Self-emulsifying composition

Abstract

The purpose of the present invention is to provide a composition having improved bioavailability of β-caryophyllene. Provided is a self-emulsifying composition comprising β-caryophyllene and one or more emulsifiers selected from the group consisting of polyglycerol fatty acid esters having an HLB value of 10 or more, polyoxyl glycerides, hydrogenated castor oil derivatives, and polyoxyethylene sorbitan fatty acid esters.

Description

self-emulsifying composition

[0001] The present invention relates to a self-emulsifying composition comprising an emulsifier and β-caryophyllene.

[0002] Beta-caryophyllene is a naturally occurring volatile compound found in essential oils obtained from plants of the Myrtaceae family, such as cloves, and is used as a flavoring agent that can be used in food products.

[0003] Beta-caryophyllene is a useful substance known for its anti-inflammatory, anti-allergic, antihistamine, antiviral, latent anti-cancer, analgesic, sedative, bactericidal, anti-inflammatory, bacteriostatic, immunostimulant, and stomachic effects.

[0004] However, β-caryophyllene has the disadvantage of being hydrophobic and having poor bioavailability.

[0005] Patent Document 1 discloses a self-emulsifying composition of β-caryophyllene.

[0006] International Publication No. 2017 / 149392

[0007] The present invention aims to provide a composition that improves the bioavailability of β-caryophyllene.

[0008] As a result of diligent research to solve the above problems, the inventors of the present invention discovered that a self-emulsifying composition can be created by mixing a specific emulsifier with β-caryophyllene, and thus completed the present invention.

[0009] In other words, the present invention relates to: (1) a self-emulsifying composition comprising one or more emulsifiers selected from the group consisting of polyglycerin fatty acid esters with an HLB value of 10 or higher, polyoxylglycerides, hydrogenated castor oil derivatives, and polyoxyethylene sorbitan fatty acid esters, and β-caryophyllene; (2) the self-emulsifying composition of (1) wherein the emulsifier is a polyglycerin fatty acid ester with an HLB value of 10 or higher; (3) the self-emulsifying composition of (1) wherein the emulsifier is one or more emulsifiers selected from the group consisting of decaglyceryl monolaurate, hexaglyceryl monolaurate, decaglyceryl monostearate, decaglyceryl monooleate, lauroyl polyoxyl-32 glyceride, PEG-60 hydrogenated castor oil, PEG-100 hydrogenated castor oil, polysorbate 20, and polysorbate 65; (4) The self-emulsifying composition of (1), further comprising sorbitan fatty acid ester, polyglycerin polyfatty acid ester and / or medium-chain fatty acid triglyceride; (5) The particle size of the emulsion self-emulsified in an aqueous medium is the median diameter (D ５０ The present invention relates to any of the following: (1) to (4) self-emulsifying compositions having a particle size of 1 μm or less; and (6) any of the following self-emulsifying compositions that do not undergo phase separation after being stored at 40°C for 8 weeks.

[0010] The present invention makes it possible to provide a self-emulsifying composition of β-caryophyllene.

[0011] Figure 1 shows the self-emulsifying compositions of formulations 1 to 3 examined in the examples, and the results after adding water. The group on the left is the self-emulsifying composition, and the group on the right is the composition after adding water. No phase separation was observed in the self-emulsifying compositions, and the composition after adding water was self-emulsified. Figure 2 shows the self-emulsifying compositions of formulations 37 to 42 examined in the examples. No phase separation was observed. Figure 3 shows the self-emulsifying compositions of formulations 37 to 42 examined in the examples, after adding water. No separation such as oil separation was observed, and self-emulsification was achieved. Figure 4 shows the compositions of formulations 50 to 55, which use sucrose fatty acid esters, examined in the examples. Phase separation occurred. Figure 5 shows the compositions of formulations 56 to 58, which use decaglyceryl distearate with an HLB of 9.5, examined in the examples, and the results after adding water. The group on the left is the composition, and the group on the right is the composition after adding water. Although no phase separation was observed in the compositions, separation of oil was observed in the composition after adding water, indicating that self-emulsification was not achieved. Figure 6 shows the self-emulsifying compositions of formulations 66-71, which were examined in the examples, with water added. No separation such as oil floating was observed, indicating that self-emulsification was achieved. Figure 7 shows the self-emulsifying compositions of formulations 72-76, which were examined in the examples, with water added. No separation such as oil floating was observed, indicating that self-emulsification was achieved. Figure 8 shows an overview of the membrane permeability test (PAMPA).

[0012] In one embodiment, the present invention provides a self-emulsifying composition comprising an emulsifier and β-caryophyllene.

[0013] In this embodiment, β-caryophyllene is a natural volatile component contained in essential oils obtained from plants of the Myrtaceae family, such as cloves, and is used as a flavoring agent that can be used in food products.

[0014] β-Caryophyllene is a compound represented by the following formula 1.

[0015] β-caryophyllene includes, but is not particularly limited to, the following isomers, however (-)-β-caryophyllene is preferred.

[0016] (-)-β-caryophyllene: (1R,1β,4E,9α)-4,11,11-trimethyl-8-methylene-bicyclo[7.2.0]undeca-4-ene (+)-β-caryophyllene: (1S,4E,9R)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undeca-4-ene

[0017] β-caryophyllene may be obtained by extraction and / or purification from plants, by synthesis, or by using commercially available products. Examples of commercially available products include those manufactured by Takasago International Corporation, Tokyo Chemical Industries Ltd., and Wako Pure Chemical Industries Ltd.

[0018] β-caryophyllene may be in its free form, or in the form of a pharmaceutically acceptable salt or ester.

[0019] Examples of pharmaceutically acceptable salts of β-caryophyllene include salts with inorganic or organic bases, or salts with basic amino acids.

[0020] Examples of inorganic bases include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; and ammonium salts and aluminum salts.

[0021] Examples of organic bases include primary amines such as ethanolamine; secondary amines such as diethylamine, diethanolamine, dicyclohexylamine, and N,N'-dibenzylethylenediamine; and tertiary amines such as trimethylamine, triethylamine, triethanolamine, pyridine, and picoline.

[0022] Examples of basic amino acids include lysine, arginine, and ornithine.

[0023] Examples of β-caryophyllene esters include β-caryophyllene esters formed by the esterification of the methyl group in β-caryophyllene with a carboxylic acid. Specifically, examples include 14-acetoxy-β-caryophyllene, which is formed by the esterification of the methyl group with a carboxylic acid.

[0024] The plants containing β-caryophyllene mentioned above are not particularly limited, but examples include cloves (Syzygium aromaticum), hemp (Cannabis sativa), rosemary (Salvia rosmarinus), and hops (Humulus lupulus).

[0025] The extraction site is not particularly limited as long as it achieves the effects of the present invention, and may be the whole plant or any necessary part (flower, flower head, flower bud, bud, inflorescence, leaf, branch, branch leaves, rhizome, root bark, root, bark, fruit, fruit peel, legume, seed, etc.). Examples of extraction sites include at least one selected from the group consisting of root, stem, leaf, and flower, preferably at least one selected from the group consisting of stem, leaf, and flower, and more preferably at least one selected from the group consisting of stem and flower.

[0026] The extraction method is not particularly limited, and known methods such as continuous extraction, immersion extraction, and countercurrent extraction can be used. Conventional extraction methods, purification methods, concentration methods, synthesis methods, and drying / powdering methods can also be employed. The extract may be the crude extract as is, or it may be a purified or concentrated extract.

[0027] For example, clove extracts can be obtained by immersing clove stems and flowers in water and / or organic solvents and filtering off the residue; the extract from which the solvent has been removed; or these as fine powders; or by dissolving, dispersing, and diluting the above extract or solvent-removed product with a suitable solvent; commercially available products can also be used.

[0028] In this specification, when using plant extracts, more specifically, the extraction solvent may be water (including hot water), methanol, ethanol, isopropanol, alcohols such as ethylene glycol, 1,3-butylene glycol, and glycerin, esters such as ethyl acetate, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, ethers such as diethyl ether and tetrahydrofuran, saturated hydrocarbons such as pentane, hexane, cyclopentane, and cyclohexane, aromatic hydrocarbons such as toluene, halogenated hydrocarbons such as dichloromethane and chloroform, and other organic solvents such as dimethylformamide and dimethyl sulfoxide (all may be aqueous or anhydrous), and may be one or any mixture of two of these solvents. Of these solvents, water, ethanol, 1,3-butylene glycol, or a mixture thereof is preferred. The extracts described herein can be obtained from various raw material companies, and they are usually sold with excipients, but are not limited to these.

[0029] For example, the extraction solvent for clove extract is not particularly limited, but it is preferably water, ethanol, or aqueous ethanol, and more preferably aqueous ethanol.

[0030] The emulsifier included in the self-emulsifying composition of this embodiment is one or more emulsifiers selected from the group consisting of polyglycerin fatty acid esters, polyoxylglycerides, hydrogenated castor oil derivatives, and polyoxyethylene sorbitan fatty acid esters, each with an HLB value of 10 or higher. In one embodiment, oleoyl polyoxyl-6 glyceride, caprylocaproyl polyoxyl-8 glyceride, and linoleyl polyoxyl-6 glyceride are excluded from the polyoxylglycerides. In another embodiment, PEG-35 hydrogenated castor oil and PEG-40 hydrogenated castor oil are excluded from the hydrogenated castor oil derivatives. In yet another embodiment, polysorbate 60, polysorbate 80, and polysorbate 85 are excluded from the polyoxyethylene sorbitan fatty acid esters.

[0031] In one embodiment, the emulsifier in this embodiment is a polyglycerol fatty acid ester. Specific examples of polyglycerin fatty acid esters include decaglyceryl monolaurate (e.g., Nikko Chemicals Co., Ltd., NIKKOL Decaglyn 1-L), hexaglyceryl monolaurate (e.g., Nikko Chemicals Co., Ltd., NIKKOL Hexaglyn 1-L), decaglyceryl monostearate (e.g., Nikko Chemicals Co., Ltd., NIKKOL Decaglyn 1-SV), hexaglyceryl monostearate (e.g., Nikko Chemicals Co., Ltd., NIKKOL Hexaglyn 1-SV), decaglyceryl monooleate (e.g., Nikko Chemicals Co., Ltd., NIKKOL Decaglyn 1-OV), hexaglyceryl monooleate (e.g., Nikko Chemicals Co., Ltd., NIKKOL Examples include, but are not limited to, Hexaglyn 1-OV. In preferred embodiments, the polyglycerin fatty acid ester is decaglyceryl monolaurate, hexaglyceryl monolaurate, decaglyceryl monostearate, or decaglyceryl monooleate. In even more preferred embodiments, the polyglycerin fatty acid ester is decaglyceryl monolaurate or hexaglyceryl monolaurate. These polyglycerin fatty acid esters are also preferred because they are permitted for use in food products in Japan.

[0032] In one embodiment, the HLB value of the polyglycerol fatty acid ester is 10 or higher, for example, 10-20, 12-18, 15-17, 10-13, etc. A polyglycerol fatty acid ester with an HLB value of 10 or higher may be mixed with an emulsifier with an HLB value of less than 10.

[0033] In one embodiment, the emulsifier in this embodiment is a polyoxylglyceride. Specific examples of polyoxylglycerides include, but are not limited to, lauroyl polyoxyl-32 glyceride (e.g., Gattefosse, Gelucire 44 / 14), caprylocaproyl polyoxyl-8 glyceride (e.g., Gattefosse, Labrasol), and stearoyl polyoxyl-32 glyceride (e.g., Gattefosse, Gelucire 50 / 13). In a preferred embodiment, the polyoxylglyceride is lauroyl polyoxyl-32 glyceride.

[0034] In one embodiment, the emulsifier in this embodiment is a vitamin E derivative. Specific examples of vitamin E derivatives include, but are not limited to, D-α-tocopherol polyethylene glycol 1000 succinic acid (e.g., Sigma-Aldrich, TPGS1000).

[0035] In one embodiment, the emulsifier in this embodiment is a hydrogenated castor oil derivative. Specific examples of hydrogenated castor oil derivatives include, but are not limited to, PEG-10 hydrogenated castor oil (e.g., Nikko Chemicals, NIKKOL HCO-10), PEG-35 hydrogenated castor oil (e.g., BASF, Kolliphor EL), PEG-40 hydrogenated castor oil (e.g., Nikko Chemicals, NIKKOL HCO-40), PEG-50 hydrogenated castor oil (e.g., Nikko Chemicals, NIKKOL HCO-50), PEG-60 hydrogenated castor oil (e.g., Nikko Chemicals, NIKKOL HCO-60), and PEG-100 hydrogenated castor oil (e.g., Nikko Chemicals, NIKKOL HCO-100). In preferred embodiments, the hydrogenated castor oil derivative is PEG-35 hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, or PEG-100 hydrogenated castor oil. In more preferred embodiments, the hydrogenated castor oil derivative is PEG-60 hydrogenated castor oil or PEG-100 hydrogenated castor oil.

[0036] In one embodiment, the emulsifier in this aspect is polyethylene glycol hydroxy fatty acid. Specific examples of polyethylene glycol hydroxy fatty acid include, but are not limited to, polyethylene glycol (15)-hydroxystearic acid (for example, BASF, Kolliphor HS15).

[0037] In one embodiment, the emulsifier in this aspect is polyoxyethylene sorbitan fatty acid ester. Specific examples of polyoxyethylene sorbitan fatty acid ester include, but are not limited to, polysorbate 20 (for example, Nikko Chemicals Co., Ltd., NIKKOL TL-10), polysorbate 40 (for example, Nikko Chemicals Co., Ltd., NIKKOL TP-10EX), polysorbate 65 (for example, Nikko Chemicals Co., Ltd., NIKKOL TS-30V), polysorbate 80 (for example, Nikko Chemicals Co., Ltd., NIKKOL TO-10V), and the like. In a preferred embodiment, the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, polysorbate 65 or polysorbate 80. In a more preferred embodiment, the polyoxyethylene sorbitan fatty acid ester is polysorbate 20 or polysorbate 65.

[0038] In one embodiment, the self-emulsifying composition of this embodiment further comprises a sorbitan fatty acid ester, a polyglycerol polyfatty acid ester, and / or a medium-chain fatty acid triglyceride. Specific examples of sorbitan fatty acid esters include, but are not limited to, sorbitan monolaurate (e.g., Nikko Chemicals, NIKKOL SL-10), sorbitan monooleate (e.g., Nikko Chemicals, NIKKOL SO-10V), sorbitan monostearate (e.g., Nikko Chemicals, NIKKOL SS-10V), and sorbitan trioleate (e.g., Nikko Chemicals, NIKKOL SO-30V). In a preferred embodiment, the sorbitan fatty acid ester is sorbitan monolaurate. Specific examples of polyglycerin polyfatty acid esters include, but are not limited to, decaglyceryl distearate (e.g., Nikko Chemicals, NIKKOL Decaglyn 2-SV), decaglyceryl tristearate (e.g., Nikko Chemicals, NIKKOL Decaglyn 3-SV), and decaglyceryl pentaoleate (e.g., Nikko Chemicals, NIKKOL Decaglyn 5-OV). In preferred embodiments, the polyglycerin polyfatty acid ester is decaglyceryl distearate. Specific examples of medium-chain fatty acid triglycerides include, but are not limited to, tri(caprylic / capric acid) glyceryl (e.g., Nikko Chemicals, NIKKOL Triester F-810). These sorbitan fatty acid esters, polyglycerol polyfatty acid esters, and medium-chain triglyceride fatty acids are also preferable because they are permitted for use in food products within Japan.

[0039] In one embodiment, a preferred combination of emulsifiers for the self-emulsifying composition of this aspect is polyglyceryl fatty acid ester and sorbitan fatty acid ester, or polyglyceryl fatty acid ester and medium-chain fatty acid triglyceride. More specific examples of combinations of emulsifiers include combinations of hexaglyceryl monolaurate or decaglyceryl monolaurate and sorbitan monolaurate or glyceryl tri (caprylate / caprate). These combinations are also preferred in that they are permitted for use in foods in Japan.

[0040] In one embodiment, a preferred combination of emulsifiers for the self-emulsifying composition of this aspect is a combination of a hydrogenated castor oil derivative or polyoxylglyceride and medium-chain fatty acid triglyceride. More specific examples of combinations of emulsifiers include combinations of caprylocaprylyl polyoxyl-8 glyceride or PEG-40 hydrogenated castor oil and glyceryl tri (caprylate / caprate).

[0041] In one embodiment, the self-emulsifying composition of this aspect may or may not contain a sucrose fatty acid ester.

[0042] The self-emulsifying composition of this aspect may or may not further contain a hydrophobic antioxidant. Examples of hydrophobic antioxidants include carotene, tocopherol (vitamin E), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), oil-soluble rosemary extract, and ubiquinol (coenzyme Q). In a preferred embodiment, the hydrophobic antioxidant is vitamin E.

[0043] In one embodiment, the content of β-caryophyllene in the self-emulsifying composition of this aspect is 1 to 50% by mass, for example, 1 to 40% by mass, 5 to 30% by mass, 10 to 20% by mass, etc.

[0044] In one embodiment, the content of the emulsifier in the self-emulsifying composition of this aspect is 40 to 99% by mass, for example, 50 to 95% by mass, 60 to 90% by mass, 70 to 85% by mass, 75 to 80% by mass, etc.

[0045] The ratio of β-caryophyllene to the emulsifier in the self-emulsifying composition of this embodiment is not particularly limited, and for example, β-caryophyllene:emulsifier (mass ratio) = 2:1 to 1:99, such as 5:4 to 1:99, 1:1 to 1:95, 4:5 to 1:80, 2:3 to 1:60, 1:2 to 1:40, 1:1 to 1:20, 1:1 to 1:15, 1:5 to 1:10, etc.

[0046] In one embodiment, the content of the hydrophobic antioxidant in the self-emulsifying composition of this embodiment is 0 to 20% by mass, for example, 5 to 10% by mass.

[0047] The self-emulsifying composition of this embodiment can maintain β-caryophyllene in a stable state. In one embodiment, the remaining percentage of β-caryophyllene after storing the self-emulsifying composition of this embodiment at 40°C for 8 weeks is 85% or more, for example, 90% or more, or 95% or more, compared to the amount of β-caryophyllene immediately after production. In this specification, the remaining percentage can be measured based on the method described in the "Stability Test" section below.

[0048] The self-emulsifying composition of this embodiment may exhibit a good emulsified state, with a small particle size in the self-emulsified liquid obtained by adding an aqueous medium. In one embodiment, the self-emulsifying composition of this embodiment, when self-emulsified by adding an aqueous medium such as water, has a particle size of D １０ The particle size is 0.5 μm or less, for example, 0.3 μm or less, 0.2 μm or less, or 0.01 to 0.5 μm. In one embodiment, the particle size of the self-emulsifying composition of this embodiment, when an aqueous medium such as water is added and self-emulsified, is D ５０ The particle size is 1 μm or less, for example, 0.5 μm or less, 0.2 μm or less, or 0.01 to 1 μm. In one embodiment, the particle size of the self-emulsifying composition of this embodiment, when an aqueous medium such as water is added and self-emulsified, is D ９０ The particle size is 3 μm or less, for example, 2 μm or less, 1 μm or less, or 0.01 to 5 μm. In this specification, the particle size can be measured using a dynamic light scattering particle size distribution analyzer. More specifically, the particle size can be measured based on the method described in the "Particle Size Measurement" section below.

[0049] The self-emulsifying composition of this embodiment may exhibit improved bioavailability. In one embodiment, the permeation rate of the self-emulsifying composition of this embodiment after 2 hours in a membrane permeation test (PAMPA) is 2 μg or more, for example, 2 to 10 μg or 3 to 7.5 μg. In one embodiment, the permeation rate of the self-emulsifying composition of this embodiment after 4 hours in PAMPA is 4 μg or more, for example, 4 to 15 μg or 5 to 12 μg. In one embodiment, the permeation rate of the self-emulsifying composition of this embodiment after 6 hours in PAMPA is 5 μg or more, for example, 5 to 20 μg or 10 to 15 μg. In one embodiment, the membrane permeation coefficient of the self-emulsifying composition of this embodiment in PAMPA is 2 × 10⁻⁶ －６ cm / sec or higher, for example, 2 to 10 x 10 －６ cm / sec, 3~5×10 －６ The value is cm / sec. In this specification, the membrane permeation test may be performed based on the method described in the section "Membrane Permeation Test (PAMPA)" below.

[0050] In one embodiment, the composition of this embodiment contains β-caryophyllene as an active ingredient and has anti-inflammatory, anti-allergic, antihistamine, antiviral, latent anti-cancer, analgesic, sedative, bactericidal, anti-inflammatory, bacteriostatic, immunostimulatory, stomachic, circadian rhythm regulating, effect of reducing or improving discomfort after drinking alcohol, anti-aging effect, and the like.

[0051] In one embodiment, the composition of this embodiment can be used, for example, by adding it to or mixing it with food and beverages, animal feed, or pet food. Alternatively, for example, it can be used as food and beverages as is. Alternatively, the composition of this embodiment can be a pharmaceutical composition or a food composition. It can be used, but is not limited to, food and beverages that explicitly or implicitly display claims relating to anti-inflammatory, anti-allergic, antihistamine, antiviral, analgesic, sedative, bactericidal, anti-inflammatory, bacteriostatic, immune stimulant, stomachic, circadian rhythm regulation, reduction or improvement of discomfort after drinking alcohol, anti-aging, etc., i.e., health foods, functional foods, foods for the sick, and foods for specified health uses.

[0052] Furthermore, even without explicitly or implicitly indicating the above-mentioned functional claims, these products can be used as so-called doctor's supplements provided by physicians in hospitals and / or clinics. For example, this includes supplements that may be suggested, prescribed, or selected by a person seeking treatment for allergies at a hospital or pharmacy.

[0053] The composition of this embodiment can be used, for example, orally, pulmonaryly, nasally, sublingually, or transdermally. Since β-caryophyllene contained in the composition of the invention is a volatile component, the above effects can be achieved not only by oral ingestion but also by nasal or pulmonary absorption. Furthermore, the effects of the present invention can also be achieved by holding the β-caryophyllene contained in the composition of this embodiment in the oral cavity by known methods such as sublingual tablets, orally disintegrating tablets, chewable tablets, buccal tablets, or candies, and then absorbing it sublingually.

[0054] The composition according to this embodiment can be used in various formulations, such as solid formulations (tablets, orally disintegrating tablets, sublingual tablets, granules, fine granules, powders, capsules, chewable tablets, buccal tablets, candies, etc.), liquid formulations (syrups, suspensions, sprays, creams, gels, ointments), and liquid foods. When preparing the composition according to this embodiment as a food composition, it can be manufactured in the same way as known pharmaceutical formulations. For example, it can be manufactured by mixing the active ingredient with a carrier such as an excipient that is acceptable as a pharmaceutical or food, and then using conventional means. The formulation form is not limited, but from the viewpoint of significantly demonstrating the effects of the present invention, it is preferably a tablet, orally disintegrating tablet, sublingual tablet, granule, powder, capsule, chewable tablet, buccal tablet, candy, spray, or liquid formulation, with sublingual tablets, capsules, chewable tablets, and buccal tablets being more preferred.

[0055] For example, tablets can be prepared by mixing an active ingredient with a pharmaceutically acceptable carrier component (such as an excipient) and then compression molding, while confectionery tablets such as candies may be prepared by injecting the mixture into a mold. Tablets may also be coated with sugar to form sugar-coated tablets. Furthermore, tablets may be single-layer tablets or multi-layer tablets such as double-layer tablets.

[0056] Granules and other powdered materials may be prepared by various granulation methods (extrusion granulation, crushing granulation, dry compaction granulation, fluid bed granulation, rolling granulation, high-speed stirring granulation, etc.), and tablets can be prepared by appropriately combining the above granulation methods and tableting methods (wet tableting, direct tableting, etc.).

[0057] Soft capsules can be formed by filling a sheet manufactured from the components of the capsule shell with capsule contents and then compressing and molding it. Manufacturing methods include flat plate type, rotary type, and seamless type. The components of the capsule shell are not particularly limited, but examples include polymer components and humectants. Examples of polymer components include gelatin, starch, pullulan, cellulose, polyvinyl alcohol, succinylated gelatin, agar, gellan gum, hydroxypropyl cellulose, ethyl cellulose, and carrageenan. The content of polymer components in the capsule shell is not particularly limited, for example, 1% by mass or more and 95% by mass relative to the capsule shell. Examples of humectants include sugars such as glucose, alcohols such as glycerin, and sugar alcohols such as sorbitol. The proportion of each component in the capsule shell of the soft capsule formulation is not particularly limited and can be set as appropriate.

[0058] In rotary (punching) manufacturing, a sheet-like capsule coating sandwiches the flowing filling material and forms a capsule shape along the holes of a rotating cylindrical mold. On the other hand, in seamless (dropping) manufacturing, the capsule coating composition and the contents are simultaneously discharged from multiple concentric nozzles, forming a seamless capsule shape.

[0059] Hard capsules can be manufactured by molding the capsule shell components into a cylindrical body and cap shape, and then filling them with contents. The components of the capsule shell of a hard capsule are not particularly limited, but examples include high molecular weight components such as gelatin, pullulan, agar, carrageenan, starch, starch hydrolysates, alginic acid, HPMC (hydroxypropyl methylcellulose), polyvinyl alcohol (PVA), starch derivatives, and gellan gum. The content of high molecular weight components in the capsule shell is not particularly limited, but for example, it is 1% by mass or more and 95% by mass or less relative to the capsule shell. The proportion of each component in the capsule shell of a hard capsule is not particularly limited and can be set as appropriate. Commercially available commercially produced capsule shells may be used for hard capsule formulations.

[0060] Furthermore, the composition according to this embodiment can be manufactured as liquid beverages such as soups, juices, fruit juices, milk, dairy beverages, whey beverages, lactic acid bacteria beverages, tea beverages, alcoholic beverages, coffee beverages, carbonated beverages, soft drinks, water beverages, cocoa beverages, jelly beverages, sports drinks, and diet drinks; semi-solid foods such as puddings and yogurts; noodles; confectionery; spreads; and the like.

[0061] When preparing the composition according to this embodiment as a food composition, various food additives may be added. Examples of food additives include antioxidants, colorants, flavorings, seasonings, sweeteners, acidulants, pH adjusters, quality stabilizers, and preservatives.

[0062] Furthermore, when preparing the composition of the present invention primarily for sublingual absorption, a form that allows for a long retention time in the oral cavity is preferred. This may be in the form of food formulations such as lozenges, chewing gum, compressed candy, chewy candy, gummy candy, caramel, or melt tablets, or in the form of saliva-permeable pouches. It may also be in the form of oral hygiene agents such as toothpaste (powdered toothpaste, moisturizing toothpaste, paste toothpaste, water-based toothpaste, etc.), mouthwash, or oral gel.

[0063] Furthermore, when preparing the composition of the present invention primarily for transpulmonary absorption, a form with a long residence time in the air is preferred, for example, and may be administered by nebulizer by administering an inhalation liquid, by spraying an inhalation aerosol by atomizer, or by inhaling an inhalation powder using an inhaler.

[0064] While not limited to this, when preparing the composition of the present invention primarily for transpulmonary absorption, it is preferable to prepare the composition in aerosol form. In this specification, an aerosol means a mixture of fine liquid or solid particles suspended in a gas and the surrounding gas. The method of preparing the composition in aerosol form is not particularly limited, and for example, the composition can be prepared using a nebulizer, a sprayer, or inhaler.

[0065] When preparing the composition of the present invention primarily for transpulmonary absorption, it is preferable to aerosolize it using a nebulizer, for example. The type of nebulizer is not particularly limited, and for example, jet, ultrasonic, compressor, and mesh nebulizers can be used. If the composition of the present invention is a liquid, for example, a soft mist inhaler may be used to aerosolize it. If the composition is a solid such as a powder, it is preferable to aerosolize the composition using a sprayer or inhaler and administer it, for example. The composition may be processed into a dosage form suitable for the sprayer or inhaler used. Examples include aerosol formulations, dry powder formulations, and inhalation suspensions.

[0066] When preparing the composition according to this embodiment primarily for transdermal absorption, it can also be used by applying it to the affected area with known liquid formulations such as creams, gels, or ointments.

[0067] The daily intake of β-caryophyllene for adults can be appropriately determined depending on the individual's condition, weight, sex, age, activity of the material, route of intake or administration, schedule of intake or administration, formulation form, or other factors. The intake of β-caryophyllene is preferably 5 mg or more, more preferably 10 mg or more, even more preferably 15 mg or more, and particularly preferably 20 mg or more. The intake of β-caryophyllene is preferably 300 mg or less, more preferably 250 mg or less, even more preferably 200 mg or less, and particularly preferably 150 mg or less. The intake of β-caryophyllene is preferably 5 to 300 mg, and examples include 10 to 300 mg, 15 to 300 mg, 20 to 300 mg, 5 to 250 mg, 10 to 250 mg, 15 to 250 mg, 20 to 250 mg, 5 to 200 mg, 10 to 200 mg, 15 to 200 mg, 20 to 200 mg, 5 to 150 mg, 10 to 150 mg, 15 to 150 mg, 20 to 150 mg, etc.

[0068] In another embodiment, when preparing the composition of the present invention primarily for transpulmonary absorption, for example, in the case of a liquid formulation, it is preferable to ingest 1 mL to 10 mL / min over 3 to 20 minutes, and in the case of a solid formulation, it is preferable to ingest 1 to 2000 μg per dose using a sprayer or inhaler.

[0069] The daily oral intake or dosage for adults may be divided according to the dosage form; for example, if it is a capsule, it may be taken in divided doses of 1 to 6 capsules, 1 to 4 capsules, 1 to 3 capsules, or 1 to 2 capsules, and if it is a tablet, it may be taken in divided doses of 1 to 6 tablets, 1 to 4 tablets, 1 to 3 tablets, or 1 to 2 tablets.

[0070] The composition of this embodiment can be taken or administered in one to several doses per day, usually 1 to 6 times per day, 1 to 3 times per day, 1 to 2 times per day, or at any period and interval, but once per day or once at the time of use is preferred.

[0071] Furthermore, in a certain embodiment, the composition of this embodiment can be used as a cosmetic composition.

[0072] The cosmetic composition of this embodiment may be effective in preventing or improving skin symptoms and diseases caused by aging.

[0073] In this specification, "cosmetic composition" includes cosmetics and quasi-drugs as defined in the Pharmaceuticals and Medical Devices Act, and includes cosmetics for use on the skin, bath additives, fragrances, etc.

[0074] Cosmetic compositions may contain commonly used ingredients as appropriate. Furthermore, the form of the cosmetic composition is not particularly limited. Examples of cosmetic compositions in this embodiment include, but are not limited to, soaps, synthetic cosmetic soaps, liquid body washes (body soaps), facial cleansers, cleansing creams, shampoos, conditioners, cleansing lotions, toners, emulsions, serums, lotions, liquid packs, paste packs, face powders, powders, powders, foundations, lipsticks, lip balms, blushes, eye makeup such as eyeliners and eyeshadows, sunscreens, suntans, hair removal products, or shaving lotions and aftershaves. These cosmetic compositions can be manufactured by methods known to those skilled in the art.

[0075] In addition to the raw materials used in the self-emulsifying composition, the cosmetic composition of this embodiment may also be used by adding ingredients commonly used in cosmetics, selected as appropriate within a range that does not impair the purpose, action, and effect of the present invention. Examples of such ingredients include, but are not limited to, surfactants, oils, humectants, softeners, texture enhancers, oiliness agents, emulsifiers, antioxidants, preservatives, fungicides, emollients, pH adjusters, chelating agents, stabilizers, UV absorbers, alcohols, silicone compounds, thickeners, viscosity modifiers, solubilizers, pearlescent agents, fragrances, cooling agents, disinfectants, antibacterial agents, natural extracts, colorants, fade inhibitors, purified water and other solvents, propellants, etc.

[0076] The β-caryophyllene content in the cosmetic composition of this embodiment can be appropriately selected depending on the application, but the total amount can range from 0.002 to 40% by mass, for example, 0.001 to 30% by mass, 0.02 to 20% by mass, or 0.01 to 10% by mass.

[0077] Furthermore, in one embodiment, the composition of this embodiment can be used as a bathroom or toiletry product or a household product.

[0078] Specific examples of bath and toiletry products or household products include, but are not limited to, bath detergents, toilet cleaners, dish soaps, laundry detergents, fabric softeners, fragrances, deodorizers, bath additives, paper towels, tissues, wet wipes, toilet paper, etc. These bath and toiletry products or household products can be manufactured by methods known to those skilled in the art.

[0079] The β-caryophyllene content in the bath and toiletry products or household products of this embodiment can be appropriately selected depending on the application, but the total amount can range from 0.002 to 40% by mass, for example, 0.001 to 30% by mass, 0.02 to 20% by mass, or 0.01 to 10% by mass.

[0080] Furthermore, in one embodiment, the composition of this embodiment can be used as an insect repellent.

[0081] The types of target pests that the insect repellent of this embodiment targets are not particularly limited. Target pests include, for example, pests that inhabit indoors and outdoors, such as house mosquitoes such as Culex pipiens, Culex tropicalis, Culex tritaeniorhynchus, Culex pipiens tritaeniorhynchus, Culex tritaeniorhynchus, Culex pipiens, Culex tritaeniorhynchus, Culex leucocephala, Culex leucocephala, Culex serrata, Aedes mosquitoes such as Aedes albopictus, Aedes togoensis, Aedes japonica, Aedes leucocephala, Aedes japonica, Culex serrata Examples include blood-sucking and biting insects such as flies, fleas, lice, bed bugs, assassin bugs, ticks, chiggers, and leeches; midges such as Chironomidae, Chironomidae, Chironomidae, Chironomidae, and Chironomidae; cockroaches such as German cockroaches, American cockroaches, Common cockroaches, Japanese cockroaches, and American cockroaches; flies; ants such as Pheidole ants, Black garden ants, Brown wrinkled ants, and Reticulated ants; termites; wasps; house centipedes; rice weevils, confused flour beetles, cigarette beetles, carpet beetles, and varied carpet beetles, which are stored grain pests.

[0082] The insect repellent according to this embodiment may also contain other insect repellent components, such as DEET.

[0083] The insect repellent of this embodiment may contain other components in addition to the raw materials used in the self-emulsifying composition, as long as they do not hinder the effects of the present invention. Examples of other components include solvents, nonionic, anionic or cationic surfactants, antioxidants such as butylhydroxytoluene; stabilizers such as citric acid and ascorbic acid; inorganic powders such as talc and silicic acid, fungicides, fungicides, deodorizers, fragrances, dyes, ultraviolet absorbers, chelating agents, retainers, pH adjusters, thickeners, and the like.

[0084] The formulation of the insect repellent in this embodiment is not particularly limited and includes, for example, liquids, emulsions, gels, pastes, aerosols, and pumps. In the case of liquids, the insect repellent can be used by impregnating a suitable cloth with it and wiping the application area. In the case of aerosols and pumps, the insect repellent can be used by spraying an appropriate amount onto application areas such as hands, feet, arms, and clothing.

[0085] The insect repellent of this embodiment can be manufactured using raw materials and methods known to those skilled in the art.

[0086] The amount of β-caryophyllene in the insect repellent of this embodiment can be appropriately selected depending on the application, but the total amount can range from 0.002 to 40% by mass, for example, 0.001 to 30% by mass, 0.02 to 20% by mass, or 0.01 to 10% by mass.

[0087] In one embodiment, the present invention provides a method for producing a self-emulsifying composition containing β-caryophyllene, comprising mixing β-caryophyllene with an emulsifier. All matters described in the above embodiment of the self-emulsifying composition are applicable to the production method of this embodiment.

[0088] In another embodiment, the present invention provides a method for producing a pharmaceutical composition, food composition, cosmetic composition, bath and toiletry product, household product, or insect repellent using the self-emulsifying composition described above. All matters described in the embodiment of the self-emulsifying composition can be applied to the method of production in this embodiment.

[0089] The present invention will be described in more detail below using examples, but the present invention is not limited to these examples.

[0090] 1. Measurement Methods The stability tests, particle size measurements, and membrane permeability tests described herein were performed according to the following methods.

[0091] (1) Stability Test i. Store the prepared composition in a screw vial with the lid closed in a constant temperature bath at 40°C, and sample immediately after preparation or after storage for 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 24 weeks. ii. Take 5 to 10 mg of the sampled sample into a 1.5 ml microtube and dissolve it in 500 to 1000 μL of methanol to a β-caryophyllene content of 1 to 2 mg / ml. iii. Dilute the above dissolved sample 10-fold with acetonitrile and quantify the amount of β-caryophyllene by HPLC under the following conditions. The percentage of β-caryophyllene compared to the amount immediately after production is defined as the residual rate.

[0092] HPLC system: Prominence (Shimadzu Corporation) Mobile phase: Phase A: Acetonitrile (85%), Phase B: 0.1% Acetic Acid (15%) Column: COSMOSIL Packed Column 5C １８ - MS-II 4.6 ID x 50 mm (Nacalai Tesque) Column temperature: 40°C Flow rate: 1 mL / min Measurement wavelength: 210 nm Injection volume: 10 μL Retention time: 4.7 min

[0093] (2) Particle size measurement: After sampling 40 mg of each composition into a 50 mL glass container, add 40 mL of distilled water and mix to prepare a self-emulsifying solution. Measure the particle size under the following conditions.

[0094] Particle size analyzer: Nanotrac UPA (Microtrac Inc.) Measurement time: 1 minute Number of measurements: 3 Particle refractive index: 1.81 Measurement temperature: Room temperature (25±3℃)

[0095] (3) Membrane Permeation Test (PAMPA) i. Sample Preparation i-1. Weigh 50 or 100 mg of each composition into a 13.5 mL screw vial, with the amount of β-caryophyllene being the final concentration after adding 10 mL of water. i-2. Add 10 mL of water to the vial and mix and disperse using a vortex mixer. i-3. Prepare a mixture of water / 10% DMSO / 5% Tween 80 as the acceptor solution. (Add 4.72 mL of Tween 80, assuming 5 g of Tween 80. 85.28 mL of water, 10 mL of DMSO, 4.72 mL of Tween 80)

[0096] ii. Membrane Permeation Test (The outline is shown in Figure 5) ii-1. For the PAMPA test, PermeaPad (registered trademark) is used. 350 μL of self-emulsifying solution is added to the lower donor side, and 200 μL of acceptor solution is added to the upper acceptor side, and it is stored in a thermostat at 25°C. ii-2. Sampling is performed after 2 hours, 4 hours, and 6 hours. After sampling 100 μL of the upper layer into a 1.5 mL microtube, 100 μL of acceptor solution is added again. ii-3. 100 μL of DMSO is added to the 1.5 mL microtube and diluted 2-fold. ii-4. The amount of β-caryophyllene permeated is quantified by HPLC. (The HPLC conditions are the same as those in the above "Stability Test".) ii-5. The membrane permeation amount and membrane permeation coefficient (P ａｐｐ ) are calculated. The calculation formula for the membrane permeation coefficient is as follows.

[0097] P ａｐｐ = (dQ / dt) / (C １ (0) × S) P ａｐｐ : Membrane permeation coefficient (cm / sec) C １ (0): Drug addition concentration on the donor side (μg / mL) S: Membrane surface area (cm ２ ) dQ / dt: Membrane permeation rate (μg / sec)

[0098] 2. Preparation of the Composition Raw materials were weighed according to the following formulation in a 13.5 mL screw vial. After heating the vial in a warm bath at 80°C for 15 minutes, it was stirred with a stirrer for 15 - 30 minutes while maintaining 80°C to prepare the composition.

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111] Of the compositions described above, phase separation was observed in formulations 50-55, 59-61, and 64-65. Furthermore, in formulations 56-58, 62, and 63, the oil phase separated upon the addition of water, and self-emulsification was not observed. For the other formulations, self-emulsifying compositions were obtained. This confirmed that self-emulsifying compositions cannot be obtained with sucrose fatty acid esters. Additionally, it was confirmed that while some compositions without phase separation were obtained with polyglycerin fatty acid esters with an HLB value of less than 10, self-emulsifying compositions could not be obtained.

[0112] 3. Storage Test The self-emulsifying composition obtained above was subjected to a storage test at 40°C, and the remaining percentage of β-caryophyllene after the storage test was determined. The remaining percentage was measured using the method described in the "Stability Test" section above. The results are shown in the table below. In the table, "Error" indicates that measurement was not possible due to an error. Also, "-" in the table indicates that measurement was not possible because phase separation occurred.

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119] For prescriptions 1-9 and 37-49, the survival rate remained above 90% after 8 weeks at 40°C. For some prescriptions, the survival rate remained above 90% even after 24 weeks at 40°C. For prescriptions 10-36, only data is available after 4 weeks at 40°C, but all maintained a survival rate above 90%, indicating favorable results.

[0120] 4. Particle Size The particle size of the self-emulsifying composition described above was measured after adding water and self-emulsifying it. The particle size was measured using the method described in "Particle Size Measurement" above. The results are shown in the table below.

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] All self-emulsifying compositions are D ５０ The particles exhibited a size of 1 μm or less, indicating that good self-emulsification was achieved.

[0129] 5. The membrane permeability of the permeable composition was tested. The amount of permeation was measured and the permeation coefficient was determined using the method described in the "Membrane Permeation Test (PAMPA)" section above. The results are shown in the table below.

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136] From the above results, no particular correlation was found between particle size and permeability. Based on a comprehensive assessment of persistence, particle size, and permeability, compositions using hexaglyceryl laurate and decaglyceryl laurate yielded good results (e.g., formulations 37-40, 46). In addition, compositions using PEG-40 hydrogenated castor oil (formulation 4) and caprylocaproyl polyoxyl-8 glyceride (formulation 8), although these are not permitted for use in food products in Japan, also yielded good results.

[0137] 7. Ratio Examination Compositions were prepared by adjusting the ratio of β-caryophyllene to emulsifier according to the following formulation, using lauroyl polyoxyl-32 glyceride (Gattefosse, Gelucire 44 / 14), PEG-60 hydrogenated castor oil (Nikko Chemicals, NIKKOL HCO-60), polysorbate 20 (Nikko Chemicals, NIKKOL TL-10), and decaglyceryl monolaurate (Nikko Chemicals, NIKKOL Decaglyn 1-L) as emulsifiers.

[0138]

[0139]

[0140] Self-emulsifying compositions were obtained for all of the above formulations. It was found that self-emulsifying compositions could be prepared with a β-caryophyllene content in the range of 1 to 50% by mass. Furthermore, it was found that self-emulsifying compositions could be obtained for all emulsifiers with a β-caryophyllene:emulsifier ratio of 1:1 to 1:99.

[0141] This invention provides a self-emulsifying composition containing β-caryophyllene. This invention can be used in fields such as food, pharmaceuticals, cosmetics, bath and toiletry products, household products, and insect repellents.

Claims

1. A self-emulsifying composition comprising one or more emulsifiers selected from the group consisting of polyglycerin fatty acid esters with an HLB value of 10 or higher, polyoxylglycerides, hydrogenated castor oil derivatives, and polyoxyethylene sorbitan fatty acid esters, and β-caryophyllene, wherein the mass ratio of β-caryophyllene to emulsifier is 5:4 to 1:

99.

2. The composition according to claim 1, wherein the emulsifier is a polyglycerol fatty acid ester with an HLB value of 10 or higher.

3. The composition according to claim 1, wherein the emulsifier is one or more emulsifiers selected from the group consisting of decaglyceryl monolaurate, hexaglyceryl monolaurate, decaglyceryl monostearate, decaglyceryl monooleate, lauroyl polyoxyl-32 glyceride, PEG-60 hydrogenated castor oil, PEG-100 hydrogenated castor oil, polysorbate 20, and polysorbate 65.

4. The composition according to claim 1, further comprising a sorbitan fatty acid ester, a polyglycerol polyfatty acid ester, and / or a medium-chain fatty acid triglyceride.

5. The particle size of the self-emulsified emulsion in an aqueous medium is the median diameter (D ５０ The composition according to any one of claims 1 to 4, wherein the size is 1 μm or less.

6. The composition according to any one of claims 1 to 4, which does not undergo phase separation after being stored at 40°C for 8 weeks.

Images