JP7093973B2 - Manufacturing method of soft capsule aggregate and soft capsule aggregate - Google Patents

Description

The present invention relates to a method for producing a soft capsule aggregate capable of producing a soft capsule aggregate having an average particle diameter of 800 μm or less, and a soft capsule aggregate having an average particle diameter of 800 μm or less covered with a gelatin film.

Soft capsules are widely used in the fields of pharmaceuticals, foods, cosmetics, pesticides and the like. When the particle size of soft capsules is reduced, the uniformity of mixing is improved when blended into powders, granulated products and high-viscosity products, and the texture and ingestion feeling are improved. Therefore, in recent years, foods and pharmaceuticals have been improved. In the above applications, microcapsules having a smaller particle size than conventional ones are required. As a method for manufacturing soft capsules, a rotary method in which two film-forming sheets are punched out to form a film, or a film in which a content liquid to be filled in a capsule from an inner nozzle using a double nozzle is used to form a capsule film from an outer nozzle. A dropping method is known in which liquids are simultaneously discharged and dropped into a curing liquid (Patent Document 1). The dropping method can produce a soft capsule having a smaller particle size than the rotary method, but the particle size of the soft capsule that can still be produced is 2 to 10 mm, and a micron-order soft capsule having a particle size of less than 1 mm is produced. Was difficult. In addition, in order to manufacture a soft capsule with a three-layer structure as a dropping method, a triple nozzle is used to simultaneously discharge the content liquid from the inner nozzle, the protective liquid from the intermediate nozzle, and the coating liquid from the outer nozzle into the curing liquid. Although a method of dropping is proposed (Patent Document 2), the particle size of the obtained soft capsule was the same as that of the double nozzle.

International Publication 2013/100013 Pamphlet Japanese Unexamined Patent Publication No. 2016-74615

An object of the present invention is to solve the above problems and to provide a method for producing a soft capsule capable of producing a soft capsule having a particle size of less than 1 mm on the order of microns, and a soft capsule aggregate having a particle size on the order of micron.

The present inventors have begun studying a method for producing soft capsules having a particle size on the order of microns. In the course of the study, the present inventors have conventionally used a triple nozzle to discharge a film liquid for forming a film from the outermost layer nozzle regardless of whether the nozzle is a double nozzle or a triple nozzle. The content liquid, which is the content of the capsule, is discharged from the inner nozzle, and the coating liquid is discharged from the intermediate nozzle. It was discharged. Then, surprisingly, it was found that the droplets formed by the content liquid and the coating liquid can be miniaturized by the action of the discharge liquid from the nozzle of the outermost layer, and a soft capsule having a fine particle size of less than 1 mm can be manufactured. .. Then, according to this method, it is possible to produce a soft capsule aggregate having a fine particle size such as an average particle size of 800 μm or less, 700 μm or less, 600 μm or less, 500 μm or less, 400 μm or less, 300 μm or less, 200 μm or less, or 100 μm or less. I found it possible. The present invention has been completed based on the above findings.

That is, the present invention is specified by the following matters.
(1) Using a triple nozzle consisting of an inner nozzle, an intermediate nozzle outside the inner nozzle, and an outer nozzle outside the intermediate nozzle, the content liquid is from the inner nozzle, the coating liquid is from the intermediate nozzle, and the coating liquid is from the outer nozzle. A method for producing a soft capsule aggregate having an average particle diameter of 800 μm or less, which comprises ejecting a carrier liquid to form droplets and curing the coating liquid of the droplets.
(2) The discharge rate of the content liquid is 0.1 to 7.5 ml / hr, the discharge speed of the coating liquid is 0.1 to 13.0 ml / hr, and the discharge speed of the carrier liquid is 0.1 to 6. The method for producing a soft capsule aggregate according to (1) above, which is characterized by having a speed of 0.0 ml / min.
(3) The method for producing a soft capsule aggregate according to (1) or (2) above, wherein the carrier liquid contains a medium-chain fatty acid triglyceride.
(4) The method for producing a soft capsule aggregate according to any one of (1) to (3) above, wherein the film solution contains gelatin.
(5) The method for producing a soft capsule aggregate according to any one of (1) to (4) above, wherein the film solution contains carrageenans.
(6) The method for producing a soft capsule aggregate according to any one of (1) to (5) above, wherein the coating liquid is cured and then washed and dried.
(7) An aggregate of soft capsules in which the contents are encapsulated with a film containing gelatin, wherein the average particle size is 800 μm or less.
(8) The soft capsule aggregate according to (7) above, wherein the film contains carrageenans.

According to the production method of the present invention, a soft capsule aggregate having an average particle size of 800 μm or less can be produced. In addition, the particle size of the manufactured soft capsule aggregate can be adjusted. According to the production method of the present invention, a soft capsule having a spherical shape, a smooth surface, and sufficient hardness can be produced. Since the soft capsule aggregate of the present invention is an aggregate of soft capsules having an average particle size of 800 μm or less, it has excellent mixing uniformity when blended into powders, granules and high-viscosity substances, and is suitable for foods and pharmaceuticals. Excellent texture and ingestion when used. In particular, when blended in a granulated product, the uniformity can be further improved by aligning the particle size of the granulated product with the particle size of the soft capsule aggregate.

It is a schematic diagram which shows one Embodiment of the triple nozzle used in the manufacturing method of this invention. It is a schematic diagram which shows one Embodiment of the manufacturing method of this invention, and the subsequent washing and drying steps. 6 is an SEM image of the soft capsule obtained in Example 5. 6 is an SEM image of the soft capsule obtained in Example 6. 6 is an SEM image of the soft capsule obtained in Example 7. It is a figure which shows the particle size distribution of the soft capsule obtained in Example 11.

The method for producing a soft capsule of the present invention uses a triple nozzle consisting of an inner nozzle, an intermediate nozzle outside the inner nozzle, and an outer nozzle outside the intermediate nozzle, and uses a triple nozzle consisting of an inner nozzle, a content liquid from the inner nozzle, and a coating liquid from the intermediate nozzle. Is characterized by ejecting a carrier liquid from the outer nozzle to form droplets and curing the coating liquid of the droplets. In the triple nozzle in the manufacturing method of the present invention, an intermediate nozzle is provided on the outside of the inner nozzle so as to surround the inner nozzle, and an outer nozzle is provided on the outside of the intermediate nozzle so as to surround the intermediate nozzle. The shape of each nozzle is not particularly limited, but from the viewpoint that the contents are not unevenly distributed and the thickness of the film is uniform, the shape of the discharge port of each nozzle is preferably annular, and each nozzle is arranged concentrically. More preferred. Further, the discharge port end faces of the nozzles may or may not be aligned. The discharge port of the inner nozzle may be slightly inside (retracted inside) from the discharge port of the intermediate nozzle, and the discharge port of the intermediate nozzle may be slightly inside (retracted inside) from the discharge port of the outer nozzle. It is desirable to be in. The flow rate of the liquid discharged from each nozzle in the manufacturing method of the present invention is such that the flow rate of the content liquid discharged from the inner nozzle is 0. 1 to 7.5 ml / hr is preferable. Examples of the flow rate of the content liquid included in this range include 0.2 to 5.0 ml / hr, 0.5 to 5.0 ml / hr, 0.2 to 3.0 ml / hr, and the like. The flow rate of the coating liquid discharged from the intermediate nozzle is preferably 0.1 to 13.0 ml / hr. The flow rates of the coating liquid included in this range are 0.2 to 13.0 ml / hr, 2.0 to 13.0 ml / hr, 0.2 to 12.0 ml / hr, 5.0 to 12.0 ml /. hr and the like are exemplified. The flow rate of the carrier liquid discharged from the outer nozzle is preferably 0.1 to 6.0 ml / min. The flow rates of the carrier liquid included in this range are 0.1 to 5.0 ml / min, 0.1 to 4.0 ml / min, 0.1 to 3.0 ml / min, and 0.2 to 6.0 ml / min. min, 0.2 to 5.0 ml / min, 0.2 to 4.0 ml / min, 0.2 to 3.0 ml / min, 0.3 to 5.0 ml / min, 0.3 to 4.0 ml / Examples thereof include min, 0.3 to 3.0 ml / min, 1.0 to 6.0 ml / min, 2.0 to 5.0 ml / min, and the like. The above flow rate is a flow rate discharged from each nozzle per unit time, and is also referred to as a discharge rate in the present specification. Further, the flow rate of the carrier liquid discharged from the outer nozzle is preferably larger than the flow rate of the content liquid discharged from the inner nozzle or the flow rate of the coating liquid discharged from the intermediate nozzle, and the flow rate of the liquid discharged from each nozzle. As for the ratio of (discharge rate), the ratio of the flow rate of the coating liquid to the flow rate of the content liquid is preferably 0.1 to 50.0. The ratio of the flow rate of the coating liquid to the flow rate of the content liquid included in this range is 0.1 to 40, 0.1 to 30, 0.1 to 20, 0.1 to 10, 0.5 to 50, 0. .5 to 40, 0.5 to 30, 0.5 to 20, 0.5 to 10, 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 10 and the like are exemplified. The ratio of the flow rate of the carrier liquid to the flow rate of the coating liquid is preferably 12.0 to 600.0. The ratio of the flow rate of the carrier liquid to the flow rate of the coating liquid included in this range is 12 to 500, 12 to 400, 12 to 300, 12 to 200, 12 to 100, 12 to 60, 50 to 600, 50 to 500. , 50-400, 50-300, 50-200, 50-100 and the like are exemplified. The area of the opening of the discharge port of the inner nozzle in the manufacturing method of the present invention is preferably 7500 to 32000 μm ² . The area of the opening of the discharge port of the intermediate nozzle is preferably 25 to 100 times the area of the opening of the discharge port of the inner nozzle. Further, in order to form minute droplets, the area of the opening of the discharge port of the outer nozzle is preferably 7500 to 38000 μm ² . In the production method of the present invention, when each liquid is discharged from the nozzle, minute droplets in which the content liquid is covered with the coating liquid are formed by the action of the carrier liquid. In the manufacturing method of the present invention, the flow rate of the content liquid discharged from the inner nozzle is 0.1 to 7.5 ml / hr, and the flow rate of the coating liquid discharged from the intermediate nozzle is 0.1 to 13.0 ml / hr. When the flow rate of the carrier liquid discharged from the outer nozzle is 0.1 to 6.0 ml / min, the average particle diameter is 400 μm or less, 300 μm or less, 200 μm or less, 100 μm or less, 10 to 400 μm, 10 to 300 μm. It is suitably used for producing soft capsules of 10 to 200 μm, 10 to 100 μm, 50 to 400 μm, 50 to 300 μm, 50 to 200 μm or 50 to 100 μm.

In the production method of the present invention, after forming droplets, a soft capsule is produced by curing the film liquid of the formed droplets. In the curing of the coating liquid, the droplets may be released into a gas to be cooled to gel the coating liquid and then cured, or the droplets may be dropped into the curing liquid in which the coating liquid gels and gelled. , May be cured. Further, in the production method of the present invention, the carrier liquid and the curing liquid remaining attached to the film can be removed by performing cleaning as necessary, and by drying this, micros as dry powder can be removed. A capsule assembly is obtained. In the production method of the present invention, the particle size can be controlled by appropriately adjusting the flow rate, flow rate, viscosity, etc. of the content liquid, the coating liquid, and the carrier liquid, and microcapsules of less than 1 mm can be manufactured. can. Further, according to the production method of the present invention, a microcapsule aggregate having an average particle diameter of 800 μm or less, 700 μm or less, 600 μm or less, 500 μm or less, 400 μm or less, 300 μm or less, 200 μm or less, or 100 μm or less is produced. be able to. Particles having a particle size on the order of micron are usually treated as aggregates, so-called powders, rather than being treated individually, and in this case, the particle size is generally expressed by the average particle size. The soft capsule aggregate in the present invention means a collection of a plurality of soft capsules, and does not mean an integrated one or an arrangement according to a specific rule. Here, the average particle size is obtained by analyzing an image taken by a microscope digital camera (DP010, Olympus Optical Industry) with an image analysis software (WinROOF, Mitani Sangyo Co., Ltd.) with a sample number (N number) of 50 or more. Can be obtained by doing.

The soft capsule produced by the production method of the present invention can be used for various purposes such as pharmaceuticals, foods, cosmetics, pesticides, etc., and the composition of the content liquid in the present invention is appropriately determined according to the application. Hereinafter, the capsule contents contained in the content liquid of the present invention will be exemplified, but the contents are not limited thereto, and a solvent may be contained as necessary. Further, the form of the content liquid may be in the form of a solution or a suspension.

As oils and fats, avocado oil, almond oil, flaxseed oil, uikyo oil, egoma oil, olive oil, olive squalane, orange oil, orange raffer oil, sesame oil, garlic oil, cacao oil, pumpkin seed oil, chamomile oil, carrot oil, cucumber Oil, beef fat fatty acid, kukui nut oil, cranberry seed oil, brown rice germ oil, rice oil, wheat germ oil, safflower oil, shea butter, liquid shea butter, perilla oil, soybean oil, evening primrose oil, camellia oil, corn oil, rapeseed Oil, sawtooth oil, honeybee oil, persic oil, parsley seed oil, sunflower oil, sunflower oil, grape seed oil, borage oil, macadamia nut oil, meadow home oil, cottonseed oil, peanut oil, turtle oil, mink oil, egg yolk oil, Fish oil, palm oil, palm kernel oil, mokuro, palm oil, long-chain, medium-chain, short-chain fatty acid triglycerides, diacylglyceride, beef fat, pork fat, squalane, squalane, pristan, and hydrogenated additives for these fats and oils, etc. Can be contained.

As waxes and waxes, shelac wax, honey wax, carnauba wax, whale wax, lanolin, liquid lanolin, reduced lanolin, hard lanolin, cyclic lanolin, lanolin wax, candelilla wax, mokurou, montan wax, cellac wax, rice wax and the like can be contained. Is. As the hydrogenated oil, it can contain a hydrogenated vegetable oil, a hydrogenated beef tallow oil, a hydrogenated pork oil, and the like obtained by hydrogenating the hydrogenated vegetable oil.

Examples of lecithins include egg yolk lecithin, soybean lecithin, enzymatically decomposed lecithin (lysolecithin), phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, disetylphosphate, stearylamine, phosphatidylglycerol, phosphatidic acid, phosphatidylinositol amine, and cardiolipin. It can contain ceramide phosphorylethanolamine, ceramidephosphorylglycerol and the like. Enzymatically degraded lecithin is obtained by allowing phospholipase _A2 to act on, for example, egg yolk lecithin and soybean lecithin.

As the mineral oil, liquid paraffin, petrolatum, paraffin, ozokelide, selecin, microcrystalline wax and the like can be contained.

As fatty acids, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, conjugated linoleic acid, linolenic acid, docosahexaenoic acid, eikosapentaenoic acid, 12-hydroxystearic acid, undecylenic acid, tall oil , Natural fatty acids such as lanolin fatty acid, synthetic fatty acids such as isononanoic acid, caproic acid, 2-ethylbutanoic acid, isoptanoic acid, 2-methylpentanoic acid, 2-ethylhexanoic acid, isoptanoic acid, and fats and oils containing these fatty acids as a fatty acid composition. Etc. can be contained.

As vitamins, vitamin A group: retinol, retinal (vitamin A1), dehydroretinal (vitamin A2), carotene, lycopene (provitamin A), vitamin B group: flusultiamine, thiamine hydrochloride, thiamin sulfate (vitamin B1) ), Riboflavin (vitamin B2), pyridoxin (vitamin B6), cyanocobalamine, methylcobalamine (vitamin B12), folic acids, nicotinic acids, pantothenic acids, biotins, choline, inositols, vitamin C group: ascorbic acid or its derivatives, Vitamin D group: Ergocalciferol (Vitamin D2), Colecalciferol (Vitamin D3), Dihydrotaxterol, Vitamin E group: Vitamin E or its derivatives, Ubiquinones, Vitamin K group: Phytonadione (Vitamin K1), Menaquinone (Vitamin) K2), menatetrenone, menadion (vitamin K3), menadiol (vitamin K4), other essential fatty acids (vitamin F), carnitine, ferulic acid, γ-orizanol, ollotic acid, vitamin Ps (rutin, eriocitrin, hesperidin), It can contain vitamin U and the like. In addition, lutein can also be contained.

As the stimulant, capsicum tincture, capsicum oil, nonylic acid vanilamide, cantalist tincture, gypsum tincture, ginger oil, mentha oil, l-menthol, camphor, benzyl nicotinate and the like can be contained.

Benzophenone derivatives (2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid sodium, dihydroxydimethoxy) are used as UV absorbers and blocking agents. Benzophenone, dihydroxydimethoxybenzophenone-sodium sulfonate, 2,4-dihydroxybenzophenone, tetrahydroxybenzophenone, etc.), paraaminobenzoic acid derivatives (paraaminocinnamic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, para Octyl dimethylaminobenzoate, etc.), methoxycinnamic acid derivatives (ethyl paramethoxycinnamic acid, isopropyl paramethoxycinnamic acid, octyl paramethoxycinnamic acid, 2-ethoxyethyl paramethoxycinnamic acid, sodium paramethoxycinnamic acid, potassium paramethoxycinnamic acid, diparamethoxy cinnamic acid mono -Glyceryl 2-ethylhexanate, etc.), cinnamic acid derivative (octyl salicylate, phenyl salicylate, homomentyl salicylate, dipropylene glycol salicylate, ethylene glycol salicylate, myristyl salicylate, methyl salicylate, etc.), anthranilic acid derivative (methyl anthranylate, etc.), urocanine Acid derivatives (cinnamic acid, ethyl urocanate, etc.), coumarin derivatives, amino acid compounds, benzotriazole derivatives, tetrazole derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, camphor derivatives, furan derivatives, pyron derivatives, nucleic acid derivatives, allantin derivatives, Nicotinic acid derivative, Vitamin B6 derivative, Umberiferon, Esculin, benzyl cinnamic acid, Synoxate, Oxybenzon, Dioxybenzone, Octabenzone, Slysobenzone, Benzoresorcinol, Arbutin, Guiaazulene, Sikonin, Baikarin, Baikarain, Belverin, Neoheliopan, Escalol, It can contain zinc oxide, talc, cinnamic acid and the like.

As whitening agents, paraaminobenzoic acid derivatives, sartylic acid derivatives, anthranyl acid derivatives, coumarin derivatives, amino acid compounds, benzotriazole derivatives, tetrazole derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, camphor derivatives, furan derivatives, pyron derivatives, nucleic acids Derivatives, allantin derivatives, nicotinic acid derivatives, vitamin C or its derivatives (vitamin C phosphate magnesium salt, vitamin C glucoside, etc.), vitamin E or its derivatives, kodiic acid or its derivatives, oxybenzone, benzophenone, arbutin, guaiazulene, ciconin , Baikarin, Baikarain, Velverin, placenta extract, ellagic acid, lucinol and the like can be contained.

As a tyrosinase activity inhibitor, vitamin C or a derivative thereof (vitamin C phosphate ester magnesium salt, vitamin C glucoside, etc.), hydroquinone or a derivative thereof (hydroquinone benzyl ether, etc.), kodiic acid or a derivative thereof, vitamin E or a derivative thereof, N. -Acetyltyrosine or its derivatives, glutathione, hydrogen peroxide, zinc peroxide, placenta extract, ellagic acid, arbutin, lucinol, silk extract, plant extracts (chamomile, mulberry, kuchinashi, touki, waremokou, clara, yomogi, watermelon, Kihada, Dokudami, Matsuhodo, Hatomugi, Odorikosou, Hop, Sanzashi, Eucalyptus, Seiyounokogirisou, Artea, Keihi, Mankeishi, Hamamelis, Karagwa or Yamagwa, Life-extending grass, Kikyo, Toshishi, Zokuji, Dried, Mao, Senkyu, Dokkatsu Psycho, bofu, hamaboufu, ogong, peony skin, shakuyaku, gennoshoko, kudzu root, licorice, quintuplet, aloe, shouma, red flower, green tea, tea, asenyaku, blueberry, turlenge) and the like can be contained.

As the melanin pigment reduction or decomposition substance, phenylmercury hexachlorophen, mercuric oxide, mercuric chloride, hydrogen peroxide solution, zinc peroxide, hydroquinone or a derivative thereof can be contained.

Hydroquinone, lactic acid bacterium extract, placenta extract, spirit turf extract, vitamin A, vitamin E, allantoin, spleen extract, thoracic gland extract, yeast extract, fermented milk extract, plant extract (aloe, ogong) as turnover promoting action and cell activating substance , Sugina, Gentiana, Gobo, Shikon, Carrot, Hamamelis, Hop, Yokuinin, Odorikosou, Senburi, Touki, Tokinsenka, Amacha, Otogirisou, Cucumber, Tachijakousou, Mannenrou, Parsley) and the like.

Astringents can contain succinic acid, allantin, zinc chloride, zinc sulfate, zinc oxide, caramine, zinc paraphenolsulfonate, potassium aluminum sulfate, resorcin, ferric chloride, tannic acid (including catechin compounds), etc. be.

As the active oxygen scavenger, SOD, catalase, glutathione peroxidase and the like can be contained.

As antioxidants, vitamin C or a salt thereof, stearic acid ester, vitamin E or a derivative thereof, nordihydroguaselethenic acid, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), hydroxytyrosole, parahydroxyanisole, It can contain propyl gallate, sesamol, sesamolin, gosipole, propolis and the like.

As a lipid peroxide production inhibitor, β-carotene, plant extracts (cultured sesame cells, Amacha, Hypericum erectum, Hamamelis, Clove, Melissa, Emmeiso, Shirakaba, Salvia, Mannenrou, Nantenmi, Agetsu, Ginkgo, Green tea), etc. can be contained. Is.

Anti-inflammatory agents include ictamol, indomethacin, kaolin, salicylic acid, sodium salicylate, methyl salicylate, acetylsalicylic acid, diphenhydramine hydrochloride, d-camfur, dl-camfur, hydrocortisone, guaiazulene, camazulene, chlorpheniramine maleate, glycyrrhizinic acid or salts thereof. , Glycyrrhetinic acid or a salt thereof, licorice extract, shikon extract, agetsu extract, propolis and the like can be contained.

As antibacterial / sterilizing / disinfecting agents, acrinol, sulfur, calcium gluconate, chlorhexidine gluconate, sulfamine, merculochrome, lactoferrin or its hydrolyzate, alkyldiaminoethylglycine chloride solution, triclosan, sodium hypochlorite, chloramine T, salaci Powders, iodine compounds, iodoform, sorbic acid or its salts, propionic acid or its salts, salicylic acid, dehydroacetic acid, parahydroxybenzoic acid esters, undecylenic acid, thiamine lauryl sulfate, thiamine lauryl nitrate, phenol, cresol, p- Chlorophenol, p-chloro-m-xylenol, p-chloro-m-cresol, timole, surfactant alcohol, o-phenylphenol, irgasan CH3565, halocarban, hexachlorophene, chlorohexidine, ethanol, methanol, isopropyl alcohol, benzyl alcohol, Ethylene glycol, propylene glycol, 2-phenoxyethanol, 1,2-pentanediol, zincpyridion, chlorobutanol, isopropylmethylphenol, nonionic surfactants (polyoxyethylene lauryl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene) Octylphenyl ether, etc.), amphoteric surfactant, anionic surfactant (sodium lauryl sulfate, lauroyl sarcosin potassium, etc.), cationic surfactant (cetyltrimethylammonium bromide, benzalkonium chloride, benzethonium chloride, methylrosanilin chloride), formaldehyde , Hexamine, Brilliant Green, Malakite Green, Crystal Violet, German, Photosensitive No. 101, Photoreceptor No. 201, Photoreceptor No. 401, N-long-chain acyl basic amino acid derivative and its acid addition salt, zinc oxide, hinokithiol, kudin , Propolis and the like can be contained.

As a moisturizing agent, glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol, glycerin tricaprylcaprate, glycolic acid (α-hydroxy acid), hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof, water-soluble chitin or Derivatives or chitosan derivatives, pyrrolidone carboxylic acid or salts thereof, sodium lactate, urea, sorbitol, amino acids or derivatives thereof (valine, leucine, isoleucine, treonine, methionine, phenylalanine, tryptophan, lysine, glycine, alanine, asparagine, glutamine, serine , Cysteine, cystine, tyrosine, proline, hydroxyproline, aspartic acid, glutamic acid, hydroxylysine, arginine, ornithine, histidine and their sulfates, phosphates, nitrates, citrates, or pyrrolidone carboxylic acids). It is possible.

As various organic acids, glycolic acid, citric acid, malic acid, tartaric acid, lactic acid, ferulic acid, phytic acid and the like can be contained.

As a hair preparation, selenium disulfide, alkylisoquinolinium bromide solution, zincpyrythion, biphenamine, thiantoll, castari tincture, ginger tincture, sugarcane tincture, quinine hydrochloride, strong ammonia water, potassium bromate, sodium bromate, thioglycol It can contain acid and the like.

As fragrances, natural animal fragrances such as jaco, civet, castorium, and ambergris, anis essential oil, angelica essential oil, Iran Iran essential oil, iris essential oil, uikyo essential oil, orange essential oil, cananga essential oil, caraway essential oil, cardamon essential oil, guayakwood essential oil, cumin. Essential oil, black letter essential oil, kayhide essential oil, cinnamon essential oil, geranium essential oil, copaiba balsam essential oil, Korean del essential oil, perilla essential oil, cedarwood essential oil, citronella essential oil, jasmine essential oil, gingergrass essential oil, cedar essential oil, spare mint essential oil, western hacker essential oil, large Scented essential oil, tuberose essential oil, choji essential oil, orange flower essential oil, winter green essential oil, true balsam essential oil, butchery essential oil, rose essential oil, palmarosa essential oil, hiba essential oil, hiba essential oil, ebony essential oil, petitgrain essential oil, bay essential oil, bechiba essential oil, bergamot essential oil , Peruvian balsam essential oil, boad rose essential oil, sardine essential oil, mandarin essential oil, eucalyptus essential oil, lime essential oil, lavender essential oil, linaroe essential oil, lemongrass essential oil, lemon essential oil, rosemary (mannen wax) essential oil, Japanese hacker essential oil and other vegetable fragrances , Other synthetic fragrances such as coffee flavor and yogurt flavor can be contained.

Furthermore, it can contain nutritional supplements and health food ingredients. Specifically, fish oil, garlic, vitamin B1, so-called egg oil (a brown to black liquid obtained by heating egg yolk over low heat for a long time using an iron pan while stirring egg yolk). And so on.

The film solution in the present invention can contain a film component usually used as a film for soft capsules, and may contain a solvent such as water if necessary. In the present invention, the film component is not particularly limited and may be either a hydrophobic film component or a hydrophilic film component, but a hydrophilic film component is preferable. Examples of the hydrophilic film component include modified gelatin such as gelatin and starched gelatin, carrageenan, agar, sodium alginate, purulan, glucomannan, arabic rubber, farceleran, euchema algae, gellan gum, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, and the like. One or a combination of two or more kinds of hydrophilic polymers such as polyvinyl alcohol and starches can be mentioned, and gelatin or modified gelatin can be preferably mentioned. In addition, the film components include plasticizers such as glycerin, sorbitol, propylene glycol and polyethylene glycol, light-shielding agents such as titanium dioxide, pH adjusters such as sodium phosphate, chelating agents such as trisodium citrate and sodium metaphosphate, and lactic acid. Gelation accelerators such as calcium and potassium chloride, surfactants such as polyglycerin fatty acid ester and phosphoric acid, flavoring agents, fragrances, preservatives, coloring agents, solubilizing agents and the like may be added. Further, various starches (including modified starch, modified starch, starch and starch decomposition products) and various polysaccharides can be contained as a film-forming agent.

The gelatin used in the film solution in the present invention is produced by heating and extracting crude collagen obtained by treating, for example, the skin, bone, tendon of cow, pig, chicken, fish, etc. with acid or alkali. I can mention what was done. Further, modified gelatin such as a hydrolyzate of gelatin, an enzymatic decomposition product, amberized gelatin, and phthalated gelatin can also be used. Any kind of gelatin can be preferably used. The jelly strength of gelatin is preferably 100 to 300 g, more preferably 130 to 250 g. The jelly strength can be measured according to JISK-6503 (2001). When gelatin and water are used as the coating liquid, the content of gelatin is preferably 1.0 to 10.0% by mass, more preferably 2.0 to 8.0% by mass with respect to water.

In the production method of the present invention, it is preferable to use carrageenans in addition to gelatin as the film component contained in the film solution. By adding carrageenans, the surface of the obtained microcapsules can be smoothed and the particle hardness can be increased. The carrageenans used in the film solution in the present invention are a kind of galactan having a sulfate group, and are known to be present in red algae. Carrageenans can be classified into three main types, Iota carrageenan (ι carrageenan), Kappa carrageenan (κ carrageenan), and Lambda carrageenan (λ carrageenan), depending on their gelling properties and structure. The Japanese food additive regulations stipulate three types: "refined carrageenan," "processed algae," and "eukema algae powder." (See List Commentary "(1999)), but these differ only in the degree of purification, and are essentially all included in the carrageenans used in the film solution in the present invention. In the present invention, ι carrageenan and κ carrageenan are preferable from the viewpoint of gelling ability. The carrageenans may be pure products or may contain standardized substances. Here, examples of the standardized substance include one or more selected from the group consisting of sugars such as sucrose, glucose, maltose, and lactose, and dextrin. Sucrose and dextrin are preferable. As the dextrin, acid-decomposed dextrin and enzymatically-decomposed dextrin are preferable. In addition, a blended raw material in which ι carrageenan and κ carrageenan are mixed in advance can also be used. The content of carrageenan used together with gelatin in the film solution is preferably 0.1 to 1.0% by mass, more preferably 0.1 to 0.8% by mass with respect to water. Further, in the production method of the present invention, as a film component contained in the film solution, a gelling agent such as carrageenan, agar, gellan gum or the like can be used instead of gelatin, and gelation of dextrin or starch decomposition products can be used. A substance that does not inhibit the above can also be used in combination as a thickening agent or a filler. By using these gelling agents, problems such as adhesion can be improved.

The carrier solution in the present invention is not particularly limited as long as it is immiscible with the film solution. For example, when the film solution contains a hydrophilic film component, various oils and fats, fatty acids, sugar ester, and aliphatic hydrocarbons are used. Hydrophobic liquids such as hydrogen, aromatic hydrocarbons, chain ethers, higher fatty acid esters, higher alcohols and terpenes can be mentioned. Specifically, saflower oil, flaxseed oil, egoma oil, olive oil, mustard oil, sesame oil, corn oil, soybean oil, evening primrose oil, terpene oil, rapeseed oil, palm oil, palm kernel oil, jojoba oil, cottonseed oil, Various animal and vegetable oils such as palm oil, peanut oil, EPA, DHA, shark liver oil, cod liver oil, medium chain fatty acid triglyceride (MCT), diacylglycerol, etc. Mineral oils such as crystallin wax can be mentioned, and MCT can be preferably mentioned. When gelatin and water are used as the coating liquid, the coating liquid is usually prepared by setting the liquid temperature to 70 to 90 ° C, but the carrier liquid can be prepared by setting the liquid temperature to 15 ° C to 25 ° C (room temperature). It is preferable from the viewpoint of delaying the conversion rate and preventing the nozzle from being clogged. The liquid temperature of the content liquid is preferably about the same as that of the film liquid. Further, in the case where the formed droplets are dropped into the curing liquid and cooled to be gelled and solidified, the curing liquid is not particularly limited as long as it is immiscible with the coating liquid, and the above carrier liquid is exemplified. You can use things. If the same ingredients are used for the carrier liquid and the curing liquid, cleaning will be easier.

Since the soft capsule of the present invention having an average particle size of 800 μm or less has a very small particle size, it is possible to obtain a texture that does not give a sense of discomfort even when added to food. Therefore, it is possible to prevent the contents from volatilizing and deteriorating in the capsule until the time of eating, and to obtain a food without discomfort of the contaminants at the time of eating. From the viewpoint of improving the texture, the average particle size is preferably 500 μm or less, more preferably 400 μm or less, preferably 300 μm or less, more preferably 200 μm or less, still more preferably 100 μm or less. Examples of the average particle size included in this range include 10 to 400 μm, 10 to 300 μm, 10 to 200 μm, 10 to 100 μm, 50 to 400 μm, 50 to 300 μm, 50 to 200 μm, 50 to 100 μm, and the like. Further, since the soft capsule of the present invention has a small particle size, it can be uniformly mixed with powders, granulated products and high-viscosity products. Further, since the particle size of the soft capsule aggregate can be adjusted, it can be blended into various base materials regardless of the type of the base material, the powder, and the particle size of the granulated product. In particular, when gelatin is used as a film, it becomes a soft capsule having sufficient strength as a film and having appropriate solubility at the time of eating. Furthermore, when carrageenans are added to the film in addition to gelatin, the surface of the soft capsule becomes smooth, and the film is excellent in uniformity and fluidity during use. Since the soft capsule of the present invention has excellent mixing uniformity with various base materials, it may be monodispersed in a base material used in pharmaceuticals, foods, cosmetics, pesticides, etc. or in a processed product obtained by further processing the mixed base material. It can exist in a state close to that. For example, when mixed with a powder or a granulated product, it can exist as a simple substance or a state close to a simple substance in the powder or the granulated product. Further, in foods, by mixing the soft capsule of the present invention with a high-viscosity substance such as a raw material for gum or dough for noodles, the soft capsule of the present invention is dispersed in the high-viscosity substance in a single state or a state close to a single substance. It exists in the same state in the solidified product.

The method for producing a soft capsule of the present invention will be further described with reference to FIGS. 1 and 2. The triple nozzle A includes an inner nozzle 1, an intermediate nozzle 2, and an outer nozzle 3. In the triple nozzle A of FIG. 1, the discharge port end surface of the inner nozzle 1 is provided at a position slightly deeper than the discharge port end surface of the intermediate nozzle 2, and the discharge port end surface of the intermediate nozzle 2 is from the discharge port end surface of the outer nozzle 3. It is installed in a slightly recessed position. The content liquid 4, the coating liquid 5, and the carrier liquid 6 are sent to the inner nozzle 1, the intermediate nozzle 2, and the outer nozzle 3 by the pump 13, respectively. When each liquid is discharged from the nozzle, droplets in which the content liquid 4 is encapsulated in the film liquid 5 are formed. By dropping the droplets onto the curing liquid 8 in the collection container 7, the coating liquid 5 of the droplets is gelled and cured to prepare a soft capsule. The state at the time of soft capsule molding can be observed by the monitor 11 connected to the microscope objective lens 9 and the CCD camera 10, and various conditions can be adjusted based on the observation to control the particle size of the soft capsule. As shown in FIG. 2, the soft capsule in the curing liquid 8 is filtered, washed, and then dried by freeze-drying or the like to obtain a dried soft capsule.

[Examples 1 to 11]
Using the concentric triple nozzles shown in FIG. 1, the content liquid (liquid temperature: 20 ° C.) consisting of an MCT solution containing 0.1% of the synthetic colorant sudanIII is shown from the inner nozzle, and Tables 1 to 3 are shown from the intermediate nozzles. A film liquid (liquid temperature: 80 ° C.) having the composition shown is discharged from an outer nozzle to form an MCT (liquid temperature: 20 ° C.) to form a three-layer droplet, and the three-layer droplet is contained in the MCT liquid (liquid temperature: 20 ° C.). 20 ° C.). The obtained capsules were freeze-dried and washed to obtain soft capsules. The discharge rate of the content liquid was 1.0 ml / hr in Examples 1 to 10, 0.2 ml / hr in Example 11, and the discharge rate of the coating liquid was 10.0 ml / hr in Examples 1 to 10. In No. 11, 0.2 ml / hr, and the discharge rate of the carrier liquid was 3.0 ml / min in Examples 1 to 10, and 0.3 ml / min in Example 11. The inner diameter of the discharge port of the inner nozzle was 250 μm, the inner diameter of the discharge port of the intermediate nozzle was 800 μm, and the inner diameter of the discharge port of the outer nozzle was 1800 μm. The following gelatins, κ carrageenan and MCT were used. The viscosity of the coating liquid of each formulation was measured using a cone plate type viscometer (DV2T, Eiko Seiki Co., Ltd.). The ratio of the discharge rate of the carrier liquid to the discharge rate of the film liquid was 18 in Examples 1 to 10 and 90 in Examples 11.
Gelatin (pork skin gelatin, manufactured by Zerice)
κ Carrageenan (manufactured by Mitsubishi Corporation Food Tech)
MCT (manufactured by Kao Corporation)

[Examples 12 to 25]
Using the same concentric triple nozzles used in Examples 1 to 11, a content liquid (liquid temperature: 20 ° C.) consisting of an MCT solution containing 0.1% of the synthetic colorant sudanIII was introduced from the inner nozzle to the intermediate nozzle. A film liquid (liquid temperature: 80 ° C.) having the composition shown in Tables 4 to 7 is discharged from the sheet, and MCT (liquid temperature: 20 ° C.) is discharged from the outer nozzle to form a three-layer droplet, and the three-layer droplet is formed. It was added dropwise to the MCT solution (liquid temperature: 20 ° C.). The obtained capsules were freeze-dried and washed to obtain soft capsules. The discharge rate of the content liquid and the discharge speed of the coating liquid were 0.2 ml / hr, and the discharge speed of the carrier liquid was the speed shown in Tables 4 to 7. The ratio of the discharge rate of the carrier liquid to the discharge rate of the film liquid was 90, 330, 570, respectively, when the discharge speed of the carrier liquid was 0.3 ml / min and 1.1 ml / min, 1.9 ml / min, respectively. ..

[Evaluation of the obtained soft capsules (Examples 1 to 25)]
(Observation of surface shape)
The surface shape of the obtained soft capsule was observed with a scanning electron microscope (SEM). The observation results are shown in FIGS. 3 to 5. FIG. 3 is an SEM image of the soft capsule obtained in Example 5, FIG. 4 is an SEM image of the soft capsule obtained in Example 6, and FIG. 5 is an SEM image of the soft capsule obtained in Example 7. By adding carrageenan to the film, soft capsules with a smooth particle surface were obtained (FIGS. 4 and 5).

(Measurement of particle size)
The images of the soft capsules obtained in the examples taken with a microscope digital camera (DP010, Olympus Optical Co., Ltd.) were analyzed using image analysis software (WinROOF, Mitani Sangyo Co., Ltd.) to determine the average particle size. The results are shown in Tables 8 and 9. As shown in Tables 8 and 9, soft capsule aggregates having an average particle size of 400 μm or less were obtained in each of the examples, and the average particle size was 300 μm or less, 200 μm or less, or 100 μm or less by adjusting the conditions. A soft capsule aggregate was obtained. The image of the soft capsule obtained in Example 11 taken with a microscope digital camera (DP010, Olympus Optical Co., Ltd.) was measured with the image analysis software ImageJ (registered trademark) 1.46r to measure the particle size of the granules from the image. A particle size distribution was created based on the results. The particle size distribution is shown in FIG. The span factor in Table 9 is an index expressed by (particle size (d ₉₀ ) in a cumulative distribution of 90% -particle size (d ₁₀ ) in a cumulative distribution of 10%) / median diameter (d ₅₀ ).

(Measurement of particle hardness)
The hardness of the obtained soft capsule was measured using a particle hardness measuring device (GRANO Win Ver4.0), and the particle hardness was determined. The results are shown in Table 10. As shown in Table 10, in each of the examples, soft capsules having sufficient hardness to protect the capsule contents were obtained.

According to the production method of the present invention, soft capsules having a particle size of less than 1 mm on the order of microns, particularly minute soft capsule aggregates having an average particle size of 800 μm or less, 500 μm or less, 400 μm or less, 300 μm or less, 200 μm or less, or 100 μm or less. Can be manufactured. The minute soft capsules obtained by the production method of the present invention can be suitably used for foods including pharmaceuticals, general foods, functional foods, health foods, beverages, cigarettes, cosmetics, pesticides and the like. General foods include, for example, confectionery such as chewing gum, candy, jelly, and chocolate, and cosmetics include toilet cosmetics such as shaving lotions, soaps, creams, and foams, colons, and deodorants. Includes agents, antiperspirants, bath oils, shampoos, hair treatment compositions, conditioners, tanning lotions, talcum powders, face creams, hand creams, eye drops and the like. For example, in the field of pharmaceuticals, it can be used as a suspension injection for subcutaneous injection or intramuscular injection, and in the field of food, it is used to add flavor components, umami components, etc. to foods such as gum and noodles. Can be used as a filter for the flavor of cigarettes. Also, if used as an insecticide or rodenticide, it can be fed to small creatures and can also be used as a herbicide that dissolves in the rain.

A Triple nozzle 1 Inner nozzle 2 Intermediate nozzle 3 Outer nozzle 4 Contents liquid 5 Coating liquid 6 Carrier liquid 7 Collection container 8 Hardening liquid 9 Microscope objective lens 10 CCD camera 11 Monitor 12 Light 13 Pump

Claims (4)

A triple nozzle consisting of an inner nozzle, an intermediate nozzle outside the inner nozzle, and an outer nozzle outside the intermediate nozzle is used, and the content liquid is contained from the inner nozzle and gelatin and water are contained from the intermediate nozzle, and the liquid temperature is 70 to 90. The coating liquid at ° C., the carrier liquid having a liquid temperature of 15 to 25 ° C. from the outer nozzle , the content liquid having a discharge rate of 0.1 to 7.5 ml / hr, and the discharge speed of the coating liquid being 0. It is characterized in that it is 1 to 13.0 ml / hr and the carrier liquid is discharged at a discharge rate of 0.1 to 6.0 ml / min to form droplets and cure the coating liquid of the droplets. A method for producing a soft capsule aggregate having an average particle size of 800 μm or less. The method for producing a soft capsule aggregate according to claim 1 , wherein the carrier liquid contains a medium-chain fatty acid triglyceride. The method for producing a soft capsule aggregate according to claim 1 or 2 , wherein the film solution contains carrageenans. The method for producing a soft capsule aggregate according to any one of claims 1 to 3 , wherein the film liquid is cured and then washed and dried.

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