Liquid composition containing a lipid-soluble organic compound, method for analyzing aerosolization rate, and method for producing the liquid composition.

Abstract

The present invention provides a liquid composition that is a PG-VG base containing a lipid-soluble organic compound, satisfying at least one of the following conditions: that the effects of the specific lipid-soluble organic compound can be fully enjoyed even when aerosolized, that liquid separation is unlikely to occur, and that crystallization is unlikely to occur. [Solution] A liquid composition is provided comprising propylene glycol, glycerin, a lipid-soluble organic compound, and a hydroxyl group-containing organic compound, wherein the lipid-soluble organic compound is a compound containing at least two oxygen atoms and at least one phenol structure, and having a molecular weight of 200 to 400, and the hydroxyl group-containing organic compound is a compound containing at least two oxygen atoms and at least one hydroxyl group, having a boiling point of 150°C or higher at room temperature and pressure, and a molecular weight of 80 or higher.

Description

[Technical Field]

[0001] The present invention relates to a liquid composition, a method for analyzing the aerosolization rate, and a method for producing a liquid composition. More specifically, the present invention relates to a liquid composition of a PG-VG base containing a lipid-soluble organic compound, a method for analyzing the aerosolization rate of a liquid composition containing a lipid-soluble organic compound, and a method for producing a liquid composition containing a lipid-soluble organic compound. [Background technology]

[0002] Propylene glycol (PG) and glycerin (VG) function as solubilizers, stabilizers, humectants, and aerosolizers. PG is also used as a preservative, while VG is used as a sweetener and thickener. They are used in many foods, beverages, cosmetics, pharmaceuticals, daily necessities, general merchandise, e-cigarettes, and other household products. Therefore, products containing these substances may be used for a variety of purposes.

[0003] On the other hand, lipid-soluble organic compounds that have phenolic or resorcinol structures as their moieties have been reported to exhibit various useful pharmacological activities. Cannabinoids are a prime example of this. Cannabinoids are a group of lipophilic, physiologically active substances mainly extracted from cannabis plants, and are known to exert psychoactive, analgesic, and anti-inflammatory effects by interacting with receptors in the brain and body.

[0004] Products that utilize PG-VG liquids, which use PG and VG as a base, include e-cigarette liquids. The use of e-cigarettes and vaporizers is attracting attention as a substitute for smoking cannabis, which has a long history. Therefore, in order to obtain the effects of the above-mentioned cannabinoids, cannabinoids are added to the liquids used in e-cigarette cartridges and volcano-type vaporizers, which generate vapor by heating the liquid to vaporize or aerosolize it.

[0005] Patent Document 1 discloses a vape liquid for e-cigarettes containing PG, VG, and cannabidiol. Non-Patent Document 1 describes that when a liquid containing tetrahydrocannabinol and β-myrcene is vaporized and the components collected by a filter are extracted and analyzed by HPLC and GC-MS, the decomposition of tetrahydrocannabinol, a type of cannabinoid, and the generation of VOCs are suppressed when the β-myrcene content in the liquid is high. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Japanese Patent Publication No. 2022-151489 [Non-patent literature]

[0007] [Non-Patent Document 1] RSC Advances, (English) 2021, Vol. 11, p.11714-11723 [Overview of the project] [Problems that the invention aims to solve]

[0008] Lipid-soluble organic compounds such as cannabinoids are lipid-soluble and therefore do not dissolve stably in glycerin. Consequently, crystallization and liquid separation have been problematic when using glycerin-containing bases. In the vape liquid described in Patent Document 1, the crystallization of cannabidiol was successfully suppressed by adding triacetin, which has emulsifying properties, but liquid separation was prone to occur, and there was room for improvement in dispersion stability. Therefore, a formulation and manufacturing method that allows cannabinoids to exhibit high dispersion stability when an appropriate amount of cannabinoid is included in a PG-VG base was desired. In particular, for bases that benefit from aerosolization, such as vape liquids, a formulation that maximizes both dispersion stability and aerosolization efficiency simultaneously is desired.

[0009] Therefore, the object of the present invention is to provide a liquid composition which is a PG-VG base containing a lipid-soluble organic compound that satisfies at least one of the following conditions: that the effects of a specific lipid-soluble organic compound can be fully enjoyed even when aerosolized, that liquid separation is unlikely to occur, and that crystallization is unlikely to occur.

[0010] Furthermore, because cannabinoids have a relatively high molecular weight, they are not very volatile, making it difficult to efficiently ingest the entire amount of cannabinoids in a liquid through vaporization inhalation. For example, while the label of e-cigarette or vaporization liquid products containing cannabinoids indicates the concentration of cannabinoids in the liquid, it was not possible to calculate the amount of cannabinoids ingested during vaporization inhalation from the concentration indicated on the label. In other words, the accurate amount of cannabinoids ingested cannot be determined without analyzing the amount of cannabinoids in the gas or aerosol produced when vaporization or aerosolization occurs, so more caution is needed when interpreting labels. In this specification, "aerosolization" is used as a concept that includes not only actual aerosolization but also vaporization, evaporation, and sublimation.

[0011] Non-patent document 1 confirms that the degradation of tetrahydrocannabinol is suppressed as the amount of β-myrcene increases, but it does not evaluate this in terms of cannabinoid aerosolization efficiency. Therefore, there has been a need for a more precise analytical and evaluation method for liquid compositions containing cannabinoids, using cannabinoid aerosolization efficiency as an indicator.

[0012] Therefore, another object of the present invention is to provide a method for more precisely analyzing and evaluating the aerosolization efficiency of lipid-soluble organic compounds in a liquid composition containing lipid-soluble organic compounds, as an indicator for evaluating the quality of the aerosolization liquid. [Means for solving the problem]

[0013] As a result of diligent research to achieve the above objective, the inventors have found that a specific liquid composition containing a lipid-soluble organic compound as a PG-VG base satisfies at least one of the following conditions: that the effects of the specific lipid-soluble organic compound can be fully enjoyed even after aerosolization, that liquid separation is unlikely to occur, and that crystallization is unlikely to occur. Furthermore, they have found that, by a specific method, the aerosolization efficiency of the lipid-soluble organic compound in a liquid composition containing the lipid-soluble organic compound can be analyzed and evaluated more precisely. The present invention was completed based on these findings.

[0014] In other words, the present invention comprises propylene glycol, glycerin, a lipid-soluble organic compound, and a hydroxyl group-containing organic compound. The above-mentioned lipid-soluble organic compound is a compound that contains at least two oxygen atoms and has at least one phenol structure, and has a molecular weight of 200 to 400. The above-mentioned hydroxyl group-containing organic compound is a liquid composition that contains at least two oxygen atoms and at least one hydroxyl group, has a boiling point of 150°C or higher at room temperature and pressure, and a molecular weight of 80 or higher.

[0015] The above hydroxyl group-containing organic compound is preferably a compound represented by the following formula (1). [ka] [In the formula, R 1 R indicates an organic group containing a hydrogen atom, a hydrocarbon group, or a heteroatom. 2 represents a hydrogen atom or a hydroxyl group, and X represents -O-, -OC(=O)-, -OC(=O)-O-, -NC(=O)-, -OC(=O)-O-, -C(=O)-O-, -C(=O)-N-, or -C(=O)-. The above organic group may bond to the carbon atoms constituting the cyclohexane ring to which X is bonded, thereby forming a ring, so that formula (1) may have a spiro structure. In addition, the carbon atoms constituting the cyclohexane ring to which X is bonded may have other substituents. Y represents a carbon atom or an oxygen atom, and a double line including a dashed line indicates a single bond or a double bond, and in the case of a double bond, R2 does not have.]

[0016] The above fat-soluble organic compound is preferably a cannabinoid.

[0017] The above hydroxy group-containing organic compound is preferably a compound containing two hydroxy groups.

[0018] The above hydroxy group-containing organic compound is preferably at least one selected from the group consisting of 3-(menthyloxy)propane-1,2-diol and p-menthane-3,8-diol.

[0019] The above liquid composition may further contain one or more selected from the group consisting of alcohol, plant extract, fragrance, and stabilizer.

[0020] In addition, the present invention provides a liquid composition containing a fat-soluble organic compound, which contains at least two oxygen atoms and has at least one phenol structure and has a molecular weight of 200 or more and 400 or less. The liquid composition is heated and / or depressurized to generate an aerosol. The above aerosol is collected and subjected to chromatographic analysis to quantitatively analyze the amount of the above fat-soluble organic compound in the above aerosol, and the aerosolization rate of the above fat-soluble organic compound in the above liquid composition is analyzed from the concentration of the above fat-soluble organic compound in the above liquid composition and the concentration of the above fat-soluble organic compound in the above aerosol. An aerosolization rate analysis method is provided.

[0021] In the above aerosolization rate analysis method, it is preferable that the value obtained by multiplying the concentration of the above fat-soluble organic compound in the above aerosol by 100 with respect to the concentration of the above fat-soluble organic compound in the above liquid composition is defined as the aerosolization rate.

[0022] The above fat-soluble organic compound is preferably a cannabinoid.

[0023] The above depressurization and / or heating is preferably performed by a smoking device and / or a suction machine.

[0024] Furthermore, the present invention provides a quality confirmation method for confirming the quality of the liquid composition by the above-mentioned aerosolization rate analysis method and diffusivity evaluation and / or crystallinity evaluation.

[0025] Furthermore, the present invention provides a storage stability evaluation method that evaluates the aerosolization stability of the lipid-soluble organic compound from the first time point to the second time point by analyzing the aerosolization rate (1) of the liquid composition at a first time point and the aerosolization rate (2) of the liquid composition at a second time point which is later in the time series than the first time point, using the aerosolization rate analysis method described above, and comparing the aerosolization rate (1) and the aerosolization rate (2).

[0026] Furthermore, the present invention is a method for producing a liquid composition containing the above-mentioned lipid-soluble organic compound. The present invention provides a method for producing a liquid composition containing a lipid-soluble organic compound, comprising analyzing the aerosolization rate of the lipid-soluble organic compound in the liquid composition using the aerosolization rate analysis method described above to confirm the quality of the liquid composition.

[0027] Furthermore, the present invention provides a method for producing a liquid composition containing a lipid-soluble organic compound, comprising: analyzing the aerosolization rate of the lipid-soluble organic compound in an nth candidate liquid composition (where n is an integer of 1 or more) containing the lipid-soluble organic compound using the aerosolization rate analysis method described above; selecting the nth candidate liquid composition if the aerosolization rate in the nth candidate is a desired value; preparing an (n+1)th candidate liquid composition containing the lipid-soluble organic compound based on the aerosolization rate if the aerosolization rate in the nth candidate is not a desired value; analyzing the aerosolization rate of the lipid-soluble organic compound in the (n+1)th candidate liquid composition using the aerosolization rate analysis method described above; and selecting the (n+1)th candidate liquid composition if the aerosolization rate in the (n+1)th candidate is a desired value. [Effects of the Invention]

[0028] The liquid composition of the present invention is a PG-VG base containing a lipid-soluble organic compound with excellent dispersion stability. According to the liquid composition of the present invention, the effects of the lipid-soluble organic compound can be fully enjoyed in many product forms, such as food, cosmetics, pharmaceuticals, and aerosolized products, due to high dispersibility, high solubility, and high aerosolization efficiency. Furthermore, it exhibits excellent stability, being less prone to liquid separation and crystallization. In addition, the aerosolization rate analysis method of the present invention allows for more precise analysis and evaluation of the aerosolization efficiency of the lipid-soluble organic compound in a liquid composition containing the lipid-soluble organic compound, serving as an indicator for evaluating the quality of the aerosolized liquid. Therefore, by subjecting various formulations with modified liquid composition compositions to the above aerosolization rate analysis method, liquid compositions (e.g., e-cigarette liquids) with appropriately adjusted aerosolization rates of the lipid-soluble organic compound can be efficiently manufactured.

[0029] In this specification, the qualitative term for the efficiency of aerosolization is "aerosolization efficiency," while the term for the specific percentage of a lipid-soluble compound that is aerosolized is "aerosolization rate." [Brief explanation of the drawing]

[0030] [Figure 1] This shows one embodiment of the flow chart for the analytical method of the present invention. [Figure 2] This shows a side view of one embodiment of the apparatus for performing the analytical method of the present invention. [Figure 3] This is a three-dimensional graph showing the Hansen solubility parameters of various compounds. [Figure 4] This is a photograph of the liquid composition of Comparative Example 5. [Figure 5] These are photographs of the liquid compositions of Example 12 (left) and Example 13 (right). [Modes for carrying out the invention]

[0031] [Liquid composition] The liquid composition of the present invention comprises at least propylene glycol, glycerin (glycerol), a lipid-soluble organic compound, and a hydroxyl group-containing organic compound. The above liquid composition is liquid at least at room temperature (25°C) and atmospheric pressure.

[0032] The above-mentioned lipid-soluble organic compound is a compound that contains at least two oxygen atoms and has at least one phenol structure, and has a molecular weight of 200 to 400. The above-mentioned phenol structure is a structure having a hydroxyl group on a carbon atom constituting a benzene ring, and for example, a resorcinol structure is also included. The above-mentioned liquid composition may contain only one of the above-mentioned lipid-soluble organic compounds, or it may contain two or more.

[0033] The number of oxygen atoms in the above-mentioned lipid-soluble organic compound is 1 or more, preferably 2 or more. Furthermore, it is preferable that each of the above-mentioned oxygen atoms is either the oxygen of a hydroxyl group or the oxygen directly bonded to a benzene ring.

[0034] The above-mentioned lipid-soluble organic compound preferably has one or more hydroxyl groups, and more preferably two or more. When there are two or more hydroxyl groups, liquid separation (phase separation) is less likely to occur in the liquid composition even when the lipid-soluble organic compound is at a high concentration (e.g., 30% by mass or more).

[0035] The number of benzene rings in the above-mentioned lipid-soluble organic compound is preferably 1 to 2, and more preferably 1 from the viewpoint of making liquid separation (phase separation) less likely to occur.

[0036] Among the above-mentioned lipid-soluble organic compounds, compounds having a phenol structure are preferred, from the viewpoint that even when the lipid-soluble organic compound is at a high concentration (e.g., 30% by mass or more), liquid separation (phase separation) is unlikely to occur in the liquid composition, and pharmacological effects can be expected. Compounds having a structure in which two hydroxyl groups are directly bonded to a benzene ring (e.g., a resorcinol structure), or compounds having two phenol structures, are particularly preferred.

[0037] Cannabinoids are preferred as the lipid-soluble organic compounds mentioned above. Examples of cannabinoids include cannabidiol (CBD), cannabidivarin (CBDV), cannabigerol (CBG), cannabinol (CBN), tetrahydrocannabinol (THC), hydroxyhexahydrocannabinol (HHC), tetrahydrocannabivarin (THCV), cannabichromene (CBC), and cannabidiolic acid (CBDA). Among these, cannabinoids having a resorcinol structure, such as CBD and CBG, are preferred, with CBD being particularly preferred. Furthermore, the cannabinoids may be derived from cannabis (phytocannabinoids) or synthetically derived cannabinoids.

[0038] The above-mentioned hydroxyl group-containing organic compound is a compound that contains at least two oxygen atoms and at least one hydroxyl group, has a boiling point of 150°C or higher at room temperature and pressure, and a molecular weight of 80 or higher. The above-mentioned liquid composition may contain only one of the above-mentioned hydroxyl group-containing organic compounds, or it may contain two or more of them. Furthermore, the above-mentioned hydroxyl group-containing organic compound may have a cooling effect, i.e., it may be a cooling agent. The above-mentioned hydroxyl group-containing organic compound is a different compound from the lipid-soluble organic compound that is formulated together with it.

[0039] The above hydroxyl group-containing organic compound has at least one hydroxyl group. The number of hydroxyl groups is preferably 1 to 3, more preferably 1 or 2, and even more preferably 2.

[0040] The boiling point of the above hydroxyl group-containing organic compound at room temperature and pressure is 150°C or higher (for example, 150 to 400°C), preferably 200°C or higher (for example, 200 to 400°C). Furthermore, it is preferable that the boiling point is lower than that of the lipid-soluble organic compound that is blended together. The boiling point is preferably 400°C or lower. Furthermore, the molecular weight of the above hydroxyl group-containing organic compound is 80 or higher (for example, 80 to 350), preferably 100 or higher (for example, 100 to 350). Furthermore, it is preferable that the molecular weight is lower than that of the lipid-soluble organic compound that is blended together.

[0041] Specifically, the hydroxy group-containing organic compound is preferably a compound represented by the following formula (1). The liquid composition may contain only one kind of the compound represented by the formula (1), or may contain two or more kinds thereof.

[0042] [Chemical formula] [In the formula, R 1 represents a hydrogen atom, a hydrocarbon group, or an organic group containing a hetero element (for example, an oxygen atom or a nitrogen atom). The organic group containing the hetero element is more preferably an organic group having a hydroxy group or an organic group having a carboxy group. R 2 represents a hydrogen atom or a hydroxy group, and X represents -O-, -O-C(=O)-, -N-C(=O)-, -O-C(=O)-O-, -C(=O)-O-, -C(=O)-N-, or -C(=O)-. The above organic group may form a ring by bonding to a carbon atom constituting the cyclohexane ring to which X is bonded, so that the formula (1) may have a spiro structure. Further, the carbon atom constituting the cyclohexane ring to which X is bonded may have another substituent. Y represents a carbon atom or an oxygen atom, and the double line including a broken line represents a single bond or a double bond. In the case of a double bond, R 2 is not present.]

[0043] In the above formula (1), at least one hydroxy group is included in either R 1 or R 2 . More preferably, either or both of R 1 and R 2 include two hydroxy groups in total.

[0044] As the ring that the above organic group may form by bonding to a carbon atom constituting the cyclohexane ring to which X is bonded, a hetero ring containing an oxygen atom is preferable, and a hetero ring composed of an oxygen atom and a carbon atom is more preferable. The above ring is preferably a 5-membered ring or a 6-membered ring. Specifically, the above ring includes a cyclic acetal structure.

[0045] The above hydroxyl group-containing organic compound preferably has a hydrogen bonding term in the Hansen solubility parameter that is between the hydrogen bonding term of propylene glycol and the hydrogen bonding term of the above lipophilic organic compound. Furthermore, the above hydroxyl group-containing organic compound preferably has a polarization term in the Hansen solubility parameter that is between the polarization term of propylene glycol and the polarization term of the above lipophilic organic compound. In these cases (especially the closer the value is to the midpoint between the values ​​of the lipophilic organic compound and propylene glycol, theoretically), liquid separation of the liquid composition is less likely to occur, and dispersion stability is superior. The range of the above hydrogen bonding term of the above hydroxyl group-containing organic compound depends on the type of above lipophilic organic compound that is blended, but is preferably 6 to 21. Furthermore, the range of the above polarization term of the above hydroxyl group-containing organic compound depends on the type of above lipophilic organic compound that is blended, but is preferably 2 to 10. Furthermore, the above hydroxyl group-containing organic compound preferably has a dispersion term in the Hansen solubility parameter that is between 15 and 18. More preferably, the hydrogen bonding term of the hydroxyl group-containing organic compound is 9.0 or higher (more preferably 9.5 or higher), or the polarization term of the hydroxyl group-containing organic compound is 4.5 or higher (more preferably 5.0 or higher), and the dispersion term of the hydroxyl group-containing organic compound is in the range of 15 to 18. The Hansen solubility parameters are values ​​calculated under conditions of 25°C. Furthermore, if the liquid composition contains two or more of the lipid-soluble organic compounds, each term in the Hansen solubility parameters of the lipid-soluble organic compounds is calculated as a value for the mixture. Furthermore, if the liquid composition contains two or more of the hydroxyl group-containing organic compounds, each term in the Hansen solubility parameters of the hydroxyl group-containing organic compounds is calculated as a value for the mixture.

[0046] Examples of compounds represented by the above formula (1) include compounds represented by the following formula. [ka]

[0047] Among the compounds represented by formula (1) above, compounds containing two hydroxyl groups (compounds containing two hydroxyl groups whose boiling point at room temperature and pressure satisfies the above range) are preferred from the viewpoint of being less prone to liquid separation and crystallization, and at least one selected from the group consisting of 3-(menthyloxy)propane-1,2-diol and p-menthane-3,8-diol is more preferred. These compounds are a concept that includes enantiomers. Furthermore, these compounds may be racemic.

[0048] The mass ratio of propylene glycol to glycerin (PG ratio) [PG / (PG+VG)] is preferably 0.5 or higher (e.g., 0.5 to 0.99), and more preferably 0.55 or higher (e.g., 0.55 to 0.99), from the viewpoint of improving the dispersibility, diffusion, and aerosolization efficiency of the above-mentioned lipid-soluble organic compound. The above-mentioned PG ratio may be 0.9 or lower, 0.85 or lower, or 0.8 or lower. When the mass% concentration of the above-mentioned lipid-soluble organic compound is 4.7% or higher and less than 9.6%, and the mass% concentration of the above-mentioned hydroxyl group-containing organic compound is 3.2% or lower, or when the mass% concentration of the above-mentioned lipid-soluble organic compound is 9.6% or higher and the mass% concentration of the above-mentioned hydroxyl group-containing organic compound is 5.3% or lower, it is preferable that the above-mentioned PG ratio is within the above range. However, the above-mentioned PG ratio may be less than 0.5. If the mass percentage concentration of the above-mentioned lipid-soluble organic compound is less than 4.7%, or the mass percentage concentration of the above-mentioned hydroxyl group-containing organic compound is greater than 5.3%, or if the mass percentage concentration of the lipid-soluble organic compound is 4.7% or more and less than 9.6%, and the mass percentage concentration of the above-mentioned hydroxyl group-containing organic compound is within the range of 3.2% to 5.3%, then the above-mentioned PG ratio may be less than 0.5. Note that, regarding the mass percentage concentration of the above-mentioned hydroxyl group-containing organic compound, if the above-mentioned liquid composition contains menthol, the concentration of the above-mentioned hydroxyl group-containing organic compound includes the mass percentage of menthol.

[0049] From the viewpoint of improving the dispersibility, diffusion, and aerosolization efficiency of the lipid-soluble organic compound, the content ratio of the hydroxyl group-containing organic compound in the above liquid composition is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and even more preferably 1% by mass or more, based on 100% by mass of the total amount of the liquid composition. The above content ratio may be, for example, 50% by mass or less, 40% by mass or less, 30% by mass or less, or 20% by mass or less. Furthermore, if menthol is included, it is preferable that the combined content ratio of the hydroxyl group-containing organic compound and menthol is within the above range.

[0050] The total proportion of PG and VG in the above liquid composition is preferably 40% by mass or more, more preferably 50% by mass or more, even more preferably 60% by mass or more, and particularly preferably 70% by mass or more, based on 100% by mass of the total amount of the liquid composition, from the viewpoint of improving the dispersibility, diffusion, and aerosolization efficiency of the above lipid-soluble organic compound. The above content is, for example, 99% by mass or less.

[0051] From the viewpoint of improving the dispersibility, diffusion, and aerosolization efficiency of the lipid-soluble organic compounds in the above liquid composition, the total proportion of the lipid-soluble organic compounds is preferably 40% by mass or less, more preferably 25% by mass or less, and even more preferably 15% by mass or less, based on 100% by mass of the total amount of the liquid composition. The above content is, for example, 0.1% by mass or more.

[0052] The liquid composition of the present invention may further contain alcohol, plant extracts, fragrances, stabilizers, and the like.

[0053] Examples of the above alcohols include ethanol, n-propanol, i-propanol, n-butanol, t-butanol, i-butylene glycol, glycerin, and other C2-C6 alcohols, but ethanol is preferred. Only one type of alcohol may be used, or two or more types may be used. The total proportion of alcohols in the above liquid composition may be, for example, 0 to 20% by mass or 0.1 to 10% by mass, based on 100% by mass of the total amount of the liquid composition, from the viewpoint of further suppressing liquid separation and crystallization.

[0054] Examples of the above fragrances include fragrance molecules such as menthol and terpenes, fragrance extracts from various plants and fruits such as peppermint and spearmint oil, and essential oils or components contained in essential oils. The above fragrances can contribute to the suppression of crystallization and improvement of dispersibility and diffusion of the above liquid composition. Only one type of fragrance may be used, or two or more types may be used. The total proportion of fragrances (especially essential oils) in the above liquid composition may be 20% by mass or less (for example, 0 to 20% by mass), 10% by mass or less, 7% by mass or less, or less than 5% by mass, based on 100% by mass of the total amount of the above liquid composition. Too much essential oil may promote liquid separation, and if the proportion of essential oil is less than 5% by mass, liquid separation (phase separation) is less likely to occur in the liquid composition even if the above lipid-soluble organic compound is at a high concentration (for example, 30% by mass or more). The above total proportion may be 0.1% by mass or more.

[0055] Furthermore, the total proportion of alcohol (especially ethanol) and fragrance (especially essential oil) in the above liquid composition may be 0 to 20% by mass or 0.1 to 10% by mass, based on 100% by mass of the total amount of the above liquid composition.

[0056] Examples of the above-mentioned stabilizers include antioxidants, degradation inhibitors, light stabilizers, UV absorbers, discoloration inhibitors, and dispersion stabilizers. These stabilizers are components that stabilize the quality of the above-mentioned liquid composition. For example, they prevent and stabilize the decomposition and degradation (reaction) of lipid-soluble organic compounds (such as cannabinoids), or stabilize the dispersion of lipid-soluble organic compounds on the base. They are sometimes referred to as preservatives. Examples of the above-mentioned antioxidants include vitamins, such as vitamin A, vitamin B, vitamin C, and vitamin E. One type of stabilizer may be used, or two or more types may be used.

[0057] The above liquid composition may contain triacetin. Triacetin can act as a dispersion stabilizer and crystallization inhibitor. Adding too much triacetin may promote liquid separation, but adding a small amount has the effect of making it easier for oils such as essential oils and lipid-soluble organic compounds to disperse in the PG-VG liquid. The preferred content of triacetin is more than 0% by mass and 10% by mass or less, based on 100% by mass of the total amount of the above liquid composition.

[0058] The above liquid composition may contain other components besides those described above. Examples of these other components include solvents other than PG and VG, and flavoring agents. The above liquid composition may also contain components that can form an aerosol when heated and / or reduced in pressure. Examples of these components include known or commonly used components that can be formulated as e-cigarette liquids, such as aerosol-forming components, oils (vegetable oils, MCT oil, etc.), and other active ingredients. The above other components may consist of only one type or two or more types. Note that "reduced pressure" refers to a decrease in pressure, which occurs, for example, through inhalation or suction.

[0059] The uses of the above liquid composition are not particularly limited and include, for example, e-cigarette (vaping) liquids, topical pharmaceutical compounds, anhydrous cosmetics such as lip balms and lip balms, gels and treatments for oral care, flavor extracts for food and beverages, pet care products, and personal lubricants. Furthermore, uses of the above liquid composition containing water include topical pharmaceuticals such as creams and ointments; cosmetics such as foundations, lotions and creams; hair care products such as shampoos, conditioners and hair styling products; oral care products such as toothpaste and mouthwash; processed foods, baked goods and beverages; pet care products such as shampoos, conditioners and grooming products for pets; and cleaning products such as household detergents and cleaning agents.

[0060] The above-mentioned hydroxyl group-containing organic compound promotes the dispersion and diffusion of the above-mentioned lipid-soluble organic compound into the PG-VG liquid. Therefore, the liquid composition of the present invention has high dispersibility, high solubility, and high aerosolization efficiency. Thus, the liquid composition of the present invention, through these effects, can fully enjoy the effects of lipid-soluble organic compounds in many product forms such as food, cosmetics, pharmaceuticals, and aerosolized products. Furthermore, it is less prone to liquid separation and crystallization, and has excellent stability. Moreover, by increasing the proportion of the above-mentioned hydroxyl group-containing organic compound, the above-mentioned lipid-soluble organic compound can be stably dispersed and dissolved even in PG-VG liquid with an even higher proportion of glycerin, suppressing crystallization and liquid separation, and producing a liquid composition with high aerosolization efficiency.

[0061] According to the liquid composition of the present invention, when a PG-VG base containing the above-mentioned lipid-soluble organic compound is added, the effects of the specific lipid-soluble organic compound can be fully enjoyed even when aerosolized, liquid separation is less likely to occur, and crystallization is less likely to occur. Therefore, even when stabilizers are added "additionally," the resulting liquid may have higher crystallinity and diffusivity compared to when the same stabilizer is added to a liquid composition that does not contain the above-mentioned lipid-soluble organic compound.

[0062] [Method for analyzing aerosolization rate] The present invention's method for analyzing the aerosolization rate (sometimes simply referred to as "the present invention's analysis method") involves heating and / or reducing the pressure of a liquid composition containing the above-mentioned lipid-soluble organic compound to generate an aerosol, collecting the aerosol and subjecting it to chromatographic analysis to quantitatively analyze the amount of the lipid-soluble organic compound in the aerosol, and analyzing the aerosolization rate of the lipid-soluble organic compound in the liquid composition from the concentration of the lipid-soluble organic compound in the liquid composition and the concentration of the lipid-soluble organic compound in the aerosol. Specifically, the aerosolization rate can be obtained by calculating the concentration of the lipid-soluble organic compound in the aerosol (vapor concentration) by using the amount of liquid consumed by aerosolization as the denominator and the amount of the lipid-soluble organic compound detected in the collected aerosol as the numerator, and then determining the ratio of the vapor concentration to the previously quantified concentration of the lipid-soluble organic compound in the liquid composition.

[0063] The lipid-soluble organic compounds targeted for aerosolization in the analytical method of the present invention are substances that are difficult to vaporize in the atmosphere. Compounds whose boiling point is difficult to measure directly have high boiling points and are not stable at high temperatures, so combustion or decomposition is likely to occur before they reach their boiling point. Therefore, it is important to analyze the aerosolization rate. On the other hand, if a component vaporizes stably at a certain temperature, it will basically vaporize with high efficiency if the temperature is controlled, so the idea of ​​calculating the aerosolization rate is not easily considered.

[0064] Furthermore, in the analytical method of the present invention, for components that are not thermally stable at high boiling points, such as cannabinoids, it is preferable to use a method that utilizes "reduced pressure" to aerosolize at low temperatures, rather than using methods that utilize "airflow" or "pressure" without "reduced pressure" as an aerosolization method, however, the aerosolization method is not particularly limited.

[0065] The following describes a typical embodiment where the above-mentioned lipid-soluble organic compound is a cannabinoid.

[0066] The above chromatographic analysis is preferably performed by liquid chromatography or gas chromatography, with liquid chromatography being more preferable due to the low thermal stability and high boiling points of some cannabinoids. The detector is not particularly limited, but MS, UV-Vis (DAD, PDA), RI, FID, etc. are preferred, and they may be coupled together as MS / MS, etc.

[0067] Figure 1 shows one embodiment of the flow of the analytical method of the present invention. As shown in Figure 1, first, a liquid composition containing cannabinoids (sometimes simply referred to as "liquid composition") is prepared for aerosolization (preparation S1). The above preparation is carried out by filling a container that can be heated and / or reduced in pressure (inhaled), such as an e-cigarette pod, with the liquid composition, and as shown in Figure 2, a side view of one embodiment of the apparatus for performing the analytical method of the present invention, the apparatus is assembled.

[0068] After the preliminary preparation S1, the above liquid composition is heated and / or subjected to reduced pressure (suction) to generate an aerosol (aerosol generation S2), and the generated aerosol is collected by a filter interposed in the path through which the aerosol flows (aerosol collection S3). For example, aerosol generation S2 and aerosol collection S3 can be performed using the apparatus 1 shown in Figure 2.

[0069] The apparatus 1 shown in Figure 2 comprises a vape device 2, a filter gauge 3, and an automatic smoking machine 4. The suction port of the vape device 2 and the insertion port of the filter gauge 3 are connected via a hose or tube. The exhaust port of the filter gauge 3 and the intake port of the automatic smoking machine 4 are also connected via a hose or tube. Alternatively, another trap (e.g., a liquid trap) may be interposed between the exhaust port of the filter gauge 3 and the intake port of the automatic smoking machine 4 to recover any excess solvent that could not be trapped by the filter gauge 3.

[0070] A commercially available e-cigarette vape device can be used as the vape device 2. Aerosol generation S2 is performed inside the vape device 2. Specifically, the liquid composition is filled into the pod portion of the vape device 2, the liquid composition is heated using the heating means of the vape device 2, and the pressure is reduced using the suction means of the automatic smoking machine to generate an aerosol containing cannabinoids.

[0071] Heating and / or depressurization may be performed individually or in combination. Furthermore, heating and / or depressurization are preferably performed by a smoking device and / or a suction machine, respectively, and as described above, device 1 can perform both. With a smoking device and / or a suction machine, puffs (suction) can be performed continuously at a constant volume and rhythm, and by operating for 5 or more puffs and taking the average, accuracy and high reproducibility can be ensured. The "smoking device" is equipped with a heating device and may also be equipped with a mechanism for blowing air or pressurizing. The "suction machine (automatic smoking machine)" is equipped with a depressurization (pump) and a suction device for a constant volume.

[0072] From the viewpoint of preventing the decomposition or combustion of cannabinoids, the heating conditions for the above liquid composition are preferably such that the maximum heating temperature is 300°C or less, preferably 250°C or less, by combining reduced pressure or the aerosolizing properties of the solvent with heating. Furthermore, from the viewpoint of wanting the aerosolization rate to be close to that during actual use, the heating conditions for the above liquid composition are preferably similar to those used when using an e-cigarette.

[0073] Aerosols generated in the vape device 2 are transported through the hose or tube from the inlet into the filter gauge 3. The filter gauge 3 has a structure in which a sheet-like collection filter is installed inside the gauge, and the aerosols transported into the filter gauge 3 are trapped by the collection filter. If the cannabinoid concentration in the liquid composition is high and the amount that can be collected is saturated, it is possible to connect filters and combine the extracts from each. The gas phase, excluding the aerosols removed by the collection filter, is transported through the hose or tube from the exhaust port of the filter gauge 3 into the automatic smoking machine 4. The gas phase transported into the automatic smoking machine 4 is discharged to the outside as outgassing (OG) through the exhaust port. The automatic smoking machine 4 is equipped with a suction unit (pressure reduction unit) and a suction volume adjustment unit, and by adjusting the suction conditions (puff volume, number of puffs, puff interval, etc.), the aerosols generated in the vape device 2 can be transported into the collection filter 3, then into the automatic smoking machine 4, and then the gas phase can be discharged to the outside through the exhaust port. Examples of known or conventional filters can be used as the collection filter. For example, glass fiber filters can be used. Commercially available automatic smoking machines 4 can be used.

[0074] Aerosol collection should ideally begin when the cannabinoid concentration in each aerosol transported from the vape device 2 has stabilized, and end within the range where the cannabinoid concentration remains stable. For this reason, for example, collection may begin after discarding several aerosols without collecting them from the start of transport.

[0075] The puff volume is preferably 10 to 100 mL (preferably 20 to 90 mL) per puff, and the puff time is preferably 1 to 5 seconds. The number of puffs is preferably 3 to 50, more preferably 5 to 30. The interval between puffs is preferably 1 to 90 seconds, more preferably 3 to 60 seconds. Assuming that the concentration of cannabinoids in the liquid composition is several tens of percent or less, within this range of conditions, by adjusting the puff volume and number of puffs, a sufficient amount of aerosol for analysis can be efficiently and reproducibly collected on the collection filter, and cannabinoids in the aerosol can be collected without deficiency (with minimal loss). For example, in the case of using an e-cigarette, by applying the above range of conditions using a glass fiber filter (DP-70 manufactured by ADVANTEC, with a retaining particle size of 0.6 μm), the above aerosol can be collected efficiently and reproducibly.

[0076] Next, the collection filter that has trapped the aerosol is immersed in the solvent (filter immersion S4). Filter immersion S4 dissolves and disperses the aerosol attached to the collection filter in the solvent, and the aerosol is transferred into the solvent to obtain an eluate. Examples of the solvent include water and organic solvents. Examples of organic solvents include lower alcohols such as methanol and ethanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethyl ether and tetrahydrofuran; esters such as ethyl acetate; sulfoxides such as dimethyl sulfoxide; halogenated hydrocarbons such as methylene chloride and chloroform; aliphatic hydrocarbons such as hexane; alicyclic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benzene and toluene; nitrogen atom-containing compounds such as acetonitrile, dimethylformamide, and N-methyl-2-pyrrolidone, and mixtures of two or more of these. Among these, lower alcohols such as ethanol, ethyl acetate, acetonitrile, and water are preferred because they have high cannabinoid extraction ability, are not too volatile or have a low flash point, and are relatively easy to handle. The immersion time is preferably within three hours, but is not particularly limited. To ensure complete extraction of cannabinoids from the collection filter, extraction may be promoted by methods such as ultrasound, heating, stirring, or shaking, as needed. If necessary, concentration or dilution (concentration adjustment) may be performed, and impurities may be removed by centrifugation or filtration. It is also preferable to perform membrane filtration at the end. Furthermore, until the method is optimized, it is desirable to confirm that complete extraction of cannabinoids has been achieved from the collection filter, and it is advisable to analyze the washing solution used to wash the collection filter to confirm that sufficient cannabinoids have been extracted.

[0077] Next, the eluate obtained in S1-S4 (eluate obtained via membrane filtration if necessary) (extract) is subjected to chromatographic analysis (chromatographic analysis S5). The cannabinoid concentration in the extract is measured by chromatographic analysis S5. The above chromatography may be either gas chromatography (GC) or liquid chromatography. For gas chromatography, known or conventional methods can be used, and it is also suitable for the analysis of terpenes and solvents in addition to cannabinoids. In GC-MS equipped with an MS detector, it is preferable to first investigate the mass-to-charge ratio (m / z) of multiple fragments characteristic of various cannabinoids in total ion detection (SCAN) mode, and then analyze that mass-to-charge ratio in selected ion detection (SIM) mode, from the viewpoint of stabilizing the sensitivity of cannabinoids and mitigating the influence of noise. In addition, derivatization may be performed before GC analysis to improve the quantitative accuracy of cannabinoids. On the other hand, liquid chromatography is preferable because it offers high accuracy and sensitivity in cannabinoid quantification without the need for derivatization, and can analyze even high molecular weight components and matrices such as emulsifiers and vegetable oils without problems.

[0078] In gas chromatography, low-polarity to medium-polarity columns are preferred. Using low-polarity to medium-polarity columns allows for efficient separation of cannabinoids containing hydroxyl or phenyl groups. Known or conventional packing materials can be used for the above columns, but examples include polysiloxanes containing phenyl and methyl groups. Side chains of polysiloxanes include diphenyl, phenylmethyl, and dimethyl groups.

[0079] For liquid chromatography, known or conventional methods can be used, and a C18 column is preferred. Furthermore, it is preferable to use water, acetonitrile, methanol, or a mixture of two or more of these as the eluent. By using a gradient elution method with these two or more mixtures, cannabinoids can be efficiently separated.

[0080] Furthermore, chromatographic analysis (chromatographic analysis S6) is performed on the above liquid composition to measure the cannabinoid concentration in the liquid composition. Chromatographic analysis S6 may be either gas chromatography or liquid chromatography. The preferred embodiment of chromatographic analysis S6 is the same as the preferred embodiment of chromatographic analysis S5. This allows for clearer separation and detection of various cannabinoids, and more accurate quantitative analysis.

[0081] The cannabinoid concentrations in chromatographic analysis S5 and chromatographic analysis S6 can be determined by creating a calibration curve using cannabinoid standard solutions prepared in advance at multiple concentrations, and then comparing the results with this calibration curve.

[0082] Next, the aerosolization rate z of the cannabinoids in the liquid composition is calculated from the ratio x [w / w%] (cannabinoid concentration in aerosol) obtained by dividing the cannabinoid weight [mg] converted from the cannabinoid concentration [ppm] measured by chromatographic analysis S5 by the amount of liquid consumed in the pod due to aerosolization [mg], and the value y obtained by converting the cannabinoid concentration [ppm] in the liquid composition measured by chromatographic analysis S6 into a weight ratio [w / w%] (aerosolization rate calculation S7). More specifically, the aerosolization rate can be calculated using the following formula (2). That is, the aerosolization rate can be obtained by multiplying the concentration of the lipid-soluble organic compound in the aerosol by 100 relative to the concentration of the lipid-soluble organic compound in the liquid composition. Aerosolization rate z[%] = x / y × 100 (2)

[0083] In addition, the stable delivery rate calculated by the following formula (3) is preferably 80% or more, more preferably 90% or more. Although atomization does not exceed 100% on the premise of y > x, when there are factors such as concentration of the liquid or influence of a high-boiling mixture, y < x may occur and the atomization rate z may exceed 100%. Therefore, when the stable delivery rate, which is an index of the reproducibility of atomization, is 80% or more, it can be considered that the variation in the atomization rate is small and highly accurate atomization is achieved. Stable delivery rate [%] = 100 - |100 - z| (3)

[0084] Chromatography is commonly used for the analysis of cannabinoids, with gas chromatography and liquid chromatography being the primary separation methods. The main detectors used to detect the separated components include FID, MS, DAD (UV), and RI. However, because cannabinoids have relatively high molecular weights, they are less volatile than terpenes, and liquid chromatography, which does not involve vaporizing the sample during analysis, is considered more stable for quantitative analysis. Furthermore, since some cannabinoids, such as THCA and CBDA, are sensitive to heat, liquid chromatography is considered more suitable for cannabinoid analysis. However, liquid compositions containing cannabinoids often also contain terpenes, which are highly volatile. Liquid chromatography is not suitable for analyzing highly volatile components, and liquid chromatography itself has limitations in its separation capabilities. On the other hand, gas chromatography, because the mobile phase is an inert gas, makes it easier to maintain excellent detection limits and quantification limits, and because the number of theoretical plates per unit time of the column can be increased, it can also achieve high separation efficiency, making it useful not only for cannabinoid analysis but also for analyzing complex terpene compositions. Furthermore, in gas chromatography, the sample is heated during analysis, so in the analysis of cannabis extracts, THCA and CBDA are converted to THC and CBD, respectively by heat. However, since THC and THCA, or CBD and CBDA, are considered to have potentially similar physiological activity, and the content is expressed as Total THC or Total CBD, this is not always a significant problem. Moreover, when the above liquid composition is used as e-cigarette liquid, even if THCA or CBDA are present, they are heated to THC and CBD upon ingestion, so it is even less of a problem. Furthermore, if a derivatization process is incorporated into the sample preparation, gas chromatography can also improve quantitative accuracy and analyze components with low thermal stability. Therefore, depending on the characteristics of the sample, it is possible to choose the appropriate instrument, either liquid chromatography or gas chromatography.

[0085] According to the analytical method of the present invention, the aerosolization rate and stable delivery rate of the lipid-soluble organic compound can be analyzed and evaluated more precisely in a liquid composition containing the lipid-soluble organic compound. Therefore, according to the present invention, the relationship between the aerosolization rate, stable delivery rate and dispersion stability of a liquid composition containing the lipid-soluble organic compound can be clarified, and a PG-VG liquid with high dispersion stability and aerosolization efficiency can be produced by using the compound represented by formula (1) above.

[0086] Furthermore, according to the analytical method of the present invention, the aerosolization rate and stable delivery rate can be calculated using only a chromatography apparatus as the analytical device. In addition, according to the analytical method of the present invention, it is possible to quantify minor cannabinoids such as CBDV, CBG, and CBN in addition to CBD, and theoretically it is also possible to analyze THC and HHC, for which samples cannot be prepared due to legal regulations. Moreover, according to the analytical method of the present invention, the aerosol cannabinoid concentration is calculated using the weight of cannabinoids in the aerosol calculated by the calibration curve method and the amount of liquid consumed by the actual measurement, so a stable aerosolization rate and stable delivery rate with little variation can be obtained.

[0087] The above analytical method can be used to calculate the intake amount (dosage) of the lipid-soluble organic compound and evaluate the intake efficiency (delivery efficiency) when a liquid composition containing the lipid-soluble organic compound is vaporized and inhaled; to search for the optimal composition of the liquid composition containing the lipid-soluble organic compound; to manufacture the liquid composition containing the lipid-soluble organic compound; and to evaluate the quality of the liquid composition containing the lipid-soluble organic compound.

[0088] [Quality confirmation method] The quality of the liquid composition containing the lipid-soluble organic compound (aerosolization rate and stable delivery rate of the lipid-soluble organic compound) can be confirmed using the above analytical method. The method of confirming the quality of the liquid composition using the above analytical method may be referred to as the "quality confirmation method of the present invention." In the quality confirmation method of the present invention, it is preferable to confirm the quality of the liquid composition by the above analytical method and by evaluating the diffusivity and / or crystallinity of the liquid composition. Although strictly speaking "diffusion" and "dispersion" are different terms, they will not be distinguished hereafter. Also, in this specification, "diffusion" and "dissolution" will not be strictly distinguished. The above diffusivity evaluation is a method for evaluating the diffusivity in the liquid composition, and the above crystallinity evaluation is a method for evaluating the crystallization inhibition in the liquid composition. The above diffusivity evaluation and crystallinity evaluation can be performed by visual inspection of the liquid composition. The above visual diffusivity evaluation can be performed based on the transparency of the liquid composition, the degree of turbidity, the presence or absence of liquid separation, etc. The above visual crystallinity evaluation can be performed based on the presence or absence of crystal formation in the liquid composition, etc. Furthermore, the diffusivity evaluation described above can also be performed by measuring the particle size distribution of the lipid-soluble organic compound in the liquid composition, with lower particle sizes indicating higher diffusivity. Both visual inspection and liquid particle size measurement may be combined, or either one may be used. The quality evaluation method for liquid compositions containing the lipid-soluble organic compound, combining the aerosolization rate analysis method, the diffusivity evaluation, and the crystallinity evaluation, is groundbreaking in that it clarifies the relationship between aerosolization efficiency, diffusivity, and crystallinity, serving as a guide for creating high-quality liquid compositions. It is even more preferable to combine the above quality evaluation method with the "Storage Stability Evaluation Method" described below.

[0089] [Method for evaluating storage stability] The storage stability of a liquid composition containing the above-mentioned lipid-soluble organic compound can be evaluated using the above-described analytical method. The above-described storage stability evaluation using the above-described analytical method may be referred to as "the storage stability evaluation method of the present invention." For example, in the storage stability evaluation method of the present invention, by utilizing the aerosolization rate analysis method, more specifically, the aerosolization rate (1) of the liquid composition at a first time point and the aerosolization rate (2) of the liquid composition at a second time point, which is later in the time series than the first time point, can be analyzed, and by comparing the aerosolization rate (1) and the aerosolization rate (2), the aerosolization stability of the lipid-soluble organic compound from the first time point to the second time point can be evaluated. Furthermore, by utilizing the diffusivity evaluation and crystallinity evaluation of the liquid composition, more specifically, the diffusivity and crystallinity can be evaluated after storage for a certain period of time (e.g., 1 day, 3 days or more, or 1 week or more), for example, under normal temperature and pressure conditions or refrigerated conditions, and by comparing this with the diffusivity and crystallinity evaluated before storage, the dispersion stability of the lipid-soluble organic compound can be evaluated. Furthermore, by adding quantitative analysis of the above-mentioned lipid-soluble organic compounds to this, more specifically, the stability of the lipid-soluble organic compounds, that is, the resistance to a decrease in content due to reactions such as decomposition and oxidation of the lipid-soluble organic compounds, can be evaluated by comparing the quantitative analysis results before and after storage.

[0090] [Method for manufacturing liquid compositions; Method for exploring formulations of liquid compositions] The present invention provides an analytical method for analyzing and evaluating the aerosolization rate and / or stable delivery rate (preferably also and diffusivity and / or crystallinity) of the lipid-soluble organic compound in a liquid composition to confirm the quality of the liquid composition, and to evaluate its storage stability as necessary. This method allows for the production of a liquid composition containing the lipid-soluble organic compound and the exploration of formulations for the liquid composition. The quality includes the aerosolization efficiency, diffusivity, and crystallinity of the lipid-soluble organic compound. More preferably, formulations for liquid compositions with a good aerosolization rate can be explored and produced within a range where no problems have been confirmed in evaluating the quality of the liquid composition regarding diffusivity and / or crystallinity (preferably also and dispersion stability, i.e., storage stability in diffusivity and crystallinity) (i.e., no liquid separation or crystallization occurs). The above quality confirmation method can be used to confirm the quality of the liquid composition.

[0091] The following describes the case where cannabinoids are used as the lipid-soluble organic compounds. Specifically, for example, the aerosolization rate (preferably further, diffusibility and / or crystallinity) of cannabinoids in the nth candidate liquid composition (e.g., the first candidate) containing cannabinoids is analyzed and evaluated using the analytical method of the present invention. If the aerosolization rate in the nth candidate is a desired value, the nth candidate liquid composition is selected. If the aerosolization rate in the nth candidate is not a desired value, the (n+1)th candidate liquid composition containing cannabinoids is prepared based on the above aerosolization rate, and the aerosolization rate of cannabinoids in the (n+1)th candidate liquid composition is analyzed and evaluated using the analytical method of the present invention (where n is an integer of 1 or more). In this way, the aerosolization rate of cannabinoids is calculated for the prepared liquid composition using the analytical method of the present invention. If the aerosolization rate is far from a desired value (e.g., 100%), the formulation of the liquid composition is readjusted, and the aerosolization rate of cannabinoids is calculated for the obtained liquid composition using the analytical method of the present invention. If the aerosolization rate of the (n+1) candidate is the desired value or close to it, the (n+1) candidate liquid composition is selected. By repeating the preparation of liquid compositions and the calculation of their aerosolization rates in this way, it is possible to produce liquid compositions in which the aerosolization rate of cannabinoids is close to the desired value. The same applies when evaluating diffusivity and / or crystallinity, but it is preferable to evaluate them using a comprehensive evaluation that also takes into account the aerosolization rate results.

[0092] The liquid composition obtained by the above method for producing the liquid composition is not particularly limited, but can be used in known or conventional applications as a liquid composition containing the above-mentioned lipid-soluble organic compound. In particular, applications in which the lipid-soluble organic compound is aerosolized are preferred, for example, use as a liquid for e-cigarettes. [Examples]

[0093] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way by these examples. Unless otherwise specified, "parts" means "parts by mass" and "%" means "percent mass".

[0094] Example 1 (Preparation of liquid composition) 3-((-)-menthoxy)propane-1,2-diol (compound C1) and CBD were mixed with PG, heated to approximately 60-70°C to completely dissolve the solid, and after cooling to room temperature, flavorings were added. Subsequently, VG was added so that the PG / PG+VG ratio (PG ratio) was 0.60, and approximately 5 g of liquid composition was prepared. The "PG ratio" indicates the mass ratio of PG to the total of PG and VG. The content ratios of each component are shown in Table 1.

[0095] Examples 2-20, Comparative Examples 1-6 (Preparation of liquid composition) Liquid compositions were prepared in the same manner as in Example 1, except that the various components and their amounts were changed as shown in Tables 1-6. Note that the addition of fragrance results in approximately 2% ethanol and 2% essential oil in the total composition. However, all samples in Tables 1-6 contain the same concentration of ethanol and essential oil, making them comparable. The timing of adding menthol and C1-C3 below is flexible; it can be done either before adding PG or after dissolving the CBD (at room temperature, immediately before adding VG).

[0096] The compounds shown in Tables 1-6 are as follows: Menthol: (-)-menthol C1:3-((-)-menthoxy)propane-1,2-diol (also known as WS-10) • C2: A mixture of (+)-cis p-menthane-3,8-diol and (+)-trans p-menthane-3,8-diol (also known as PMD-38) • C3:(-)-Menthyl lactate (also known as Frescolat-ML)

[0097] <Rating> The following evaluations were performed on each liquid composition obtained in Examples 1-20 and Comparative Examples 1-6.

[0098] (1) Appearance, diffusivity, and crystallinity Each liquid composition shown in Tables 1-6 was placed in a vial, and the appearance of the liquid composition was visually observed after the respective standing times shown in Tables 1-6. The diffusivity and crystallinity were then evaluated based on the appearance of the liquid composition from immediately after stirring to after one week of standing, according to the following evaluation criteria. The results are shown in Tables 1-6. [Evaluation Criteria for Diffusibility] A: Clear immediately after stirring. B: The cloudiness remains after standing for one week. C: Liquid separation after standing for 1 week. D: Liquid separation after standing for 1 day. [Criteria for evaluating crystallinity] X: No crystallization Y: Slightly crystallized Z: Intense crystallization

[0099] (2) Aerosolization rate (HPLC) <Aerosol collection> For each liquid composition shown in Tables 1 to 6, aerosols were generated and collected using the apparatus 1 shown in Figure 2 by the following method. For liquid compositions that had undergone liquid separation (or crystallization), aerosols were generated using the liquid composition before liquid separation (or before crystallization).

[0100] Two grams of liquid composition were filled into the pod portion of the e-cigarette vape device 2. A tube connected to the mouthpiece of the newly charged vape device 2, which was filled with the liquid composition, was connected to the insertion port of a PP filter gauge 3, which had a glass fiber filter installed inside. Furthermore, the exhaust port of the filter gauge 3 was connected to the intake port of the automatic smoker 4 with a tube. The inhalation conditions of the automatic smoker 4 were set to a puff volume of 55 mL / 3 sec, 10 puffs, and a puff interval of 5 seconds, and the automatic smoker 4 was operated to perform vaping. To exclude the aerosol collected during the first 10 puffs, the glass fiber filter in the filter gauge was replaced with a new filter. Next, the inhalation conditions for the automatic smoking device 4 were set to a puff volume of 55 mL / 3 sec, 15 puffs per minute, and a puff interval of 5 seconds, and the automatic smoking device 4 was operated to perform vaping. In this way, the aerosol generated from the liquid composition was trapped by a glass fiber filter. Furthermore, after operating the automatic smoking machine 4 with an ice-cooled trap containing acetone or alcohol between the filter gauge 3 and the automatic smoking machine 4, analysis of the acetone or alcohol trap solution by GC-MS confirmed that no CBD was detected, thus confirming in advance that all CBD is collected by the glass fiber filter under these conditions.

[0101] The equipment used in the above aerosol collection method is as follows: Vape device pod: Model number "GPC003", Material "PCTG", Resistance 1.1±0.1Ω, Manufactured by HONG KONG GLEEHEAVEN CO.,LIMITED Glass fiber filter: Product name "DP-70", particle size retention 0.6 μm, manufactured by Advantech Toyo Co., Ltd. Automatic smoking machine: Product name "TMP-80", manufactured by Tokuki Co., Ltd.

[0102] <Aerosol solution extraction> A glass fiber filter that had collected the aerosol was immersed in 15 mL of ethanol for 3 hours, and ultrasonic vibration (40 kHz) was performed for 10 minutes. Then, the solution was sampled, filtered through a membrane filter (0.2 μm), and diluted to an appropriate concentration for HPLC to prepare an HPLC sample. In addition, to confirm that all of the CBD attached to the glass fiber filter was extracted into the above solution, for the solution obtained by immersing the glass fiber filter in 15 mL of ethanol three times (the first time for 4 hours, the second time for 1 hour, and the third time for 30 minutes), the sample taken from the 15 mL solution obtained in the first immersion was designated as sample X, the sample taken from the 45 mL solution obtained by combining three portions was designated as sample Y, and the sample taken from the fourth extraction solution obtained by immersing the glass fiber filter after three immersions (i.e., after performing sufficient extraction work) in ethanol and stirring for 10 minutes was designated as sample Z. When these three types of solutions were quantitatively analyzed by GC-MS, the value obtained by multiplying the CBD concentration of the combined sample Y by 3 was almost the same as the CBD concentration of the 15 mL ethanol solution X after the first 4-hour immersion (i.e., almost no CBD was extracted in the second and third immersions), and the CBD concentration of the fourth extraction solution Z was about 1.5% of the CBD concentration of the 15 mL ethanol solution X after the first 4-hour immersion. From this, it was confirmed that almost 100% (>98%) of the CBD was extracted into the solution in the first 4-hour immersion. Furthermore, it was also confirmed by analysis that the CBD concentrations detected in the 3-hour and 4-hour immersions were almost the same.

[0103] <HPLC Analysis> HPLC analysis was performed on the HPLC samples obtained as described above. An Agilent Technologies, Inc. "1260 Infinity II LC system" was used for HPLC. The column used was "Agilent Poroshell 120 EC-C18" (3.0 × 100 mm, 2.7 μm). The column temperature was set to 35°C, and a gradient elution method was employed using a mixture of 0.1 vol% formic acid aqueous solution and 0.1 vol% formic acid acetonitrile solution (mobile phase). Component detection (228 nm) was performed using a diode array detector. Under these conditions, major cannabinoids such as CBDV, CBD, CBG, CBN, CBC, and THC can theoretically be analyzed without problems. Tables 1-6 show the aerosolization rates of CBD calculated based on the HPLC analysis. The aerosolization rate (%) is calculated using the formula [(weight concentration in aerosol / weight concentration in liquid composition) × 100], where "weight concentration in aerosol" is the value obtained by dividing the weight of CBD contained in one puff by the amount of liquid consumed in one puff (change in pod weight).

[0104] The above aerosolization rate is calculated as described above using the formula [(weight concentration in aerosol / weight concentration in liquid composition) × 100]. The reason the numerator in the formula is "weight concentration in aerosol" is that if the evaluation is based only on the weight of aerosol per puff, the value can vary greatly from puff to puff or from device to device, even when using the same device (the same automatic smoking machine or the same vape device pod), making simple comparison of values ​​difficult. However, by considering the weight concentration of aerosol per puff, the variation in values ​​from puff to puff or from device to device to device is small, allowing for simple comparison of values. As a result, the above aerosolization rates can be simply compared as shown in Tables 1 to 6. Therefore, the above aerosolization rate in this method does not indicate the amount of aerosolization in one puff (i.e., the ease of aerosolization). Note that "good aerosolization rate" means that the aerosolization rate is close to 100%.

[0105] [Table 1]

[0106] As can be seen from Table 1, the liquid compositions of Examples 1 to 3, which contain the compound represented by formula (1), exhibit higher crystallization inhibition compared to the liquid composition of Comparative Example 1, which does not contain the compound represented by formula (1). Furthermore, considering that CBD crystallizes in the liquid composition of Comparative Example 1, it can be said that the liquid compositions of Examples 1 to 3 achieve a better aerosolization rate compared to the liquid composition of Comparative Example 1 in actual handling. In addition, the liquid compositions of Examples 1 to 2 show a better aerosolization rate than the liquid composition of Example 3, which has lower diffusivity.

[0107] [Table 2]

[0108] A comparison of Comparative Example 1 in Table 1 with Comparative Examples 2 and 3 in Table 2 shows that adding menthol slightly suppresses crystallization, and a higher amount of menthol results in a better aerosolization rate. However, as can be seen from a comparison of Comparative Examples 2 and 3 and Examples 4 and 5 in Table 2, the liquid compositions of Examples 4 and 5, which further contain the compound represented by formula (1), exhibit higher diffusivity, higher crystallization suppression, and a better aerosolization rate compared to the liquid compositions of Comparative Examples 2 and 3, which do not contain the compound represented by formula (1). Comparing Comparative Examples 2 and 3, it appears that the lower the diffusivity, the higher the aerosolization rate. However, since crystallization can occur in a short time in the liquid composition of Comparative Example 2, its effect cannot be ignored, and a simple comparison is not possible in such cases. Furthermore, as mentioned above, all measurements of the aerosolization rate were performed before crystallization and liquid separation occurred. Therefore, it can be seen that if liquid separation occurs in Comparative Example 3, the stable delivery rate may decrease compared to Examples 4 and 5 in actual handling.

[0109] [Table 3]

[0110] As can be seen from Table 3, under conditions where the CBD content is 10%, the liquid compositions of Examples 6, 7, and 9, to which the compound represented by formula (1) was added, were shown to achieve a better aerosolization rate compared to Comparative Example 4, to which menthol was added.

[0111] Here, Hansen solubility parameters were calculated for menthol and various cooling agents (compounds C1-C3), and a three-dimensional graph plotting hydrophobicity, hydrogen bonding, and polarity was created, as shown in Figure 3(a). Then, as shown in Figure 3(b), water and glycerin, which promote CBD crystallization, were assigned a score of 0, while triacetin, PG, menthol, and C1-C3, which were experimentally verified to be effective in inhibiting CBD crystallization and not having excessively low dispersibility in PG-VG solvents, were assigned a score of 1. Hansen solubility spheres containing components with a score of 1 were created, and the relative energy difference (RED) expressed as Ra / Ro was calculated, where Ro (radius) was the radius of the solubility sphere (interaction radius) and Ra was the distance from the center of the solubility sphere to the Hansen solubility parameter of each cooling agent. As a result, the RED values ​​were 0.76 for menthol, 0.61 for C1, and 0.52 for C2. The values ​​for C1 and C2 were judged to be similar, and it was determined that they show similar trends in aerosolization rate, diffusivity, and crystallinity. However, the RED calculated here is based solely on the solubility spheres obtained within the scope verified in this experiment, and therefore does not limit the compounds represented by formula (1) to any particular category. Furthermore, the behavior when using C1 and C2 is similar, as can be seen from the results of Examples 1 and 2, and Examples 4 and 5. Given these results and the similarity in crystallinity and appearance in Examples 8 and 9, the aerosolization rate of Example 8 is evaluated to be about the same as that of Example 9. In addition, in Examples 10 and 11, where the PG ratio is slightly higher than in Examples 8 and 9, the aerosolization rate was better than in Examples 8 and 9, and the diffusivity was also improved.

[0112] [Table 4]

[0113] As can be seen from Table 4, under the condition of a CBD content of 10%, the liquid compositions of Examples 12 and 13, to which the compound represented by formula (1) was added, achieved a better aerosolization rate than Comparative Example 5, to which triacetin was added. Furthermore, although the diffusivity evaluation was D for all, this is a qualitative evaluation result. Upon closer observation and differentiation, the degree of liquid separation after standing for one day showed that the liquid composition of Comparative Example 5 (Figure 4) exhibited clearer liquid separation than Example 12 (Figure 5 left) and Example 13 (Figure 5 right), suggesting that Examples 12 and 13 had higher diffusivity. Referring further to Table 3, for example, Examples 10 and 11 achieved higher diffusivity and a higher aerosolization rate than Example 9. Thus, from the above results and the results in Tables 1-3, it is shown that higher diffusivity tends to lead to a better aerosolization rate. Even under the condition of a PG ratio of 0.65, Examples 14-17 and 19 showed higher diffusivity than Comparative Example 6, and Examples 14 and 15 showed better aerosolization rates than Comparative Example 6. Therefore, it is estimated that the aerosolization rates of Examples 16, 17, and 19 are equivalent to those of Examples 14 and 15. Furthermore, since Examples 18 and 20 also showed high diffusivity similar to Examples 14 and 15, it is estimated that their aerosolization rates are also equivalent to those of Examples 14 and 15. Thus, even if the CBD content is increased, high diffusivity and a good high aerosolization rate can be achieved by increasing the PG ratio and the addition ratio of the compound represented by formula (1).

[0114] [Table 5]

[0115] Table 5 also shows that, compared to Comparative Example 1 (no cooling agent added), adding menthol suppresses crystallization while decreasing diffusivity (Comparative Examples 2 and 3). In contrast, adding C1 or C2 suppresses crystallization while maintaining diffusivity (Examples 1, 2, 4, and 5). Thus, it can be seen that adding the compound represented by formula (1) improves diffusivity and crystallinity, effects not present with menthol.

[0116] [Table 6]

[0117] Furthermore, Table 6 shows that in systems containing C1 or C2, the higher the PG ratio, the better the diffusivity and crystallinity evaluations become. Thus, it can be seen that in systems containing the compound represented by formula (1), a higher PG ratio improves the diffusivity and crystallinity evaluations.

[0118] Example 21 The liquid composition of Example 18 and the liquid composition of Example 18 with ethanol equivalent to 2% of the total mass of the liquid composition added were stored in a refrigerator at 10°C for one day. As a result, crystallization was observed in the liquid composition of Example 18 at 10°C, but no crystallization was observed in the ethanol-added sample even after one week of refrigeration at 10°C. From this result, it is considered that the addition of ethanol can suppress crystallization. Furthermore, from the results of previous examples, it is considered that there is a trend in the composition of the liquid composition and its crystallization suppression and liquid separation suppression capabilities as shown in Table 7 (positive: higher values ​​result in higher crystallization, negative: higher values ​​result in lower crystallization). For example, triacetin is considered to suppress crystallization but promote liquid separation, as seen in the comparison between the examples and comparative examples. While there are no experimental results comparing the presence or absence of essential oils, and it cannot be definitively stated as shown in Table 7 based on the comparison of the examples and comparative examples, it is thought that the properties of HSP may fall between those of oil and triacetin, and since easily crystallizing CBD dissolves in essential oils, the liquid separation inhibitory effect and crystallization inhibitory effect may be similar to those of triacetin.

[0119] [Table 7]

[0120] Comparative Example 7, Examples 22-41 (Preparation of liquid composition) Liquid compositions were prepared in the same manner as in Example 1, except that the various components to be blended and their amounts were changed as shown in Tables 8-10. However, the timing of adding solids at room temperature, such as menthol, was before adding PG, and the timing of adding C1, triacetin, and essential oils was immediately before adding VG at room temperature.

[0121] The compounds shown in Tables 8-10 are as follows: ·WS-23: 2-Isopropyl-N,2,3-trimethylbutylamide

[0122] <Rating> The following evaluations were performed on each liquid composition obtained in Examples 22-41 and Comparative Example 7.

[0123] (3) Separability and crystallinity Each liquid composition shown in Tables 8-10 was placed in a vial and allowed to stand for 1-3 days to confirm that its appearance had stabilized. The appearance of the liquid composition was then visually observed. Separability and crystallinity were evaluated based on the appearance using the following criteria. However, since crystallinity can precipitate after a long period, follow-up observations were conducted for several weeks. The results are shown in Tables 8-10. In the table, "*" indicates that three-phase separation was initially observed but resolved over time. [Separability] When a liquid composition in a vial that has been left to stand separates into two phases, and the phase with the higher liquid level is designated as the first phase and the phase with the lower liquid level as the second phase, the value calculated as 2 × second phase / (first phase + second phase) is defined as the "degree of separation" and is shown in the "Separability" column of the table. [Criteria for evaluating crystallinity] None: No crystallization after 40 days. Yes: Crystallization occurred after 40 days.

[0124] [Table 8]

[0125] [Table 9]

[0126] [Table 10]

[0127] In Tables 8-10, "separability" indicates that a higher number indicates a higher likelihood of phase separation, while a lower number indicates superior diffusivity, with values ​​of 0.30 or less indicating particularly excellent diffusivity. As shown in Tables 8-9, even when CBG was used as the lipid-soluble organic compound, it was determined that the addition of a hydroxyl group-containing organic compound improved diffusivity, based on comparison with Comparative Example 7. Furthermore, as shown in Tables 8-9, it was confirmed that crystallization was unlikely to occur even when the lipid-soluble organic compound was blended at a high concentration of 30% by mass. From these results, it was determined that for lipid-soluble organic compounds having a resorcinol structure, such as CBG and CBD, adding a hydroxyl group-containing organic compound resulted in even better diffusivity and even less crystallization, even at high concentrations of 20% by mass or more (and even 30% by mass) of the lipid-soluble organic compound. Furthermore, as shown in Table 10, a comparison of Examples 39-41 confirmed that even when CBN was used as the lipid-soluble organic compound, crystallization tended to become less likely as the amount of hydroxyl group-containing organic compound added increased, thus confirming the effect of adding hydroxyl group-containing organic compounds. In particular, a comparison of Examples 26 and 27, and the results of Examples 39-41, indicated that CBG exhibited lower separation values ​​and superior diffusivity compared to CBN at high concentrations, making it less prone to crystallization. [Explanation of symbols]

[0128] 1 device 2 Vape devices 3. Filter gauge 4 Automatic smoking machines

Claims

1. It contains propylene glycol, glycerin, lipid-soluble organic compounds, and hydroxyl group-containing organic compounds. The aforementioned lipid-soluble organic compound is a compound that contains at least two oxygen atoms and has at least one phenol structure, and has a molecular weight of 200 or more and 400 or less. The hydroxyl group-containing organic compound is a liquid composition that contains at least two oxygen atoms and at least one hydroxyl group, has a boiling point of 150°C or higher at room temperature and pressure, and a molecular weight of 80 or higher.

2. The liquid composition according to claim 1, wherein the hydroxyl group-containing organic compound is a compound represented by the following formula (1). 【Chemistry 1】 [In the formula, R １ R represents an organic group containing a hydrogen atom, a hydrocarbon group, or a heteroatom. ２ represents a hydrogen atom or a hydroxyl group, and X represents -O-, -O-C(=O)-, -O-C(=O)-O-, -N-C(=O)-, -O-C(=O)-O-, -C(=O)-O-, -C(=O)-N-, or -C(=O)-. The organic group may bond to the carbon atoms constituting the cyclohexane ring to which X is bonded, thereby forming a ring, so that formula (1) may have a spiro structure. The carbon atoms constituting the cyclohexane ring to which X is bonded may also have other substituents. Y represents a carbon atom or an oxygen atom, and a double line including a dashed line indicates a single bond or a double bond, and in the case of a double bond, R ２ It does not have.

3. The liquid composition according to claim 1 or 2, wherein the lipid-soluble organic compound is a cannabinoid.

4. The liquid composition according to claim 1 or 2, wherein the hydroxyl group-containing organic compound is a compound containing two hydroxyl groups.

5. The liquid composition according to claim 1 or 2, wherein the hydroxyl group-containing organic compound is at least one selected from the group consisting of 3-(menthyloxy)propane-1,2-diol and p-menthane-3,8-diol.

6. The liquid composition according to claim 1 or 2, further comprising one or more selected from the group consisting of alcohol, plant extracts, fragrances, and stabilizers.

7. A liquid composition containing a lipid-soluble organic compound that has at least two oxygen atoms and at least one phenol structure, and a molecular weight of 200 to 400, is heated and / or reduced in pressure to generate an aerosol. A method for analyzing the aerosolization rate, comprising collecting the aerosol and subjecting it to chromatographic analysis to quantitatively analyze the amount of the lipid-soluble organic compound in the aerosol, and analyzing the aerosolization rate of the lipid-soluble organic compound in the liquid composition from the concentration of the lipid-soluble organic compound in the liquid composition and the concentration of the lipid-soluble organic compound in the aerosol.

8. The aerosolization rate analysis method according to claim 7, wherein the aerosolization rate is defined as the value obtained by multiplying the concentration of the lipid-soluble organic compound in the aerosol by 100 relative to the concentration of the lipid-soluble organic compound in the liquid composition.

9. The aerosolization rate analysis method according to claim 7 or 8, wherein the lipid-soluble organic compound is a cannabinoid.

10. The aerosolization rate analysis method according to claim 7 or 8, wherein the aforementioned depressurization and / or heating is performed by a smoking device and / or suction device.

11. A method for confirming the quality of a liquid composition by an aerosolization rate analysis method according to claim 7 or 8, and by evaluating diffusivity and / or crystallinity.

12. A method for evaluating storage stability, comprising: analyzing the aerosolization rate (1) of the liquid composition at a first time point and the aerosolization rate (2) of the liquid composition at a second time point which is later in the time series than the first time point, using the aerosolization rate analysis method according to claim 7 or 8; and evaluating the aerosolization stability of the lipid-soluble organic compound from the first time point to the second time point by comparing the aerosolization rate (1) and the aerosolization rate (2).

13. A method for producing a liquid composition containing the aforementioned lipid-soluble organic compound, A method for producing a liquid composition containing a lipid-soluble organic compound, comprising analyzing the aerosolization rate of the lipid-soluble organic compound in the liquid composition using the aerosolization rate analysis method described in claim 7 or 8 to confirm the quality of the liquid composition.

14. A method for producing a liquid composition containing a lipid-soluble organic compound, comprising: analyzing the aerosolization rate of the lipid-soluble organic compound in an nth candidate (where n is an integer of 1 or more) liquid composition containing the lipid-soluble organic compound using the aerosolization rate analysis method described in claim 7 or 8; selecting the nth candidate liquid composition if the aerosolization rate in the nth candidate is a desired value; preparing an (n+1)th candidate liquid composition containing the lipid-soluble organic compound based on the aerosolization rate if the aerosolization rate in the nth candidate is not a desired value; and analyzing the aerosolization rate of the lipid-soluble organic compound in the (n+1)th candidate liquid composition using the aerosolization rate analysis method described in claim 7 or 8; selecting the (n+1)th candidate liquid composition if the aerosolization rate in the (n+1)th candidate is a desired value.

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