JP2019214622A - Oral composition - Google Patents

Abstract

To provide a stable oral composition.SOLUTION: An oral composition is prepared that comprises teprenone, monoterpene, and antacid. There is also provided a method of preventing change in the color tone of teprenone with monoterpene and antacid. There is further provided a solid formulation comprising teprenone, monoterpene, and antacid.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a composition for internal use comprising (A) teprenone, (B) a monoterpene, and (C) an antacid.

  Teprenone is used to improve gastric mucosal lesions (erosion, bleeding, rash, edema), acute gastritis, acute exacerbation of chronic gastritis and gastric ulcer.

  Improving the stability of teprenone has been a challenge, and various attempts have been made.

  Techniques for stabilizing teprenone include, for example, a method of adding an antioxidant such as vitamin E (Patent Document 1), a method of adding L-ascorbic acid fatty acid ester (Patent Document 2), and a method of adding glycine (Patent Document 3) and the like are known.

Japanese Patent Publication No. 62-9096 JP-A-6-56658 JP 2001-213770 A

  There is a need for the development of a medicament as a composition for internal use having excellent stability.

  The present invention has been made as a result of intensive studies focusing on the fact that a preparation containing teprenone tends to change in color tone due to the effects of oxidation and the like. That is, a formulation containing teprenone that can suppress color change of a formulation containing teprenone and has an excellent effect on treatment of gastrointestinal diseases and that can be stored for a long time has been developed, and the present invention has been completed. .

That is, the present invention
[1]
(A) Teprenone (sometimes referred to herein as component (A)), (B) monoterpene (sometimes referred to as component (B) herein), and (C) antacid ( Composition for internal use, which may be (C) component in the specification);
[2]
The oral administration composition according to item [1], wherein (A) 1 part by mass of teprenone and (C) 1 to 50 parts by mass of an antacid;
[3]
(C) the composition for internal use according to the above [1] or [2], wherein the antacid is an inorganic compound-based antacid;
[4]
(C) the antacid is an oxide of sodium, calcium, magnesium and / or aluminum; a hydroxide of sodium, calcium, magnesium and / or aluminum; a carbonate of sodium, calcium, magnesium and / or aluminum; Phosphates of calcium, magnesium and / or aluminum; silicates of sodium, calcium, magnesium and / or aluminum; and composites of these oxides, hydroxides, carbonates, phosphates and / or silicates The composition for internal use according to any one of the above [1] to [3], which is at least one selected from the group consisting of:
[5]
(A) The composition for internal use according to any one of the above [1] to [4], containing 100 to 150 mg of teprenone as a daily dose;
[6]
The composition for internal use according to any one of the above [1] to [5], which is a solid preparation;
[7]
It is intended to provide a method for suppressing a change in color tone of the composition by blending (A) teprenone, (B) monoterpene, and (C) an antacid to the composition.

  The composition for internal use of the present invention contains teprenone and may be a solid preparation. The composition for internal use according to the present invention can suppress the change in color tone over time and can be stored for a long time.

FIG. 1 is a diagram showing a change in color tone between a composition for internal use of the present invention and a comparative object. FIG. 2 is a diagram showing a change in color tone between the composition for internal use of the present invention and a comparative object. FIG. 3 is a view showing a change in color tone between the composition for internal use of the present invention and a comparative object.

[Composition for internal use]
The composition for internal use of the present invention contains (A) teprenone, (B) monoterpene, and (C) an antacid. In addition, the "composition for internal use" of the present invention is not particularly limited as long as it is a composition that can be taken internally, and will be described in detail later.

  In the composition for internal use of the present invention, (B) the monoterpene and (C) the antacid enhance the mucosal improvement effect of (A) teprenone, but at the same time, the color tone change due to oxidation or the like alone , The change in color tone of teprenone can be suppressed.

<(A) component>
(A) Teprenone (chemical name: (5E, 9E, 13E) -6,10,14,18-Tetramethylnonadeca-5,9,13,17-tetraen-2-one and (5Z, 9E, 13E) -6, A mixture of 10,14,18-Tetramethylnonadeca-5,9,13,17-tetraen-2-one) is a compound represented by the following structural formula, and is a compound for gastric mucosal lesions (erosion, bleeding, rash, edema) It is used for the treatment of amelioration, acute gastritis, acute exacerbation of chronic gastritis and gastric ulcer. It can be obtained as a commercial product or can be produced by a known production method.
(Structural formula)

  The dose (dose) of (A) teprenone according to the composition for internal use of the present invention may vary depending on the condition of the patient (weight, age, symptoms, physical condition, etc.), the dosage form of the composition for internal use of the present invention, and the like. On the other hand, from the viewpoint of achieving a sufficient effect on diseases related to the gastric mucosa, a larger amount tends to be more preferable, while a smaller amount tends to be preferable from the viewpoint of suppressing the occurrence of side effects. From the viewpoint that the effect of the present invention is more remarkably exhibited, the oral administration composition of the present invention contains teprenone as a daily dose, preferably 30 to 300 mg, more preferably 60 to 200 mg, and still more preferably 100 to 200 mg. -150 mg, particularly preferably 112.5 mg.

  The content of teprenone in the composition for internal use of the present invention is usually 0.1 to 50 w / w%, preferably 1 to 30 w / w%, more preferably 2 to 10 w / w%.

<(B) component>
The monoterpene (B) in the composition for internal use of the present invention has a structure composed of two isoprene units and is a compound known as a cooling agent or the like. For the present invention, any pharmaceutically or physiologically acceptable monoterpene can be used. The monoterpene may be in the d-form, the l-form or the dl-form.

  Specifically, examples of the monoterpene include acyclic monoterpenes such as geraniol, nerol, myrcenol, linalool, linalool acetate, and lavandulol; monocyclic monoterpenes such as menthol, limonene, anethole, eugenol, and hinokitiol; Bicyclic monoterpenes such as camphor, borneol, isoborneol, cineol, pinene; and the like, but are not limited thereto. Among them, from the viewpoint of more reliably exerting a high effect, preferably monocyclic monoterpenes and bicyclic monoterpenes, more preferably menthol, camphor, eugenol, geraniol, borneol, hinokitiol, Menthol and camphor are more preferred, and menthol is still more preferred. These monoterpenes may be used alone or in any combination of two or more.

  Further, as the monoterpene, an essential oil containing the same may be used. Such essential oils include cool mint oil, peppermint oil, peppermint oil, eucalyptus oil, bergamot oil, spearmint oil, rose oil, camphor oil and the like. For example, examples of essential oils containing menthol and camphor include cool mint oil, peppermint oil, peppermint oil, camphor oil, fennel oil, cauliflower oil, and lemon oil. These essential oils can be collected from plants by known methods. Examples of such known essential oil extracting methods include a steam distillation method, a method of adding a plant to deodorized animal oil and fat to adsorb the essential oil and then extracting the essential oil with ethanol, and a method of extracting a plant with an organic oil such as hexane or benzene. After extracting with a solvent or a supercritical fluid and dissolving the extraction solvent in ethanol, the solvent is extracted by evaporating the ethanol and collecting the residue. Monoterpenes can also be recovered from essential oils by various types of chromatography.

  The dose (dose) of (B) monoterpene according to the composition for internal use of the present invention may vary depending on the condition (body weight, age, symptoms, physical condition, etc.) of the patient and the dosage form of the composition for internal use of the present invention. However, from the viewpoint of sufficiently enhancing the effect of teprenone on diseases related to the gastric mucosa, a larger amount tends to be preferable, while a smaller amount tends to be preferable from the viewpoint of suppressing the occurrence of side effects. It is in.

  From the viewpoint that the effect of the present invention is more remarkably exhibited, the composition for internal use of the present invention is preferably such that the total amount of the (B) monoterpene contained in the composition as a daily dose is as monoterpene. Contains 0.2 to 60 mg, more preferably 1 to 36 mg, and still more preferably 2 to 20 mg. In addition, the amount and ratio of the monoterpene in the present invention refer to the amount and ratio when converted to monoterpene even when contained as an essential oil in the composition.

When the composition for internal use of the present invention contains menthol as a monoterpene as a daily dose, for example, preferably 0.1 to 30 mg, more preferably 0.3 to 25 mg, and still more preferably , 0.5 to 18 mg, particularly preferably 1 to 10 mg.

When the composition for internal use of the present invention contains (B) an essential oil containing a monoterpene as a daily dose, it is preferably 0.1 to 50 mg as an essential oil as a daily dose. More preferably, it contains 0.5 to 40 mg, and still more preferably 1 to 30 mg.

  The content of monoterpene in the composition for internal use of the present invention is usually 0.001 to 10 w / w%, preferably 0.01 to 5 w / w%, more preferably 0.01 to 2 w / w%. is there.

  The composition for internal use according to the present invention provides (A) a more remarkable effect of the present invention such as a viewpoint of sufficiently enhancing the effect of teprenone on diseases related to gastric mucosa and a viewpoint of improving suppression of color tone change. From the viewpoint of cost effectiveness, (B) monoterpene is preferably 0.001 to 1.5 parts by mass, more preferably 0.003 to 1 part by mass, and still more preferably 1 part by mass of teprenone. Is contained in an amount of 0.005 to 0.5 part by mass, particularly preferably 0.01 to 0.3 part by mass.

<(C) component>
The antacid (C) in the composition for internal use of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable, and may be any of an inorganic compound, a crude drug, and an amino acid. It may be.

  Examples of the inorganic compound-based antacid include sodium, calcium, magnesium and / or aluminum oxides; sodium, calcium, magnesium and / or aluminum hydroxides; sodium, calcium, magnesium and / or aluminum carbonates; , Calcium, magnesium and / or aluminum phosphates; sodium, calcium, magnesium and / or aluminum silicates; and oxides, hydroxides, carbonates, phosphates and / or silicates thereof. One or more selected from the group consisting of composites is preferred. Specifically, magnesium carbonate, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium aluminate silicate, magnesium aluminate metasilicate, synthetic aluminum silicate, magnesium aluminate hydroxide, sodium hydrogen carbonate, precipitated calcium carbonate, anhydrous Calcium hydrogen phosphate, calcium hydrogen phosphate, dried aluminum hydroxide gel, aluminum hydroxide gel, synthetic hydrotalcite, aluminum hydroxide-sodium hydrogen carbonate co-precipitated product, aluminum hydroxide-magnesium carbonate mixed dry gel, hydroxylated Aluminum / magnesium carbonate / calcium carbonate coprecipitated products.

  Examples of crude drug-based antacids include squid bone, Ishige, Borei, and funnel extract.

  Examples of the amino acid-based antacid include aminoacetic acid, dihydroxyaluminum aminoacetate and the like.

  Preferably, an inorganic compound-based antacid and a funnel extract are mentioned, and an inorganic compound-based antacid is more preferred. Among the above inorganic compound-based antacids, magnesium carbonate, magnesium silicate aluminate, magnesium metasilicate aluminate, magnesium hydroxide, sodium hydrogen carbonate, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, and synthetic hydrotalcite are particularly preferable. . In the present invention, two or more of these antacids may be contained.

  From the viewpoint that the effect of the present invention is more remarkably exhibited, the composition for internal use according to the present invention, as a daily dose, is preferably 10% as the total amount of the (C) antacid contained in the composition. 5,000 mg, more preferably 100-3000 mg, even more preferably 800-2,500 mg.

  The content of the antacid (C) in the composition for internal use of the present invention is not limited, but is usually 10 to 99 w / w%, preferably 20 to 70 w / w% based on the total amount of the composition for internal use. And more preferably 25 to 50% w / w.

  The composition for internal use according to the present invention provides (A) a more remarkable effect of the present invention such as a viewpoint of sufficiently enhancing the effect of teprenone on diseases related to gastric mucosa and a viewpoint of improving suppression of color tone change. From the viewpoint of cost effectiveness, (A) 1 part by mass of teprenone, (C) antacid is preferably 0.2 to 100 parts by mass, more preferably 1 to 50 parts by mass, and still more preferably 3 parts by mass. -30 parts by mass, particularly preferably 5-20 parts by mass.

The composition for internal use according to the present invention contains (A) 10-300 mg of teprenone and (B) as a daily dose from the viewpoint of high effects on diseases related to gastric mucosa and low side effects (eg, drowsiness). ) 0.1 to 50 mg of a monoterpene and 10 to 5000 mg of an antacid (C),
More preferably, (A) contains 50 to 200 mg of teprenone, (B) 0.5 to 30 mg of monoterpene, and (C) 100 to 3000 mg of antacid.
It is further preferable that (A) 100 to 150 mg of teprenone, (B) 1 to 15 mg of monoterpene, and (C) 1000 to 2500 mg of antacid are contained.

  The composition for internal use of the present invention can be usually administered 1 to 3 times a day, preferably 3 times a day. Therefore, the composition for internal use according to the present invention for single administration preferably contains the above-mentioned daily dose divided by the number of times of daily administration.

  The color tone of the composition for internal use according to the present embodiment is obtained by blending a compound imparting suppression of color change over time in addition to the components (A), (B) and (C). The change can be suppressed more remarkably.

  As long as the effects of the present invention are sufficiently exerted, a herbal medicine and / or an extract thereof may be exemplified.

  Kokuboku and Sojutsu are known herbal medicines that can be used by oral administration, and may be pharmaceutically, pharmacologically or physiologically acceptable. The crude drugs include crude drugs themselves, cut products thereof (crushed products, powders, etc.), crude drug extracts (extracts), and the like. In addition, the crude drug extract can be prepared from the crude drug using an extractant such as water, ethanol, a mixture of water and ethanol, and used as a dry extract, tincture, flow extract, soft extract, etc., according to a known technique. be able to.

  In the present invention, powders and extracts (extracts) are used from the viewpoints of efficiently obtaining a composition for internal use having a constant quality such as the content and properties of the active ingredient and the ease of handling, etc. Is preferred. That is, as the sorghum, the sorghum powder, the sorghum water extract, and the sorghum ethanol extract are preferable. As the soju beet, powder of soju bean, aqueous extract of soju and ethanol extract of soju are preferable. These can be obtained as commercial products or can be produced according to known methods. For example, there may be mentioned Kokuboku, Kokuboku end, Souchutsu, Soujutsu end listed in the 16th revised Japanese Pharmacopoeia, and dried extracts, soft extracts, tinctures and the like made from these as raw materials.

  In addition, the total content of kokuboku and / or citrus per daily dose of the composition for internal use of the present invention is preferably 10 to 10000 mg, more preferably 100 to 2000 mg, and still more preferably 1000, in terms of the crude drug. １1500 mg. In addition, in this specification, "the amount equivalent to a crude drug" means the amount of a crude drug (crude drug mixture) necessary to prepare a powder or extract of pearl or citrus.

  In the composition for internal use of the present invention, the total content of (C) kokuboku and / or sojutsu per 1 part by weight of teprenone is preferably 1 to 90 parts by weight, and preferably 1 to 35 parts by weight in terms of the crude drug. Parts by weight, more preferably 5 to 20 parts by weight.

The composition for internal use of the present invention comprises the component (A) as long as the effects of the present invention are sufficiently exhibited.
In addition to the component (B) and the component (C), various other components (pharmacologically active components and physiologically active components) may be contained, if necessary, or may be used in combination therewith. The kind of such a component is not particularly limited, and examples thereof include a stomachic, a digestive medicine, an intestinal medicine, an antidiarrheal, an analgesic / spasmodic, a mucous membrane repairing agent, and an antifoaming agent. In the present invention, the following components are exemplified, but the present invention is not limited to these components. The amounts of these components are appropriately selected according to the type of preparation, the type of active ingredient, and the like.

  Stomach medicines: Anise seeds, aloe, fennel, turmeric, eelgrass, life-prolonging grass, ogon, oak, orange, processed garlic, gejutsu, cuckoo, colum root, keigan, citrus, pheasant, cauliflower, gentianana, kojin, koboku, goshyu, pepper , Colombo, Consulango, Sansho, Yamana, Shisoshi, Shukusha, Shokyo, Shoshuku, Blue skin, Iris, Centaurium grass, Assemblage, Soyou, Daifeng, Daio, Chicset ginseng, Clove, Chimp, Pepper, Spruce, Nigaki, Crude drugs such as nutmeg, carrot, peppermint (including mint), lip repellent (hihatsu), sandalwood, hops, homica extract, sleeping vegetables (suisyouyou), mocktail, yakuchi, ryutan, ryokyo, etc., or ginger oil , Pepper oil, clove oil Spruce oil, animal bile (including non-endless), betaine hydrochloride, glutamic acid hydrochloride, carnitine chloride, bethanechol chloride, dry yeast and the like.

  Digestive: starch digestive enzyme, protein digestive enzyme, fat digestive enzyme, fibrinolytic enzyme, ursodesoxycholic acid, oxycholanates, cholic acid, bile powder, bile extract (end), dehydrocholic acid, animal bile (Including Utan).

  Intestinal drugs: crude drugs such as Akabashi Kashiwa, Asenyaku, Ubai, Ketsumeishi, Gennoshoko and the like, extracts thereof, and live bacteria for intestinal regulation.

  Antidiarrheal: Herbal medicine such as asenyaku, ubay, oubaku, spinach, kujin, gennoshoko, quintet, hawthorn, assembly, lupine, etc. or extract thereof, acrinol, berberine chloride, guaiacol, creosote, phenyl salicylate, guaiacol carbonate, berberine tannate, Bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth hypogallate, tannic acid, albumin tannate, methylene thymol tannin, kaolin, natural aluminum silicate, aluminum hydroxynaphthoate, pectin, medicinal charcoal, calcium lactate and the like.

  Analgesic and antispasmodic agents: Crude drugs such as Engosaku, Licorice, Peony, Belladonna or extracts thereof, oxyphencycline hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, methyl atropine bromide, methyl anisotropine bromide, methyl bromide Scopolamine, methyl-l-hyostiamine bromide, methylbenactidium bromide, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, funnel root total alkaloid citrate, papaverine hydrochloride, ethyl aminobenzoate and the like.

  Mucosal repair agent: crude drugs such as red buds, ergosac, licorice or extracts thereof, sodium azulene sulfonate, aldioxa, glycyrrhizic acid and its salts, L-glutamine, copper copper chlorophyllin, copper copper chlorophyllin sodium, histidine hydrochloride, pig gastric wall pepsin hydrolyzate Porcine gastric wall acid hydrolyzate, methyl methionine sulfonium chloride, gefarnate, cetraxate hydrochloride, sucralfate hydrate (sucrose sulfate aluminum salt), sofacolcon, etc.

  Antifoaming agent: dimethyl polysimexane and the like.

  The composition for internal use of the present invention is preferably a composition for oral administration. The dosage forms include tablets (including quick disintegrating tablets in the mouth, chewable tablets, effervescent tablets, jelly-shaped drops, etc.), troches, granules, pills, dry syrups, powders (including fine granules) ), Solid preparations such as capsules (including hard capsules and soft capsules), liquids, suspensions, emulsions, syrups, elixirs, limonades, tinctures, extracts, jellies, gels And liposome preparations. Among them, a solid agent containing teprenone and a monoterpene is preferable from the viewpoints of further exhibiting the effects of the present invention and versatility, and particularly a solid agent prepared through granulation. You may. Solids include granules, tablets, troches, hard capsules, soft capsules, dry syrups and the like, and granules and tablets are particularly preferred.

  The composition for internal use of the present invention may contain appropriate additives depending on the dosage form. Examples of such additives include excipients (eg, sucrose, lactose, crystalline cellulose, light anhydrous silicic acid, etc.) and lubricants (eg, solid formulations (eg, tablets, capsules, powders, etc.)). Sucrose fatty acid ester, magnesium stearate, talc, etc.), disintegrant (eg, low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, etc.), foaming agent (eg, sodium bicarbonate, etc.), fluidizing agent (For example, sodium metasilicate aluminate, light silicic anhydride, etc.). The pharmaceutical uses of these additives may be other than those described above. Additives in the case of liquid preparations (eg, syrups, liquids, suspensions, soft capsule contents, hard capsule contents, etc.) include oily bases (eg, olive oil, corn oil, Vegetable oils such as soybean oil, sesame oil and cottonseed oil; medium-chain fatty acid triglycerides and the like), aqueous bases (eg, macrogol 400, water), gel bases (eg, carboxyvinyl polymer, gum etc.), surfactants (eg, , Polysorbate 80, hydrogenated castor oil, glycerin fatty acid ester, sorbitan sesquioleate, etc.), suspending agents (eg, beeswax wax, various surfactants, soybean lecithin, etc.), dispersants, emulsifiers, stabilizers, buffers , Dissolution aids, pH adjusters, preservatives (preservatives) and the like. In any case, an antioxidant, a sweetener, a sour agent, a coloring agent, a flavor, a flavoring agent, and the like may be appropriately added to these compositions.

  The composition for internal use according to the present invention contains (A) teprenone, (B) monoterpene, (C) an antacid, and optionally other physiologically active ingredients and additives, depending on the dosage form. It can be obtained by formulating by a conventional method.

  In addition, the composition for internal use according to the present invention specifically has the effects of protecting the mucous membrane of the stomach, enhancing the mucous of the stomach, enhancing the blood flow of the gastric mucosa, increasing the resistance to stomach acid, and reducing the amount of stomach acid. It exerts excellent therapeutic and preventive effects on gastritis, stomach ulcers and stomach dysfunction combined with the regulating effect of stomach. In particular, the composition for internal use of the present invention is used for improving gastric ulcer, gastric mucosal lesions (erosion, bleeding, redness, edema), treating acute gastritis, acute exacerbation of chronic gastritis, and the like. In addition, leaning (stomach leaning), overeating (overeating), overdrinking (overdrinking), heartburn, anorexia (decreased appetite), stomach bloating (including those due to indigestion), abdominal bloating (dyspepsia) ), Nausea (upset, upset stomach, upset hangover / sickness, nausea, nausea), vomiting, chest stomach, excessive stomach acidity, heavy stomach, weak stomach, stomach pain, stomach discomfort, digestion promotion , Indigestion, abdominal pain, incision (colic, epilepsy), burping, stomach, diarrhea (including diarrhea due to indigestion and diarrhea with abdominal pain), per meal, It can be suitably used for purposes such as water regulation, bowel control (to regulate bowel movement), loose stool, and constipation. Of these, the composition for internal use of the present invention, particularly containing (A) teprenone, B) monoterpene, and (C) an antacid, alleviates the symptoms of leaning of the stomach, heartburn, and rough stomach mucosa. I do.

  The composition for internal use of the present invention may be a single preparation obtained by simultaneously preparing A) teprenone, B) monoterpene, and (C) an antacid, or may be prepared separately. It may be a combination of two formulations, but is preferably prepared as a single formulation.

  The present invention relates to a preparation of a composition for internal use, comprising (A) teprenone, (B) a monoterpene, and (C) an antacid.

  By containing (A) teprenone, B) monoterpene, and (C) an antacid, the preparation of the above-mentioned composition for internal use has an enhanced gastric mucosal protective effect, and is remarkably effective against diseases and symptoms related to gastric mucosa. It has an excellent therapeutic and / or preventive effect. In particular, it has an effect on leaning of the stomach, heartburn, and rough stomach mucosa.

  In the preparation of the above-mentioned composition for internal use, the ratio of (B) the monoterpene is 0.005 to 0.5 part by mass, and (C) the antacid is 0.5 to 1 part by mass of teprenone. It is preferably contained in a proportion of 60 parts by mass, particularly preferably (B) in a proportion of 0.01 to 0.3 parts by mass of monoterpene and (C) in a proportion of 5 to 20 parts by mass of antacid. Is preferred.

  The composition for internal use may contain (A) 30 to 50 mg of teprenone per preparation.

  The composition for internal use may contain (B) 0.1 to 10 mg of the monoterpene per preparation.

  The composition for internal use preferably contains (C) 50 to 1000 mg of the antacid per preparation.

[Method of suppressing color change of teprenone]
The present invention also relates to a method for suppressing the color change of (A) teprenone by (B) a monoterpene and (C) an antacid. For example, coexistence of (A) teprenone, (B) monoterpene, and (C) an antacid in the composition for internal use of the present invention imparts good suppression of color tone change to the composition for internal use. be able to. Here, “suppress color tone change” and “provide good suppression of color tone change” can be used in the same meaning, and (A) the color tone change of the composition is more than the color tone change of teprenone alone. It means that there is little change. For example, the color tone change rate of the Δa value measured by a color difference meter by a measurement method according to the examples is preferably 70% or less, more preferably 50%, and particularly preferably 40% or less. preferable. Also in this method, the amount of the (B) monoterpene, the amount of the (A) teprenone, the amount of the optional component (C) the antacid, and the component ratio thereof are the same as in the case of the composition for internal use.

[Method for producing solid preparation]
The present invention also relates to a method for producing a solid preparation, which comprises mixing (A) teprenone, (B) monoterpene, and (C) an antacid to produce a composition for internal use. Also in this method, the amount of (B) the monoterpene, the amount of (A) teprenone, the amount of the (C) antacid, and the component ratio thereof are the same as in the case of the composition for internal use.

  The composition for internal use according to the present invention comprises, for example, a component (A), a component (B), a component (C), other components to be added as desired, and additives to be added as required, which are commonly used in the art. It is manufactured by mixing and stirring according to the method described above.

  The apparatus for mixing and stirring is not particularly limited, and for example, a high-speed stirrer or a high-speed pulverizer such as a commercially available biomixer or homojetter can be used.

  Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

(Test Example 1)
Based on the formulation shown in Table 1, Comparative Examples 1-1 to 1-2 and Examples 1-1 to 1-5 were prepared. Specifically, L-menthol was dissolved in anhydrous alcohol and triturated with light anhydrous silicic acid. For Comparative Example 1-1 containing no L-menthol, only anhydrous alcohol was mixed with light anhydrous silicic acid. It was placed in a mortar, all other ingredients were weighed and mixed. In addition, the formulation example shown in Table 1 is 562.5 mg of an antacid for 112.5 mg of teprenone when converted to a daily dose. About the color difference Δa of the prepared formulation, the initial value was measured using a color difference meter SPECTROPHOTOMETER CM-5 (manufactured by Konica Minolta), the remaining amount was sealed in a glass standard bottle, and stored in a thermostat at 60 ° C. for 2 weeks. . Two weeks later, the color difference of the sample was measured in the same manner using a color difference meter.

The color tone change rate of each sample with respect to the color tone change of Comparative Example 1-1 was calculated using Equation 1. The results are shown in FIG.
(Equation 1) Color tone change rate (%) = (color difference of 2-week-old product of each sample−color difference of initial product of each sample) / (color difference of 2-week-old product of Comparative Example 1-1−comparative example 1-1) Color difference of initial product) x 100

  In Table 1, the unit of the numerical value is g. Hereinafter, the same applies to Tables 2, 3 and 4.

  By blending menthol and various antacids, the color change was remarkably suppressed (Examples 1-1 to 1-5).

(Test Example 2)
A test was conducted in the same manner as in Test Example 1 using the formulations shown in Table 2. In addition, the formulation example shown in Table 2 is 112.5 mg of teprenone and 1125 mg of an antacid when converted to a daily dose. The results are shown in FIG.

Even when the mixing ratio of the component (A) and the component (C) was changed, the change in color tone could be suppressed by mixing menthol and various antacids (Examples 2-1 to 2-2). .

(Test Example 3)
Using the formulations shown in Table 3, tests were conducted in the same manner as in Test Example 1. In addition, the formulation examples shown in Table 3 are 112.5 mg of teprenone and 2250 mg of antacids in terms of daily dose. The results are shown in FIG.

Even when the mixing ratio of the component (A) and the component (C) was changed, a change in color tone could be suppressed by mixing menthol and various antacids (Example 3).

(Test Example 4)
The test was performed in the same manner as in Test Example 1 except that the formulations shown in Table 4 were stored in a thermostat at 60 ° C. for one week. The color tone change rate in Example 4-1 was calculated according to Equation 2, and the same was true for Example 4-2. The results are shown in Table 4.
(Equation 2) Color tone change rate (%) with respect to the corresponding comparative example = (color difference of one week old product of Example 4-1−color difference of initial product of Example 4-1) / (1 of Comparative Example 4-1) Color difference of week-old product-color difference of initial product of Comparative Example 4-1) x 100

Even when the concentration of the component (B) was changed, a change in color tone could be suppressed by blending menthol and various antacids (Examples 4-1 to 4-2).

Formulation Examples 1 to 14 (tablets)
For the formulation examples shown in Tables 5 and 6, tablets are produced using a known technique.

Formulation Examples 15 to 28 (powder)
Powders (Formulation Examples 15 to 28) are produced using the same components and proportions as in Formulation Examples 1 to 14 described in Tables 5 and 6 using known techniques.

Formulation Examples 29 to 42 (granules)
Granules (Formulation Examples 29 to 42) are produced using the same components and proportions as in Formulation Examples 1 to 14 described in Tables 5 and 6 using a known technique.

Formulation Examples 43 to 49 (soft capsules)
For the formulation examples shown in Table 7, soft capsules are produced using a known technique.

Claims (1)

The invention described in the specification of the present application.

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