peak observed in ATD) without giving rise to a decomposition and / or without reacting with each other .
    On the other hand, if propyiene glycol and THC vaporize simultaneously between 105 and 112 ° C (1 single vaporization peak observed in ATD), the mixture produces a relatively significant residue (0.31%), indicating a certain thermal instability of the mixture.
    1,3-Propanediol (PDO) and 1,3-butanediol (BDO) in mixture with THC, constitute thermally stable formulations, which vaporize without inter and intramolecular reaction, or production of non-vaporizable residue.
    [000179] Thus, the thermal stability of 1,3-propanediol (PDO) and of and 1,3-butanediol (BDO) as well as their absence of hot reaction with THC, demonstrate their interest in the formulation of cannabinoids intended for personal vaporizers.
    Relative to formulations containing glycerin, only the formulation 20% GV-80% PG + THC, leads to 2 distinct peaks of vaporization, corresponding on the one hand to the evaporation of THC and propyiene glycol and on the other hand glycerol. This reflects the non-perfectly homogeneous nature of said formulation. Similarly, only the 20% GV-80% PG + THC formulation leads to a relatively substantial residue (0.71% by weight), confirming the non-homogeneous and thermally unstable nature of said formulation. The 20% GV-40% PDO mixture leads to a co-vaporization of 1,3propanediol (PDO) and glycerol, which constitutes an advantage in terms of homogeneity of the aerosol produced by this mixture.
    In summary, in terms of thermal stability and homogeneity, the vaporizable liquid formulations comprising 1,3-propanediol (PDO) or 1,3 butanediol (BDO) and glycerol are stable and homogeneous and in fact, perfectly adapted to personal vaporizers, in order to guarantee their harmlessness under the conditions of use and measurement of these devices.
    Example 12: Evaluation of the vaporization of vaporizable liquid formulations based on THC.
    The vaporizable liquid formulations of Example 11 were subjected to an aerosolization / vaporization test as described in the French standard XP D-90-300-3 and relating to the dosages of the emissions emitted by the heated personal vaporizers containing nicotine liquids. This method makes it possible to determine whether a formulation is stable to vaporization (absence of formation of volatile toxic aldehydes) and to quantify the quantities of aerosols formed. The test is carried out by filling the vaporizer tank with 2.5 m! of formulation. The characteristics of the vaporizer used to generate the aerosols are as follows:
    - diameter: 16.6 mm;
    - length: 64 mm;
    - length (without Drid Tip): 44 mm;
    - pyrex tank capacity: 2.5 ml;
    - resistance: 1.5 Ohm;
    - resistance type: Dual Coil;
    - material: stainless steel;
    - heating power: 8 to 20 Watts (the power applied during the test was 9 Watts).
    The results obtained are summarized in Table 8 below:
    Formulation Volatile aldehydes (* ppm / 200puffs) Quantity of aerosol g / 200 puffs Formaldehy of Acetaldehy from Acroleiborn PDO + THC 10 mq / ml ND ND ND 1.190 BDO + THC 10 mq / ml ND ND ND 0.956 PG + THC 10 mg / ml ND ND ND 1,283 20% GV + 80% PG + THC 10 mq / ml ND ND ND 0.803 20% GV + 80% PDO + THC 10 mg / ml ND ND ND 0.832 20% GV + 80% BDO + THC 10 mq / ml ND ND ND 0.958 25% GV + 55% PDO + 20%CBD extract Elixinol® (1) ND ND ND 1,692 25% GV + 55% BDO + 20% CBD extract Elixinol® (l) ND ND ND 1,329 25% GV + 80% PG + 20% ExtractCBD Elixinol® (1) 17 26 12 1,492
    (1) The protocol of standard XP D-90-300-3 has been modified since the heating power applied has been fixed at 15 W.
    The conclusions are presented below.
    Formulations based on THC and 1,3-propanediol (PDO) (BDO) are highly aerosolizable / vaporizable since or of 1,3masses
    Table 8: Analysis of aerosols according to French standard XP D-90-300-3 [000184] [000185] butanediol of aerosols recovered after 200 puffs are important and significant.
    Formulations based on THC and 1,3-propanediol (PDO) butanediol (BDO) are thermally stable since no 1,3 or aldehyde resulting from the thermolysis of the supporting solvents is detected.
    Relative to formulations based on glycerol and a CBD extract (Exinol®), in terms of aerosolization / vaporization, the formulations based on 1,3 propanediol (PDO) or 1,3-butanediol ( BDO) or propylene glycol are aerosolizable in view of the very significant quantities of aerosol formed (> 1.3 g after 200 puffs). It is noted that the formulation based on 1,3-propanediol (PDO) induces more aerosol than those based on propylene and 1,3-butanediol (BDO).
    Formulations based on 1,3-propanediol (PDO) or 1,3-butanediol (BDO) do not lead to any formation of toxic volatile aldehydes, unlike that based on propylene glycol.
    Example 13: Preparation of a vaporizable liquid formulation based on THC, on CBD free of toxic or undesirable substances [000190] In this example, it was undertaken to produce a vaporizable liquid composition from a total extract sativa cannabis oil.
    In a glass mixer equipped with mechanical stirring, a refrigerant, a double heating jacket and a nitrogen inlet, the following ingredients are precisely mixed in order to prepare 30 g of solution:
    % by weight of refined hemp oil (supplied by the company Olvéa);
    1.0% by weight of Δ-9 THC (supplied by Sigma-Aldrich);
    1.0% by weight of CBD (supplied by Sigma-Aldrich);
    10.0% by weight of myrcene (supplied by Sigma-Aldrich);
    8.0% by weight of cariophyllene (supplied by Sigma-Aldrich);
    3.0% limonene (supplied by Sigma-Aldrich);
    3.0% β-pinene (supplied by Sigma-Aldrich).
    The mixture is first of all rendered inert by a very slight continuous flow of nitrogen (10 ml / minute) for 20 minutes. The mixture is then brought with stirring to a temperature of 80 ° C and thus maintained for 45 minutes.
    In a second step, the mixture is cooled to room temperature. This gives approximately 30 g of a CHl formulation. In an assembly identical to the previous one, 10 g of CH1 formulation are mixed, 10 g of 1,3-propanediol (PDO) (sold by the company DuPont Tate & Lyle under the reference Zemea®).
    With stirring and constant nitrogen flow, the mixture is then brought to the temperature of 100 ° C and maintained at this temperature for one hour.
    The mixture is then slowly cooled to room temperature.
    A two-phase solution is obtained which is then centrifuged at 1000 rpm. The two clarified phases are separated in a separating funnel. This gives the formulation CH2 which corresponds to the heavy phase.
    We then proceed to analyze the formulations according to the method described Romano & coll ("Cannabis Oil: chemical evaluation of an upcoming cannabis-based medicine", Luigi L Romano, Arno Hazekamp, Cannabinoids 2013; l (l): l-ll).
    The results are presented in table 9 below:
    Criterion / Formulation CH1 CH2 Appearance at 20 ° C Clear solution Clear solution Kinematic viscosity, Cp at 20 ° C 49.2 52.4 Saponification index, mq KOH / q 191.2 <1.0 THC content,% by weight 0.91 0.83 CBD content,% by weight 0.89 0.81 Myrcene content,% by weight 9.8 0.9 Carriophyllene content,% by weight 8.2 1.2 Limonene content,% by weight 2.9 0.3 Β-pinene content,% by weight 2z8 .................................................. ............... Q / 4
    Table 9: Analysis of the formulations CH1 and CH2 The process described leads to a formulation CH2 having the following characteristics:
    - The viscosity at 20 ° C of the CH2 formulation is relatively close to that of 1,3propanediol (PDO);
    - CH2 has a very low saponification index compared to the mother formulation CH1, demonstrating that it is free of undesirable lipid compounds;
    - CH2 is highly depleted in allergenic terpenes compared to the mother formulation CH1.
    These results demonstrate that 1,3-propanediol (PDO) makes it possible to obtain, from an oily extract of cannabis (non-aerosolizable), vaporizable liquid formulations containing similar proportions of cannabinoids and free of the molecules of concern. inhalation are terpene compounds and unwanted lipid compounds.
    权利要求:
    Claims (12)
    [1" id="c-fr-0001]
    1. Liquid vaporizable formulation comprising at least one cannabinoid compound and at least one diol chosen from the diols of Formula (I):
    R, - H /—— C -— A I —CH — ή / H -tCH 2 i — C --- R 2I ΛOH , CH 3 / * / n 1 "'n |OH1 ·· Formula (I)
    in which :
    R1 and R2 are identical or different, and are chosen from the group consisting of a hydrogen atom (-H) or an alkyl radical comprising from 1 to 2 carbon atoms;
    m + n = 1 or m + n = 2;
    n = 0 or n = 1 or n = 2;
    m = 0 or m = l;
    the diol being in the form of a mixture of isomers and / or of isolated isomer when it comprises one or more asymmetric carbon atoms.
    [2" id="c-fr-0002]
    2. liquid vaporizable formulation according to claim 1, characterized in that said at least one diol is chosen from diols of formula I in which the alkyl radical is chosen from the group consisting of methyl (-CH3) and ethyl (-CH2CH3) radicals ).
    [3" id="c-fr-0003]
    3. Liquid vaporizable formulation according to any one of the preceding claims, characterized in that said at least one diol of Formula (I) is chosen from the group consisting of 1,3-propanediol (Ri = R2 = H, n = l , m = 0), 1,3-butanediol (Ri = H, R2 = CH3, n = l, m = O), 1,4-butanediol (Ri = R2 = H, n = 2, m = 0 ), 2-methyl-1,3propanediol (Ri = H, R2 = CH3, n = 0, m = l), and mixtures thereof.
    [4" id="c-fr-0004]
    4. liquid vaporizable formulation according to any one of the preceding claims, characterized in that said at least one cannabinoid compound is chosen from the group consisting of tetrahydrocannabinols (THCs), and in particular delta-9 tetrahydrocannabidiols (A9-THCs), and more particularly delta-9 tetrahydrocannabidiols form A (A9-THCA) and delta-9 tetrahydrocannabidiols form B (A9-THCB), and delta-8 tetrahydrocannabidiol (A8-THC), cannabidiols (CBDs), and in particular delta-9 cannabidiols (A9-CBDs) and delta-8 cannabidiols (A8-CBDs), cannabigerols (CBGs), cannabichromenes (CBCs), cannabicyclols (CBLs), cannabielsoines (CBEAs), and cannabinodiols (CBNAs) and CBNs), cannabitriols (CBTs), cannabinoids comprising a furan or chroman motif, and mixtures thereof.
    [5" id="c-fr-0005]
    5. Liquid vaporizable formulation according to any one of the preceding claims, characterized in that said at least one cannabinoid compound is provided by a plant extract, and in that the level of terpene compounds in said formulation is less than 5% by weight relative to the total weight of said vaporizable liquid formulation.
    [6" id="c-fr-0006]
    6. liquid vaporizable formulation any one of the preceding claims, characterized in that said at least one cannabinoid compound is provided by a plant extract, and in that the level of undesirable lipid compounds, in said formulation is less than 5% by weight relative to the total weight of said vaporizable liquid formulation.
    [7" id="c-fr-0007]
    7. Method for detoxifying an oil comprising at least one cannabinoid compound, comprising at least the following successive steps:
    step 1: bringing said oil into contact with at least one diol chosen from the diols of Formula (I):
    R! - not -ch-4 Rz OHOH ï Formula (I)
    in which :
    R 1 and R 2 are identical or different, and are chosen from the group consisting of a hydrogen atom (-H) or an alkyl radical comprising from 1 to 2 carbon atoms;
    m + n = 1 or m + n = 2;
    n = 0 or n = 1 or n = 2;
    m = 0 or m = l;
    the diol being in the form of a mixture of isomers and / or of isolated isomer when it comprises one or more asymmetric carbon atoms;
    - step 2: heating the mixture;
    - step 3: phase separation;
    - step 4: recovery of the heavy phase.
    [8" id="c-fr-0008]
    8. A method of detoxifying an oil comprising at least one cannabinoid compound, according to claim 7, characterized in that said at least one diol of Formula (I) is chosen from the group consisting of 1,3-propanediol (Ri = R.2 = H, n = l, m = 0), 1,3-butanediol (Ri = H, R2 = CH3, n = l, m = 0), 1,4-butanediol (Ri = R2 = H, n = 2, m = 0), 2-methyl-1,3-propanediol (Ri = H, R2 = CH3, n = 0, m = l) and their mixtures.
    [9" id="c-fr-0009]
    9. A method of detoxifying an oil comprising at least one cannabinoid compound, according to any one of claims 7 to 8, characterized in that said heating step is carried out by heating at atmospheric pressure (760 mm Hg) of said mixture up to a temperature between 300 and 100 ° C and for a period of time between 10 and 600 minutes.
    [10" id="c-fr-0010]
    10. A method of detoxifying an oil comprising at least one cannabinoid compound, according to any one of claims 7 to 8, characterized in that said heating step is carried out by heating under vacuum said mixture to a temperature between 300 and 100 ° C and for a period of time between 10 minutes and 600 minutes.
    [11" id="c-fr-0011]
    11. A method of detoxifying an oil comprising at least one cannabinoid compound, according to any one of claims 7 to 10, characterized in that said phase separation step is carried out by means of centrifugation.
    [12" id="c-fr-0012]
    12. A method of detoxifying an oil comprising at least one cannabinoid compound, according to any one of claims 7 to 11, characterized in that said detoxification is a deterpenation and / or a delipidation.
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    同族专利:
    公开号 | 公开日
    FR3062303B1|2019-11-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    EP2207528A2|2007-10-05|2010-07-21|STI Pharmaceuticals Ltd.|Pharmaceutical composition|US11040932B2|2018-10-10|2021-06-22|Treehouse Biotech, Inc.|Synthesis of cannabigerol|
    US11084770B2|2016-12-07|2021-08-10|Treehouse Biotech, Inc.|Cannabis extracts|
    US11202771B2|2018-01-31|2021-12-21|Treehouse Biotech, Inc.|Hemp powder|
    FR3113563A1|2020-09-03|2022-03-04|Cids France|Use of plant phytocannabinoids extracted by distillation method for the manufacture of e-liquids|
    法律状态:
    2018-01-23| PLFP| Fee payment|Year of fee payment: 2 |
    2018-08-03| PLSC| Publication of the preliminary search report|Effective date: 20180803 |
    2019-02-28| PLFP| Fee payment|Year of fee payment: 3 |
    2019-09-13| TP| Transmission of property|Owner name: LABORATOIRES CERES, FR Effective date: 20190809 |
    2020-01-31| PLFP| Fee payment|Year of fee payment: 4 |
    2021-02-20| PLFP| Fee payment|Year of fee payment: 5 |
    2022-02-26| PLFP| Fee payment|Year of fee payment: 6 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1750853A|FR3062303B1|2017-02-01|2017-02-01|LIQUID VAPORIZABLE FORMULATION COMPRISING AT LEAST ONE DIOL AND AT LEAST ONE CANNABINOID COMPOUND|
    FR1750853|2017-02-01|FR1750853A| FR3062303B1|2017-02-01|2017-02-01|LIQUID VAPORIZABLE FORMULATION COMPRISING AT LEAST ONE DIOL AND AT LEAST ONE CANNABINOID COMPOUND|
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