Aqueous cannabidiol composition and cannabidiol-containing pharmaceutical preparation containing the same

Abstract

The present invention provides an aqueous cannabidiol composition containing (a) cannabidiol and (b) additives including a tocopherol ester, a polysorbate, and a poloxamer, and containing water as a solvent. The aqueous solution composition is advantageous for solubilizing cannabidiol, and the solubility of cannabidiol can be improved using a small amount of a solubilizing agent. An orally disintegrating film prepared using the composition exhibits excellent stability of cannabidiol over time.

Description

[Technical Field]

[0001] This application claims priority to Korean Patent Application Nos. 10-2023-0069795, filed on May 31, 2023, 10-2023-0069796, filed on May 31, 2023, 10-2023-0069797, filed on May 31, 2023, and 10-2023-0035440, filed on March 17, 2023, and the contents disclosed in the specifications and drawings of these applications are incorporated herein in their entirety. The present invention relates to an aqueous cannabidiol composition and a pharmaceutical formulation containing the same, and more specifically to an aqueous cannabidiol composition having improved solubility, stability, etc. of cannabidiol, and a pharmaceutical formulation containing the aqueous cannabidiol composition. [Background technology]

[0002] Cannabidiol (also abbreviated as CBD) is a cannabinoid chemically designated 2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol. Its empirical formula is C 21 H 30 CBD is a cannabinoid that occurs naturally in the plant Cannabis sativa L. It is O2 and has a molecular weight of 314.46. Pure CBD is typically found as an oil or isolate, a white or pale yellow crystalline solid that is insoluble in water but soluble in organic solvents.

[0003] Cannabidiol is a plant cannabinoid discovered in 1940. Cannabinoids are natural and synthetic compounds structurally or pharmacologically related to components of the cannabis plant or endogenous agonists (endocannabinoids) of the cannabinoid receptors CB1 or CB2. Cannabidiol, a cannabinoid, is known for its excellent medical efficacy and effectiveness. It is known to be used to treat asthma, glaucoma, various cancers, Parkinson's disease, seizures, dementia, arthritis, obesity, and anxiety disorders. It is also known to have antibiotic and tension-relieving effects.

[0004] Of the cannabinoids contained in cannabis, the substance with the greatest psychotropic effect is Δ9-tetrahydrocannabinol (THC). Pure cannabidiol isolate, from which THC, which is highly harmful to the human body, has been removed, is commonly provided as CBD oil.

[0005] CBD isolate is a pure, purified form of cannabidiol (CBD) obtained by removing other compounds from hemp (cannabis) cannabidiol. This CBD isolate is in powder form, and has extremely low solubility in water, making it difficult to provide as an aqueous solution. Furthermore, the difficulty of blending it with water-soluble polymer films limits the dosage form available. Additionally, cannabidiol is highly hydrophobic and insoluble in water. For this reason, numerous patents have been filed that attempt to increase the bioavailability of CBD by using compositions that partially utilize organic solvents.

[0006] Furthermore, CBD is unstable under various storage conditions, such as pH, temperature, and light, making it difficult to formulate. Furthermore, due to its poor stability over time, the CBD content in a dosage form tends to decrease over time, resulting in a decline in efficacy when formulated as a pharmaceutical. Purified CBD is typically dispersed in an oil phase, but one of the major causes of stability loss when mixed with oil is oxidative rancidity. In an effort to prevent oxidative rancidity, the inventors investigated methods for reducing the effect of the lone electron pair in oxygen molecules and studied the structure of cannabidiol. As a result, they developed a CBD aqueous solution and a CBD-containing formulation that are soluble in water and do not mix with the oil phase, resulting in improved stability over time. Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention aims to solve the above-mentioned problems by providing a CBD aqueous solution composition that stably contains CBD while improving its solubility in water, and a pharmaceutical formulation containing the same. The CBD can exist in a stable colloidal state in 100% water without using an organic solvent, and the dissolution rate is significantly improved. The present invention also aims to provide a water-soluble formulation.

[0008] One embodiment of the present invention provides an aqueous CBD solution composition that stably contains more than 100 mg of CBD (particularly powdered CBD) in 1 mL of water and that passes through a membrane filter of 0.45 μm or less at a rate of 90% or more.

[0009] The present invention aims to solve the above-mentioned problems and provide a new CBD aqueous solution, CBD-containing formulation, or method for producing the same that can stably contain CBD.

[0010] The present invention aims to solve the problem of CBD instability that has been a problem in conventional CBD-containing preparations, and to provide a CBD-containing orally disintegrating film that has excellent stability over time. [Means for solving the problem]

[0011] One embodiment of the present invention provides an aqueous cannabidiol (CBD) composition with excellent solubility. In particular, the present invention provides an aqueous cannabidiol composition containing purified cannabidiol with a purity of 99% or higher. Another embodiment of the present invention provides an aqueous cannabidiol solution or a cannabidiol formulation containing the same, which has improved stability of cannabidiol in a dosage form.

[0012] One embodiment of the present invention is an aqueous cannabidiol composition comprising water as a solvent, The composition provides an aqueous cannabidiol composition containing (a) cannabidiol and (b) additives including esters of tocopherol, polysorbates, and poloxamers.

[0013] Preferably, the solvent is substantially free of other organic solvents besides water. Here, "substantially free" means that the solvent contains less than 3 wt%, less than 2.5 wt%, less than 2 wt%, less than 1 wt%, less than 0.5 wt%, or less than 0.1 wt%, based on the total weight of the solvent. The organic solvent may be at least one selected from polar and nonpolar solvents, including commonly used hydrocarbons, alcohols, ethers, ketones, butanol, amines, etc., such as acetic acid, methanol, ethanol, propanol, butanol, acetone, and chloroform. The additive may include tocopherol esters, polysorbates, and poloxamers. One embodiment of the present invention may provide an aqueous cannabidiol solution composition with improved solubility and stability. As used herein, cannabidiol may preferably include a purified cannabidiol (isolate), and the purified cannabidiol (or purified cannabidiol) refers to pure cannabidiol obtained from plants known as hemp or cannabis, from which other compounds have been removed, resulting in an impurity content of less than 1%.

[0014] The cannabidiol whose solubility can be improved through one embodiment of the present invention may include cannabidiol in a powdered state, preferably in a powdered state, and may include highly pure crystalline isolated cannabidiol, more preferably highly pure crystalline isolated cannabidiol with an impurity content of less than 1%, i.e., CBD powder having a purity of 99%. As used herein, CBD isolate may be understood to mean powdered CBD.

[0015] The present inventors have confirmed that additives necessary for producing cannabidiol, particularly isolated crystalline cannabidiol, as an aqueous solution preferably contain tocopherol esters, polysorbates, and poloxamers. Aqueous solutions of cannabidiol containing these additives easily solubilize purified cannabidiol, facilitating the production of aqueous solutions of purified CBD, and providing excellent stability over time for CBD-containing film formulations.

[0016] In one embodiment, the aqueous solution composition may further include α-tocopherol as an additive (b). By including α-tocopherol as an additive (b), the temporal stability of CBD in an orally dissolving film prepared from the aqueous solution composition can be improved.

[0017] The additive (b) will now be described in more detail.

[0018] Preferably, the additive (b) may be a solubilizing agent for solubilizing the cannabidiol in water.

[0019] In one embodiment of the present invention, the tocopherol ester is an ester derivative of tocopherol, and the tocopherol ester may include any one selected from the group consisting of tocopheryl acetate (ethyl acetate of tocopherol), tocopheryl linoleate (linoleic acid ester of tocopherol), tocopheryl linoleate / oleate (a mixture of linoleic acid ester and oleic acid ester of tocopherol), tocopheryl nicotinate (nicotinic acid ester of tocopherol), and tocopheryl succinate (succinic acid ester of tocopherol), preferably any one of tocopheryl acetate and tocopheryl linoleate, more preferably tocopheryl acetate. The tocopherol ester, when used together with polysorbate and poloxamer, can improve the solubility of cannabidiol in water, and tocopheryl acetate is particularly preferred for its advantageous use in improving the solubility and / or stability of cannabidiol.

[0020] The composition contains a polysorbate, and may contain any one selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, preferably any one selected from the group consisting of polysorbate 20 and polysorbate 40, and most preferably polysorbate 20. Polysorbate 20 has excellent compatibility with other additives, a superior solubilizing effect, and is advantageous in improving the stability of CBD over time.

[0021] The composition comprises a poloxamer, the poloxamer being poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 283, poloxamer 284, poloxamer 285, poloxamer 288, poloxamer 289, poloxamer 290, poloxamer 300, poloxamer 301, poloxamer 302, poloxamer 303, poloxamer 304, poloxamer 305, poloxamer 306, poloxamer 307, poloxamer 308, poloxamer 309, poloxamer 310, poloxamer 311, poloxamer 312, poloxamer 313, poloxamer 314, poloxamer 315, poloxamer 316, poloxamer 317, poloxamer 318, poloxamer 319, poloxamer 320, poloxamer 321, poloxam The composition may comprise one or more selected from the group consisting of Poloxamer 284, Poloxamer 288, Poloxamer 331, Poloxamer 333, Poloxamer 334, Poloxamer 335, Poloxamer 338, Poloxamer 401, Poloxamer 402, Poloxamer 403, and Poloxamer 407, preferably any one selected from the group consisting of Poloxamer 181, Poloxamer 182, Poloxamer 183, Poloxamer 184, Poloxamer 185, and Poloxamer 188, and more preferably Poloxamer 188. The composition, particularly when poloxamer 188 and polysorbate 20 are used together, can improve the solubility or dispersibility of cannabidiol, allowing cannabidiol to exist in solution and reducing recrystallization or precipitation.

[0022] As used herein, the term "solubility improved" or "solubilized" may be understood to mean that a substance that is poorly soluble in water (particularly the purified CBD product of the present invention) is uniformly dispersed in water or maintained in a stable solution state, for example, in the form of an emulsion.

[0023] As used herein, improved stability means that the cannabidiol content in the aqueous solution or formulation has not decreased, or has decreased very little, compared to when it was first produced, and may mean that the change in CBD content compared to when it was first produced is within ±10% by weight, preferably within ±8% by weight compared to when it was produced, more preferably within ±7% by weight compared to when it was produced, even more preferably within ±6% by weight compared to when it was produced, even more preferably within ±5% by weight compared to when it was produced, even more preferably within ±4% by weight compared to when it was produced, and even more preferably within ±3% by weight compared to when it was produced.

[0024] One embodiment of the present invention provides a cannabidiol aqueous solution composition, which contains water as a solvent and comprises or consists of cannabidiol, tocopheryl acetate, polysorbate, and poloxamer. Preferably, the aqueous solution composition comprises or consists of purified cannabidiol, tocopheryl acetate, polysorbate 20, and poloxamer 188. The aqueous solution composition improves the solubility of cannabidiol, so that cannabidiol exists in solution and does not recrystallize or precipitate. The cannabidiol can be mixed into an aqueous solution containing water as a solvent, and preferably uniformly dispersed or dissolved. The aqueous solution composition significantly reduces changes in cannabidiol content even during long-term storage of cannabidiol.

[0025] According to one embodiment, the aqueous solution composition allows the cannabidiol mixed with the additives to form microcapsules with a small average particle size, thereby improving its solubility in water and increasing its rate of absorption by the body. Preferably, the cannabidiol dispersed in the aqueous solution composition of the present invention has an average particle size of 0.5 μm or less. Cannabidiol dispersed or dissolved in the cannabidiol aqueous solution of the present invention is capable of passing through a 0.45 μm membrane filter, with at least 90% of the total weight of cannabidiol contained in the composition being more preferably 92% or more, and even more preferably 95% or more. This can be understood to mean that the cannabidiol is uniformly dispersed in the aqueous solution and no precipitation occurs.

[0026] In an aqueous solution composition according to one embodiment of the present invention, the cannabidiol and the additive may be mixed in a content ratio appropriate for homogenizing the cannabidiol. Preferably, the cannabidiol and additive contained in the aqueous solution composition are mixed in a weight ratio of 1:0.1-10, preferably 1:0.5-5, and more preferably 1:0.8-1.5. In one embodiment, the additive may be included in an amount of 4 wt%-25 wt%, preferably 5 wt%-23 wt%, and more preferably 5 wt%-20 wt%, based on the total weight of the aqueous solution composition including water. While large amounts of additives are typically used to dissolve purified CBD, which is an insoluble component, the additive combination of the present invention can stably contain a large amount of cannabidiol (e.g., 100 mg or more per ml of water) even when used in small amounts, as described above.

[0027] In another embodiment of the present invention, the additives include tocopherol esters, polysorbates, and poloxamers to improve solubility, and the components used as the additives are preferably mixed in a weight ratio of 1:0.05-3:0.05-3, preferably 1:0.1-2:0.1-2, more preferably 1:0.2-1.5:0.2-1.5, and most preferably 1:0.2-1.5:0.2-1.5. The above content ranges are advantageous for achieving the objectives of the present invention, and cannabidiol solubility is excellent, significantly improving precipitation rate.

[0028] In another embodiment of the present invention, the aqueous solution composition may further contain α-tocopherol as an additive. That is, α-tocopherol may be further included in the combination of additives including the tocopherol ester, polysorbate, and poloxamer. When α-tocopherol is mixed with polysorbate and poloxamer without the tocopherol ester, it inhibits the solubilization of CBD. However, when used together with the tocopherol ester, it not only provides excellent solubilization but also exhibits excellent effects on the stability of CBD over time. In particular, the tocopherol ester may preferably include tocopheryl acetate. More preferably, the α-tocopherol may be included in the aqueous solution composition in the same amount as the tocopherol ester.

[0029] In this specification, unless otherwise specified, the content of additives contained in the cannabidiol aqueous solution composition and the blending ratio of additives to cannabidiol can be understood to include the case where α-tocopherol is contained in the additive (b). The α-tocopherol may be contained in the CBD aqueous solution or may be mixed separately with the CBD aqueous solution during the production process of the CBD-containing orally disintegrating film. The order of mixing the α-tocopherol is not particularly limited.

[0030] One embodiment of the present invention provides a method for preparing an aqueous solution of purified cannabidiol and a method for preparing a CBD-containing orally disintegrating film containing the aqueous solution composition. Preferably, one embodiment provides a method for solubilizing purified cannabidiol in water. In one embodiment, the method includes the steps of: (S1) mixing purified cannabidiol with an additive to prepare a mixture; (S2) adding the mixture prepared in step (S1) to a solvent containing water; and (S3) stirring the solvent containing the mixture prepared in step (S2). The purified cannabidiol has an impurity content of less than 1%, and the additive includes a tocopherol ester, polysorbate, and poloxamer.

[0031] According to another embodiment, the additive in step (S1) may further contain α-tocopherol as needed. The additive may contain both a tocopherol ester and α-tocopherol, and when α-tocopherol is included, the α-tocopherol may be added in the same amount as the tocopherol ester.

[0032] Specifically, the cannabidiol additive may be contained in an amount of 4% by weight to 25% by weight based on the total weight of the aqueous solution composition containing water.

[0033] The tocopherol ester may include any one selected from the group consisting of tocopheryl acetate, tocopheryl linoleate, tocopheryl linoleate / oleate, tocopheryl nicotinate, and tocopheryl succinate.

[0034] The polysorbate may include any one selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0035] The poloxamer may include any one selected from the group consisting of poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, and poloxamer 407. Preferably, the additives may include cannabidiol, tocopheryl acetate, polysorbate 20, and poloxamer 188.

[0036] The cannabidiol and the additive may be mixed in a weight ratio of 1:0.1 to 10, preferably 1:0.5 to 5, more preferably 1:0.8 to 1.5. Preferably, the mixing ratio of cannabidiol and the additive is understood to be the mixing ratio of cannabidiol to a mixture of a tocopherol ester, a polysorbate, and a poloxamer, or the mixing ratio of cannabidiol to a mixture of α-tocopherol, a tocopherol ester, a polysorbate, and a poloxamer.

[0037] The additive may be prepared by mixing the tocopherol ester, polysorbate, and poloxamer in a weight ratio of 1:0.05-3:0.05-3, preferably 1:0.1-2:0.1-2, more preferably 1:0.2-1.5:0.2-1.5, and most preferably 1:0.2-1.5:0.2-1.5.

[0038] The step (S3) may contain more than 100 mg of CBD in 1 mL of water, and may be stirred so that 90% or more of the total content of the aqueous solution composition passes through a membrane filter of 0.45 μm or less.

[0039] The composition prepared by the solubilization method of the present invention does not undergo any precipitate deposition for up to 2 months in an accelerated test at 40°C without any change in its content.

[0040] Preferably, the aqueous solution composition may have a pH of 5 to 8.5, preferably 5.5 to 8, preferably 6 to 7.5, preferably 6.5 to 7. Excellent solubility can be exhibited within this pH range. Furthermore, the composition may further comprise a step of sterilization (S4) as needed. The sterilization may be performed using a variety of methods commonly used in the art.

[0041] The temperature of the aqueous solution composition may be 20° C. to 65° C., preferably 25° C. to 55° C., at 1 atmosphere. Within the above temperature range, the aqueous solution composition has excellent solubility, is easily mixed with the additives, and is well dissolved in water, making it possible to obtain a stable aqueous solution composition.

[0042] In the step (S1), the mixture may be prepared by mixing water at 1 atmosphere and a temperature of 20°C to 65°C.

[0043] In step (S2), the solvent includes water, and the water may be hard water, soft water, seawater, brackish water, fresh water, groundwater, distilled water, etc. In addition to water, various additional solvents may be used as long as the additive does not affect the solubilization of cannabidiol, but the solvent may be used within a limited range taking into account the compatibility of the additive.

[0044] In the step (S3), the stirring can be performed using various stirrers. The stirring can be performed at room temperature (25°C). Stirring devices such as a continuous stirred tank reactor, a homogenizer, a turbine agitator, a paddle mixer, etc. can be used without limitation.

[0045] In another embodiment, the additives in step (S1) include tocopheryl acetate, polysorbate 20, and poloxamer 188, and may further include α-tocopherol. In one embodiment, the order of mixing the additives in step (S1) may be such that, taking into consideration solubility and stability over time, tocopheryl acetate, polysorbate 20, and poloxamer 188 are mixed with cannabidiol first, followed by α-tocopherol.

[0046] Another embodiment of the present invention provides an orally dissolving cannabidiol formulation comprising an aqueous cannabidiol composition according to one embodiment of the present invention and a water-soluble polymer for film formation. The orally dissolving (and / or disintegrating) formulation is not particularly limited in form, and may be any dosage form in which 80% or more of the entire film dissolves, disperses, or disintegrates within 2 minutes, preferably within 1 minute and 30 seconds, and more preferably within 1 minute after oral administration. The orally dissolving (and / or disintegrating) formulation may be used interchangeably with terms such as film, strip, or orally disintegrating film, and may be understood to mean a dosage form that is applied to the oral cavity, e.g., on the tongue, oral mucosa, or under the tongue, and dissolved for administration.

[0047] The orally dissolving formulation may further comprise a thickener, a flavoring agent, and / or a sweetener. The thickener, flavoring agent, and sweetener may include any of those commonly used in the art, without limitation. The thickener may comprise any one selected from the group consisting of xanthan gum, guar gum, and gum arabic. For purposes of the present invention, the thickener may comprise xanthan gum, gum arabic, or a mixture thereof. The thickener may be present in an amount of 3% to 10% by weight, or 4% to 8% by weight, based on the total weight of the dried film, to provide a viscosity and dryness suitable for preparing a film from a water-soluble polymer. The orally dissolving film of the present invention may further comprise a sweetener to mask the bitterness of cannabidiol in the mouth. The sweetener may be one or more selected from the group consisting of sucralose, neohesperidin, aspartame, stevioside, sorbitol, and mannitol, and more preferably two or more sweeteners may be used to mask the bitterness of cannabidiol. The sweetener may be contained in the dried film in an amount of 1 to 10% by weight, preferably 3 to 9% by weight, based on the total weight of the film.

[0048] In one embodiment of the present invention, the water-soluble polymer is used as a substrate for forming a film, and preferably polyvinyl alcohol is used as the film-forming substrate. The polyvinyl alcohol is preferably a polymer having a number average molecular weight of 1,000 to 100,000, more preferably 10,000 to 50,000, even more preferably 15,000 to 60,000, and most preferably 20,000 to 30,000, among polyvinyl alcohols having various molecular weights and degrees of saponification, taking into consideration film formulation, dispersibility and solubility of cannabidiol, and process (viscosity of the formulation liquid).

[0049] In the film, cannabidiol and water-soluble polymer may be mixed at a weight ratio of 1:0.1-5, preferably 1:0.5-3, more preferably 1:0.8-1.5, and even more preferably 1:0.9-1.2, taking into consideration the solubility, dispersibility, and dosage form of cannabidiol. The above content ranges are advantageous for achieving the objects of the present invention.

[0050] The present invention allows the cannabidiol orally dissolving film to contain a large amount of cannabidiol. Specifically, when the additive of the present invention is used, the cannabidiol content may be 10 to 60% by weight, preferably 13 to 50% by weight, and more preferably 15 to 30% by weight, based on the total weight of the film.

[0051] The aqueous solution composition of the present invention has an extremely low CBD precipitation rate and excellent solubility and stability, and while it stably contains more than 100 mg of CBD per mL of water, 90% or more of the total content of the aqueous solution composition can pass through a membrane filter of 0.45 μm or less.

[0052] The CBD-containing formulation of the present invention may exhibit a change in CBD content within ±10% by weight relative to the initial production level over 3 to 4 days at temperatures above 60°C, and even at temperatures between 75°C and 85°C. The orally disintegrating formulation (or film) may contain α-tocopherol. [Effects of the Invention]

[0053] The present invention allows a large amount of cannabidiol to be dissolved in water. A large amount of cannabidiol can be dissolved in water even with a small amount of additives. In particular, since it is not possible to use a large amount of additives compared to the content of the substrate when producing a film dosage form, the present invention has the advantage of being able to improve the solubility and / or stability of CBD while using minimal additives.

[0054] Furthermore, according to the present invention, there is no need to use any organic solvent to dissolve CBD in water, which is highly advantageous in terms of production, management, safety, etc.

[0055] The present invention can also improve the stability of CBD.

[0056] The drawings attached to this specification illustrate preferred embodiments of the present invention and, together with the above-mentioned description of the invention, serve to facilitate a further understanding of the technical concept of the present invention, and the present invention should not be interpreted as being limited to only the matters described in the drawings. [Brief explanation of the drawings]

[0057] [Figure 1] The images show aqueous solutions containing CBD without CBD isolate dissolved in them. From the left, these are aqueous solutions containing glycerin, lecithin, polyethylene glycol 400, 30% simethicone emulsion, and polysorbate 80 mixed with corn oil as solubilizers. The CBD is unable to dissolve and has precipitated or formed crystals. [Figure 2] This shows the final mixed state of the CBD aqueous solution composition having the composition in Table 5. It can be seen that the aqueous solution composition containing CBD isolate is stably emulsified. [Figure 3] The graph shows the degree of CBD precipitation in Comparative Example 1 (left) and Example 1 (right). When tocopheryl acetate was added (right), a stable CBD emulsion was formed, but when tocopherol was added (left), the CBD precipitated in a crystalline state. [Figure 4] This is the result of comparing CBD stability within CBD-containing compositions. DETAILED DESCRIPTION OF THE INVENTION

[0058] Hereinafter, the present invention will be described in detail with reference to examples to aid in understanding the present invention. However, the examples according to the present invention may be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to those with average knowledge in the field to which the present invention belongs. In this specification, "%" should be understood to mean % by weight unless otherwise specified.

[0059] [Preliminary experiment for producing a CBD aqueous solution composition] Screening tests were conducted to determine the effectiveness of each component individually and / or in combination to dissolve powdered CBD purified product in water.

[0060] The experiment was carried out as follows.

[0061] After mixing CBD with each component in a 1:1 ratio, the state of the mixture was visually observed. Specifically, water was added to the mixture, and the state was observed.

[0062] "◯" indicates that no precipitation occurred after the addition of water, "△" indicates that some solids remained before the addition of water or that precipitation occurred after the addition of water, and "×" indicates that the solid was not dissolved without the addition of water.

[0063] [Table 1]

[0064] Based on the results in Table 1, ingredients suitable for CBD solubilization were initially selected. As can be seen from Table 1, among ingredients that can be used as solubilizers, corn oil, polyethylene glycol 400, polysorbate 80, polysorbate 20, polyethylene glycol 200, etc. were considered as suitable solubilizers for CBD aqueous solutions. Because compatibility with other ingredients is important for the characteristics of the CBD aqueous solution used in the formulation, additional solubilizers were mixed with the selected primary ingredients to check the degree of CBD dissolution.

[0065] "◎" indicates a very homogeneous dispersion, "○" indicates a dispersion with no observed crystals, "△" indicates an unmixed and undispersed state, "×" indicates phase separation, oil lumps, or crystals observed, and "-" indicates that the experiment was not performed.

[0066] [Table 2]

[0067] We confirmed that even ingredients known as common solubilizers are not suitable for solubilizing CBD isolate. Furthermore, even if a compound is deemed suitable for mixing CBD, when mixed with other ingredients, crystallization or precipitation of CBD is observed, making it unsuitable for producing a CBD aqueous solution.

[0068] [Production of CBD aqueous solution composition] We confirmed that the solubilization degree of purified CBD can be improved by selecting a mixture of two or more special solubilizers. Based on the above experimental results, we selected candidate solubilizers for purified CBD.

[0069] Due to the nature of powdered CBD purified products, there was a problem of CBD settling or solidifying in water, but it was initially confirmed that the following combinations were excellent for solubilization.

[0070] The degree of solubilization was evaluated using a combination of solubilizers as shown in Table 3 below.

[0071] [Table 3]

[0072] Among the above combinations, the precipitation rate of CBD in aqueous solution was confirmed for each CBD concentration using Preparation Examples 2 and 4, which are particularly excellent in solubilization. Here, H means that a high concentration of CBD was added, and L means that a low concentration of CBD was added.

[0073] [Table 4]

[0074] The selected samples from Production Examples 2 and 4 were analyzed after filtering through a 0.45 μm filter at each concentration.

[0075] Here, the high concentration is 110 mg / mL (set concentration) of CBD isolate, and the low concentration is 55 mg / mL (half the set concentration) of CBD isolate.

[0076] In the case of b-14-k, the amount of CBD lost after filtering was greater than before. This indicates that the CBD was not uniformly dispersed and there was a significant amount of precipitation. This is thought to be due to a decrease in the saturated solubility and / or microemulsion efficiency caused by a decrease in the solubilizing effect in water.

[0077] From the above results, Production Example 2, which showed stable content results at both high and low concentrations, was selected as the final formulation.

[0078] [Final selected aqueous solution containing purified CBD] [Table 5]

[0079] The aqueous solution composition obtained by dissolving a high content of purified CBD (99.5% purity) in water is shown in Example 1 in the table above. Polysorbate 20, tocopheryl acetate, and poloxamer P188 were used as solubilizers, with no other solubilizers added. Prior to producing the orally dissolving film, tocopherol was added to the CBD aqueous solution instead of tocopheryl acetate to produce an aqueous CBD solution, which was then passed through a 0.45 μm filter to check the precipitation rate of CBD.

[0080] As a result, the CBD content was maintained after passing through the filter in Example 1, but the CBD content was significantly reduced after passing through the filter in Comparative Example 1. Furthermore, visual observation confirmed that the degree of CBD solubilization in the solution in Comparative Example 1 was lower than that in Example 1. The results are shown in Figure 3.

[0081] In the past, purified CBD products with high content were difficult to dissolve in water, resulting in considerable precipitation. However, by using the composition of the present invention, CBD can be stably dissolved in water without the use of organic solvents.

[0082] An orally dissolving film containing purified CBD (Example 2) was prepared using an aqueous CBD solution with the following composition: Components 1 to 4 were added to water and homogenized using a homogenizer (Ultra Turrax T-25, IKA). The remaining components were added and homogenized again using the same homogenizer. The film-preparing solution was then degassed under vacuum at 30°C, cooled to room temperature, and coated onto a polyethylene terephthalate (PET) film to an appropriate thickness. The film was then dried at 60°C to produce an orally disintegrating formulation containing purified cannabidiol.

[0083] [Table 6]

[0084] Through the above-mentioned experiments, a CBD-containing oral film was prepared. The composition for preparing the film showed almost no precipitation of CBD isolate. It was confirmed that CBD was stably dispersed in the aqueous solution for film preparation and was well dissolved in water. This demonstrates that film preparation is easy even with an aqueous CBD solution, rather than an oil form.

[0085] [Confirming the stability of CBD-containing films over time] The stability over time of the orally disintegrating film of Example 2 having the composition shown in Table 6 was confirmed.

[0086] The CBD-containing orally disintegrating film described in Korean Patent Application No. 10-2019-0097649, which has the composition shown in Table 7 below, was used as Comparative Example 2 to confirm the stability of CBD over time in the orally disintegrating film.

[0087] [Table 7]

[0088] The films were packaged in airtight containers and left under harsh conditions for 0, 24, and 72 hours, and the CBD content was then confirmed by liquid chromatography (HPLC).

[0089] The stability over time of the CBD purified product, a commercially available CBD formulation, Example 2, and Comparative Example 2 was confirmed, and the results are shown in Table 8. As a result, the orally disintegrating film showed a tendency for the CBD content to decrease rapidly, but the orally disintegrating film of the present invention maintained the CBD content to an excellent extent, showing a tendency similar to the normal decomposition rate of general CBD purified products.

[0090] [Table 8]

[0091] Further, an additional experiment was conducted to increase the stability of the orally disintegrating film of Example 2. Table 9 below shows the results of examining the CBD content over time for films prepared by further adding α-tocopherol and BHT (butylated hydroxytoluene) to the composition of the orally disintegrating film of Example 2.

[0092] [Table 9]

[0093] The results showed that the addition of α-tocopherol did not decrease the CBD content. This is thought to be because the microemulsion prevented the CBD from coming into contact with water, preventing its decomposition. This is likely due to the effect of the interaction between α-tocopheryl acetate and α-tocopherol, but the above results should not be interpreted as being limited to this assumption.

[0094] In particular, the addition of BHT, a known antioxidant, contrary to expectations that it would prevent the decomposition of CBD, actually accelerated the decomposition of CBD, resulting in a rapid decrease in CBD content. When sodium citrate, a known preservative, was added instead of BHT, the color changed immediately after production, making it unsuitable for the manufacture of orally disintegrating films.

[0095] The changes in CBD content shown in Tables 8 and 9 above are shown graphically in Figure 4.

[0096] As can be seen from Figure 4, the formulation of the present invention has excellent stability over time. In particular, it provides a CBD-containing film formulation that alleviates the problem of CBD content reduction, which is a problem with CBD-containing formulations, and exhibits minimal change in content within the formulation. [Industrial Applicability]

[0097] The present invention provides a CBD-containing film formulation with improved cannabidiol solubility.

[0098] The present invention also provides a CBD-containing film formulation with improved cannabidiol stability.

Claims

1. 1. A cannabidiol aqueous solution composition comprising water as a solvent, The composition comprises: (a) cannabidiol; (b) an excipient comprising an ester of tocopherol, a polysorbate, and a poloxamer; 1. A cannabidiol aqueous solution composition comprising:

2. The cannabidiol aqueous solution composition according to claim 1, wherein the aqueous solution composition further contains α-tocopherol as an additive (b).

3. 2. The cannabidiol aqueous solution composition according to claim 1, wherein the cannabidiol is a highly purified cannabidiol having a purity of 99% or more.

4. 3. The cannabidiol aqueous solution composition of claim 1, wherein the additive is present in an amount of 4% to 25% by weight based on the total weight of the aqueous solution composition.

5. The cannabidiol aqueous solution composition of claim 1, wherein the tocopherol ester (b) comprises any one selected from the group consisting of tocopheryl acetate, tocopheryl linoleate, tocopheryl linoleate / oleate, tocopheryl nicotinate, and tocopheryl succinate.

6. The cannabidiol aqueous solution composition of claim 1, wherein the polysorbate (b) is any one selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

7. The poloxamers in (b) include poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, and poloxamer 407. The cannabidiol aqueous solution composition of claim 1, comprising any one selected from the group consisting of:

8. 10. The cannabidiol aqueous solution composition of claim 1, wherein the cannabidiol aqueous solution composition comprises or consists of cannabidiol, tocopheryl acetate, polysorbate 20, poloxamer 188, and water.

9. 3. The cannabidiol aqueous solution composition according to claim 1 or claim 2, wherein the cannabidiol (a) and the additive (b) are mixed in a weight ratio of 1:0.8 to 1.

5.

10. 3. The cannabidiol aqueous solution composition of claim 1 or claim 2, wherein the additive is a mixture of an ester of tocopherol, a polysorbate, and a poloxamer in a weight ratio of 1:0.8 to 1.2:1.8 to 2.

5.

11. The aqueous solution composition contains more than 100 mg of CBD in 1 mL of water, 3. The cannabidiol aqueous solution composition of claim 1, wherein 90% or more of the CBD contained in the aqueous solution composition passes through a membrane filter of 0.45 μm or less.

12. The cannabidiol aqueous solution composition according to any one of claims 1 to 10, a water-soluble polymer for film formation; 1. A cannabidiol orally dissolving film comprising:

13. The cannabidiol oral dissolving film of claim 12, wherein the water-soluble polymer for forming the film includes polyvinyl alcohol and gums.

14. 14. The cannabidiol orally dissolving film of claim 13, wherein the polyvinyl alcohol is a polyvinyl alcohol having a number average molecular weight of 15,000 to 60,000.

15. The cannabidiol orally dissolving film of claim 12, wherein the film is a mixture of cannabidiol and a water-soluble polymer in a weight ratio of 1:0.8 to 1.

5.

16. 13. The cannabidiol orally dissolving film of claim 12, wherein the film comprises 15% to 30% cannabidiol by weight based on the total weight of the film.

17. The cannabidiol orally dissolving film of claim 12, wherein the change in CBD content of the cannabidiol contained in the cannabidiol orally dissolving film at a temperature of 60°C or higher over 72 hours is within ±10% by weight compared to the initial production time.

18. 13. The cannabidiol orally dissolving film of claim 12, wherein the film contains no or less than 3% by weight of other organic solvents other than water based on the total weight of the solvents.

19. (S1) preparing a mixture by mixing a cannabidiol purified product with an additive for solubilizing the cannabidiol purified product; (S2) adding the mixture prepared in the step (S1) to a solvent containing water; (S3) a step of stirring the solvent in the (S2) step, The cannabidiol purified product has an impurity content of less than 1%; The additive in the (S1) step comprises any one selected from the group consisting of tocopherol esters, polysorbates, and poloxamers.

20. The method for producing a cannabidiol purified product aqueous solution according to claim 19, wherein the additive in the (S1) step further contains α-tocopherol.

21. The solvent in step (S2) contains water, and other organic solvents other than water are contained in an amount of less than 3 wt.% or are not contained in the total weight of the solvent.

22. 20. The method for producing a purified cannabidiol aqueous solution according to claim 19, wherein the cannabidiol additive is contained in an amount of 4% by weight to 25% by weight based on the total weight of the aqueous solution composition including water.

23. 20. The method for producing a cannabidiol purified product aqueous solution according to claim 19, wherein the additives include tocopheryl acetate, polysorbate 20, and poloxamer 188.

Images