JP6832195B2 - Oral liquids and oral solids - Google Patents

Description

The present invention relates to oral preparations.

Oral preparations are taken by mouth and move through the body while releasing medicinal ingredients in the digestive organs such as the stomach and intestines. Conventionally, in such oral preparations, various studies have been conducted such as controlling the release rate of the medicinal ingredient released from the oral preparation in order to enhance the absorbability in the digestive organ in which the medicinal ingredient is desired to be absorbed. ..
For example, Patent Document 1 contains a liquid auxiliary agent that facilitates swallowing of a drug and contains a water-soluble polymer that gels under acidic conditions, and the breaking stress of the gel is about 3.00 × 10 ^2. A liquid matrix having N / m ² or more and exerting an action of controlling the release rate of a drug by gelling in the stomach is disclosed.
Patent Document 2 discloses a solid composition containing an anionic polymer electrolyte, an acidic substance and a drug, and the drug release rate is not easily affected by the liquidity (pH) of the outside world such as in the digestive tract.
In Patent Document 3, 30 to 70% by weight of xanthan gum as a sustained-release base material and an inorganic electrolyte as a main ingredient are contained in the tablet, and the inorganic electrolyte is controlled to be gradually released. Sustained-release tablets are disclosed.
Patent Document 4 describes nuclei of tablets, granules or fine granules in which the release of the active ingredient is controlled and containing a specific imidazole compound or a salt thereof or an optically active substance thereof as an active ingredient, and hydroxypropylmethyl cellulose. It is a mixture of two or more kinds selected from phthalate, cellulose acetate phthalate and the like with different release conditions, and has a pH-dependent soluble release control film containing a polymer substance that dissolves in the range of pH 6.0 or more and pH 7.5 or less. Tablets, granules or fine granules are disclosed.

Japanese Unexamined Patent Publication No. 2004-2320 Japanese Unexamined Patent Publication No. 6-247843 Japanese Unexamined Patent Publication No. 4-316515 Japanese Unexamined Patent Publication No. 2013-155181

However, in the techniques of Patent Documents 1 to 4, the viscosity of the preparation may decrease in an environment with a high salt concentration. Therefore, in the intestine having a salt concentration of about 0.6% by mass, the preparation may not be retained in the intestine, and the physiologically active ingredients and the like contained in the preparation may not be continuously absorbed in the intestine. ..
Further, as an oral preparation, it is desired that it has high fluidity (low viscosity) and is easy to ingest when ingested by mouth.
That is, the oral preparation is required to have low viscosity and good fluidity in the oral cavity having a low salt concentration, and to thicken and enhance the retention in the intestine having a high salt concentration.
Therefore, an object of the present invention is an oral preparation that thickens when the salt concentration increases.

As a result of diligent studies, the present inventors have found that the following oral preparations can solve the above-mentioned problems.
That is, the present invention has the following configuration.
[1] (A) Carboxymethyl cellulose or a salt thereof having a viscosity of a 1% by mass aqueous solution at 25 ° C. of 250 to 2000 mPa · s, and (B) an aluminum-containing compound are contained, and [100 × the component (B)]. / An oral preparation having a mass ratio represented by [the component (A)) of 4 to 10.
[2] The component (B) is at least one selected from the group consisting of potassium aluminum sulfate, aluminum glycinate, dry aluminum hydroxide gel, magnesium aluminate aluminate, and magnesium aluminate silicate. [1] Oral preparations described in.
[3] The oral preparation according to [1] or [2], wherein the content of the component (A) is 0.3 to 1% by mass.
[4] The oral preparation according to any one of [1] to [3], wherein the degree of etherification of the component (A) is 0.6 to 1.0.
[5] The oral preparation according to any one of [1] to [4], which further contains (C) a physiologically active ingredient.
[6] The oral preparation according to any one of [1] to [5], wherein the dosage form of the oral preparation is a granule, a tablet, a capsule, a pill, a liquid, a gummy or a jelly.

The oral preparation of the present invention thickens as the salt concentration increases.

The oral preparation of the present invention comprises (A) carboxymethyl cellulose or a salt thereof ((A) component) having a viscosity of a 1% by mass aqueous solution of 250 to 2000 mPa · s at 25 ° C., and (B) an aluminum-containing compound ((B)). Ingredient) and.
The mass ratio represented by [100 × the component (B)] / [the component (A)] is 4 to 10.

In the present invention, the salt concentration means the concentration of sodium chloride measured by an ion chromatograph test method or a sodium selective ion electrode.
In the present invention, a high salt concentration means that the salt concentration is 0.5% by mass or more. In the present invention, the environment having a high salt concentration means an environment containing 0.5% by mass or more of salt. From the viewpoint that the effects of the present invention can be more easily enjoyed, the environment having a high salt concentration is preferably an environment containing 0.5 to 1.5% by mass of salt, and an environment containing 0.5 to 1.2% by mass of salt. Is more preferable, and an environment containing 0.5 to 1.0% by mass is further preferable. Examples of the environment having a high salt concentration include an intestinal environment.
Further, in the present invention, a low salt concentration means that the salt concentration is less than 0.5% by mass. The environment having a low salt concentration means, for example, an environment in which salt is contained in an amount of 0% by mass or more and less than 0.5% by mass. From the viewpoint that the effects of the present invention can be more easily enjoyed, as an environment having a low salt concentration, an environment containing 0 to 0.3% by mass of salt is preferable, and an environment containing 0 to 0.1% by mass is more preferable. The environment may be 0% by mass, that is, a salt-free environment (salt-free). Examples of the environment having a low salt concentration include an oral environment.

The oral preparation of the present invention is, for example, granules (powder, granules, enteric granules, etc.), tablets (bare tablets, sugar-coated tablets, coated tablets, enteric-coated tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, etc.). , Capsules, pills, liquids, gummy agents, troches, jelly agents, etc.

When the oral preparation of the present invention is a liquid preparation, the viscosity of the oral preparation of the liquid preparation is preferably less than 3000 mPa · s, more preferably less than 2000 mPa · s, still more preferably less than 1000 mPa · s in an environment where the salt concentration is low. When the viscosity of the oral preparation is in the above-mentioned preferable range, for example, it has high fluidity in the oral cavity, and it becomes easy to obtain good ingestibility. In addition, the handleability at the time of manufacturing the oral preparation becomes good, and the preparation becomes easy to manufacture.
The viscosity of the oral preparation is preferably more than 0 mPa · s and less than 3000 mPa · s, more preferably more than 0 mPa · s and less than 2000 mPa · s, and even more preferably more than 0 mPa · s and less than 1000 mPa · s in an environment with a low salt concentration.

The viscosity of the oral preparation of the liquid preparation is preferably 3000 mPa · s or more, more preferably 4000 mPa · s or more, further preferably 5000 mPa · s or more, and particularly preferably 6000 mPa · s or more in an environment with a high salt concentration. When the viscosity of the oral preparation is in the above-mentioned preferable range, for example, the fluidity of the oral preparation is lowered in the intestine and the retention in the intestine is enhanced. This facilitates the continuous absorption of physiologically active ingredients and the like contained in the oral preparation in the intestine. It also reduces the rate of intestinal juice transfer. Therefore, the oral preparation of the present invention can be easily applied to the improvement of irritable bowel syndrome and the like.
The viscosity of the oral preparation of the liquid preparation is preferably 3000 mPa · s or more and 18000 mPa · s or less, more preferably 4000 mPa · s or more and 15000 mPa · s or less, and further preferably 5000 mPa · s or more and 12000 mPa · s or less in an environment with a high salt concentration. , 6000 mPa · s or more and 10000 mPa · s or less is particularly preferable.

In the oral preparation of the liquid preparation, the difference between the viscosity in an environment with a high salt concentration and the viscosity in an environment with a low salt concentration is preferably 800 mPa · s or more, more preferably 1000 mPa · s or more, still more preferably 2000 mPa · s or more. 3000 or more is particularly preferable. Among the 3000 mPa · s or more, 4000 mPa · s or more is preferable, 5000 mPa · s or more is more preferable, and 6000 mPa · s or more is further preferable.
When the above difference is equal to or greater than the above lower limit, for example, the fluidity of the oral preparation is high in the oral cavity, good ingestibility is obtained, and the fluidity of the oral preparation is lowered in the intestine, resulting in high retention. It will be easier to obtain.
In the oral preparation, the difference between the viscosity in an environment with a high salt concentration and the viscosity in an environment with a low salt concentration is preferably 800 mPa · s or more and 18,000 mPa · s or less, and 1000 mPa · s or more and 15,000 mPa · s or less. More preferably, it is more preferably 2000 mPa · s or more and 12000 mPa · s or less, and particularly preferably 3000 mPa · s or more and 10000 mPa · s or less. Among the ranges of 3000 mPa · s or more and 10000 mPa · s or less, 4000 mPa · s or more and 10000 mPa · s or less is preferable, 5000 mPa · s or more and 10000 mPa · s or less is more preferable, and 6000 mPa · s or more and 10000 mPa · s or less is further preferable.

<Ingredient (A)>
The component (A) is carboxymethyl cellulose or a salt thereof, which has a viscosity of a 1% by mass aqueous solution at 25 ° C. of 250 to 2000 mPa · s. Hereinafter, carboxymethyl cellulose or a salt thereof is referred to as "CMC".
When the viscosity of the 1% by mass aqueous solution at 25 ° C. is 250 mPa · s or more, the viscosity is low and the fluidity is enhanced in an environment where the salt concentration is low. In addition, a thickening effect can be obtained in an environment with a high salt concentration.
When the viscosity of the 1% by mass aqueous solution at 25 ° C. is 2000 mPa · s or less, the viscosity is low and the fluidity is maintained in an environment with a low salt concentration, and a good thickening effect can be obtained in an environment with a high salt concentration.
On the other hand, in CMC where the viscosity of the 1% by mass aqueous solution at 25 ° C. is less than 250 mPa · s, the thickening effect cannot be obtained in an environment with a high salt concentration. In CMC where the viscosity of the 1% by mass aqueous solution at 25 ° C. is more than 2000 mPa · s, the viscosity becomes high in an environment with a low salt concentration, and a sufficient thickening effect cannot be obtained in an environment with a high salt concentration.
As the component (A), CMC having a viscosity of 1% by mass aqueous solution at 25 ° C. of 250 to 2000 mPa · s is preferable, CMC having a viscosity of 1100 to 1900 mPa · s is more preferable, and CMC having a viscosity of 1200 to 1800 mPa · s is more preferable. More preferred.
The method for measuring the viscosity in the present invention is as described in Examples.

As the component (A), CMC having an etherification degree of 0.6 to 1.0 is preferable, and CMC having a degree of etherification of 0.79 to 0.85 is more preferable.
When the degree of etherification of CMC is at least the above lower limit value, cross-linking with the component (B) is well formed in an environment with a high salt concentration such as an intestinal environment, and a thickening effect can be easily obtained.
When the degree of etherification of CMC is not more than the above upper limit value, aggregation of CMC is unlikely to occur in an environment having a high salt concentration such as an intestinal environment.
The degree of etherification means the degree of substitution of carboxymethyl groups per unit of anhydrous glucose in cellulose. For example, a CMC with a degree of etherification of 1.0 has one carboxymethyl group per unit of anhydrous glucose in cellulose.

The particle size of the CMC is not particularly limited, and for example, one having an average particle size of 180 μm or less can be used. In the present invention, the average particle size means a volume average particle size, and indicates a value measured by a laser diffraction / scattering method. For example, it is measured using a laser diffraction / scattering type particle size distribution measuring device.
The pH of the 1% by mass aqueous solution of CMC is not particularly limited, and for example, 6.0 to 8.5 can be used.

The content of the component (A) is preferably 0.3 to 90% by mass, more preferably 0.4 to 85% by mass, based on the total mass of the oral preparation.
When the oral preparation is a liquid preparation, it is preferably 0.3 to 1% by mass, more preferably 0.4 to 0.7% by mass. In the case of a solid agent, 10 to 90% by mass is preferable, and 20 to 85% by mass is preferable. When the dose is set to the lower limit or higher, the dose is reduced, so that the dose is improved.
When the content of the component (A) is at least the above lower limit value, the thickening effect can be easily obtained in an environment having a high salt concentration such as an intestinal environment. When the content of the component (A) is not more than the above upper limit value, the viscosity does not become too high in an environment where the salt concentration is low. Therefore, for example, the viscosity does not become too high in the oral cavity and the ingestibility is improved. In particular, when the dosage form of the oral preparation is a liquid preparation, an orally disintegrating tablet, a troche preparation, etc., the ingestibility is improved. For example, a liquid preparation has good fluidity and is easy to swallow, and an orally disintegrating tablet or a troche preparation suppresses stickiness in the oral cavity and is easy to take.

The single dose of the component (A) is preferably 300 mg to 1000 mg, more preferably 400 mg to 700 mg.
When the dose of the component (A) per dose is at least the above lower limit value, the thickening effect in an environment with a high salt concentration can be easily obtained. When the single dose of the component (A) is not more than the above upper limit value, the single dose is reduced, which is preferable in terms of compliance. In addition, since the viscosity does not become too high in an environment where the salt concentration is low, the ingestibility is easily improved. In particular, when the dosage form of the oral preparation is a liquid preparation, an orally disintegrating tablet, a troche preparation, or the like, the ingestibility is more likely to be enhanced.

As the component (A), a synthetic product or a commercially available product may be used. Examples of commercially available products include the product name "P-815C" manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd.

<Ingredient (B)>
The component (B) is an aluminum-containing compound. By containing the component (B) in addition to the component (A) described above, the oral preparation of the present invention can obtain a thickening effect in an environment with a high salt concentration.
Examples of the component (B) include potassium aluminum sulfate, aluminum glycinate, dry aluminum hydroxide gel, magnesium aluminate metasilicate, magnesium aluminate silicate, and the like.
As the component (B), potassium aluminum sulfate, aluminum glycinate, magnesium aluminometasilicate are preferable, and potassium aluminum sulfate is more preferable, from the viewpoint that a thickening effect can be more easily obtained in an environment with a high salt concentration.

The content of the component (B) is preferably 0.012 to 9% by mass, more preferably 0.016 to 8.5% by mass, based on the total mass of the oral preparation.
When the oral preparation is a liquid preparation, 0.012 to 0.1% by mass is preferable, and 0.016 to 0.07% by mass is more preferable. In the case of a solid agent, 0.4 to 9% by mass is preferable, and 0.8 to 8.5% by mass is preferable.
When the content of the component (B) is at least the above lower limit value, the thickening effect in an environment with a high salt concentration can be easily obtained.
When the content of the component (B) is not more than the above upper limit value, the viscosity does not become too high in an environment where the salt concentration is low, and the ingestibility is easily improved. In addition, the thickening effect can be easily obtained in an environment with a high salt concentration.
In particular, when a liquid preparation, an orally disintegrating tablet, or a troche preparation is used, the ingestibility is likely to be enhanced. In addition, when the oral preparation is produced, the handleability is improved when the component (A) and the component (B) are added to water, and the oral preparation can be easily produced.

Mass ratio represented by [100 x component (B)] / [component (A)] [Mass percentage of the content of component (B) with respect to the content of component (A), hereinafter simply "B / Also called "A ratio". ] Is 4 to 10, preferably 6 to 8. When the B / A ratio is at least the above lower limit value, a sufficient thickening effect can be obtained in an environment with a high salt concentration. When the B / A ratio is not more than the upper limit value, the viscosity is lowered and the fluidity is enhanced in an environment where the salt concentration is low. In addition, a sufficient thickening effect can be obtained in an environment with a high salt concentration.

The ion equivalent ratio of the component (A) to the component (B) is preferably 0.03 to 0.39. When the ion equivalent ratio is at least the lower limit value, the thickening effect can be easily obtained in an environment with a high salt concentration. When the ion equivalent ratio is not more than the upper limit value, the viscosity does not become too high in an environment where the salt concentration is low, and good fluidity can be easily obtained. Therefore, it becomes easy to obtain good ingestibility. Further, the handleability is improved when the oral preparation is manufactured, and the oral preparation can be easily manufactured.
The ion equivalent ratio in the present invention is a value indicated by [molar concentration of aluminum in component (B) x 3 (valence of aluminum)] / [molar concentration of component (A) x degree of etherification]. is there.

<Arbitrary ingredient>
The oral preparation may contain any component other than the component (A) and the component (B).
Examples of the optional component include a physiologically active component (component (C)), an additive added to a solid agent, a liquid agent, or the like.

<Ingredient (C)>
The component (C) is a physiologically active component. The component (C), for example, antipyretic analgesics, anti-inflammatory agents, antihistamines, antiallergic agents, antitussive expectorants, antidiarrheals, abdominal pain agents, laxatives, H ₂ receptor antagonists, analgesic antispasmodics, vitamins and the like.

Examples of antipyretic analgesic and anti-inflammatory agents include acetaminophen, phenacetin, mefenamic acid, diclofenac, aspirin, etenzamid, salicylamide, salicylic acid, flurbiprofen, ketoprofen, fenbuphen, mepyrizol, indomethacin, loxoprofen, anhydrous caffeine and the like. Be done.

Examples of antihistamine / antiallergic agents include cyproheptadine hydrochloride hydrate, diphenhydramine, cremastine fumarate, azelastine hydrochloride, oxatomide, mequitazine, epinastine hydrochloride, ebastine, cetirizine hydrochloride, fexofenadine hydrochloride, and olopatadine hydrochloride. , Loratadine and the like.

Antitussive expectorants include, for example, codeine phosphate, dextrometholphan hydrochloride, dimemorphan phosphate, tipepidin hibenzate, methoxyphenamine hydrochloride, trimetoxol hydrochloride, carbocysteine, acetylcysteine. , Ethylcysteine, bromhexine hydrochloride, therapeptase, lysozyme chloride, ambroxol, theophylline, aminophyllin and the like.

Antidiarrheals and abdominal pain agents include, for example, funnel extract, shakuyaku extract, engosaku, kanzo, loperamide hydrochloride, creosote, acrinol, phenyl salicylate, guayacol, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth subcalcate, Albumin tannate, kaolin, pectin, precipitated calcium carbonate, calcium lactate, calcium hydrogen phosphate, asenyaku, ubi, gennoshoko, quintuplet, sanzashi, kujin, semburi, youbaihi, koboku, trimebtin maleate, thikidium bromide, mepenzolate bromide, Examples include loperamide, creosote, red mega wrinkles, and antidiarrheal.

Examples of the intestinal regulator include viable bacterial components. Examples of viable bacterial components include bifidobacteria and lactic acid bacteria. Examples of bifidobacteria include bifidobacteria longum, bifidobacteria and bifidobacteria. Examples of lactic acid bacteria include Lactobacillus acidophilus, Streptococcus faecalis and the like.

The H ₂ receptor antagonists, e.g., famotidine, cimetidine, ranitidine hydrochloride, nizatidine, and the like hydrochloric roxatidine acetate is.

Examples of the analgesic and antispasmodic agent include N-methylscopolamine methylsulfate, scopolamine hydrobromic acid, methylatropine bromide, methylscopolamine bromide, belladonna extract, ethyl aminobenzoate, butylscopolamine bromide, thimepidium bromide and the like. Be done.

Examples of vitamins include vitamin A or a derivative thereof (retinol, retinol palmitate, etc.), vitamin B or a derivative thereof (vitamin B1 such as thiamine nitrate, vitamin B2 such as riboflavin sodium phosphate, vitamin B6 such as pyridoxin hydrochloride, etc. Examples thereof include vitamin B12, nicotinic acid amide, vitamin B5 such as calcium pantothenate), vitamin C or a derivative thereof (ascorbic acid, etc.), vitamin D or a derivative thereof, vitamin E or a derivative thereof (tocopherol, tocopherol acetate, etc.).

In addition to the above, as the component (C), for example, glucuronolactone, hyaluronic acid, royal jelly, carnitine chloride, taurine and the like may be used.
As the component (C), one type may be used alone, or two or more types may be used in combination.

When the oral preparation is a solid preparation (tablet, granule, orally disintegrating tablet, chewable tablet, etc.), the additives added include excipients, binders, disintegrants, sweeteners, preservatives, and fragrances. , Pigments and the like.
Examples of excipients include lactose, cornstarch, crystalline cellulose, potato starch; sugar alcohols such as mannitol, erythritol, xylitol, sorbitol, palatinit, and lactitol.
Examples of the binder include hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethyl cellulose, gum arabic, pregelatinized starch, sodium alginate, carboxyvinyl polymer, agar, honey and the like.
Examples of the disintegrant include crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose and the like.
Examples of the sweetener include sucrose, fructose, aspartame, acesulfame potassium, stevia, purified sucrose, saccharin, glycyrrhizin and the like.
Examples of the preservative include parabens, paraoxybenzoic acid ester, sodium benzoate and the like.
Examples of the flavor include menthol, limonene, orange flavor, lychee flavor, lemon flavor, lime flavor, strawberry flavor, pineapple flavor, mint flavor, grapefruit flavor and the like.
Examples of the pigment include caramel, carmine, carotene solution, β-carotene, copper chlorophyll, sodium copper chlorophyllin and the like.
Any one of these additives may be used alone, or two or more of these additives may be used in combination.

Examples of additives added when the oral preparation is a liquid agent, gummies, jelly agent, paste agent or the like include pH adjusters, sweeteners, thickeners, preservatives / preservatives, stabilizers and the like.
Examples of the pH adjuster include succinic acid, acetic acid, ammonium acetate, tartaric acid, sodium tartrate, borax, lactic acid, calcium lactate hydrate, sodium lactate, malic acid and the like.
Examples of sweeteners include sucrose, liquid sugar, fructose, fructose-glucose liquid, glucose-fructose liquid sugar, reduced maltose water candy, brown sugar, high fructose liquid sugar, glucose, powdered reduced maltose water candy, water candy, and high glucose. Water candy, lactose, sucrose, refined sucrose, purified sucrose spherical granules, honey, purified honey, simple syrup, erythritol, xylitol, D-sorbitol, D-sorbitol solution, multitoll, fructose solution, maltose, D-mannitol, aspartame , Acesulfam potassium, Amacha extract, licorice extract, saccharin, sodium saccharin, sucrose, stevia extract, neotheme, somatin, glycine, dipotassium glycyrrhizinate, disodium glycyrrhizinate, trisoamium glycyrrhizinate, monoammonium glycyrrhizinate, licorice, etc. Can be mentioned.

Examples of the thickener include natural water-soluble polymers such as agar, gelatin, pectin, carrageenan, locust bean gum, gellan gum, xanthan gum, guar gum, purulan, arabic rubber, glucomannan, curdlan, alginic acid, and alginate; Examples thereof include synthetic water-soluble polymers such as alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, polyacrylic acid, polyacrylic acid partially neutralized product, polyacrylate, and polyacrylic acid partially neutralized product salt.
Examples of preservatives and preservatives include benzoic acid, sodium benzoate, ethanol, sodium edetate, dry sodium sulfite, canten, dl-camfur, citric acid, sodium citrate, glycerin, salicylic acid, sodium salicylate, phenyl salicylate, etc. Dibutylhydroxytoluene, D-sorbitol, sorbic acid, potassium sorbate, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, propylene Glycol, l-menthol, eucalyptus oil and the like can be mentioned.
Stabilizers include L-ascorbic acid stearate, sodium L-ascorbate, sodium L-aspartate, aminoethylsulfonic acid, DL-alanine, sodium hydrogen sulfite, sodium sulfite, L-arginine, sodium alginate, alginic acid. Propropylene glycol, albumin, sulfur, inositol, disodium calcium edetate, erythorbic acid, sodium elsorbate, calcium chloride, sodium chloride, magnesium chloride, cysteine hydrochloride, cacao butter, fructose, carboxyvinyl polymer, carmellose calcium, carmellose sodium , Hydrous silicon dioxide, dry sodium carbonate, xanthan gum, xylitol, calcium citrate, glycerin fatty acid ester, disodium glycyrrhizinate, light anhydrous silicic acid, crystalline cellulose, tocopherol acetate, sodium acetate, β-cyclodextrin, sucrose fatty acid ester, Calcium hydroxide, purified gelatin, purified soy lecithin, sorbitan sesquioleate, cetanol, gelatin, sorbitan fatty acid ester, D-sorbitol solution, soybean oil unsaponifiable matter, dextran, natural vitamin E, tocopherol, d-δ-tocopherol, nicotine Acid amide, lactose, concentrated glycerin, calcium pantothenate, microcrystalline cellulose, hydroxypropyl cellulose, sodium pyrosulfate, butyl hydroxyanisole, glucose, fumarate-sodium, bentonite, propyl gallate, polyacrylic acid partial neutralizer, poly Oxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polysorbate, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol / dibutyl ether mixture, macrogol, maltose, D-mannitol, anhydrous sodium pyrophosphate, sodium metaphosphate, methylcellulose, mono Examples thereof include glycerin stearate, medicated charcoal, sodium lauryl sulfate, and egg white albumin.
Any one of these additives may be used alone, or two or more of these additives may be used in combination.

The oral preparation of the present invention includes granules (powder, granules, enteric granules, etc.), tablets (bare tablets, sugar-coated tablets, coated tablets, enteric-coated tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, etc.), capsules. It is a preparation of agents, pills, liquids, gummy agents, troches, jelly agents, etc.
The oral preparation of the present invention has high fluidity in an environment with a low salt concentration, and thickens and / or gels in an environment with a high salt concentration, thereby reducing the fluidity and increasing the retention.
Therefore, the oral preparation of the present invention has good handleability at the time of manufacture of the preparation, and has high fluidity in the oral cavity or stomach where the salt concentration is low, so that good ingestibility can be obtained. In addition, in the intestine where the salt concentration is high, thickening and / or gelation reduces the fluidity and prolongs the residence time in the intestine, so that the physiologically active ingredients contained in the oral preparation are sustained. Absorbed in the intestine.
From the viewpoint of further enjoying the effects of the present invention, liquid preparations, gummies, orally disintegrating tablets, lozenges, jellies and the like are preferable, and liquid preparations are particularly preferable.
In addition, from the viewpoint of further enjoying the effects of the present invention, drowsiness preventives, antispasmodics, intestinal regulators, antiallergic agents, gastrointestinal agents, antidiarrheals, and antipyretic analgesics are preferable. Gastrointestinal and antidiarrheal drugs are particularly preferred. Furthermore, the oral preparation of the present invention can be applied to ameliorate irritable bowel syndrome.

The oral preparation of the present invention is produced by a conventional method according to the dosage form. For example, when the oral preparation of the present invention is a granule or a tablet, the ingredients of the oral preparation (components (A) and (B) and optionally optional ingredients) are mixed as they are, or the above-mentioned combination is used. Granules (granule, fine granule, powder) can be obtained by granulating or coating a part or all of the components and then mixing them to produce a granular mixture. In addition, the granular mixture can be tableted and further coated, if necessary, to form tablets.
The oral preparation of the present invention is not particularly limited as long as it is a liquid preparation, but it can be produced, for example, in accordance with the section "Liquid preparation" in the general rules of the Japanese Pharmacopoeia. At this time, treatments such as filtration and sterilization may be performed.

As described above, since the oral preparation of the present invention contains the component (A) and the component (B) in a specific mass ratio, the viscosity does not become too high in an environment where the salt concentration is low, and the salt concentration is high. It becomes thicker in the environment.
Therefore, the oral preparation of the present invention has good handleability and is easy to manufacture in an environment where the salt concentration is low, for example, when the preparation is manufactured. It has high fluidity in the oral cavity and stomach, and good ingestibility can be obtained. In addition, in an environment with a high salt concentration, for example, in the intestine, the viscosity increases and the fluidity decreases and stays. As a result, the physiologically active ingredients and the like contained in the oral preparation can be continuously absorbed.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to the following description.

(Ingredients used)
<Ingredient (A)>
A-1: Carboxymethyl cellulose, "Product name: P-815C", manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd., viscosity of 1% by mass aqueous solution (25 ° C.): 300 mPa · s, degree of etherification: 0.82. A-2 stored under room temperature conditions for 3 years.
A-2: Carboxymethyl cellulose, "Product name: P-815C", manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd., viscosity of 1% by mass aqueous solution (25 ° C.): 1500 mPa · s, degree of etherification: 0.82.

<Comparison component of (A') component and (A) component>
A'-1: Carboxymethyl cellulose, "Product name: F-BSH-12", manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd., viscosity of 1% by mass aqueous solution (25 ° C.): 2770 mPa · s, degree of etherification: 0.7.
A'-2: Carboxymethyl cellulose, "Product name: AG gum M", manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd., viscosity of 1% by mass aqueous solution: 60.5 mPa · s.
A'-3: Sodium alginate, "Product name: Kimika algin I-8", manufactured by Kimika Co., Ltd., viscosity of 1% aqueous solution (25 ° C): 800 to 900 mPa · s.
A'-4: Xanthan gum, "Product name: Echo gum", manufactured by DSP Gokyo Food & Chemical Co., Ltd. Viscosity of 1% aqueous solution (25 ° C): 1000 mPa · s.
A'-5: Hydroxypropyl cellulose, "Product name: HPC-H", manufactured by Nippon Soda Corporation, viscosity of 1% aqueous solution (25 ° C.): 1000-4000 mPa · s.

<Ingredient (B)>
B-1: Potassium aluminum sulfate, "reagent", manufactured by Wako Pure Chemical Industries, Ltd.
B-2: Aluminum glycinate, "Product name: Glycinal", manufactured by Kyowa Chemical Industry Co., Ltd.
B-3: Dry aluminum hydroxide gel, "Product name: S-100", manufactured by Kyowa Chemical Industry Co., Ltd.
B-4: Magnesium aluminate metasilicate, "Product name: Neucillin", manufactured by Fuji Chemical Industry Co., Ltd.
B-5: Magnesium aluminate silicate, "Product name: Synthetic aluminum silicate", manufactured by Kyowa Chemical Industry Co., Ltd.

<Comparison component of (B') component and (B) component>
B'-1: Calcium lactate, "reagent", manufactured by Wako Pure Chemical Industries, Ltd.
B'-2: Potassium chloride, "reagent", manufactured by Wako Pure Chemical Industries, Ltd.

(Examples 1 to 17, Comparative Examples 1 to 13)
According to the composition of Tables 1 to 3, the components (A) and (B) were added to water and sufficiently stirred, and then the pH was adjusted to 4.5 to 6.0 with NaOH, and Examples 1 to 17 were compared. Oral preparations (liquids) of Examples 1 and 2 were obtained.
Oral preparations of Comparative Examples 3, 4, 9, 11 to 12 were obtained in the same manner as in Example 1 except that the component (A') was used instead of the component (A).
Oral preparations of Comparative Examples 5 and 6 were obtained in the same manner as in Example 1 except that the component (B') was used instead of the component (B).
The oral preparations of Comparative Examples 10 and 13 were prepared in the same manner as in Example 1 except that the component (A') was used instead of the component (A) and the component (B') was used instead of the component (B). Obtained.
Oral preparations of Comparative Examples 7 and 8 were obtained in the same manner as in Example 1 except that the component (A) or the component (B) was not added.
Tables 1 to 3 show the composition (blending component, content (mass%)) of the obtained oral preparations of each example.
If there is a blank compounding ingredient in the table, that compounding ingredient is not blended.
In the table, the content of the compounding component indicates the net conversion amount.
The "appropriate amount" indicating the content of the pH adjuster is the amount required to adjust the pH of the oral preparation within the above range.
"Balance" indicating the content of water means the balance added so that the total amount (% by mass) of all the ingredients contained in the oral preparation is 100% by mass.
In the table, the "B / A ratio" of Comparative Examples 3 to 4, 9, 11 to 12 indicates the mass ratio represented by "100 x (B) component / (A') component", and Comparative Examples 5 to 5 The “B / A ratio” of 6 indicates the mass ratio represented by “100 × (B') component / (A) component”, and the “B / A ratio” of Comparative Examples 10 and 13 is “100 ×”. The mass ratio represented by "(B') component / (A') component" is shown.

<Viscosity measurement method>
The viscosity measurement in the present invention was carried out in accordance with the viscosity measurement method described in the 15th revised Japanese Pharmacopoeia general test method.
The viscosity was measured by adjusting the oral preparation to be measured to 25 ° C. and using a single cylindrical rotary viscometer (Brookfield type viscometer). As the viscometer, RB-80L (manufactured by Toki Sangyo Co., Ltd.) was used.
The viscosity of the oral preparation is a value measured 1 minute after the rotor is rotated under the condition of 60 rpm and the rotation is started. The rotor used for the measurement is the rotor No. 1-2 (when the viscosity of the oral preparation is less than 100 mPa · s), Rotor No. 3 (when the viscosity of the oral preparation is 100 to 5000 mPa · s), Rotor No. 4 (when the viscosity of the oral preparation exceeds 5000 mPa · s).

<Evaluation method of thickening effect>
For the oral preparations of each example, the viscosity (viscosity (1)) in an environment with a low salt concentration and the viscosity (viscosity (2)) in an environment with a high salt concentration were measured, and the thickening effect was evaluated as follows. ..
The evaluation results are shown in Tables 1 to 3.
If the viscosity (2) is larger than the viscosity (1), it can be said that it has a thickening effect in an environment with a high salt concentration. Further, it can be said that the larger the difference between the viscosity (2) and the viscosity (1), the higher the thickening effect.
In the present invention, the viscosity (2) was larger than the viscosity (1) [viscosity (1) <viscosity (2)], and the evaluation of the viscosity (2) passed A to D.

[Measuring method of viscosity (1)]
For the oral preparations of each example, the viscosity measured according to the above <Viscosity measuring method> was defined as viscosity (1). The viscosity (1) is the viscosity of the oral preparation when the salt is not contained (salt concentration is 0% by mass).
In addition, the viscosity (1) was classified according to the following criteria. In addition, in the following criteria, if it is A to C, it can be evaluated that the fluidity of the oral preparation is high and it is easy to obtain good ingestibility in the oral cavity. A is most preferable as a criterion for determining the viscosity (1).
<< Criteria for viscosity (1) >>
A: 0 mPa · s or more and less than 1000 mPa · s.
B: 1000 mPa · s or more and less than 2000 mPa · s.
C: 2000 mPa · s or more and less than 3000 mPa · s.
D: 3000 mPa · s or more.

[Measuring method of viscosity (2)]
Sodium chloride equivalent to 0.6% by mass was added to the oral preparations of each example after the viscosity (1) was measured, and the mixture was sufficiently stirred. The pH was then adjusted to 4.5-6.0 with NaOH. After that, the viscosity was measured according to the above <Viscosity measuring method>, and the viscosity was defined as viscosity (2).
In addition, the viscosity (2) was classified and evaluated according to the following criteria. If it is A to D in the following criteria, it can be evaluated that the oral preparation is thickened in the intestine and the retention is enhanced. A is most preferable as a criterion for determining the viscosity (2).
<< Criteria for viscosity (2) >>
A: 6000 mPa · s or more.
B: 5000 mPa · s or more and less than 6000 mPa · s.
C: 4000 mPa · s or more and less than 5000 mPa · s.
D: 3000 mPa · s or more and less than 4000 mPa · s.
E: Less than 3000 mPa · s.

As shown in Tables 1 to 3, the oral preparations of Examples 1 to 17 to which the present invention is applied have viscosity (1) <viscosity (2), and the evaluation of viscosity (2) is A to D. It was confirmed that it has a sufficient thickening effect in an environment with a high salt concentration.
On the other hand, in the oral preparations of Comparative Examples 1 to 13 which did not satisfy the requirements of the present invention, the evaluation of the viscosity (2) was E, and a sufficient thickening effect could not be obtained in an environment with a high salt concentration.

Next, a composition example of the oral preparation of the present invention in each dosage form will be shown. However, the oral preparation of the present invention is not limited to the following composition examples.

<Solid agent (1 dose: 2 tablets)>
A-1 500mg
B-1 40 mg
Crystalline cellulose 50 mg
Crosspovidone 20 mg
Magnesium stearate 2 mg
l-menthol 0.5 mg
Grapefruit flavor 1mg
B / A ratio = 8
The above components were mixed by a conventional method and tableted to obtain a solid preparation.

<Gummy agent a (single dose: 3 tablets)>
A-1 500mg
B-1 40 mg
Pectin 100 mg
2000 mg of water
Citric acid 150 mg
Sugar 1000mg
Apple fragrance 10mg
B / A ratio = 8
Water was added to A-1, B-1 and pectin and mixed. Citric acid, sugar and spices were added to this and mixed to make a dough. This dough was filled in a mold and cooled and solidified to obtain a gummy agent. Alternatively, the dough is injected into a starch mold (for example, a recess formed by filling a tray with starch, compacting the surface flat to form a starch layer, and then pressing a convex shape against the starch layer). Then, it was allowed to stand for about 24 hours. During this standing, the moisture liberated from the dough was transferred to the starch mold and the dough solidified. Then, the solidified dough was taken out, starch powder was removed, and it was used as a gummy agent.
Further, the obtained gummy agent may be coated with edible oil or fat or shavings. This coating makes it easier to prevent the gummies from binding to each other.

<Gummy agent b (1 dose: 3 tablets)>
A-1 500mg
B-1 40 mg
Gelatin 100 mg
Syrup 300mg
1/5 concentrated grape juice 50mg
Water 1500mg
Citric acid 150 mg
Sugar 1000mg
Grape fragrance 10mg
B / A ratio = 8
Water was added to A-1, B-1 and sugar and mixed. Gelatin and starch syrup previously swollen with water were added and dissolved by heating, and 1/5 concentrated grape juice, citric acid diluted 5 times with water, and grape flavor were added and mixed to obtain a dough. This dough was filled in a mold and cooled and solidified to obtain a gummy agent. Alternatively, the dough is injected into a starch mold (for example, a recess formed by filling a tray with starch, compacting the surface flat to form a starch layer, and then pressing a convex shape against the starch layer). Then, it was allowed to stand for about 24 hours. During this standing, the moisture liberated from the dough was transferred to the starch mold and the dough solidified. Then, the solidified dough was taken out, starch powder was removed, and it was used as a gummy agent.
Further, the obtained gummy agent may be coated with edible oil or fat or shavings. This coating makes it easier to prevent the gummies from binding to each other.

<Liquid (single dose: 100 mL)>
A-1 500mg
B-1 40 mg
Apple juice 100mg
Glucose 2000 mg
Sodium benzoate 60 mg
Lactic acid 30 mg
Honey 3000mg
Apple fragrance 20mg
Water residue B / A ratio = 8
Water was added to A-1 and B-1 and the mixture was sufficiently stirred. Then, other components were added and mixed to produce a liquid preparation.

<Jelly agent (single dose: 100 mL)>
A-1 500mg
B-1 30 mg
Gelatin 1000mg
Sugar 2000mg
Sodium citrate 100 mg
Citric acid 100 mg
Sucralose 40 mg
Grape fragrance 300mg
Water residue B / A ratio = 6
Water was added to A-1 and B-1 and mixed. Gelatin, sugar and sodium citrate, which had been swollen in water in advance, were added thereto and dissolved by heating, and then other components were further added and stirred (citric acid was added as an aqueous solution). After that, it was cooled to produce a jelly agent.
In each of the dosage form composition examples shown above, even if A-1 is replaced with A-2, an oral preparation having the same effect can be obtained.

Claims (6)

It contains (A) carboxymethyl cellulose or a salt thereof having a viscosity of a 1% by mass aqueous solution at 25 ° C. of 250 to 2000 mPa · s, and (B) an aluminum-containing compound.
An oral liquid or oral solid preparation having a mass ratio of 4 to 10 represented by [100 × the component (B)] / [the component (A)].
In the case of the oral solution, the content of the component (A) is 0.3 to 1% by mass, and the content of the component (B) is 0.012 to 0.1% by mass.
In the case of the oral solid preparation, the content of the component (A) is 10 to 90% by mass, and the content of the component (B) is 0.4 to 9% by mass . The first aspect of claim 1, wherein the component (B) is at least one selected from the group consisting of potassium aluminum sulfate, aluminum glycinate, dry aluminum hydroxide gel, magnesium aluminate aluminate, and magnesium aluminate silicate. Oral solution or oral solid . The oral liquid or oral solid according to claim 1 or 2, wherein the single dose of the component (A) is 300 to 1000 mg. The oral liquid or oral solid according to any one of claims 1 to 3, wherein the degree of etherification of the component (A) is 0.6 to 1.0. The oral solution or oral solid according to any one of claims 1 to 4, further comprising (C) a physiologically active ingredient. Dosage form of the oral solid agent, granular agent, tablets, capsules, pills, a grayed Mi agent or jellies, oral solution or oral solid preparations according to any one of claims 1-5.