JP2013079201A - Capsule agent filled with liquid composition containing caffeines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a capsule agent capable of suppressing a crystal deposition of filled caffeines and having a good appearance and superior stability.SOLUTION: There is provided a capsule agent made of a pigment-containing capsule film filled with a caffeine-containing liquid composition.

Description

  The present invention relates to a capsule filled with a liquid composition containing caffeine. In detail, it is related with the capsule with which the liquid composition containing caffeine was filled in the capsule made from the capsule skin.

  Caffeine is a central nervous stimulant classified as a xanthine derivative, and exhibits an effect of enhancing antipyretic analgesic effect and an effect of temporarily removing fatigue. In anticipation of such action, caffeine is blended in antipyretic analgesics, general cold medicines, antitussive expectorants, oral rhinitis drugs, motion sickness prevention drugs, and nourishing tonics (Non-patent Document 1).

  However, since caffeine has low water solubility (Non-Patent Document 2), there is a problem that crystal precipitation is likely to occur. When such crystals are precipitated, not only may the effect be affected, but also the appearance will be inferior, and the commercial value of the antipyretic analgesics and the like will decrease.

  Under such a background, means for suppressing crystal precipitation of caffeine contained in the capsule filling liquid has been studied. For example, in a capsule filling liquid containing caffeine, polyethylene glycol, lactic acid and water are used in combination, and caffeine and lactic acid are blended at a specific ratio (Patent Document 1), or polyethylene glycol, phosphoric acid and water are combined. And a combination of caffeine and phosphoric acid in a specific ratio (Patent Document 2) has been proposed.

JP 2006-089415 A JP 2006-062999 A

OTC Handbook 2008-09 Academic Information Distribution Center, Inc. pp. 198-199 15th Amendment Japanese Pharmacopoeia Manual Sasakawa Shoten Co., Ltd. C-927-934

However, the action of caffeine to suppress crystal precipitation exhibited by the capsule filling liquids described in Patent Documents 1 and 2 has not been sufficiently satisfactory.
Accordingly, an object of the present invention is to provide a capsule that suppresses crystal precipitation of filled caffeine and has a good appearance and excellent stability.

  Thus, as a result of diligent investigations to solve the above problems, the present inventor was completely unexpectedly made by adding a pigment to the capsule skin filled with caffeine. The present inventors have found that a capsule having a good appearance and excellent stability can be obtained by suppressing the crystal precipitation of caffeine filled in the capsule.

  That is, this invention provides the capsule with which the liquid composition containing caffeine was filled in the capsule manufactured with the capsule skin containing a pigment | dye.

  The capsule of the present invention has little crystal precipitation of the filled caffeine, and has a good appearance and excellent stability.

  The capsule of the present invention is obtained by filling a liquid composition containing caffeine into a capsule made of a capsule skin containing a pigment. First, the capsule skin will be described in detail.

The pigment contained in the capsule skin is not particularly limited, but edible red No. 2, edible red No. 3, edible red No. 40, edible red No. 102, edible red No. 104, edible red No. 105, edible red No. 106, edible Yellow No. 4, Edible Yellow No. 4 Aluminum Lake, Edible Yellow No. 5, Edible Green No. 3, Edible Blue No. 1, Edible Blue No. 2, Red Cabbage, Red Radish, Anato, Anthocyanin, Turmeric, Cacao, Caramel, Gardenia, Chlorophyll , Cochineal, perilla, capsicum, paprika, beet red, grape skin, grape juice, flavonoids, red yeast rice, safflower, berries, purple corn, purple potato, lac, etc., which can be used alone or in combination of two or more .
Among these, caramel is particularly preferable from the viewpoint of suppressing crystal precipitation of caffeine. Such caramel can be obtained by heat-treating carbohydrates such as glucose, fructose, galactose, maltose, sucrose, sucrose, invert sugar, water candy, starch hydrolysate, sugar beet or other sugars. In addition, commercially available products such as those manufactured by Ikeda Saccharified Industries, Ltd.

  As content of the said pigment | dye, 0.0001-5 mass% is preferable in a capsule skin from a viewpoint of crystal precipitation suppression of caffeine, 0.0005-1 mass% is more preferable, 0.001-0 More preferably, 5 mass% is more preferable, and 0.01-0.5 mass% is especially preferable.

  Moreover, as a content ratio of the said pigment | dye and caffeine contained in a liquid composition, a pigment | dye is 0.0005-0.0 with respect to 1 mass part of caffeine from a viewpoint of crystal precipitation suppression of caffeine. It is preferably 1 part by mass, more preferably 0.00075 to 0.09 part by mass, still more preferably 0.001 to 0.07 part by mass, and 0.0015 to 0.07 part by mass. Is particularly preferred.

  The capsule skin used in the present invention contains a base in addition to the above pigment. Examples of such a base include gelatin, hypromellose, pullulan, polyvinyl alcohol, a polyvinyl alcohol copolymer (preferably a copolymer of polyvinyl alcohol, methyl methacrylate and acrylic acid or a salt thereof), macrogol and the like. These may be used alone or in combination of two or more. Among these, gelatin, macrogol, and polyvinyl alcohol copolymer are preferable.

  The gelatin is not particularly limited, and examples thereof include sol-gel change with heat change, and examples thereof include gelatin made from cattle, pigs, birds, fish and the like, and acylated gelatin such as succinylated gelatin.

  The average molecular weight of the macrogol is preferably 950 to 25000, and more preferably 2500 to 4000. Examples of such macro goals include macro goal 1000, macro goal 1500, macro goal 1540, macro goal 4000, and macro goal 6000. Among these, Macrogol 4000 is preferable.

  Moreover, although content of a base is about 60-99 mass% normally in a capsule skin, 65-95 mass% is preferable and 65-90 mass% is more preferable. When gelatin and macrogol are used in combination, the gelatin content is preferably 50 to 95% by mass, more preferably 64.5 to 90% by mass, and 64.5 to 80% by mass in the capsule skin. Further preferred. On the other hand, the content of macrogol is preferably 0.1 to 15% by mass, and more preferably 0.3 to 10% by mass in the capsule skin.

In addition to the pigment and base, the capsule skin is a plasticizer such as glycerin, mannitol, sorbitol, sucrose, fructose, propylene glycol; gum arabic, alginic acid, carrageenan, agar, xanthan gum, guar gum, glucomannan , Gellan gum, tamarind gum, fur cerelan, pectin, locust bean gum and other gelling agents; preservatives; fragrances; disintegrants; surfactants; water and the like, and if necessary, ammonium chloride Gelling aids such as potassium chloride, calcium chloride, sodium chloride, potassium citrate, sodium citrate, magnesium sulfate, and potassium phosphate may be included.
When the plasticizer is used, the content ratio of the plasticizer to the base is usually about 0.0001 to 0.5 parts by mass of the plasticizer with respect to 1 part by mass of the base. It is preferable that it is -0.4 mass part, and it is more preferable that it is 0.003-0.02 mass part.
Moreover, content of water is about 1-25 mass% normally in a capsule skin, Preferably it is 5-20 mass%.

  Next, the liquid composition used in the present invention will be described. Such a liquid composition contains caffeine.

  Although the said caffeine is not specifically limited, For example, caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, a citrate caffeine etc. are mentioned, These can be used individually or in mixture of 2 or more types.

  The content of caffeine in the liquid composition may be determined by appropriately examining the dose per day according to the sex, age, symptoms, etc. of the user, but 10 to 1000 mg per day. The amount that can be taken is preferred, the amount that can be taken 20 to 800 mg is more preferred, and the amount that can be taken 30 to 600 mg is even more preferred. And when caffeine is a caffeine hydrate and / or anhydrous caffeine, the amount which can be taken | dosed 30-150 mg per day is especially preferable, On the other hand, when it is a sodium benzoate caffeine, it is per day. , 60-300 mg is particularly preferred.

Moreover, although content of the said caffeine is about 0.1-20 mass% normally in a liquid composition, 0.25-10 mass% is preferable, 0.5-7.5 mass% is preferable. More preferably, 1-5 mass% is especially preferable.
In addition, the said caffeine can be manufactured by a well-known method, and a commercial item can also be used for it.

  Moreover, as a liquid composition used by this invention, what contains a cellulose derivative and a thickening agent other than the said caffeine is preferable. These can be used alone or in combination of two or more.

  Examples of the cellulose derivative include alkyl celluloses such as methyl cellulose, ethyl cellulose, and propyl cellulose; hydroxyalkyl celluloses such as hydroxyethyl cellulose and hydroxypropyl cellulose (hyprose); and hydroxyalkylalkyl celluloses such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose (hypromellose). An ester of hydroxyalkylalkylcellulose such as hydroxypropylmethylcellulose acetate succinate and hydroxypropylmethylcellulose phthalate; a carboxyalkyl cell such as carboxymethylcellulose, potassium carboxymethylcellulose, carboxymethylcellulose calcium and carboxymethylcellulose sodium; Over scan, or a salt thereof; carboxyalkyl cellulose derivatives such as croscarmellose sodium; carboxyalkyl carboxyalkyl alkylcelluloses such as ethyl cellulose, and these can be used alone, or two or more kinds. Among these, from the viewpoint of suppressing crystal precipitation of caffeine, hydroxyalkylalkylcellulose is preferable, and hydroxypropylmethylcellulose (hypromellose) is particularly preferable. Examples of such hydroxypropyl methylcellulose (hypromellose) include hydroxypropylmethylcellulose 1828, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910, and the like.

The hypromellose preferably has a methoxy group content of 15 to 45% by mass, and more preferably 25 to 35% by mass. On the other hand, the hydroxypropoxy group content is preferably 1 to 35% by mass, and more preferably 5 to 15% by mass.
Moreover, as a viscosity of a hypromellose, 1-20 mPa * s is preferable and 2-10 mPa * s is more preferable. The viscosity can be measured according to the first method (capillary viscometer method) of viscosity measurement method of Japanese Pharmacopoeia using an aqueous solution (20 ° C.) obtained by dissolving 2 g of sample in 98 mL of water.

  As content of the said cellulose derivative, 0.01-5 mass% is preferable in a liquid composition, 0.03-3 mass% is more preferable, 0.05-2 mass% is still more preferable, 1% by mass is particularly preferred. By controlling the content to be 0.1% by mass or more, the caffeine crystal precipitation suppressing action is improved.

  Moreover, as content ratio of the said caffeine and a cellulose derivative, a cellulose derivative is 0.01-5 mass parts with respect to 1 mass part of caffeine from a viewpoint of crystal precipitation suppression of caffeine. Preferably, it is 0.02 to 4 parts by mass, more preferably 0.03 to 3 parts by mass, and particularly preferably 0.1 to 1 part by mass. By controlling the content ratio of such a cellulose derivative to 0.1 parts by mass or more, the caffeine crystal precipitation suppressing action is improved.

  Examples of the thickening agent include sodium alginate, carboxyvinyl polymer, xanthan gum, glycerin, sorbitol, polyvinyl pyrrolidone, polyvinyl alcohol, macrogol 4000, macrogol 6000, etc., and these may be used alone or in combination of two or more. it can. Among such thickening agents, polyvinylpyrrolidone is preferable from the viewpoint of suppressing crystal precipitation of caffeine. As such K value of polyvinylpyrrolidone, 5-100 are preferable and 10-50 are more preferable. The K value is a viscosity characteristic value that correlates with the molecular weight, and means a value calculated by applying a relative viscosity value (25 ° C.) measured by a capillary viscometer to the Fikenscher equation.

  Moreover, as content ratio of the said caffeine and a thickening agent, it is preferable that a thickening agent is 0.5-8 mass parts with respect to 1 mass part of caffeine, 0.75-6. It is more preferable that it is a mass part, and it is especially preferable that it is 1-4 mass parts.

Moreover, the said liquid composition may contain medicinal components other than the said caffeine.
Examples of the medicinal ingredients include antipyretic analgesics, antihistamines, antitussives, noscapine, bronchodilators, expectorants, hypnotic sedatives, vitamins, anti-inflammatory agents, gastric mucosal protective agents, anticholinergic agents, antiemetics, inorganic Salts, amino acids, calcium salts, magnesium salts, glucuronic acids, herbal medicines, Chinese herbal formulas, xanthine components, ursodeoxycholic acid, orotic acid, gamma-oryzanol, adenosine triphosphate and its salts, diisopropylamine dichloroacetate Liver hydrolyzate, inositol, carnitine chloride, rutin and the like. In addition, these can be used individually or in combination of 2 or more types.

  Examples of the antipyretic analgesic agent include aspirin, aspirin aluminum, acetaminophen, isopropylantipyrine, ibuprofen, etenzamide, sazapyrine, salicylamide, sodium salicylate, thiaramide hydrochloride, lactylphenetidine, loxoprofen sodium hydrate, and the like. .

  Examples of the antihistamine include azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, ebastine, emedastine fumarate, carbinoxamine diphenyl disulfonate, carbinoxamine maleate Clemastine fumarate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, ketotifen fumarate, dipheterol hydrochloride, difeterol phosphate, diphenidol hydrochloride, diphenylpyraline hydrochloride, diphenyl Pyraline theocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, dimenhydrinate triprolyzine hydrochloride, tripelenamine hydrochloride, tonsilamine salt Salt, pheniramine maleate, phenetazine hydrochloride, phenetadine tannate, promethazine hydrochloride, promethazine methylene disalicylate, mequitazine, methodirazine hydrochloride, mebhydrolinapadisylate, emedastine fumarate, etc. Is mentioned.

  Examples of the antitussive include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, codeine phosphate hydrate, dihydrocodeine phosphate, dibutate sodium, Examples include dimemorphan phosphate, dextromethorphan hydrobromide, dextromethorphan / phenolphthaline salt, tipepidine citrate, tipepidine hibenzate, guaifenesin, potassium guaiacol sulfonate, and the like.

  Examples of the noscapine include noscapine hydrochloride and noscapine.

  Examples of the bronchodilator include trimethquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, methylephedrine, dl-methylephedrine hydrochloride, l-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, methoxyphenamine hydrochloride and the like can be mentioned.

  Examples of the expectorants include ambroxol hydrochloride, ammonia fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, bromohexine hydrochloride, methylcysteine hydrochloride, l-menthol, lysozyme hydrochloride, and the like. .

  Examples of the hypnotic sedative include allyl isopropyl acetyl urea and bromovalerylurea.

Examples of the vitamins include retinols, liver oils, vitamin B group (vitamin B ₁ , vitamin B ₂ , vitamin B ₃ , vitamin B ₅ , vitamin B ₆ , vitamin B ₇ , vitamin B ₉ and vitamin B ₁₂ ). , Vitamin C, vitamin D, vitamin E, vitamin U, hesperidin and derivatives thereof and salts thereof (for example, retinol acetate, retinol palmitate, vitamin A oil, liver oil, strong liver oil, thiamine, thiamine chloride hydrochloride, Thiamine nitrate, dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisibutamine, bisbenchamine, prosultiamine, benfotiamine, thiamine diphosphate , Riboflavin, riboflavin phosphate , Riboflavin butyrate, sodium riboflavin phosphate, nicotinic acid, nicotinamide, inositol hexanicotinate, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, hepronicart, pantothenic acid, panthenol, panthetin, pantothene Calcium phosphate, sodium pantothenate, coenzyme A, pyridoxine hydrochloride, pyridoxal phosphate, pyridoxamine hydrochloride, biotin, folic acid, dihydrofolic acid, tetrahydrofolic acid, cyanocobalamin, mecobalamin, hydroxocobalamin, deoxyadenosylcobalamin, ascorbic acid, ascorbine Acid sodium, calcium ascorbate, ergocalciferol, cholecalciferol, d-α-tocophero succinate Dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, d-α-tocopherol acetate, dl-α-tocopherol acetate, d-α-tocopherol, dl-α-tocopherol and dl-nicotinic acid dl- α-tocopherol, methylmethionine sulfonium chloride, hesperidin, etc.).

  Examples of the anti-inflammatory agent include glycyrrhizic acid and derivatives thereof and salts thereof (for example, dipotassium glycyrrhizinate and monoammonium glycyrrhizinate), seaprose, semi-alkaline proteinase, serrapeptase, tranexamic acid, proctase, pronase, bromelain and the like. Is mentioned.

  Examples of the gastric mucosa protective agent include aminoacetic acid, aldioxa, magnesium silicate, gefarnate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel , Aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide / potassium aluminum sulfate coprecipitation product , Sucralfate, cetraxate hydrochloride, sofalcone, magnesium carbonate, teprenone, copper chlorophyllin potassium, copper chlorophyllin sodium, magnesium aluminate metasilicate, methylmethionine Sulfo chloride, and the like.

  Examples of the anticholinergic agent include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datsura extract, tipidium bromide, methixene hydrochloride, methyl atropine bromide, methyl anisotropine bromide, methyl Scopolamine bromide, methyl-1-hyostiamine bromide, methylbenactidium bromide, papaverine hydrochloride, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, iodide isopropamide, diphenylpiperidinomethyl iodide Examples include dioxolane, funnel extract, funnel root, funnel root total alkaloid citrate.

  Examples of the antiemetic include ethyl aminobenzoate, cerium oxalate, and piperidylacetylaminoethyl ethylbenzoate.

  Examples of the inorganic salts include potassium chloride, calcium chloride, sodium chloride, sodium hydrogen carbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and the like. It is done.

  Examples of the amino acids include L-cysteine cysteine, L-aspartate potassium, L-aspartate magnesium, L-aspartate potassium / magnesium, L-cysteine, L-lysine hydrochloride, L-arginine hydrochloride, L-methionine. DL-methionine, L-isoleucine, L-leucine, L-phenylalanine, L-threonine, L-tryptophan, L-valine, aminoethylsulfonic acid, sodium chondroitin sulfate and the like.

  Examples of the calcium salts include calcium glycerophosphate, calcium gluconate, precipitated calcium carbonate, calcium lactate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, calcium citrate and the like.

  Examples of the magnesium salts include magnesium carbonate.

  Examples of the glucuronic acids include glucuronolactone and glucuronic acid amide.

  The herbal medicines include, for example, akamegashiwa (red buds), asenyaku (asenyaku), inyokaku (horny gourd), fennel (yuka), turmeric (depressed gold), elephant kogyo (yakugoka), engosaku (yangkou), enmaiso ( Life-prolonging grass), Japanese cypress (yellow coral), Japanese cypress (yellow coral), Japanese cypress (yellow spirit), Japanese cypress (yellow coral), Japanese cypress (cherry skin), Japanese laurel (yellow ream), Onji (distant), Chinese cabbage (marine kidney), Japanese cypress (How many crabs), gadgets (garbage), valerian grasses, camomile, guarana, caronin, licorice, licorice, bellflowers, kyonin, apricots, cucumber Kashiwa), Krategus, Keigai, Kakihi (Keiko), Ketsumeishi (Keiko), Gentiana, Gennoshouko (current evidence), Koujin (Red soup), Koubushi (Katsukiko), Go U (beef yellow), trash (Gomiko), Psycho (Saiko), saishin (Spicy), sansho (Yamamuro), Zion (purple candy), dicoppi (earthbone skin), peonies (glaze), musk (mushroom), Shajin, Shazenshi (car front child), Shazenso (car front grass), Beast gall (including Yutan (bear gall)), Syougyo (ginger), Giryu (land dragon), Xinyi (spicy), Sexan (stone)蒜), Senega, Senkyu (Ryukyu), Zenko (Mae-Hu), Senburi (Senhwa), Sojutsu (、), Sohakuhi (Mulberry white skin), Soyo (Suyo), Taisan (Daegu), Taisou (Otsugi) , Chikutsutsu carrot (bamboo ginseng), clove (clove), chimpi (Chen), touki (together), tokon (napping root), Nantenjitsu (southern), carrot (carrot), baimo (shellfish mother), bacmondou ( Mumon winter), mint (light load), Hange (half summer), ba Nukauka (Banka), Hampi (anti-nose), Bikaku (white), Bakujutsu (white birch), Bukuryu (茯苓), Bowie (prevented), Buttonpi (peony skin), Borei (oyster), Maou (mao), Herbal medicines such as Yokuinin (Yokujin), Rokujo (deer), royal jelly, and extracts thereof (extract, tincture, dried extract, etc.) and the like can be mentioned.

  Examples of the above-mentioned Kampo prescriptions include, for example, Kakkon-yu, Kami-Kaisu-yu, Kami-san, Katsue-yu, Koso-san, Saiko-Kei-to, Sho-saiko-to, Juzen-taiho-to, Koken-chu-yu, Kosei-ryu Hot water, Seishin lotus drink, Mumon Fuyu-yu, Hanka-koboku-yu, Hachimi-jio-maru, Hochuekki-to, Rikkunshi-yu, Mao-yu, etc.

  Examples of the xanthine-based component include aminophylline, diprofylline, theophylline, proxyphylline and the like.

  Among the medicinal components other than caffeine as described above, (1) From the viewpoint of being used as an antipyretic analgesic, a general cold medicine, etc., antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotic sedatives, antihypertensives Contains one or more selected from the group consisting of choline agents, etc. (2) includes one or more selected from the group consisting of antihistamines, antitussives, etc. from the viewpoint of being used as an antitussive expectorant (3) Including one or more selected from the group consisting of antihistamines, bronchodilators, anticholinergics, anti-inflammatory agents, lysozyme hydrochloride, herbal medicines, etc. (4) Antihistamines, anticholinergic agents, antiemetics, hypnotic sedatives, sodium bicarbonate, menthol, vitamins (1) From the viewpoint of being used as a nutrient, vitamins, inorganic salts, amino acids, calcium salts, magnesium salts, glucuronic acids, herbal medicines, Chinese medicine Those containing one or more selected from the group consisting of prescriptions and other drugs are preferred.

  Moreover, content of medicinal components other than these caffeine is not specifically limited, For example, it is about 10-40 mass% in a liquid composition, and 15-30 mass% is preferable.

  Moreover, the liquid composition of this invention may contain the additive normally used for pharmaceuticals other than the above-mentioned component other than a solvent, the said cellulose derivative, and a thickening agent. In addition, these can be used individually or in combination of 2 or more types.

The solvent is not particularly limited. For example, a volatile or non-volatile solvent that is immiscible with water or not soluble in water (vegetable oil, aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, ethers, esters, higher Alcohols), non-volatile solvents miscible with water, water, polyhydric alcohols and the like. Among these, those that can be filled in capsules are preferable, and water and polyhydric alcohols are more preferable, and a mixed solution of water and polyhydric alcohols is particularly preferable, from the viewpoint of suppressing caffeine crystal precipitation and suppressing capsule softening. . Moreover, as such a polyhydric alcohol, a macrogol having an average molecular weight of about 100 to 800 is preferable. The average molecular weight of such macrogol is preferably 150 to 700, more preferably 190 to 630. Examples of such macro goals include macro goal 200, macro goal 300, macro goal 400, and macro goal 600. Among these, the macro goal 400 is particularly preferable.
Although content of the said solvent is not specifically limited, For example, it is about 60-90 mass% in a liquid composition, and 60-85 mass% is preferable.

  Examples of additives usually used for pharmaceuticals other than the cellulose derivative and the thickening agent include a pH adjuster, a dye, and a surfactant.

  As the pH adjuster, in view of the stability of the capsule shell of the liquid composition, a pH adjuster that can be adjusted to an acidic to neutral range (preferably an acidic range) is preferable. Examples of such pH regulators include adipic acid, ascorbic acid, benzoic acid, erythorbic acid, hydrochloric acid, citric acid, glutamic acid, succinic acid, acetic acid, tartaric acid, lactic acid, phosphoric acid, fumaric acid, maleic acid, malic acid. And the like. In addition, as content of lactic acid and / or phosphoric acid among such pH adjusters, 0-5 mass% is preferable, 0-1 mass% is more preferable, 0 mass% is especially preferable. Even when such lactic acid or phosphoric acid is at a low concentration or when lactic acid or phosphoric acid is not used, the present invention suppresses caffeine crystal precipitation.

  Examples of the colorant include food red 2, food red 3, food red 40, food red 102, food red 104, food red 105, food red 106, food red 106, food yellow 4, food yellow 4 No. Aluminum Lake, Edible Yellow No. 5, Edible Green No. 3, Edible Blue No. 1, Edible Blue No. 2, Red Cabbage, Red Radish, Anato, Anthocyanin, Turmeric, Cacao, Caramel, Gardenia, Chlorophyll, Cochineal, Perilla, Pepper, Examples include paprika, beet red, grape skin, grape juice, flavonoids, red yeast rice, safflower, berries, purple corn, purple potato, and rack.

  Examples of the surfactant include glyceryl monohexanoate, glyceryl monooctanoate, glyceryl monodecanoate, glyceryl monolaurate, glyceryl dioctanoate, glyceryl didecanoate, glyceryl decanoate, glyceryl monomyristate, and glyceryl monostearate. Glycerol fatty acid esters such as glyceryl monooleate; sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate; Polyoxyethylene alkyl ethers such as lauromacrogol; stearic acid polyoxyl 40, stearic acid polyoxyl 45, stearin Polyoxyethylene fatty acid esters such as polyoxyl 55; Nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85 Is mentioned.

  Content of additives other than the said cellulose derivative and thickening agent is not specifically limited, It can be made to contain in the range which does not prevent the effect of this invention.

  The color tone of the liquid composition of the present invention is preferably transparent and clear.

Next, the properties of the capsule of the present invention will be described.
The capsule of the present invention includes both hard capsules and soft capsules, and hard capsules are preferred.
The color of the capsule skin used in the present invention is not particularly limited, but from the viewpoint of the commercial value of the capsule, it is preferably transparent or translucent so that the filled liquid can be visually observed.
The capsule may have a warm color (red to orange to yellow). However, the capsule is transparent or translucent to the extent that it can be visually observed. preferable. This brings about an image of warmth, calmness, stability and security, and can be relaxed to relieve symptoms.

  In addition, the capsule of this invention can be manufactured in accordance with a conventional method. For example, after gelatin is water-absorbed and swelled, it is dissolved by heating, and then an appropriate amount of pigment, macrogol and glycerin to be contained in the capsule skin is added, an antiseptic is added if desired, and the viscosity is adjusted appropriately. A capsule forming jelly is obtained by defoaming, and the jelly is formed into a capsule using a capsule forming apparatus, and the capsule is filled with the liquid composition of the present invention to obtain a hard capsule. In addition, gelatin is water-swelled and then dissolved by heating, and then an appropriate amount of pigment, macrogol and glycerin to be contained in the capsule skin is added, and if desired, a plasticizer, preservative, etc. are added, and viscosity is appropriately adjusted. After adjusting, defoaming treatment is performed to obtain a capsule-forming jelly. The capsule (soft capsule) of the present invention can be produced by using the obtained jelly and the liquid of the present invention based on a rotary die method, a dropping method or the like.

  And even if the capsule of this invention is preserve | saved for a long time under low temperature conditions, there is little crystal precipitation of caffeine contained in the filled liquid composition, and it has a favorable external appearance and outstanding stability. Therefore, since the solubility of caffeine is high, an immediate effect can be expected when it is administered to humans, and the product value is expected to improve, greatly contributing to compliance.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.

Production Example 1
Anhydrous caffeine 4 g, hypromellose 0.7 g, ibuprofen 45 g, dl-methylephedrine hydrochloride 6 g, d-chlorpheniramine maleate 0.35 g, codeine phosphate hydrate 2.4 g, ambroxol hydrochloride 4.5 g , L-menthol 4 g, polyvinylpyrrolidone 10 g, macrogol 400 175.1 g and purified water 28.6 g were mixed to obtain a liquid composition (capsule filling liquid).

Example 1 Hard capsule 10.0 liters of purified water was added to 10.0 kg of gelatin and allowed to stand naturally for about 1-2 hours to swell with water absorption. After the gelatin swells sufficiently, it is heated to 60 ° C. and stirred to uniformly dissolve the gelatin. Further, 1.0 kg of an aqueous solution (5% by mass concentration) of macrogol 4000 and 5 g of caramel pigment are added to this gelatin solution. In addition, after stirring and adjusting the viscosity, defoaming treatment was performed to obtain a capsule-forming jelly. This jelly is charged into a capsule forming device, size 1 capsules are formed (80 mg per capsule), filled with 471 mg of the liquid composition prepared in Production Example 1, and hard capsules (water in the capsule skin) Content: about 15% by mass).
The obtained hard capsule was a transparent liquid filled in an amber transparent capsule skin.

Comparative Example 1 Hard Capsule 18.0 liters of purified water was added to 10.0 kg of gelatin and allowed to stand naturally for about 1 to 2 hours for water absorption and swelling. After the gelatin swells sufficiently, the mixture is heated to 60 ° C. and stirred to uniformly dissolve the gelatin. Further, 1.0 kg of an aqueous solution (5% by mass concentration) of Macrogol 4000 is added to the gelatin solution and stirred. After adjusting the viscosity, defoaming treatment was performed to obtain a capsule-forming jelly. This jelly is charged into a capsule forming device, size 1 capsules are formed (80 mg per capsule), filled with 471 mg of the liquid composition prepared in Production Example 1, and hard capsules (water in the capsule skin) Content: about 15% by mass).
The obtained hard capsule was a transparent capsule skin filled with a transparent liquid.

Test example 1
Prepare 40 capsules obtained in Example 1 and Comparative Example 1 and observe them immediately after production and after storage for 2 weeks and 1 month to confirm the presence or absence of caffeine crystal precipitation. The stability was evaluated. Table 1 below shows the number of capsules in which crystal precipitation was confirmed among 40 capsules.

None of the capsules of Example 1 had caffeine crystallized after storage for 1 month (0/40).
On the other hand, in the capsule of Comparative Example 1, 3 capsules out of 40 capsules were crystallized after storage for 2 weeks, and 6 capsules out of 40 capsules were crystallized after storage for 1 month.

Production Example 2
Anhydrous caffeine 4 g, hypromellose 0.7 g, ibuprofen 45 g, dl-methylephedrine hydrochloride 6 g, d-chlorpheniramine maleate 0.35 g, codeine phosphate hydrate 2.4 g, bromohexine hydrochloride 1.2 g, l -4 g of menthol, 10 g of polyvinylpyrrolidone, 178 g of Macrogol 400 and 29 g of purified water were mixed to obtain a liquid composition (capsule filling liquid).

Example 2 Hard capsule 10.0 liters of purified water was added to 10.0 kg of gelatin and allowed to stand naturally for about 1 to 2 hours to swell with water absorption. After the gelatin swells sufficiently, it is heated to 60 ° C. and stirred to uniformly dissolve the gelatin. Further, 1.0 kg of an aqueous solution (5% by mass concentration) of macrogol 4000 and 5 g of caramel pigment are added to this gelatin solution. In addition, after stirring and adjusting the viscosity, defoaming treatment was performed to obtain a capsule-forming jelly. This jelly is charged into a capsule forming apparatus, size 1 capsules are formed (80 mg per capsule), filled with 471 mg of the liquid composition prepared in Production Example 2, and hard capsules (water in the capsule skin) Content: about 15% by mass).
The obtained hard capsule was a transparent liquid filled in an amber transparent capsule skin.
In addition, no crystal precipitation was observed in such a hard capsule even after one month had passed under the storage condition at -5 ° C.

Example 3 Soft Capsule 10.0 liters of purified water was added to 9.0 kg of gelatin and allowed to stand naturally for about 1-2 hours to swell with water absorption. After the gelatin swells sufficiently, it is heated to 60 ° C. and stirred to uniformly dissolve the gelatin. Further, 1 kg of concentrated glycerin and 1.0 kg of an aqueous solution of macrogol 4000 (concentration of 5% by mass) are added to this gelatin solution. And 27 g of caramel color was added and stirred to adjust its viscosity, followed by defoaming treatment to obtain a capsule-forming jelly. Using this jelly, in a rotary capsule filling machine, 471 mg of the liquid composition produced in Production Example 1 was filled, and a total amount of 660 mg of soft capsules (water content in capsule skin: about 8% by mass) Manufactured.

Example 4 Soft capsule 10.0 liters of purified water was added to 9.0 kg of gelatin and allowed to stand naturally for about 1-2 hours to swell with water absorption. After the gelatin swells sufficiently, it is heated to 60 ° C. and stirred to uniformly dissolve the gelatin. Further, 1 kg of concentrated glycerin and 1.0 kg of an aqueous solution of macrogol 4000 (concentration of 5% by mass) are added to this gelatin solution. And 20 g of caramel color were added and stirred to adjust the viscosity, followed by defoaming treatment to obtain a capsule-forming jelly. Using this jelly, in a rotary capsule filling machine, 471 mg of the liquid composition produced in Production Example 2 was filled, and a total amount of 660 mg of soft capsules (water content in capsule skin: about 8% by mass) Manufactured.

Claims (3)

  A capsule in which a liquid composition containing caffeine is filled in a capsule made of a capsule skin containing a pigment.   The dye is food red No. 2, food red No. 3, food red No. 40, food red No. 102, food red No. 104, food red No. 105, food red No. 106, food yellow No. 4, food yellow No. 4 aluminum lake, Edible Yellow No. 5, Edible Green No. 3, Edible Blue No. 1, Edible Blue No. 2, Red Cabbage, Red Radish, Anato, Anthocyanin, Turmeric, Cacao, Caramel, Gardenia, Chlorophyll, Cochineal, Perilla, Pepper, Paprika, Beet Red The capsule according to claim 1, wherein the capsule is one or more selected from grape skin, grape juice, flavonoid, red yeast rice, safflower, berries, purple corn, purple potato, and lac.   A capsule in which a liquid composition containing caffeine is filled in a capsule made of a capsule shell containing caramel.