JP5977062B2 - Caffeine-containing liquid composition and capsule filled with the composition - Google Patents

Description

  The present invention relates to a liquid composition containing caffeine and a capsule filled with the composition.

  Caffeine is a central nervous stimulant classified as a xanthine derivative, and exhibits an action of enhancing antipyretic analgesic action and 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 caffeine crystals are precipitated, not only may the effect be affected, but also the appearance may be inferior, and the commercial value of the aforementioned antipyretic analgesics and the like is reduced.

  Under such a background, means for suppressing caffeine crystal precipitation in a liquid composition 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. Used in combination with caffeine and phosphoric acid at a specific ratio (Patent Document 2).

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 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 292 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 235

However, the caffeine crystal precipitation inhibiting action exhibited by the capsule filling liquids described in Patent Documents 1 and 2 has not been sufficiently satisfactory.
In addition, bromhexine and ambroxol have an expectorant action, so they are included in general cold medicines, antitussive expectorants, etc. (Non-Patent Documents 3 and 4), and common cold medicines combining caffeine with these expectorants are known. However, it is desired to improve the appearance and stability of capsules such as general cold medicines containing such caffeine.
Accordingly, an object of the present invention is to provide a liquid composition that suppresses crystal precipitation of caffeine and has excellent appearance stability, and a capsule filled with the composition.

  Thus, as a result of intensive studies, the present inventors have found that a liquid composition excellent in appearance stability can be obtained by using caffeine and expectorant in combination with polyvinylpyrrolidone to suppress caffeine crystal precipitation. It was found that capsules having good appearance and stability can be obtained by filling the composition into capsules.

That is, the present invention provides a liquid composition containing caffeine, expectorant and polyvinylpyrrolidone.
Moreover, this invention provides the capsule which filled the said liquid composition in the capsule.

  The liquid composition of the present invention has excellent appearance stability with little crystal precipitation of caffeine. Therefore, according to the present invention, a capsule having a good appearance and excellent stability can be provided.

  The liquid composition of the present invention contains caffeine, expectorant and polyvinylpyrrolidone. First, these components will be described in detail.

  Examples of the caffeine in the present invention include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate. These can be used alone or in combination of two or more.

  The content of caffeine in the liquid composition of the present invention may be determined by appropriately examining the dose per day according to the sex, age, symptoms, etc. of the user, The amount that can be taken 10 to 1000 mg 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 still 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.

  Examples of expectorants in the present invention include, for example, ambroxol hydrochloride, ammonia fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacol sulfonate, potassium cresolsulfonate, bromhexine hydrochloride, methylcysteine Examples thereof include hydrochloride and lysozyme hydrochloride, and these can be used alone or in combination of two or more. Among these, ambroxol hydrochloride and bromohexine hydrochloride are particularly preferable.

  The content of the expectorant in the liquid composition of the present invention may be determined by appropriately examining the daily dose according to the sex, age, symptoms, etc. of the user. For example, when the expectorant is bromhexine hydrochloride, the amount that can be taken 0.1 to 50 mg per day is preferable, the amount that can be taken 0.5 to 25 mg is more preferable, and the amount that can be taken 1 to 15 mg is particularly preferable. When the expectorant is ambroxol hydrochloride, the amount that can be taken 0.1 to 150 mg per day is preferable, the amount that can be taken 0.5 to 100 mg is more preferable, and the amount that can be taken 1 to 50 mg is particularly preferable.

  The content of the expectorant is usually about 0.001 to 20% by mass in the total mass of the liquid composition, preferably 0.004 to 10% by mass, and more preferably 0.02 to 7% by mass. 0.02 to 5% by mass is more preferable, 0.04 to 4% by mass is further preferable, and 0.1 to 2% by mass is particularly preferable.

  Moreover, as content ratio of the said caffeine and an expectorant, it is preferable that an expectorant is 0.01-10 mass parts with respect to 1 mass part of caffeine, 0.05-5 mass parts More preferably, it is 0.1-2 parts by mass.

The polyvinyl pyrrolidone is a linear polymer of N-vinyl-2-pyrrolidone.
Moreover, as 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.
Examples of such polyvinyl pyrrolidone include polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25, polyvinyl pyrrolidone K30, and polyvinyl pyrrolidone K90. Among these, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, and polyvinylpyrrolidone K30 are preferable.

  As content of the said polyvinyl pyrrolidone, 0.5-10 mass% is preferable in a liquid composition, 1-7.5 mass% is more preferable, 2-5 mass% is further more preferable.

  Moreover, as content ratio of the said caffeine and polyvinylpyrrolidone, from a soluble viewpoint of caffeine, it is that polyvinylpyrrolidone is 0.5-8 mass parts with respect to 1 mass part of caffeine. Preferably, it is 0.75-6 mass parts, and it is especially preferable that it is 1-4 mass parts.

Moreover, the liquid composition of this invention may contain medicinal components other than the said caffeine and expectorant.
Examples of the above-mentioned medicinal ingredients include antipyretic analgesics, antihistamines, antitussives, noscapine, bronchodilators, hypnotic sedatives, vitamins, anti-inflammatory agents, gastric mucosal protective agents, anticholinergics, herbal medicines, Kampo prescriptions, xanthines System components 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, Dimemorphan phosphate, dextromethorphan hydrobromide, dextromethorphan / phenolphthalin salt, tipepidine citrate, tipepidine hibenzate, 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 hypnotic sedative include allyl isopropyl acetyl urea and bromovalerylurea.

  Examples of the vitamins include vitamin B group (vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9 and vitamin B12), vitamin C, hesperidin and derivatives thereof, and salts thereof ( For example, thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisbutiamine, bisbenchamine, prosulfur Thiamine, benfotiamine, thiamine diphosphate, riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin sodium phosphate, panthenol, pantethine, calcium pantothenate, sodium pantothenate Potassium, pyridoxine hydrochloride, pyridoxal phosphate esters, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, 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, scopolamine hydrobromide, datsura extract, tipidium bromide, methixene hydrochloride, methyl atropine bromide, methyl anisotropin bromide, methyl scopolamine bromide, methyl -L-hyostiamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, iodopropamide iodide, diphenylpiperidinomethyldioxolane, funnel extract, funnel root, And funnel root total alkaloid citrate.

Examples of the herbal medicines include, for example, akamegashiwa (red buds), asenyaku (asenyaku), inyokaku (horny sheep moth), fennel (yuka), turmeric (depressed gold), engosaku (yeonkou), enmeiso (extended herb), ogon (yellow)岑), Ousei (yellow spirit), Oubak (yellow cocoon), Spruce (cherry bark), Auren (yellow ren), Onji (distant), Gajutsu (wet), valerian (deer herb), chamomile, caronin (karojin) , Licorice, liquorice, bellflower, kyonin, cucumber, cucumber, cocoon, cinnamon, ketsumeishi, gentian, gennoshouko (current evidence) , Koubushi (Katsukiko), Gouou (beef yellow), Goshi (Gomiko), Saishin (Spicy), Salamander (Sancho), Zion (Purple skin), Peonies (Gakuyaku) , Musk, shajin, shazenshi (car front child), shazenso (car front grass), beast gall (including yutan (bear gall)), ginger, giryu, shin ii Pepper), Sexan (Seki), Senega, Senkyu (river cucumber), Zenko (maehu), Semburi (Senshu), Sojutsu (蒼朮), Sohakuhi (mulberry white skin), Soyo (Soba), Taisan (Oiso) , 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), bankouka (bancho flower), Hampi (anti-nose), peony (white bean), peanut (white moth), bukkuri (茯苓), button pi (peony skin), Boray, mao (mao), rokjo Antler) Crude drugs and extracts thereof such as (extract, tincture, dry extract, etc.) and the like.

  Examples of the above-mentioned Kampo prescription include Kakkon-to, Katsue-yu, Koso-san, Saiko-Kei-do, Sho-saiko-to, Shosei-ryu, Mumon-tou-yu, Hanka-kopaku-to, Mao-to, and the like.

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

  Among the medicinal ingredients other than the above caffeine and expectorant, antipyretic analgesics, antihistamines and antitussives are preferable. Also, by using these in combination, headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain ( Menstrual pain), pain relief, chills, antipyretic fever, cold symptoms (nasal discharge, stuffy nose, sneezing, sore throat, chills, fever, headache, joint pain, muscle pain), acute rhinitis Efficacy or effect for various symptoms (sneezing, runny nose (nasal discharge)), stuffy nose, sore eyes, sore throat, head-health, etc. due to allergic rhinitis or sinusitis It is done.

  Moreover, content of medicinal ingredients other than these caffeine and expectorant is not specifically limited, However, In a liquid composition, it is about 10-40 mass% normally, 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 and the said polyvinylpyrrolidone. 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 capable of being filled in capsules are preferable, and water and polyhydric alcohols are more preferable, and a mixture of water and polyhydric alcohols is particularly preferable from the viewpoints of solubility of caffeine and suppression of softening of the capsule film. 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, In a liquid composition, it is about 60-90 mass% normally, and 60-85 mass% is preferable.
Moreover, as content ratio of the said caffeine and a solvent, it is preferable that a solvent is 35-100 mass parts with respect to 1 mass part of caffeine, It is more preferable that it is 40-90 mass parts, 45 It is especially preferable that it is -80 mass parts.

  Examples of additives usually used for pharmaceuticals other than the polyvinylpyrrolidone include other thickeners, pH adjusters, dyes, and surfactants.

  Examples of the other thickening agent include sodium alginate, carboxyvinyl polymer, xanthan gum, glycerin, sorbitol, polyvinyl alcohol, macrogol 4000, macrogol 6000, and the like.

  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 the additive normally used for pharmaceuticals other than the said polyvinylpyrrolidone is not specifically limited, It can contain in the range which does not prevent the effect of this invention.

Next, properties of the liquid composition of the present invention will be described.
The color tone of the liquid composition of the present invention is preferably transparent and clear. Moreover, since the liquid composition of the present invention is excellent in appearance stability, it is suitable for use as a liquid filled in a capsule (preferably a transparent capsule).

Next, the capsule of the present invention will be described.
The capsule of the present invention is a capsule filled with the aforementioned liquid composition.
The capsule preferably contains a base in the film. Examples of such a base include gelatin, hypromellose, pullulan, polyvinyl alcohol, polyvinyl alcohol copolymer (preferably, a copolymer of polyvinyl alcohol, methyl methacrylate and acrylic acid or a salt thereof), and the like. It can 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.

  In addition, the content of the base is usually about 60 to 99.5% by mass in the capsule film, but is preferably 65 to 99% by mass. When gelatin and macrogol are used in combination, the gelatin content is preferably 50 to 99.5% by mass, more preferably 65 to 99% by mass, based on the total capsule film. The content of macrogol is preferably 0.5 to 15% by mass in the capsule film, and more preferably 1 to 10% by mass.

In addition to the above base, the capsule film is made of plasticizers such as glycerin, mannitol, sorbitol, sucrose, fructose, propylene glycol, macrogol; gum arabic, alginic acid, carrageenan, agar, xanthan gum, guar gum, gluco It may contain gelling agents such as mannan, gellan gum, tamarind gum, fur celerin, pectin, locust bean gum, etc., and if necessary, ammonium chloride, potassium chloride, calcium chloride, sodium chloride, potassium citrate, sodium citrate Gelling aids such as magnesium sulfate and potassium phosphate may be included.
Although the said plasticizer is about 1-50 mass% normally with respect to a base, 5-40 mass% is preferable and 5-15 mass% is more preferable.

  In addition to the above-mentioned base, plasticizer, gelling agent and gelling aid, for example, 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, Pepper, Paprika, Beet Red, Grape Skin, Grape Juice, Flavonoid, Scarlet, Safflower, Berries, Purple Corn, Purple Potato, Rack Pigments such as titanium oxide, polyvinyl acetal diethylaminoacetate, preservatives, fragrances, disintegrants, surfactants, etc. It may be Idei.

The capsule of the present invention includes both hard capsules and soft capsules.
The color of the capsule film 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, gelatin is swollen with water, dissolved by heating, and then an appropriate amount of macrogol or glycerin to be contained in the capsule film is added, and if necessary, a dye or a preservative is added, and the viscosity is adjusted appropriately, followed by removal. Capsule molding jelly is obtained by foam treatment, and the jelly is molded into a capsule using a capsule molding 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 melted by heating, and then an appropriate amount of macrogol or glycerin to be contained in the capsule film is added. If desired, a plasticizer, a pigment, a preservative, etc. are added to appropriately adjust the viscosity. After the adjustment, 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 liquid composition of this invention is preserve | saved for a long time under low temperature conditions, there is little crystal precipitation of caffeine, and it has the outstanding external appearance stability. Thus, since the solubility of caffeine is high, when the liquid composition of the present invention is administered to a human, a rapid effect can be expected. In addition, the above-mentioned excellent appearance stability is expected to improve the product value, which greatly contributes to compliance.
Moreover, according to the present invention, a capsule having a good appearance and excellent stability and having a high commercial value can be provided.

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

Example 1
Ambroxol hydrochloride 4.5 g, anhydrous caffeine 4 g, polyvinylpyrrolidone (Povidone K30, manufactured by BASF) 10 g, hypromellose (hydroxypropylmethylcellulose 2910: manufactured by Shin-Etsu Chemical) 0.7 g, ibuprofen 45 g, dl-methylephedrine hydrochloride 6 g of salt, 0.35 g of d-chlorpheniramine maleate, 2.4 g of codeine phosphate hydrate, 4 g of l-menthol, 175.1 g of macrogol and 28.6 g of purified water were mixed to prepare a liquid composition (capsule filling) Liquid).

Example 2
A liquid composition (capsule filling solution) was obtained in the same manner as in Example 1 except that 4.5 g of ambroxol hydrochloride was replaced with 1.2 g of bromohexine hydrochloride.

Comparative Example 1
A liquid composition (capsule filling liquid) was obtained in the same manner as in Example 1 except that polyvinylpyrrolidone was not added.

Test example 1
For the liquid compositions obtained in Examples 1 and 2 and Comparative Example 1, the appearance stability is confirmed by visual observation immediately after production and after storage for 1 month at 5 ° C. to confirm the presence or absence of crystal precipitation. evaluated. The results are shown in Table 1.
(Evaluation criteria)
Crystal precipitation did not occur: ○
Crystal precipitation occurred: ×

  As shown in Table 1, the liquid compositions of Examples 1 and 2 using polyvinylpyrrolidone in addition to anhydrous caffeine and expectorant (ambroxol hydrochloride or bromohexine hydrochloride) were not only immediately after production but also at 5 ° C. Even after one month passed under the storage conditions, no crystal precipitation was observed, and the appearance stability was excellent.

Production Example 1 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 dissolve the gelatin uniformly. Further, 1 kg of concentrated glycerin and an aqueous solution of macrogol 4000 (concentration of 5% by mass) are added to the gelatin solution. In addition, after stirring and adjusting the viscosity, defoaming treatment was performed to obtain a capsule-forming jelly. Using this jelly, 471 mg of the liquid composition produced in Example 1 was filled with a rotary capsule filling machine to produce a soft capsule.
The obtained soft capsule was a transparent capsule filled with a transparent liquid. In addition, no crystal precipitation was observed when the soft capsule was stored for 6 months at 5 ° C.

Production Example 2 Soft capsule The same as in Production Example 1 except that the amount of the macrogol 4000 aqueous solution was changed from 1.0 kg (5% by mass concentration) to 0.5 kg (2.5% by mass concentration). Soft capsules were produced.

Production Example 3 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 to swell and absorb water. After the gelatin swells sufficiently, warm to 60 ° C. and stir to dissolve the gelatin uniformly. Further, 1.0 kg of an aqueous solution of macrogol 4000 (5% by mass concentration) and 3 g of caramel color are added to this gelatin solution. 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, a size 1 capsule is formed, and 471 mg of the liquid composition produced in Example 1 is filled into the capsule using a rotary capsule filling machine to produce a hard capsule. did.
The obtained hard capsule was a caramel-colored transparent capsule filled with a transparent liquid.

Production Example 4 Hard Capsule Capsules were molded in the same manner as in Production Example 3 except that the capsule size was changed from No. 1 to No. 0.
Next, loxoprofen sodium hydrate: 20.43 g, anhydrous caffeine: 4 g, dl-methylephedrine hydrochloride: 6 g, d-chlorpheniramine maleate: 0.35 g, guaifenesin: 25 g, povidone: 10 g, hypromellose : 0.8 g, Macrogol 400: 192.4 g, Benzoic acid: 8 g and Purified water: 31.4 g were mixed to obtain a liquid composition (capsule filling liquid). Moreover, such a liquid composition was clear.
Then, the capsule was filled with the liquid composition so that the content of loxoprofen sodium hydrate per capsule was 34.05 mg (30 mg in terms of anhydrous loxoprofen sodium) to produce a hard capsule.

Production Example 5 Soft capsules 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 3 g of caramel color were added and stirred to adjust the viscosity, followed by defoaming to obtain a capsule-forming jelly. Using this jelly, 471 mg of the liquid composition produced in Example 1 was filled with a rotary capsule filling machine to produce a soft capsule.
The obtained soft capsule was a transparent capsule filled with a transparent liquid. In addition, no crystal precipitation was observed even when the soft capsule was stored at −5 ° C. for 2 months.

Claims (4)

A capsule filled with a liquid composition containing caffeine, expectorant , polyvinylpyrrolidone , ibuprofen, water and macrogol . The capsule according to claim 1, wherein the caffeine is one or more selected from caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine and caffeine citrate. An expectorant selected from ambroxol hydrochloride, ammonia fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, potassium guaiacol sulfonate, potassium cresolsulfonate, bromhexine hydrochloride, methylcysteine hydrochloride and lysozyme hydrochloride The capsule according to claim 1 or 2, which is one kind or two or more kinds. The capsule according to any one of claims 1 to 3, wherein the expectorant is one or more selected from ambroxol hydrochloride and bromhexine hydrochloride.