Self-emulsifying components

Abstract

This invention provides a composition that improves the bioavailability of β-caryophyllene. [Solution] Polyglycerin fatty acid esters with an HLB value of 10 or more, polyoxyglycerin It consists of lydo, hydrogenated castor oil derivative, and polyoxyethylene sorbitan fatty acid ester. A self-emulsifying composition comprising one or more emulsifiers selected from the group and β-caryophyllene.

Description

[Technical Field]

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

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

[0003] β-caryophyllene has anti-inflammatory, anti-allergic, antihistamine, and antiviral effects. Anti-cancer effect, latent anti-cancer effect, analgesic effect, sedative effect, bactericidal effect, anti-inflammatory effect, bacteriostatic effect, immune effect It is a useful substance known for its stimulating and stomach-strengthening effects.

[0004] However, β-caryophyllene is hydrophobic and has poor bioavailability. This is a drawback.

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

[0006] [Patent Document 1] International Publication No. 2017 / 149392 [Overview of the project] [Problems that the invention aims to solve]

[0007] The present invention provides a composition that improves the bioavailability of β-caryophyllene. The purpose is to achieve this. [Means for solving the problem]

[0008] The inventors of the present invention have diligently studied to solve the above problems and have found that a specific emulsifier and β-caryophyll We discovered that a self-emulsifying composition can be created by mixing with Len, and thus completed the present invention. Ta.

[0009] In other words, the present invention: (1) Polyglycerin fatty acid esters, polyoxylglycerides, and water with an HLB value of 10 or higher. Selected from the group consisting of castor oil derivatives and polyoxyethylene sorbitan fatty acid esters. A self-emulsifying composition comprising one or more selected emulsifiers and β-caryophyllene; (2) The emulsifier is a polyglycerin fatty acid ester with an HLB value of 10 or higher, the same as in (1) emulsifying composition; (3) Emulsifiers include decaglyceryl monolaurate, hexaglyceryl monolaurate, mono Decaglyceryl stearate, decaglyceryl monooleate, lauroyl polyoxyl -32 Glycerides, PEG-60 Hydrogenated Castor Oil, PEG-100 Hydrogenated Castor Oil, Polysorbate One or more emulsifiers selected from the group consisting of bait 20 and polysorbate 65. (1) Self-emulsifying composition; (4) Furthermore, sorbitan fatty acid esters, polyglycerin polyfatty acid esters and / or A self-emulsifying composition of (1) containing medium-chain fatty acid triglycerides; (5) The particle size of the emulsion that self-emulsifies in an aqueous medium is the median diameter (D 50 ) 1 μm or less One of the following self-emulsifying compositions: (1) to (4); (6) Self-emulsifying of any of (1) to (4) that does not undergo phase separation after storage at 40°C for 8 weeks. composition, Regarding. [Effects of the Invention]

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

Brief Description of the Drawings

[0011] [Figure 1] Figure 1 is a diagram showing the self-emulsifying compositions of Formulations 1 to 3 examined in the examples and those obtained by adding water thereto. The group on the left is the self-emulsifying composition, and the group on the right is the one obtained by adding water. No phase separation is observed in the self-emulsifying composition, and the one obtained by adding water can self-emulsify. [Figure 2] Figure 2 is a diagram showing the self-emulsifying compositions of Formulations 37 to 42 examined in the examples. No phase separation is observed. [Figure 3] Figure 3 is a diagram showing the self-emulsifying compositions of Formulations 37 to 42 examined in the examples to which water has been added. No separation such as oil floating is observed, and they can self-emulsify. [Figure 4] Figure 4 is a diagram showing the compositions of Formulations 50 to 55 using sucrose fatty acid ester examined in the examples. Phase separation has occurred. [Figure 5] Figure 5 is a diagram showing the compositions of Formulations 56 to 58 using decaglyceryl distearate with HLB 9.5 examined in the examples and those obtained by adding water thereto. The group on the left is the composition, and the group on the right is the one obtained by adding water. Although no phase separation is observed in the composition, separation of the oil component is observed in the one obtained by adding water, and self-emulsification cannot be achieved. [Figure 6] Figure 6 is a diagram showing an overview of the membrane permeation test (PAMPA).

Modes for Carrying Out the Invention

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

[0013] The β-caryophyllene in this aspect is a natural volatile component contained in essential oils obtained from plants of the Myrtaceae family such as cloves, and is used as a fragrance that can also be used in foods. <00​ It is.

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

[0015] β-caryophyllene includes, but is not limited to, the following isomers, but (-)-β-caryophyllene It is preferable that it be Riofilene.

[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, or by synthesis. You may also use commercially available products. For example, commercially available products include those manufactured by Takasago International Corporation. Products manufactured by Tokyo Chemical Industries, Ltd. and Wako Pure Chemical Industries, Ltd. are known to be produced by these companies.

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

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

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

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

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

[0023] As an ester of β-caryophyllene, for example, the methyl group in β-caryophyllene is One example is the esterified form of β-caryophyllene, which is formed by esterification with rubonic acid. Yes, it is possible. Specifically, for example, when a methyl group is esterified with a carboxylic acid, a 14- Examples include acetoxy-β-caryophyllene.

[0024] The plants containing the above-mentioned β-caryophyllene are not particularly limited, but for example, Robe (Syzygium aromaticum), Asa (Cannabis sat) iva), rosemary (Salvia rosmarinus), hops (Humul) Examples include *Us lupulus*, etc.

[0025] The extraction site is not particularly limited as long as it achieves the effects of the present invention, and can be the whole plant or The necessary parts are (flower, flower head, flower bud, bud, flower spike, leaf, branch, branch leaves, rhizome, root bark, root, bark, fruit) Any of the following may be used: fruit, peel, legume, seeds, etc. The part extracted may be, for example, root, stem, leaves. And, at least one species selected from the group consisting of flowers, including stems, leaves, and flowers Preferably, at least one species is selected from the group consisting of stems and flowers. At least one of these is more preferable.

[0026] The extraction method is not particularly limited; known methods such as continuous extraction, immersion extraction, and countercurrent extraction may be used. This can be done using conventional extraction methods, purification methods, concentration methods, synthesis methods, drying and powdering methods, etc. The extract may be the crude extract as is, or it may be a purified version of the crude extract, or concentrated. It's fine even if it's a rationalized version.

[0027] For example, clove extract is made from the stems and flowers of the clove plant, and is extracted with water and / or organic solvents. The extract is obtained by immersion extraction and filtering off the residue, and the solvent is removed from this extract. The above-mentioned extract or solvent-removed product, or their fine powder, or the above-mentioned extract or solvent-removed product, using a suitable solvent Dissolved, dispersed, or diluted products can be used, and commercially available products can also be used. .

[0028] In this specification, when using plant extracts, more specifically, water is used as the extraction solvent. (including hot water), methanol, ethanol, isopropanol, ethylene glycol, 1, 3-Butylene glycol, alcohols such as glycerin, esters such as ethyl acetate, Ketones such as cetone and methyl ethyl ketone, nitriles such as acetonitrile, diethyl Ethers such as ethers, tetrahydrofurans, pentane, hexane, cyclopentane, Saturated hydrocarbons such as cyclohexane, aromatic hydrocarbons such as toluene, dichlorometh Halogenated hydrocarbons such as chloroform, and other dimethylformamide, dimethyl Use organic solvents such as sulfoxides (which may be entirely water-containing or anhydrous) as appropriate. It may contain one or any mixture of two solvents. Water, ethanol, 1,3-butylene glycol, or a mixture thereof is preferred. The extracts listed in the details can be obtained from various raw material companies, and they are usually excipients. They are often sold as a set including this, but this is not limited to that.

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

[0030] The emulsifier contained in the self-emulsifying composition of this embodiment is polyglycerin lipid with an HLB value of 10 or higher. Fatty acid esters, polyoxylglycerides, hydrogenated castor oil derivatives and polyoxyethylene One or more emulsifiers selected from the group consisting of sorbitan fatty acid esters. In terms of form, polyoxylglycerides are converted into oleoyl polyoxyl-6 glycerides. Caprylocaproyl polyoxyl-8 glyceride, linoleyl polyoxyl-6 glyceride The 'd' is removed. Also, in one embodiment, PEG-35 hydrogenated castor oil derivatives are used. Castor oil and PEG-40 hydrogenated castor oil are removed. In other embodiments, polyoxyen Polysorbate 60, polysorbate 80, and Polysorbate 85 will be removed.

[0031] In one embodiment, the emulsifier in this embodiment is a polyglycerin fatty acid ester. For example, decaglyceryl monolaurate is a specific example of a polyglycerol fatty acid ester. For example, Nikko Chemicals Co., Ltd., NIKKOL Decaglyn 1-L), Monolauri Hexaglyceryl phosphate (e.g., Nikko Chemicals Co., Ltd., NIKKOL Hexagly n 1-L), Decaglyceryl monostearate (e.g., Nikko Chemicals Co., Ltd., NI KKOL Decaglyn 1-SV), hexaglyceryl monostearate (for example) Nikko Chemicals Co., Ltd., NIKKOL Hexaglyn 1-SV), Monoolein Decaglyceryl acid (e.g., Nikko Chemicals Co., Ltd., NIKKOL Decaglyn) 1-OV), hexaglyceryl monooleate (e.g., Nikko Chemicals Co., Ltd., NIK Examples include KOL Hexaglyn 1-OV, but are not limited to these. In a more accurate embodiment, the polyglycerol fatty acid ester is decaglyceryl monolaurate. Hexaglyceryl monolaurate, decaglyceryl monostearate, or monoolein Decaglyceryl acid. In a more preferred embodiment, polyglycerol fatty acid ester. These are decaglyceryl monolaurate or hexaglyceryl monolaurate. Polyglycerin fatty acid esters are permitted for use in food products in Japan. The fact that they are present is also a positive point.

[0032] In one embodiment, the HLB value of the polyglycerin fatty acid ester is 10 or higher, for example. These ranges include 10-20, 12-18, 15-17, and 10-13. Note that HLB values ​​above 10 are also included. A polyglycerol fatty acid ester may be mixed with an emulsifier with an HLB value of less than 10.

[0033] In one embodiment, the emulsifier in this embodiment is polyoxylglyceride. A specific example of polyoxyglyceride is lauroyl polyoxyl-32 glyceride (for example) Gattefosse GmbH, Gelucire 44 / 14), Caprilo Caproilpo Lioxyl-8 glyceride (e.g., Gattefosse, Labrasol), Thearoyl polyoxyl-32 glyceride (e.g., Gattefosse, Gelu) Examples include, but are not limited to, cire 50 / 13. Preferred Embodiments Therefore, polyoxylglyceride is lauroyl polyoxyl-32 glyceride.

[0034] In one embodiment, the emulsifier in this embodiment is a vitamin E derivative. As a specific example of an E derivative, D-α-tocopherol polyethylene glycol 1000 koha One example is citric acid (for example, Sigma-Aldrich's TPGS1000), but It is not limited to this.

[0035] In one embodiment, the emulsifier in this embodiment is a hydrogenated castor oil derivative. As a specific example of castor oil derivatives, PEG-10 hydrogenated castor oil (for example, Nikko Chemicals Co., Ltd.) NIKKOL HCO-10), PEG-35 Hydrogenated Castor Oil (e.g., BASF, Ko Illiphor EL), PEG-40 Hydrogenated Castor Oil (e.g., Nikko Chemicals, NI) KKOL HCO-40), PEG-50 Hydrogenated Castor Oil (e.g., Nikko Chemicals Co., Ltd., N IKKOL HCO-50), PEG-60 Hydrogenated Castor Oil (for example, Nikko Chemicals Co., Ltd.) NIKKOL HCO-60), PEG-100 Hydrogenated Castor Oil (e.g., Nikko Chemicals) Examples include, but are not limited to, NIKKOL HCO-100. In a more accurate embodiment, the hydrogenated castor oil derivative is PEG-35 hydrogenated castor oil, PEG-40 hydrogenated castor oil Castor oil, PEG-60 hydrogenated castor oil, or PEG-100 hydrogenated castor oil. In the most recent embodiment, the hydrogenated castor oil derivative is PEG-60 hydrogenated castor oil or PEG-1 It is hydrogenated castor oil.

[0036] In one embodiment, the emulsifier in this embodiment is polyethylene glycol hydroxy It is a fatty acid. A specific example of polyethylene glycol hydroxy fatty acid is polyethylene. Glycol(15)-hydroxystearic acid (e.g., BASF, Kolliphor) HS15) is one example, but it is not limited to this.

[0037] In one embodiment, the emulsifier in this embodiment is polyoxyethylene sorbitan fat. It is an acid ester. A specific example of polyoxyethylene sorbitan fatty acid ester is poly Solvate 20 (e.g., Nikko Chemicals, NIKKOL TL-10), Polysolvate T40 (for example, Nikko Chemicals Co., Ltd., NIKKOL TP-10EX), Polysorbate 6 5 (for example, Nikko Chemicals, NIKKOL TS-30V), Polysorbate 80 (example) Examples include Nikko Chemicals Co., Ltd. (NIKKOL TO-10V), but these are not the only ones. Not determined. In preferred embodiments, polyoxyethylene sorbitan fatty acid ester is The more preferred is resorbate 20, polysorbate 65, or polysorbate 80. In the embodiment, polyoxyethylene sorbitan fatty acid ester is polysorbate 20 or It is polysorbate 65.

[0038] In one embodiment, the self-emulsifying composition of this embodiment further comprises sorbitan fatty acid ester , containing polyglycerol polyfatty acid esters and / or medium-chain fatty acid triglycerides. A specific example of a sorbitan fatty acid ester is sorbitan monolaurate (for example, Nikko Chemical (Kalz Corporation, NIKKOL SL-10), sorbitan monooleate (e.g., Nikko Chemical Co.) Luz Corporation, NIKKOL SO-10V), sorbitan monostearate (e.g., Nikko Chemical) Kals Corporation, NIKKOL SS-10V), sorbitan trioleate (for example, Nikko Chemical) Examples include, but are not limited to, those from Kals Corporation (NIKKOL SO-30V). In a preferred embodiment, the sorbitan fatty acid ester is sorbitan monolaurate. Examples of polyglycerol polyfatty acid esters include decaglyceryl distearate (example) For example, Nikko Chemicals Co., Ltd., NIKKOL Decaglyn 2-SV, Tristearin Decaglyceryl acid (e.g., Nikko Chemicals, NIKKOL Decaglyn 3-S) V), Decaglyceryl pentaoleate (e.g., Nikko Chemicals, Inc., NIKKOL De Examples include, but are not limited to, caglyn 5-OV. Preferred implementation In this context, polyglycerol polyfatty acid ester is decaglyceryl distearate. A specific example of a chain fatty acid triglyceride is tri(caprylic / capric acid) glyceryl( For example, Nikko Chemicals Co., Ltd. produces NIKKOL Triester F-810, but These sorbitan fatty acid esters, polyglycerin polyfatty acid esters Medium-chain triglycerides are permitted for use in food products in Japan. The fact that they are present is also a positive point.

[0039] In one embodiment, a preferred combination of emulsifiers for the self-emulsifying composition of this embodiment is, Liglycerin fatty acid esters and sorbitan fatty acid esters, or polyglycerin fats These are fatty acid esters and medium-chain triglyceride fatty acids. More specific combinations of emulsifiers. Examples include hexaglyceryl monolaurate or decaglyceryl monolaurate, Combination with sorbitan monolaurate or caprylic / capric triglyceride These combinations are permitted for use in food products within Japan. It is also desirable in that respect.

[0040] In one embodiment, a preferred combination of emulsifiers for the self-emulsifying composition of this embodiment is water Combinations of castor oil derivatives or polyoxylglycerides with medium-chain triglyceride fatty acids It is a combination. As a more specific example of an emulsifier combination, caprylocaproyl polio Xyl-8 glyceride or PEG-40 hydrogenated castor oil and tri(caprylic / caprin) One example is a combination with glyceryl acid.

[0041] In one embodiment, the self-emulsifying composition of this embodiment may contain a sucrose fatty acid ester. It does not need to be included.

[0042] The self-emulsifying composition of this embodiment may further contain a hydrophobic antioxidant, or may not contain one. It may also be used. Examples of hydrophobic antioxidants include carotene, tocopherol (vitamin E), and b Chilled hydroxyanisole (BHA), butylated hydroxytoluene (BHT), oil-soluble Examples include rosemary extract and ubiquinol (coenzyme Q). Preferred fruits In terms of application methods, the hydrophobic antioxidant is vitamin E.

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

[0044] In one embodiment, the emulsifier content in the self-emulsifying composition of this embodiment is 40 to 99% by mass. %, e.g. 50-95% by mass, 60-90% by mass, 70-85% by mass, 75-80% by mass And so on.

[0045] The ratio of β-caryophyllene to the emulsifier in the self-emulsifying composition of this embodiment is not particularly limited. For example, the ratio of β-caryophyllene to emulsifier (mass ratio) is 2:1 to 1:20, and for example, 1:1 Examples include ~1:15, 1:5~1:10, etc.

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

[0047] The self-emulsifying composition of this embodiment can maintain β-caryophyllene in a stable state. In terms of form, when the self-emulsifying composition of this embodiment is stored at 40°C for 8 weeks, β-caryophylle The remaining percentage of β-caryophyllene is 85% or more compared to the amount of β-caryophyllene immediately after manufacturing, for example, 9 The remaining percentage is 0% or more, and 95% or more. In this specification, the remaining percentage is as described in the "Stability Test" section below. It can be measured based on the method described.

[0048] The self-emulsifying composition of this embodiment has a small particle size in the self-emulsifying liquid obtained by adding an aqueous medium. This may result in a good emulsified state. In one embodiment, the self-emulsification of this embodiment The composition, when self-emulsified by adding an aqueous medium such as water, has a particle size of D 10 0.5 μm For example, the following are 0.3 μm or less, 0.2 μm or less, and 0.01 to 0.5 μm. In terms of form, the self-emulsifying composition of this embodiment, when an aqueous medium such as water is added and self-emulsifies... The particle size is D 50 For example, 1 μm or less, 0.5 μm or less, 0.2 μm or less, 0.01 μm or less. It is 1 μm. In one embodiment, the self-emulsifying composition of this embodiment is an aqueous medium such as water. The particle size when added and self-emulsified is D 90 3μm or less, e.g. 2μm or less, 1μm or less The particle size ranges from 0.01 to 5 μm. In this specification, particle size is measured using dynamic light scattering particle size distribution measurement. It can be measured using a standard instrument. More specifically, particle size is described in the "Particle Size Measurement" section below. It can be measured based on the established method.

[0049] The self-emulsifying composition of this embodiment may exhibit improved bioavailability. In terms of form, the self-emulsifying composition of this embodiment showed the results after 2 hours in a membrane permeability test (PAMPA). The amount transmitted is 2 μg or more, for example, 2 to 10 μg or 3 to 7.5 μg. In one embodiment, Therefore, the amount of PAMPA permeated by the self-emulsifying composition of this embodiment after 4 hours is 4 μg or more, for example. The amounts are 4-15 μg and 5-12 μg. In one embodiment, the self-emulsifying composition of this embodiment The amount of permeation after 6 hours in PAMPA is 5 μg or more, for example, 5-20 μg, 10-15 This is μg. In one embodiment, the membrane permeability of the self-emulsifying composition of this embodiment in PAMPA is The coefficient is 2 × 10 -6 cm / sec or faster, for example, 2 to 10 × 10 -6 cm / sec, 3 ~5×10 -6 The rate is cm / sec. In this specification, the membrane permeation test is referred to as the "membrane permeation test" below. This can be implemented based on the method described in the section "(PAMPA)".

[0050] In one embodiment, the composition of this embodiment uses β-caryophyllene as an active ingredient, and is anti Inflammatory effect, anti-allergic effect, antihistamine effect, antiviral effect, latent anti-cancer effect, Analgesic effect, sedative effect, bactericidal effect, anti-inflammatory effect, bacteriostatic effect, immune stimulating effect, stomachic effect, internal It has effects such as regulating the body's metabolism, reducing or improving discomfort after drinking alcohol, and anti-aging effects.

[0051] In one embodiment, the composition of this embodiment is used, for example, as an additive to food and beverages, animal feed, and pet food. It can be added to or mixed with these. Alternatively, for example, it can be used as is with food and beverages. It can be used as such. Alternatively, the composition of this embodiment can be used as a pharmaceutical composition or a food composition. It can be used, but is not limited to, anti-inflammatory, anti-allergic, antihistamine, and antiviral effects. Pain relief, sedation, antiseptic, anti-inflammatory, bacteriostatic, immune stimulant, stomachic, circadian rhythm regulation, relief of discomfort after drinking alcohol Food and beverages that explicitly or implicitly display claims related to reduction or improvement, anti-aging, etc., i.e., health It can be used as a food, a functional food, a food for sick people, and a food for specified health uses.

[0052] Furthermore, even if the above-mentioned functional claims are not explicitly or implicitly stated, hospitals and / or It can be used as a so-called doctor's supplement provided by a doctor at a clinic. For example, if someone seeks medical attention for an allergy, they may be offered a prescription at the hospital or pharmacy. Other possible supplements include:

[0053] The composition of this embodiment can be used, for example, orally, pulmonaryly, or nasally, sublingually, or transdermally. It can be used for various purposes. The β-caryophyllene contained in the composition of the invention is a volatile component. Therefore, the above effects can be achieved not only through oral ingestion, but also through nasal and pulmonary absorption. Furthermore, the β-caryophyllene contained in the composition of this embodiment is used in sublingual tablets and orally disintegrating tablets. Tablets, chewable tablets, buccal tablets, candies, etc., are held in the oral cavity by known methods and absorbed sublingually. The effects of the present invention can also be achieved by doing so.

[0054] The composition of this embodiment may be, for example, a solid dosage form (tablet, orally disintegrating tablet, sublingual tablet, granule, fine granule). (Powder, capsules, chewable tablets, buccal tablets, candies, etc.) and liquid preparations (syrup, suspension) It can be used in various formulations such as ointments, sprays, creams, gels, and liquid foods. This can be done. When preparing the composition of this embodiment as a food composition, it can be done in the same way as known pharmaceutical preparations. It can be manufactured, for example, by combining an active ingredient with excipients that are acceptable as pharmaceuticals or food products. After mixing with a carrier, etc., it can be manufactured using conventional methods. The formulation forms are: While not limited to these, tablets, orally disintegrating tablets, and sublingual tablets are preferred in order to significantly enhance the effects of the present invention. , granules, powders, capsules, chewable tablets, buccal tablets, candies, sprays or liquids It is preferable to use sublingual tablets, capsules, chewable tablets, or buccal tablets.

[0055] For example, in the case of tablets, the active ingredient is mixed with a pharmaceutically acceptable carrier component (such as an excipient). It can be prepared by compression molding, and confectionery tablets such as candy are injected into a mold. It may also be prepared by the following method. The tablets may be coated with sugar to make sugar-coated tablets. Furthermore, the tablets may be single-layer tablets or multi-layer tablets such as double-layer tablets.

[0056] Granular materials such as powders are produced using various granulation methods (extrusion granulation, crushing granulation, dry compaction granulation, flow granulation). The tablets may be prepared by methods such as dynamic granulation, rolling granulation, or high-speed stirring granulation. The product can be prepared by appropriately combining methods such as granulation and tableting (wet tableting and direct tableting).

[0057] Soft capsules consist of a sheet made from the components of the capsule shell, in which the capsule contents are filled. It can be formed by filling and compression molding. Manufacturing methods include flat plate type and rotary type. Examples include seamless designs. The components of the capsule coating are not particularly limited, but for example, Examples of polymer components include high molecular weight components and humectants. Examples of high molecular weight components include gelatin and starch. N, pullulan, cellulose, polyvinyl alcohol, succinylated gelatin, agar, gellan Examples include gum, hydroxypropyl cellulose, ethyl cellulose, and carrageenan. The content of polymer components in the capsule coating is not particularly limited; for example, the capsule coating The amount is between 1% by mass and 95% by mass. Furthermore, as a humectant, for example, glucose... Sugars such as sucrose, alcohols such as glycerin, sugar alcohols such as sorbitol, etc. These include the proportions of each component in the capsule shell of a soft capsule formulation, which are not particularly limited. It can be set as needed.

[0058] Rotary method (punching method) manufacturing involves a sheet-like capsule coating that fills with a fluid material. An object is held between the holes of a rotating cylindrical mold and formed into a capsule shape. Meanwhile, The nozzleless (droplet) manufacturing method involves dispensing the capsule coating composition and contents from multiple concentric nozzles. They are dispensed simultaneously, forming a seamless capsule shape.

[0059] Hard capsules are formed by molding the capsule membrane components into a cylindrical body and cap. It can be manufactured by forming a shell and filling it with contents. Formation of the capsule shell of a hard capsule The ingredients are not particularly limited, but for example, gelatin, pullulan, agar, carrageenan, starch Starch hydrolysates, alginic acid and HPMC (hydroxypropyl methylcellulose), Examples include high molecular weight components such as vinyl alcohol (PVA), starch derivatives, and gellan gum. The content of high-molecular-weight components in the capsule coating is not particularly limited, but for example, The concentration is 1% by mass or more and 95% by mass or less relative to the cell coating. Capsule coating of hard capsules The proportions of each ingredient inside are not particularly restricted and can be set as appropriate. (Note: Made of hard capsule material) The capsule coating for the agent may be a commercially available product.

[0060] Also, soups, juices, fruit juices, milk, dairy drinks, whey drinks, lactic acid bacteria drinks, tea Food, alcoholic beverages, coffee beverages, carbonated beverages, soft drinks, water beverages, cocoa beverages, jelly Liquid beverages such as solid drinks, sports drinks, and diet drinks, and semi-solid beverages such as pudding and yogurt. The composition according to this embodiment can be manufactured as a food product, noodle, confectionery, spread, etc. .

[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, Examples include pH adjusters, quality stabilizers, and preservatives.

[0062] Furthermore, when preparing the composition of the present invention primarily for sublingual absorption, for example, in the oral cavity A form with a long retention time is preferred, such as lozenges, chewing gum, compressed candy, and Food formulations such as yogurt candy, gummy candy, caramel, and melt tablets, saliva It may be in the form of a liquid-permeable pouch, and toothpaste (powder toothpaste, moisturizing toothpaste, paste toothpaste) These are formulations of oral hygiene products such as water, toothpaste, mouthwash, and oral gel. That's fine.

[0063] Furthermore, when preparing the composition of the present invention primarily for transpulmonary absorption, for example, in the air A form with a long residence time is preferred, and the method involves administering the inhalation solution by nebulizer, inhalation A method of spraying an aerosol agent using a sprayer, or inhaling an inhalation powder using an inhaler. Methods such as [mentioning specific methods] are also acceptable.

[0064] While not limited to this, when preparing the composition of the present invention primarily for transpulmonary absorption, the combination It is preferable to carry out the process by aerosolizing the product. In this specification, aerosol means gas This refers to a mixture of tiny liquid or solid particles suspended throughout the body and the surrounding gas. The method of forming the aerosol is not particularly limited and can be, for example, a nebulizer, a sprayer, or inhaler. The composition can be aerosolized by this method.

[0065] When preparing the composition of the present invention primarily for transpulmonary absorption, for example, a nebulizer can be used. It is preferable to use aerosolization. The type of nebulizer is not particularly limited, for example If you use a jet, ultrasonic, compressor, or mesh nebulizer, This can be done. If the composition of the present invention is a liquid, for example, soft to aerosolize it. A mist inhaler may be used. Also, if the composition is a solid such as a powder, for example, It is preferable to administer the composition by aerosolizing it using a sprayer or inhaler. The composition is The product may be processed into a dosage form suitable for the sprayer or inhaler to be used. For example, an aerosol formulation. Examples include dry powder formulations and inhalation suspensions.

[0066] When preparing the composition according to this embodiment primarily for transdermal absorption, for example, a cream formulation, Apply known liquid preparations such as gels and ointments to areas where allergic symptoms, inflammation, etc. have occurred. It can also be used with [this method].

[0067] The recommended daily intake of β-caryophyllene for adults varies depending on individual condition, weight, sex, age, and genetics. The activity of the material, the route of ingestion or administration, the schedule of ingestion or administration, the formulation, or other The appropriate amount can be determined depending on the factors. For example, the intake of β-caryophyllene is 5 mg. The above is preferable, 10 mg or more is more preferable, 15 mg or more is even more preferable, and 20 mg The above is particularly preferable. The intake of β-caryophyllene is preferably, for example, 300 mg or less. More preferably 250 mg or less, even more preferably 200 mg or less, and 150 mg or less Particularly preferable. The intake of β-caryophyllene is preferably, for example, 5 to 300 mg. 0~300mg, 15~300mg, 20~300mg, 5~250mg, 10~250 mg, 15~250mg, 20~250mg, 5~200mg, 10~200mg, 15 ~200mg, 20~200mg, 5~150mg, 10~150mg, 15~150m Examples include g, 20-150 mg, etc.

[0068] In another embodiment, the composition of the present invention is prepared primarily for transpulmonary absorption. In some cases, for example, with liquid formulations, the dosage is 1 mL to 10 mL / min, taken over 3 to 20 minutes. Preferably, in the case of a solid formulation, 1 to 2000 μg is administered per use using a sprayer or inhaler, etc. Therefore, it is preferable to ingest it.

[0069] The daily oral intake or dosage for adults will vary depending on the dosage form, for example, If it's a capsule formulation, the dosage is 1-6 capsules, 1-4 capsules, 1-3 capsules, or 1-2 capsules. It is also acceptable to take it in divided capsules; for example, if it is a tablet, take 1-6 tablets, 1-4 tablets, or 1-3 tablets. Alternatively, you may take one or two tablets at a time.

[0070] The composition of this embodiment is administered once to several times a day, usually 1 to 6 times a day, 1 to 3 times a day, or 1 day It may be taken or administered once or twice or at any time and interval, but once a day or Sometimes once is preferable.

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

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

[0073] In this specification, "cosmetic composition" refers to cosmetics and quasi-drugs as defined in the Pharmaceuticals and Medical Devices Act. This includes cosmetics, bath products, fragrances, and other items used on the skin.

[0074] Cosmetic compositions can contain commonly used ingredients as appropriate. The form of the finished product is not particularly limited. Examples of cosmetic compositions in this embodiment include soap, synthetic Cleansing products such as cosmetic soaps, liquid body washes (body soaps), and facial cleansers. Cleansing cream, shampoo, conditioner, cleansing lotion, toner, emulsion, serum, Lotions, liquid packs, paste packs, and other face masks; face powders, liquid face powders, and paste face powders. Cosmetics such as powder, dusting powder, foundation, lipstick, lip balm, lipstick, blush, etc. Products such as eye makeup, eyeliner, eyeshadow, sunscreen, and suntan. Cosmetics, depilatory cosmetics, or shaving lotions and aftershaves Examples include, but are not limited to, shaving cosmetics such as lotions. Cosmetic compositions can be manufactured by methods known to those skilled in the art.

[0075] The cosmetic composition of this embodiment includes, in addition to the raw materials used in self-emulsifying compositions, raw materials commonly used in cosmetics. The ingredients are appropriately selected and added within a range that does not impair the purpose, action, and effect of the present invention. This is possible. Examples of such ingredients include surfactants, oils, humectants, softeners, Texture enhancer, oiliness enhancer, emulsifier, antioxidant, preservative, fungicide, emollient, pH adjuster. Agents, chelating agents, stabilizers, UV absorbers, alcohols, silicon compounds, thickeners, viscosity Degree adjuster, solubilizer, pearlescent agent, fragrance, cooling agent, disinfectant, antibacterial agent, natural extract, colorant Examples include, but are not limited to, colorfastness inhibitors, purified water and other solvents, and propellants.

[0076] The β-caryophyllene content in the cosmetic composition of this embodiment is appropriately selected depending on the intended use. You can choose, but in total, it should be between 0.002 and 40% by mass, for example, between 0.001 and 30% by mass. Examples include %, 0.02-20 mass%, and 0.01-10 mass.

[0077] Furthermore, in one embodiment, the composition of this embodiment is used in bathroom and toiletry products or house products. It can be used as a fixed product.

[0078] Examples of bath and toiletry products or household products include bath cleaners, toy cleaners Laundry detergent, dish soap, laundry detergent, fabric softener, air freshener, deodorizer, bath additive, paper Examples include towels, tissues, wet wipes, toilet paper, etc. These bathroom and toiletry products or household products are available to those skilled in the art. It can be manufactured by methods known to the public.

[0079] In the present embodiment of bath and toiletry products or household products, β-caryophylle The amount of ions can be appropriately selected depending on the application, but the total amount should be between 0.002 and 40. mass%, for example 0.001~30 mass%, 0.02~20 mass%, 0.01~10 mass% It can be listed.

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

[0081] The types of target pests that the insect repellent of this embodiment targets are not particularly limited. For example, these are pests that live both indoors and outdoors, such as the Japanese house mosquito (Culex pipiens), tropical house mosquito (Culex japonica), and common house mosquito (Culex pipiens). Mosquitoes, including Culex tritaeniorhynchus and other house mosquitoes, squid such as Culex pipiens, Asian tiger mosquitoes, Aedes aegypti, Aedes togo, Aedes virosa, Aedes japonica, Aedes leucomaensis, Aedes japonica, Aedes leucomaensis, etc. Aedes mosquitoes, swamp mosquitoes such as Aedes japonica, long-tailed deer such as Aedes japonica, and Chinese mosquitoes. Anopheles mosquitoes such as Anopheles japonica and Anopheles tridentata, and species such as Anopheles japonica and Anopheles japonica. Black flies, horseflies such as the common horsefly and the Japanese white-banded horsefly, house dust mites, dust mites, flour mites, Mites such as predatory mites, sandflies, midges, tsetse flies, fleas, lice , the blood-sucking and biting of bed bugs, assassin bugs, ticks, chiggers, leeches, etc. Pests: Chironomus spp., Chironomus spp., Chironomus rufipes, Chironomus rufipes, Chironomus spp., Chironomus spp. Midges such as Japanese midges, German cockroaches, Oriental cockroaches, American cockroaches, and Japanese cockroaches. Cockroaches such as the common cockroach, brown cockroach, flies, large-headed ants, black garden ants, brown cockroaches Ants such as the Russian weasel and the reticulated ant, termites, wasps, house centipedes, centipedes, and dwarf weevils Insects, confused flour beetles, cigarette beetles, varied carpet beetles, and other insects. Examples include insects and other 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, in addition to the raw materials used in the self-emulsifying composition, inhibits the effects of the present invention. Other components may be included, but only to the extent that they do not cause any adverse reactions. Examples of other components include solvents, nonionic and anionic compounds. Cationic surfactants, antioxidants such as butylhydroxytoluene; citric acid, etc. Stabilizers such as scorbic acid; inorganic powders such as talc and silica; disinfectants, fungicides, deodorizers, fragrances. Examples include agents, fragrances, dyes, UV absorbers, chelating agents, fixatives, pH adjusters, and thickeners. ru.

[0084] The formulation of the insect repellent in this embodiment is not particularly limited, and may include, for example, liquid, emulsion, gel, or paste. Examples include aerosols and pump-type formulations. In the case of liquid formulations, the insect repellent is contained in an appropriate cloth or similar material. It can be used by dipping the area and wiping it, etc. Also, in the case of aerosol or pump-type agents... In addition, insect repellents are used by spraying an appropriate amount onto the application area, such as hands, feet, arms, and clothing. It is possible.

[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 is appropriately selected depending on the intended use. It is possible, but in total, 0.002 to 40% by mass, for example, 0.001 to 30% by mass. Examples include 0.02 to 20% by mass and 0.01 to 10% by mass.

[0087] In one aspect, the present invention comprises mixing β-caryophyllene with an emulsifier. - Provides a method for producing a self-emulsifying composition containing caryophyllene. All the matters described in the previous section can be applied to the manufacturing method of this embodiment.

[0088] In another embodiment, the present invention relates to a pharmaceutical composition, a food composition, and a self-emulsifying composition using the above-mentioned self-emulsifying composition. Products, cosmetic compositions, bath and toiletry products, household products, or insect repellents A manufacturing method is provided. All matters described in the above embodiment of the self-emulsifying composition are applicable to the manufacturing of this embodiment. Applicable to the method. [Examples]

[0089] The present invention will be described in more detail below using examples, but the present invention is not limited to these examples. That's not something you should say.

[0090] 1.Measurement method 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-capped vial in a 40°C constant temperature bath. Then, immediately after preparation or after storage for 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 24 weeks, sample To do it. ii. Take 5-10 mg of the sampled sample into a 1.5 ml microtube, and β - Mix 500-1000 μL of methanol to achieve a caryophyllene concentration of 1-2 mg / ml. It dissolves. iii. Dilute the above dissolved sample 10-fold with acetonitrile and perform HPLC under the following conditions. The amount of β-caryophyllene is quantified. The percentage of β-caryophyllene compared to immediately after production. This is the survival rate.

[0092] HPLC conditions Equipment: 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. 6ID x 50 mm (Nacalai Tesque Co.) Column temperature: 40℃ Flow rate: 1mL / min Measurement wavelength: 210nm Injection volume: 10μL Retention time: 4.7 minutes

[0093] (2) Particle size measurement After sampling 40 mg of each composition into a 50 mL glass container, add 40 mL of distilled water. In addition, a self-emulsifying solution is prepared by mixing. The particle size is then measured under the following conditions.

[0094] Particle size measurement Equipment: Nanotrac UPA (Microtrac) Measurement time: 1 minute Number of measurements: 3 Particle refractive index: 1.81 Measurement temperature: room temperature (25±3℃)

[0095] (3) Membrane permeability test (PAMPA) i. Sample preparation i-1. Weigh 50 or 100 mg of each composition as the amount of β-caryophyllene into a 13.5 mL screw vial so that the final concentration is 1 mg / mL when 10 mL of water is added. i-2. Add 10 mL of water to the above vial and mix and disperse by vortexing. i-3. Prepare a water / 10% DMSO / 5% Tween 80 mixture as the acceptor solution. (Add 4.72 mL of Tween 80 as 5 g. 85.28 mL of water, 10 mL of DMSO, 4.72 mL of Tween 80)

[0096] ii. Membrane permeability test (The outline is shown in Figure 5) ii-1. Use PermeaPad (registered trademark) for the PAMPA test. Add 350 μL of the self-emulsifying solution to the lower donor side and 200 μL of the acceptor solution to the upper acceptor side, and store in a constant temperature bath 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, add 100 μL of the acceptor solution again. ii-3. Add 100 μL of DMSO to a 1.5 mL microtube and dilute it 2-fold. ii-4. Quantify the amount of β-caryophyllene permeated by HPLC. (The HPLC conditions are the same as those in the above "Stability test".) ii-5. Calculate the membrane permeation amount and the membrane permeability coefficient (P app ). The calculation formula for the membrane permeability coefficient is as follows.

[0097] P app = (dQ / dt) / (C1(0)×S) P app : Membrane permeability coefficient (cm / sec) C1(0): Drug addition concentration on the donor side (μg / mL) ​​​​​​​​​​S: Surface area of ​​the film (cm²) 2 ) dQ / dt: Membrane permeation rate (μg / sec)

[0098] 2. Preparation of the composition The raw materials were weighed into 13.5 mL screw vials according to the following formulation. The vials were 80 After heating in a bath at ℃ for 15 minutes, maintain the temperature at 80℃ and stir with a stirrer for 15-30 minutes, then combine. The finished product was prepared.

[0099] [Table 1]

[0100] [Table 2]

[0101] [Table 3]

[0102] [Table 4]

[0103] [Table 5]

[0104] [Table 6]

[0105] [Table 7]

[0106] [Table 8]

[0107] [Table 9]

[0108] [Table 10]

[0109] [Table 11]

[0110] [Table 12]

[0111] Phase separation was observed in formulations 50-55, 59-61, and 64-65 of the above compositions. Furthermore, in formulations 56-58, 62, and 63, the oil phase separates when water is added, self No emulsification was observed. For formulations other than those mentioned above, self-emulsifying compositions were obtained. This confirmed that a self-emulsifying composition could not be obtained with sucrose fatty acid esters. In polyglycerol fatty acid esters with an HLB value of less than 10, some compositions do not exhibit phase separation. Although some compounds were obtained, it was confirmed that a self-emulsifying composition 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 β after the storage test was measured. - The remaining percentage of caryophyllene was determined. The measurement of the remaining percentage was as described in the "Stability Test" section above. The procedure was carried out in accordance with the law. The results are shown in the table below. Note that "Error" in the table indicates that the measurement was not completed due to the error. This indicates that it was not measured. Also, a "-" in the table indicates that measurement was not performed due to phase separation. show.

[0113]

Table 13

[0114]

Table 14

[0115]

Table 15

[0116]

Table 16

[0117]

Table 17

[0118]

Table 18

[0119] Prescriptions 1 to 9 and 37 to 49 all maintained a residual rate of 90% or more after 8 weeks at 40°C. For some prescriptions, the residual rate was still maintained at 90% or more after 24 weeks at 40°C. For prescriptions 10 to 36, only the data after 4 weeks at 40°C were available, but all maintained a residual rate of 90% or more, and good results were obtained.

[0120] Particle size The particle size of the self-emulsifying composition obtained by adding water to the above self-emulsifying composition was measured. The measurement of the particle size was carried out using the method described in the above "Particle size measurement". The results are shown in the following table.

[0121]

Table 19

[0122]

Table 20

[0123]

Table 21

[0124]

Table 22

[0125]

Table 23

[0126]

Table 24

[0127]

Table 25

[0128] Any of the self-emulsifying compositions showed a particle size of 1 μm or less at D 50 indicating that good self-emulsification was achieved. and

[0129] 5. Permeability The membrane permeability of the composition was tested. The permeation amount was measured according to the method described in the section of the above-mentioned "membrane permeation test (PAMPA)", and the permeation coefficient was determined. The results are shown in the following table.

[0130]

Table 26

[0131]

Table 27

[0132]

Table 28

[0133]

Table 29

[0134]

Table 30

[0135]

Table 31

[0136] From the above results, no particular correlation was observed between the particle size results and the permeability results. Remaining When comprehensively judging the persistence, particle size, and permeability, the results of the compositions using hexaglyceryl laurate and decaglyceryl laurate were good (for example, Formulations 37 to 40, 46). Also, although it cannot be used in foods in Japan, the results of the compositions using PEG-40 hydrogenated castor oil (Formulation 4) and caprylocapryl polyoxyl-8 glyceride (Formulation 8) were also good.

Industrial Applicability

[0137] The present invention provides a self-emulsifying composition containing β-caryophyllene. The present invention can be used in fields such as foods, pharmaceuticals, cosmetics, bath and toiletry products, household products, and pest 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 (excluding oleoyl polyoxyl-6 glyceride, caprylocaproyl polyoxyl-8 glyceride, and linoleyl polyoxyl-6 glyceride), hydrogenated castor oil derivatives (excluding PEG-35 hydrogenated castor oil and PEG-40 hydrogenated castor oil), and polyoxyethylene sorbitan fatty acid esters (excluding polysorbate 60, polysorbate 80, and polysorbate 85), and β-caryophyllene.

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 an emulsion that self-emulsifies 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.

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