Self-emulsifying composition

Abstract

A composition having improved bioavailability of β-caryophyllene is provided. The present invention relates to a polyglycerol fatty acid ester having an HLB value of 10 or more, a polyoxylglycerol fatty acid ester having an HLB value of 10 or more, and a polyoxylglycerol fatty acid ester having an HLB value of 10 or more. Lido, 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 contained in essential oils obtained from cloves, which are plants of the Myrtaceae family. It is a natural volatile component that is used as a flavoring agent in foods.

[0003] β-caryophyllene has anti-inflammatory, anti-allergic, anti-histamine and anti-viral properties. anti-cancer effect, analgesic effect, sedative effect, bactericidal effect, anti-inflammatory effect, bacteriostatic effect, immune effect It is known to have stimulating and stomachic effects and is a useful substance.

[0004] However, β-caryophyllene is hydrophobic and has poor bioavailability. This has the following disadvantage.

[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 Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention provides compositions with improved bioavailability of β-caryophyllene. The purpose of this document is to: [Means for solving the problem]

[0008] As a result of intensive research to solve the above problems, the present inventors have found that a specific emulsifier and β-caryophyllus The inventors discovered that a self-emulsifying composition can be prepared by mixing ethylene with water, and completed the present invention. Ta.

[0009] That is, the present invention provides: (1) Polyglycerol fatty acid ester with an HLB value of 10 or more, polyoxylglyceride, water Selected from the group consisting of hydrogenated castor oil derivatives and polyoxyethylene sorbitan fatty acid esters. a self-emulsifying composition comprising one or more emulsifiers selected from the group consisting of β-caryophyllene; (2) The emulsifier is a polyglycerol fatty acid ester having an HLB value of 10 or more. emulsifying composition; (3) The emulsifier is decaglyceryl monolaurate, hexaglyceryl monolaurate, mono Decaglyceryl stearate, Decaglyceryl monooleate, Lauroyl polyoxyl -32 glyceride, PEG-60 hydrogenated castor oil, PEG-100 hydrogenated castor oil, polysol and one or more emulsifiers selected from the group consisting of polysorbate 20 and polysorbate 65. , (1) A self-emulsifying composition; (4) Further, sorbitan fatty acid esters, polyglycerol polyfatty acid esters and / or or a medium-chain triglyceride; (5) The particle size of the emulsion self-emulsified in an aqueous medium is the median diameter (D 50 ) less than 1μm A self-emulsifying composition according to any one of (1) to (4), wherein (6) A self-emulsifying agent selected from any of (1) to (4) that does not undergo phase separation after storage at 40°C for 8 weeks. composition, Regarding. Effect 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] Fig. 1 shows the self-emulsifying compositions of formulations 1 to 3 examined in the examples and those to which water was added. The group on the left is the self-emulsifying composition, and the group on the right is the composition to which water was added. No phase separation was observed in the self-emulsifying composition, and the composition to which water was added was self-emulsified. [Diagram 2] 2 shows the self-emulsifying compositions of formulations 37 to 42 examined in the examples. No phase separation was observed. [Diagram 3] 3 is a diagram showing the self-emulsifying compositions of formulations 37 to 42 examined in the examples when water is added. No separation such as oil floating was observed, and self-emulsification was achieved. [Figure 4] 4 shows the compositions of Formulations 50 to 55 using sucrose fatty acid esters examined in the Examples. Phase separation occurs. [Diagram 5] 5 shows the compositions of formulas 56 to 58 using decaglyceryl distearate with HLB 9.5, which were examined in the examples, and those to which water was added. The group on the left is the composition, and the group on the right is the one to which water was added. Although no phase separation was observed in the composition, separation of oil was observed in the one to which water was added, and self-emulsification was not achieved. [Figure 6] FIG. 6 shows an outline of the membrane permeation test (PAMPA). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

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

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

[0015] β-Caryophyllene includes the following isomers, including but not limited to (-)-β-caryophyllene: It is preferably lyophyllene.

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

[0017] β-Caryophyllene may be obtained by extraction and / or purification from plants, or it may be obtained synthetically. Commercially available products may be used, for example, Takasago International Corporation's Products manufactured by Tokyo Chemical Industry Co., Ltd. and Wako Pure Chemical Industries, Ltd. are known.

[0018] β-Caryophyllene may be in the free form or in the form of a pharma- ceutically acceptable salt or ester. It may be in the form of a terephthalate.

[0019] Pharmaceutically acceptable salts of β-caryophyllene include, for example, inorganic bases or organic salts. Examples of the salt include salts with basic groups, and salts with basic amino acids.

[0020] Inorganic bases include, for example, alkali metal salts such as sodium and potassium; calcium and Alkaline earth metal salts such as magnesium; ammonium salts, aluminum salts, etc. .

[0021] Examples of the organic base include primary amines such as ethanolamine; diethylamine; Diethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine Secondary amines such as trimethylamine, triethylamine, triethanolamine, Examples of the tertiary amines include 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 Examples of the esters of β-caryophyllene include those formed by esterifying carboxylic acid with Specifically, for example, the 14- Acetoxy-β-caryophyllene and the like can be mentioned.

[0024] The above-mentioned β-caryophyllene-containing plant is not particularly limited, but for example, Robe (Syzygium aromaticum), Cannabis sativa iva), rosemary (Salvia rosmarinus), hops (Humul us lupulus) etc.

[0025] The part to be extracted is not particularly limited as long as the effect of the present invention is exhibited, and the whole plant or are the necessary parts (flowers, flower heads, flower buds, flower heads, leaves, branches, branches and leaves, rhizomes, root bark, roots, bark, fruit The parts to be extracted may be, for example, roots, stems, leaves, and flowers, and at least one selected from the group consisting of stems, leaves, and flowers. At least one selected from the group consisting of stems and flowers is preferred. It is more preferable that at least one of the above be used.

[0026] The extraction method is not particularly limited, and known methods such as continuous extraction, immersion extraction, and countercurrent extraction may be used. The conventional extraction method, purification method, concentration method, synthesis method, dry powder method, etc. can be used. The extract may be a crude extract as it is, or may be a product of further purification treatment, or may be a product of a concentration treatment. It is also acceptable to use a method that has been developed based on the above.

[0027] As an example, clove extracts are extracted from the stems and flowers of cloves using water and / or organic solvents. The extract is obtained by immersing the extract in water and filtering the residue, and removing the solvent from the extract. or fine powder thereof, or the above extract or the solvent-removed product, using a suitable solvent. It is possible to use a solution that has been dissolved, dispersed, or diluted by means of a solvent, or a commercially available product can be used. .

[0028] In the present specification, when a plant extract is used, more specifically, water ( (including hot water), methanol, ethanol, isopropanol, ethylene glycol, 1, Alcohols such as 3-butylene glycol, glycerin, esters such as ethyl acetate, Ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, diethyl Ethers such as ether, tetrahydrofuran, pentane, hexane, cyclopentane, Saturated hydrocarbons such as cyclohexane, aromatic hydrocarbons such as toluene, dichloromethane halogenated hydrocarbons such as chloroform, dimethylformamide, dimethyl Sulfoxides and other organic solvents (which may be all water-containing or anhydrous) may be used appropriately. These solvents may be used alone or in any mixture of two or more. Water, ethanol, 1,3-butylene glycol or a mixture thereof is preferred. The extracts described in the specification are available from various raw material companies and are usually In many cases, they are sold in a form that includes, but is not limited to, the above.

[0029] For example, the extraction solvent for the clove extract is not particularly limited, but may be water, ethanol, or It is preferable that the ethanol used is water-containing ethanol, and it is more preferable that the ethanol used is water-containing ethanol.

[0030] The emulsifier contained in the self-emulsifying composition of this embodiment is a polyglycerin lipid having an HLB value of 10 or more. Fatty acid esters, polyoxylglycerides, hydrogenated castor oil derivatives and polyoxyethylene sorbitan fatty acid esters. In terms of form, polyoxylglycerides include oleoyl polyoxyl-6 glyceride; Caprylocaproyl Polyoxyl-8 Glyceride, Linoleyl Polyoxyl-6 Glyceride In one embodiment, the hydrogenated castor oil derivatives include PEG-35 hydrogenated castor oil. Castor oil and PEG-40 hydrogenated castor oil are excluded. Polysorbate 60, polysorbate 80, and and polysorbate 85 are excluded.

[0031] In one embodiment, the emulsifier in this aspect is a polyglycerol fatty acid ester. Specific examples of polyglycerol fatty acid esters include decaglyceryl monolaurate (e.g., For example, Nikko Chemicals Co., Ltd., NIKKOL Decaglyn 1-L, Monolauryl Hexaglyceryl phosphate (e.g., NIKKOL Hexaglyceryl phosphate) n 1-L), decaglyceryl monostearate (e.g., Nikko Chemicals Co., Ltd., NI KKOL Decaglyn 1-SV), Hexaglyceryl Monostearate (e.g. , Nikko Chemicals Co., Ltd., NIKKOL Hexaglyn 1-SV), Monoolein Decaglyceryl acetate (e.g., NIKKOL Decaglyn 1-OV), hexaglyceryl monooleate (e.g., Nikko Chemicals Co., Ltd., NIK Examples of suitable glycerols include, but are not limited to, KOL Hexaglyn 1-OV. In a preferred embodiment, the polyglycerol fatty acid ester is decaglyceryl monolaurate, Hexaglyceryl Monolaurate, Decaglyceryl Monostearate or Monoolein In a further preferred embodiment, the polyglycerol fatty acid ester is decaglyceryl acid. is decaglyceryl monolaurate or hexaglyceryl monolaurate. Polyglycerol fatty acid esters are permitted for use in food in Japan. This is also preferable in that

[0032] In one embodiment, the polyglycerol fatty acid ester has an HLB value of 10 or more, e.g. 10~20, 12~18, 15~17, 10~13, etc. HLB value is 10 or more. The polyglycerol fatty acid ester may be mixed with an emulsifier having an HLB value of less than 10.

[0033] In one embodiment, the emulsifier in this aspect is a polyoxylglyceride. A specific example of a polyoxylglyceride is lauroyl polyoxyl-32 glyceride (e.g. For example, Gattefosse, Gelucire 44 / 14), Caprylocaproyl Poly Trioxyl-8 glyceride (e.g., Labrasol, Gattefosse), thearyl polyoxyl-32 glyceride (e.g., Gattefosse, Gelu cire 50 / 13), but are not limited to these. In the present invention, the polyoxylglyceride is lauroyl polyoxyl-32 glyceride.

[0034] In one embodiment, the emulsifier in this aspect is a vitamin E derivative. A specific example of an E derivative is D-α-tocopherol polyethylene glycol 1000 coha. Examples of suitable glycerols include glycerol (e.g., TPGS1000, Sigma-Aldrich). Not limited to:

[0035] In one embodiment, the emulsifier in this aspect is a hydrogenated castor oil derivative. A specific example of a malt oil derivative is PEG-10 hydrogenated castor oil (e.g., Nikko Chemicals, NIKKOL HCO-10), PEG-35 hydrogenated castor oil (e.g., BASF, Ko lliphor EL), PEG-40 hydrogenated castor oil (e.g., Nikko Chemicals, NI KKOL HCO-40), PEG-50 hydrogenated castor oil (e.g., Nikko Chemicals, N IKKOL HCO-50), PEG-60 hydrogenated castor oil (e.g., Nikko Chemicals, NIKKOL HCO-60), PEG-100 hydrogenated castor oil (e.g., Nikko Chemicals Examples of the fluororesin include, but are not limited to, NIKKOL HCO-100 (manufactured by NIKKOL Co., Ltd.). In a preferred 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 a preferred embodiment, the hydrogenated castor oil derivative is PEG-60 hydrogenated castor oil or PEG-1 00 hydrogenated castor oil.

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

[0037] In one embodiment, the emulsifier in this aspect is a polyoxyethylene sorbitan fat. Specific examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan fatty acid esters. Sorbate 20 (e.g., Nikko Chemicals, NIKKOL TL-10), Polysorbate Polysorbate 40 (e.g., Nikko Chemicals, NIKKOL TP-10EX), Polysorbate 6 5 (e.g., Nikko Chemicals, NIKKOL TS-30V), polysorbate 80 (e.g., Examples include, but are not limited to, Nikko Chemicals' NIKKOL TO-10V. In a preferred embodiment, the polyoxyethylene sorbitan fatty acid ester is Polysorbate 20, Polysorbate 65 or Polysorbate 80. More preferred In an embodiment, the polyoxyethylene sorbitan fatty acid ester is polysorbate 20 or is polysorbate 65.

[0038] In one embodiment, the self-emulsifying composition of this aspect further comprises a sorbitan fatty acid ester. , polyglycerol polyfatty acid esters and / or medium chain triglycerides. A specific example of a sorbitan fatty acid ester is sorbitan monolaurate (e.g., Nikko Chemical Co., Ltd. Cals Corporation, NIKKOL SL-10), sorbitan monooleate (e.g., Nikko Chemical NIKKOL SO-10V), sorbitan monostearate (e.g., Nikko Chemical Cals, NIKKOL SS-10V), sorbitan trioleate (e.g., Nikko Chemical Examples of the optical fiber filter include, but are not limited to, NIKKOL SO-30V (Calz, Inc.). In a preferred embodiment, the sorbitan fatty acid ester is sorbitan monolaurate. Specific examples of polyglycerol polyfatty acid esters include decaglyceryl distearate (e.g. For example, Nikko Chemicals' NIKKOL Decaglyn 2-SV), tristearin Decaglyceryl acetate (e.g., NIKKOL Decaglyn 3-S, Nikko Chemicals) V), decaglyceryl pentaoleate (e.g., Nikko Chemicals, NIKKOL De caglyn 5-OV), but are not limited to these. In one embodiment, the polyglycerol polyfatty acid ester is decaglyceryl distearate. A specific example of a chain triglyceride is tri(caprylic / capric acid)glyceryl ( For example, Nikko Chemicals' NIKKOL Triester F-810 can be mentioned. These sorbitan fatty acid esters, polyglycerol polyfatty acid esters, In Japan, esters and medium-chain triglycerides are permitted for use in food. This is also preferable in that

[0039] In one embodiment, the preferred combination of emulsifiers for the self-emulsifying composition of this aspect is Ligylcerol fatty acid ester and sorbitan fatty acid ester, or polyglycerol fat Fatty acid esters and medium chain triglycerides. More specific combinations of emulsifiers Examples of the glyceryl monolaurate include hexaglyceryl monolaurate and decaglyceryl monolaurate. In combination with sorbitan monolaurate or tri(caprylic / capric)glyceryl These combinations are approved for use in food products in Japan. It is also favorable in that

[0040] In one embodiment, a preferred combination of emulsifiers for the self-emulsifying composition of this aspect is water. Combination of hydrogenated castor oil derivatives or polyoxylglycerides with medium-chain fatty acid triglycerides A more specific example of a combination of emulsifiers is caprylocaproyl polio. Xyl-8 glyceride or PEG-40 hydrogenated castor oil and tri(caprylic / capric) and glyceryl stearate.

[0041] In some embodiments, the self-emulsifying composition of this aspect may include a sucrose fatty acid ester. , may not be included.

[0042] The self-emulsifying composition of this embodiment may or may not further comprise a hydrophobic antioxidant. Examples of hydrophobic antioxidants include carotene, tocopherol (vitamin E), and bromine. Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), oil-soluble Preferred ingredients include rosemary extract and ubiquinol (coenzyme Q). In an embodiment, 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 % by mass, for example, 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 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 mass ratio of β-caryophyllene to emulsifier is 2:1 to 1:20, for example 1:1 ~1:15, 1:5~1:10, etc.

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

[0047] The self-emulsifying composition of this embodiment can maintain β-caryophyllene in a stable state. In terms of form, the β-caryophyllene content when the self-emulsifying composition of this embodiment was stored at 40° C. for 8 weeks was The residual rate of β-caryophyllene is 85% or more, e.g., 9% or less, compared to the amount of β-caryophyllene immediately after production. In this specification, the residual rate is defined as the residual rate in the "Stability Test" section below. It can be measured according to the methods described.

[0048] The self-emulsifying composition of this embodiment has a small particle size of the self-emulsified liquid self-emulsified by adding an aqueous medium. In one embodiment, the self-emulsifying agent of this embodiment may exhibit a good emulsification state. The composition has a particle size of D when self-emulsified by adding an aqueous medium such as water. 10 0.5μm For example, the thickness is 0.3 μm or less, 0.2 μm or less, or 0.01 to 0.5 μm. In the embodiment, the self-emulsifying composition of the present invention is a self-emulsifying composition that is self-emulsified by adding an aqueous medium such as water. The particle diameter of D 50 1μm or less, for example, 0.5μm or less, 0.2μm or less, 0.01~ In one embodiment, the self-emulsifying composition of this aspect is prepared by dissolving an aqueous medium such as water in water. The particle size when added and self-emulsified is D 90 3μm or less, e.g. 2μm or less, 1μm or less In this specification, the particle size is measured by a dynamic light scattering particle size distribution measurement. More specifically, the particle size can be measured using a measuring device as described in the "Particle Size Measurement" section below. It can be measured based on the method used.

[0049] The self-emulsifying compositions of this embodiment may exhibit improved bioavailability. In the embodiment, the self-emulsifying composition of the present invention is subjected to a membrane permeation test (PAMPA) after 2 hours. The amount of permeation is 2 μg or more, for example, 2 to 10 μg, or 3 to 7.5 μg. The permeation amount of the self-emulsifying composition of this embodiment in PAMPA after 4 hours is 4 μg or more, e.g. In one embodiment, the self-emulsifying composition of this aspect is preferably 4 to 15 μg, more preferably 5 to 12 μg. The amount of permeation after 6 hours in PAMPA is 5 μg or more, for example, 5 to 20 μg, 10 to 15 In one embodiment, the membrane permeability of the self-emulsifying composition of this embodiment in PAMPA is The overshoot coefficient is 2×10 -6 cm / sec or more, e.g., 2 to 10×10 -6 cm / sec, 3 ~5×10 -6 In this specification, the membrane permeation test is the same as the "Membrane Permeation Test" described below. This can be carried out based on the method described in the "PAMPA" section.

[0050] In one embodiment, the composition of this aspect contains β-caryophyllene as an active ingredient and has an anti- Anti-inflammatory, anti-allergic, anti-histamine, anti-viral, potential anti-cancer, Analgesic, sedative, bactericidal, anti-inflammatory, bacteriostatic, immunostimulating, stomachic, and intestinal It has a weight-regulating effect, a reduction or improvement effect of discomfort after drinking alcohol, and an anti-aging effect.

[0051] In one embodiment, the composition of this aspect is, for example, added to food, beverages, feed, or pet food. It can be used as it is, for example, in food and beverages. Alternatively, the composition of this embodiment can be used as a pharmaceutical composition or a food composition. These include, but are not limited to, anti-inflammatory, anti-allergic, anti-histamine, anti-viral, etc. , analgesic, sedative, antiseptic, anti-inflammatory, bacteriostatic, immune stimulating, stomachic, regulating the biological clock, relieving discomfort after drinking alcohol Food and drink that expressly or implies claims related to reducing or improving cholesterol, anti-aging, etc., i.e. health It can be used as a food, a functional food, a food for the sick, or a food for specified health uses.

[0052] In addition, even if no indication of the above functionality is expressly or implied, hospitals and / or It can be used as a so-called doctor's supplement provided by a doctor at a clinic. For example, if a patient visits a hospital or pharmacy for an allergy consultation, the hospital or pharmacy may recommend and prescribe medication. or supplements that can be selected.

[0053] The composition of this embodiment can be administered, for example, orally, pulmonary, nasally, sublingually, or transdermally. The β-caryophyllene contained in the composition of the invention is a volatile component. Therefore, the above effects can be achieved not only by oral ingestion, but also by nasal and pulmonary absorption. In addition, the β-caryophyllene contained in the composition of this embodiment can be used in the form of a sublingual tablet, an oral disintegrating tablet, or the like. The tablets are held in the oral cavity by known methods such as tablets, chewable tablets, buccal tablets, and candies, and are absorbed sublingually. The effects of the present invention can also be achieved by doing so.

[0054] The composition of this embodiment can be, for example, a solid preparation (tablet, orally disintegrating tablet, sublingual tablet, granule, fine granule, etc. , powders, capsules, chewable tablets, buccal tablets, candies, etc.) and liquids (syrups, suspensions, etc.) It can be used in various formulations such as tablets, sprays, creams, gels, ointments, and liquid foods. When the composition of this embodiment is prepared as a food composition, it can be prepared in the same manner as known pharmaceutical preparations. For example, the active ingredient and excipients acceptable for pharmaceuticals and foods can be used in the manufacture of pharmaceuticals. After mixing with the carrier, etc., the composition can be manufactured using conventional means. From the viewpoint of exhibiting the effects of the present invention remarkably, the present invention is not limited to the above, but may be applied to tablets, orally disintegrating tablets, sublingual tablets, etc. , granules, powders, capsules, chewable tablets, buccal tablets, lozenges, sprays or liquids. It is preferable that the tablet is administered as a sublingual tablet, a capsule, a chewable tablet, or a buccal tablet.

[0055] For example, in the case of tablets, the active ingredient is mixed with a pharma- ceutical acceptable carrier ingredient (such as an excipient). Candy and other confectionery tablets can be prepared by pouring them into a mold. The tablets may be prepared by a method such as the above. The tablets may be sugar-coated to form sugar-coated tablets. Furthermore, the tablet may be a single-layer tablet or a layered tablet such as a two-layer tablet.

[0056] Granules and other powders are produced using various granulation methods (extrusion granulation, crushing granulation, dry compaction granulation, flow granulation, etc.). The tablets may be prepared by the above-mentioned methods. It can be prepared by appropriately combining granulation, tableting (wet tableting, direct tableting), etc.

[0057] Soft capsules are made by filling capsule contents into a sheet made from the capsule shell components. The manufacturing method is flat plate type, rotary type, etc. The components of the capsule shell are not particularly limited, but examples thereof include Examples of the polymer component include gelatin, starch, and the like. pullulan, cellulose, polyvinyl alcohol, succinylated gelatin, agar, gellan gum, hydroxypropyl cellulose, ethyl cellulose, carrageenan, etc. The content of the polymer component in the capsule shell is not particularly limited. For example, The amount of the moisturizing agent is 1% by mass or more and 95% by mass or less. sugars such as maltose, alcohols such as glycerin, sugar alcohols such as sorbitol, etc. The blending ratio of each component in the capsule shell of a soft capsule formulation is not particularly limited. It can be set appropriately.

[0058] The rotary method (punching method) is a method in which a sheet-shaped capsule shell is pressed against the flowing filling material. The object is sandwiched between the mold and formed into a capsule shape along the hole of a rotating cylindrical mold. The capsule shell composition and contents are dispensed from multiple concentric nozzles in the drip-type method. are extruded at the same time and formed into a seamless capsule shape.

[0059] Hard capsules are made by molding the capsule membrane components into a cylindrical body and cap shape. The capsule shell of the hard capsule is then filled with the contents. The component is not particularly limited, but examples thereof include gelatin, pullulan, agar, carrageenan, and starch. , starch hydrolysis products, alginic acid, HPMC (hydroxypropyl methylcellulose), poly Examples of polymeric components include polyvinyl alcohol (PVA), starch derivatives, and gellan gum. The content of the polymer component in the capsule shell is not particularly limited. For example, The content is 1% by mass or more and 95% by mass or less of the cell membrane. Capsule membrane of hard capsule The blending ratio of each ingredient in the hard capsule is not particularly limited and can be set appropriately. The capsule coating of the agent may be a commercially available product.

[0060] Also, soups, juices, fruit juice drinks, milk, dairy drinks, whey drinks, lactic acid bacteria drinks, tea drinks drinks, alcoholic beverages, coffee drinks, carbonated drinks, soft drinks, water drinks, cocoa drinks, jelly Liquid beverages such as liquefied beverages, sports drinks, and diet drinks, as well as semi-solid beverages such as pudding and yogurt The composition of this embodiment can be manufactured as molded foods, noodles, confectioneries, spreads, etc. .

[0061] When the composition of this embodiment is prepared as a food composition, various food additives may be added. Food additives include, for example, antioxidants, colorings, flavorings, seasonings, sweeteners, acidulants, Examples include pH adjusters, quality stabilizers, preservatives, etc.

[0062] In addition, when the composition of the present invention is prepared mainly for sublingual absorption, it is preferably administered, for example, in the oral cavity. Forms with long retention times at room temperature are preferred, such as troches, chewing gum, tableted candies, and cheese. Food formulations such as chewy candy, gummy candy, caramel, melt tablets, etc., saliva It may be in the form of a liquid-permeable pouch, and toothpaste (toothpaste powder, moisturizing toothpaste, toothpaste It is used in formulations such as oral hygiene products such as toothpaste, water toothpaste, mouthwash, and oral gel. It is also possible.

[0063] In addition, when the composition of the present invention is prepared mainly for pulmonary absorption, for example, A method of administering the inhalation liquid preparation by a nebulizer, A method of spraying an aerosol agent with a nebulizer, or a method of inhaling a powdered inhalation agent with an inhaler. The method may be a method of making the material

[0064] Although not limited thereto, when the composition of the present invention is prepared mainly for pulmonary absorption, Preferably, the composition is aerosolized. It means a mixture of tiny liquid or solid particles suspended in the body and the surrounding gas. The method for making the composition into an aerosol form is not particularly limited, and examples of the method include a nebulizer, a sprayer, and an inhaler. The composition can be aerosolized by.

[0065] When the composition of the present invention is prepared mainly for pulmonary absorption, it can be administered using, for example, a nebulizer. The type of nebulizer is not particularly limited, and examples thereof include For example, jet, ultrasonic, compressor, or mesh nebulizers can be used. When the composition of the present invention is a liquid, it can be, for example, soft-dissolved in water for aerosolization. A mist inhaler may be used. Also, when the composition is a solid such as a powder, for example, The composition is preferably administered by aerosolization using a nebulizer or inhaler. The composition may be processed into a suitable formulation for use with a nebulizer or inhaler. For example, an aerosol formulation may be used. , dry powder formulations, and inhalation suspensions.

[0066] When the composition of this embodiment is prepared mainly for percutaneous absorption, it may be prepared in the form of, for example, a cream, Apply a known liquid preparation such as gel or ointment to the area where allergic symptoms or inflammation have occurred. It is also possible to use it in the following way.

[0067] The daily intake of β-caryophyllene for adults depends on the individual's condition, weight, sex, age, and nutritional value. the activity of the agent, the route of ingestion or administration, the schedule of ingestion or administration, the formulation or other The amount of β-caryophyllene to be taken can be determined appropriately depending on the factors. For example, the amount of β-caryophyllene to be taken is 5 mg. Preferably, 10 mg or more, more preferably, 15 mg or more, even more preferably, 20 mg or more More than or equal to 300 mg is particularly preferred. The amount of β-caryophyllene to be ingested is preferably, for example, 300 mg or less. Preferably, the amount is less than 250 mg, more preferably less than 200 mg, and even more preferably less than 150 mg. The amount of β-caryophyllene to be ingested is preferably, for example, 5 to 300 mg, and more preferably, 1 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 g, 20 to 150 mg, etc.

[0068] In another embodiment, the composition of the present invention is prepared primarily for pulmonary absorption. For example, in the case of liquid preparations, the dosage is 1 mL to 10 mL / min for 3 to 20 minutes. In the case of a solid formulation, 1 to 2000 μg is preferably administered per dose using a nebulizer or inhaler. Therefore, it is preferable to ingest it.

[0069] The daily oral intake or dosage for adults is determined according to the dosage form, e.g. For capsules, 1-6 capsules, 1-4 capsules, 1-3 capsules, or 1-2 capsules You may take the medicine in capsules. For example, you may take 1-6 tablets, 1-4 tablets, 1-3 tablets, Alternatively, it may be taken in 1-2 divided tablets.

[0070] The composition of this embodiment is administered once or several times a day, typically 1 to 6 times a day, 1 to 3 times a day, or It may be taken or administered once or twice a day or at any time and interval, but should not be taken more than once a day. Sometimes once is preferable.

[0071] In an embodiment, the composition of this aspect can be used as a cosmetic composition. Cut.

[0072] The cosmetic composition of this embodiment is specifically intended to prevent skin symptoms and diseases caused by aging. It may be effective in preventing or ameliorating.

[0073] In this specification, the term "cosmetic composition" refers to cosmetics and quasi-drugs as defined in the Pharmaceutical and Medical Device Act. These include cosmetics, bath additives, and fragrances that are applied to the skin.

[0074] The cosmetic composition may contain any of the commonly used ingredients. The form of the composition is not particularly limited. The cosmetic composition of this embodiment may be, for example, a soap, a synthetic Cosmetic soap, liquid body wash (body soap), face wash and other cleansing products, cleansing products Cream, shampoo, conditioner, cleansing lotion, lotion, milky lotion, serum, Packs such as lotions, liquid packs, paste packs, powdered powders, water powders, kneaded powders, etc. Powder, dusting powder, foundation, lipstick, lip balm, lipstick, blusher, and other cosmetics cosmetics for the eyes such as eyeliner, eyeshadow, sunscreen, suntan Cosmetics, hair removal cosmetics, shaving lotions, aftershave lotions These include, but are not limited to, shaving cosmetics such as lotions. The cosmetic composition may be prepared by any method 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 contain ingredients that are commonly used in cosmetics. The ingredients that can be used are appropriately selected and added within the range that does not impair the purpose, action, and effect of the present invention. Such ingredients include, for example, surfactants, oils, moisturizers, softeners, Texture improver, oiliness agent, emulsifier, antioxidant, preservative, antifungal agent, emollient, pH adjuster agents, chelating agents, stabilizers, UV absorbers, alcohols, silicon compounds, thickeners, viscosity enhancers Tonicity regulator, solubilizer, pearlizing agent, fragrance, cooling agent, disinfectant, antibacterial agent, natural extract, colorant , anti-fading agents, purified water and other solvents, propellants, etc., but are not limited to these.

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

[0077] In one embodiment, the composition of this aspect is a bath / toiletry product or home care product. It can be used as a staple product.

[0078] Examples of bathroom and toiletry products or household products include bathroom detergents, toy cleaners, etc. Laundry detergent, dishwashing detergent, laundry detergent, fabric softener, air freshener, deodorant, bath additives, paper Examples include towels, tissues, wet tissues, toilet paper, etc. These bath and toiletry products or household products are not limited to those described above. The compound can be prepared by known methods.

[0079] The present invention relates to a bath / toiletry product or household product that contains β-caryophyllus. The content of phosphate can be appropriately selected depending on the application, etc., but the total amount should be 0.002 to 40 mass%, for example 0.001~30 mass%, 0.02~20 mass%, 0.01~10 mass% Some examples include:

[0080] In some embodiments, the composition of this aspect can be used as a pest repellent. do.

[0081] The type of pest that the pest repellent of this embodiment targets is not particularly limited. For example, there are pests that live indoors and outdoors, such as Culex pipiens, Culex quinquefasciatus, and Culex mosquito. Mosquitoes, Culex tritaeniorhynchus and other Culex pipiens species, squids such as the Asian giant squid, Asian tiger mosquitoes, Aedes aegypti, Aedes togoi, Aedes vexans, Aedes sieboldii, Aedes niger, Aedes niger, etc. Aedes mosquitoes, marshes such as Asimadarano numbica, long-billed deer such as Kinpara long-billed deer, Anopheles mosquitoes such as Anopheles stephensi, Anopheles minimus, and other Anopheles species, as well as the spotted spotted fly, Juniperus sieboldii, and other species such as Juniperus nigricans. Black flies, horse flies, horseflies such as the white-banded fly, house mites, dust mites, and flour mites. Mites such as chiggers, sandflies, biting midges, tsetse flies, fleas, lice Blood-sucking and biting insects such as bedbugs, assassin bugs, ticks, chiggers, and leeches Pests, midges, giant midges, red midges, striped midges, giant mountain midges Chironomids and other midges, German cockroaches, Smoky brown cockroaches, American cockroaches, and Japanese cockroaches Cockroaches such as brown cockroaches, brown cockroaches, flies, Japanese wood ants, black mountain ants, brown wood ... Ants such as the brown ant and the water ant, termites, wasps, centipedes, centipedes, rice weevils Bugs, red flour beetles, cigarette beetles, stag beetles, stag beetles, stag beetles Examples include stored grain pests such as bugs.

[0082] The pest repellent of this embodiment may contain other pest repellent components, such as DEET.

[0083] In addition to the raw materials used in the self-emulsifying composition, the pest repellent of this embodiment also contains Other components may be included as long as they do not cause any damage to the product. Examples of other components include solvents, nonionic, anionic, etc. ionic or cationic surfactants, antioxidants such as butylhydroxytoluene; citric acid, Stabilizers such as scorbic acid; inorganic powders such as talc and silicic acid; disinfectants, antifungal agents, deodorants, fragrances agents, fragrances, colorants, UV absorbers, chelating agents, retention agents, pH adjusters, thickeners, etc. do.

[0084] The formulation of the pest repellent of this embodiment is not particularly limited, and may be, for example, a liquid, emulsion, gel, or paste. In the case of liquid formulations, the pest repellent is contained in a suitable cloth, etc. It can be used by dipping it in water and wiping the area to be applied. In the case of aerosol or pump formulations, In this case, the pest repellent is used by spraying an appropriate amount on the application area, such as the hands, feet, arms, clothes, etc. It is possible.

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

[0086] The content of β-caryophyllene in the pest repellent of this embodiment can be appropriately selected depending on the application, etc. However, the total amount is 0.002 to 40 mass%, for example, 0.001 to 30 mass%. , 0.02 to 20 mass %, and 0.01 to 10 mass %.

[0087] In one embodiment, the present invention provides a method for producing a β-caryophyllene-based emulsion comprising mixing β-caryophyllene with an emulsifier. The present invention provides a method for producing a self-emulsifying composition containing caryophyllene. All of the matters described above can be applied to the manufacturing method of this embodiment.

[0088] In another aspect, the present invention relates to a pharmaceutical composition, a food composition, or the like, which uses the self-emulsifying composition. products, cosmetic compositions, bath and toiletry products, household products, or pest repellents The above-mentioned matters described in the embodiment of the self-emulsifying composition are all included in the manufacturing method of this embodiment. The method can be applied. 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 the case.

[0090] 1.Measurement method The stability test, particle size measurement, and membrane permeation test in this specification were carried out according to the following methods. .

[0091] (1) Stability testing i. The prepared composition is stored in a screw vial with the lid closed in a thermostatic chamber at 40°C. The samples were then sampled immediately after preparation or after storage for 2, 4, 8, 12, or 24 weeks. Do it. ii. Take 5 to 10 mg of the sample in a 1.5 ml microtube and measure β - Add 500-1000μL of methanol to give a caryophyllene content of 1-2mg / ml Dissolve. iii. The dissolved sample was diluted 10 times with acetonitrile and analyzed by HPLC under the following conditions. The amount of β-caryophyllene is quantified as follows: Percentage of β-caryophyllene compared to that immediately after production 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×50 mm (Nacalai Tesque) Column temperature: 40℃ Flow rate: 1mL / min Measurement wavelength: 210nm Injection volume: 10μL Retention time: 4.7 minutes

[0093] (2) Particle size measurement 40 mg of each composition was sampled in a 50 mL glass container, and then 40 mL of distilled water was added. The particles are then mixed together to prepare a self-emulsifying liquid, the particle size of which is 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-1.1 Each composition was mixed in a 3.5 mL screw vial with water to measure the amount of β-caryophyllene. Weigh out 50 or 100 mg so that the final concentration when 10 mL is added is 1 mg / mL. do. i-2. Add 10 mL of water to the above vial and vortex to disperse. i-3. Prepare a mixture of water / 10% DMSO / 5% Tween 80 as the acceptor solution. (Add 4.72mL of Tween 80 (5g). Add 85.28mL of water and 1 mL of DMSO. 0mL, Tween80 4.72mL)

[0096] ii. Membrane permeation test (outline shown in Figure 5) ii-1. PermeaPad® was used for the PAMPA test, and the donor side of the lower layer Add 350 μL of the self-emulsifying solution to the top layer and 200 μL of the acceptor solution to the top layer. and store in a constant temperature bath at 25°C. ii-2. Sampling was performed after 2, 4 and 6 hours, and 100 μL of the upper layer was removed. After sampling into a 5 mL microtube, add 100 μL of acceptor solution again. . ii-3.Add 100 μL of DMSO to a 1.5 mL microtube to dilute 2-fold. ii-4. The amount of β-caryophyllene that permeated was quantified using HPLC. (HPLC conditions were , Same as "Stability Test" above.) ii-5. Membrane permeation amount and membrane permeability coefficient (P app The membrane permeability coefficient is calculated using the following formula: As shown below.

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

[0098] 2. Preparation of the Composition The raw materials were weighed out according to the following recipe into a 13.5 mL screw vial. After heating in a 15-minute bath at 80°C, the mixture was stirred for 15 to 30 minutes at 80°C. The composition 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] Of the above compositions, phase separation was observed in formulations 50 to 55, 59 to 61, and 64 to 65. In addition, for formulations 56-58, 62, and 63, the oil phase separated when water was added, and the self- No emulsification was observed. For the formulations other than those mentioned above, a self-emulsifying composition was obtained. It was confirmed that a self-emulsifying composition cannot be obtained using sucrose fatty acid esters. In the case of polyglycerol fatty acid esters with an HLB value of less than 10, some compositions do not have phase separation. However, it was confirmed that a self-emulsifying composition could not be obtained.

[0112] 3. Preservation test The self-emulsifying composition obtained above was subjected to a storage test at 40°C. The residual rate of caryophyllene was measured. The residual rate was measured according to the method described in the "Stability Test" section above. The results are shown in the table below. In the table, "Error" indicates that the measurement could not be performed due to an error. In the table, "-" indicates that no measurement was 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] All formulations 1 to 9 and 37 to 49 maintained a survival rate of 90% or more after 8 weeks at 40°C. For some formulations, the survival rate remained at 90% or more even after 24 weeks at 40°C. For 0-36, there is only data after 4 weeks at 40°C, but all of them maintained a survival rate of 90% or more. The results were satisfactory.

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

[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 is D 50 The particle size was less than 1 μm, indicating good self-milk. It was shown that the above-mentioned goal had been achieved.

[0129] 5. Transparency The membrane permeability of the composition was tested according to the method described in the "Membrane Permeability Test (PAMPA)" section above. The permeation rate was measured and the permeation coefficient was calculated. The results are shown in the table below.

[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 found between the particle size results and the permeability results. As a result of comprehensively judging the solubility, particle size, and permeability, hexaglyceryl laurate, lauric acid Compositions using decaglyceryl acid gave good results (e.g., formulations 37-40, 46). In addition, although it cannot be used in food in Japan, PEG-40 hydrogenated castor oil (formulation 4), The composition using caprylocaproyl polyoxyl-8 glyceride (formulation 8) also showed good results. It was good. [Industrial Applicability]

[0137] The present invention provides a self-emulsifying composition containing β-caryophyllene. products, cosmetics, bath and toiletry products, household products, and pest repellents. is available.

Claims

1. A self-emulsifying composition comprising 50 to 99% by mass of one or more emulsifiers selected from the group consisting of polyglycerin fatty acid esters having an HLB value of 10 or more, 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 1 to 40% by mass of β-caryophyllene.

2. The composition of claim 1 , wherein the emulsifier is a polyglycerol fatty acid ester having an HLB value of 10 or more.

3. 2. The composition of 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 of claim 1 further comprising a sorbitan fatty acid ester, a polyglycerol polyfatty acid ester, and / or a medium chain triglyceride.

5. The particle size of the emulsion self-emulsified in the aqueous medium is the median diameter (D ５０ The composition according to any one of claims 1 to 4, wherein the particle 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 storage at 40°C for 8 weeks.

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