JP6771274B2 - Oral composition - Google Patents

Description

The present invention relates to an oral composition comprising (A) teprenone, (B) monoterpene, and (C) an antacid.

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

Improving the stability of teprenone has become an issue, and various attempts have been made.

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

Tokukousho 62-9096 Japanese Unexamined Patent Publication No. 6-566658 Japanese Unexamined Patent Publication No. 2001-213770

There is a need for the development of a drug as an internal composition having excellent stability.

The present invention has been made as a result of diligent studies focusing on the fact that a preparation containing teprenone is likely to cause a color change due to the influence of oxidation and the like. That is, the present invention has been completed by developing a long-term storable preparation containing teprenone, which can suppress the color change of the preparation containing teprenone and has an excellent effect on the treatment of digestive diseases. ..

That is, the present invention
[1]
(A) Teprenone (sometimes referred to as component (A) herein), (B) monoterpenes (sometimes referred to as component (B) herein), and (C) antacids (the present). An internal composition comprising (may be the component (C) in the specification);
[2]
(A) The composition for internal use according to item [1], which contains (C) an antacid in a ratio of 1 to 50 parts by mass with respect to 1 part by mass of teprenone;
[3]
(C) The composition for internal use according to the above [1] or the above [2], wherein the antacid is an inorganic compound-based antacid;
[4]
(C) The oxidant 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; sodium, Calcium, magnesium and / or aluminum phosphates; sodium, calcium, magnesium and / or aluminum silicates; 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 one or more selected from the group consisting of substances;
[5]
(A) The composition for internal use according to any one of the above [1] to [4], which contains 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 agent;
[7]
A method of suppressing a change in color tone of the composition by blending (A) teprenone, (B) monoterpene, and (C) an antacid into the composition;
Etc. are provided.

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

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

[Composition for internal use]
The composition for internal use of the present invention contains (A) teprenone, (B) monoterpene, and (C) an antacid. 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 details will be described later.

In the composition for internal use of the present invention, (B) monoterpene and (C) antacid enhance the mucosal improving effect of (A) teprenone, but at the same time, the color tone changes due to oxidation or the like alone. It is possible to suppress the change in color tone of teprenone having a large value.

<Ingredient (A)>
(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 for gastric mucosal lesions (erosion, bleeding, rash, edema). It is used for improvement, treatment of acute gastritis, acute exacerbation of chronic gastritis and gastric ulcer. It can be obtained as a commercially available product or manufactured by a known manufacturing method. (Structural formula)

The dose (dose) of (A) teprenone according to the oral composition of the present invention may vary depending on the patient's condition (body weight, age, symptom, physical condition, etc.), the dosage form of the oral composition of the present invention, and the like. From the viewpoint of exerting a sufficient effect on diseases related to gastric mucosa, the larger amount tends to be preferable, while from the viewpoint of suppressing the occurrence of side effects, the smaller amount tends to be preferable. From the viewpoint of exerting the effect of the present invention more remarkably, the oral composition of the present invention contains, preferably 30 to 300 mg, more preferably 60 to 200 mg, and further preferably 100 of teprenone as a daily dose. It contains ~ 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%, and more preferably 2 to 10 w / w%.

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

Specifically, as monoterpenes, acyclic monoterpenes such as geraniol, nerol, milsenol, linalool, linalool acetate, lavandulol; monocyclic monoterpenes such as menthol, limonene, anator, eugenol, hinokithiol; Bicyclic monoterpenes such as camphor, borneol, isobornol, cineol, pinene; and the like, but are not limited thereto. Among them, monoterpene and bicyclic monoterpenes are preferable, and menthol, camphor, eugenol, geraniol, borneol, and hinokithiol are preferable from the viewpoint of more surely exerting a high effect. More preferably, it is menthol or camphor, and even more preferably, it is menthol. One of these monoterpenes may be used alone, or two or more thereof may be used in any combination.

Further, as the monoterpene, an essential oil containing the monoterpene may be used. Examples of such essential oils include cool mint oil, peppermint oil, peppermint oil, eucalyptus oil, bergamot oil, spare mint oil, rose oil, and cypress oil. For example, examples of the essential oil containing menthol and camphor include cool mint oil, peppermint oil, peppermint oil, camphor oil, uikyo oil, kehi oil, and lemon oil. These essential oils can be collected from plants by known methods. As such known essential oil extraction methods, a steam distillation method, an oil / fat adsorption method in which a plant is added to deodorized animal oil / fat to adsorb the essential oil and then the essential oil is extracted with ethanol, and the plant is organic such as hexane or benzene. Examples thereof include a solvent extraction method and a pressing method in which extraction is performed with a solvent or a supercritical fluid, the extraction solvent is dissolved in ethanol, and then the ethanol is evaporated to collect the residue. Monoterpenes can also be recovered from essential oils by various chromatographies.

The dose (dose) of (B) monoterpene according to the oral composition of the present invention may vary depending on the patient's condition (weight, age, symptom, physical condition, etc.), the dosage form of the oral composition of the present invention, and the like. However, from the viewpoint of sufficiently enhancing the effect of teprenone on diseases related to the gastric mucosa, a large amount tends to be preferable, while a small amount tends to be preferable from the viewpoint of suppressing the occurrence of side effects. It is in.

From the viewpoint of exerting the effect of the present invention more remarkably, the composition for internal use of the present invention preferably contains the total amount of (B) monoterpene contained in the composition as the daily dose. Contains 0.2 to 60 mg, more preferably 1 to 36 mg, still more preferably 2 to 20 mg. The amount and ratio of monoterpenes in the present invention refers to the amount and ratio when converted to monoterpenes even when they are contained as essential oils in the composition.

The orally-administered composition of the present invention preferably contains menthol as a monoterpene, for example, as a daily dose, preferably 0.1 to 30 mg, more preferably 0.3 to 25 mg, and even more preferably. , 0.5-18 mg, particularly preferably 1-10 mg.

When the composition for internal use of the present invention contains (B) an essential oil containing monoterpene as a daily dose, the daily dose of the essential oil is preferably 0.1 to 50 mg. More preferably, it contains 0.5 to 40 mg, and even 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%, and more preferably 0.01 to 2 w / w%. is there.

The composition for internal use of the present invention has a viewpoint of (A) exerting more remarkable effects 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 change. From the viewpoint of cost effectiveness, (A) monoterpene is preferably 0.001 to 1.5 parts by mass, more preferably 0.003 to 1 part by mass, still more preferably, with respect to 1 part by mass of teprenone. Is contained in an amount of 0.005 to 0.5 parts by mass, particularly preferably 0.01 to 0.3 parts by mass.

<Component (C)>
The (C) antacid agent 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 inorganic compound type, crude drug type and amino acid type. It may be.

Inorganic compound acid oxidants include oxides of sodium, calcium, magnesium and / or aluminum; hydroxides of sodium, calcium, magnesium and / or aluminum; carbonates of sodium, calcium, magnesium and / or aluminum; sodium. Phosphates of calcium, magnesium and / or aluminum; silicates of sodium, calcium, magnesium and / or aluminum; and of these oxides, hydroxides, carbonates, phosphates and / or silicates One or more selected from the group consisting of composites is preferable. Specifically, magnesium carbonate, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium silicate aluminate, magnesium aluminometasilicate, synthetic aluminum silicate, magnesium hydroxide alumina, sodium hydrogen carbonate, precipitated calcium carbonate, anhydrous. Calcium hydrogen phosphate, calcium hydrogen phosphate, dry aluminum hydroxide gel, aluminum hydroxide gel, synthetic hydrotalcite, aluminum hydroxide / sodium hydrogen carbonate co-precipitate product, aluminum hydroxide / magnesium carbonate mixture dry gel, hydroxide Examples include aluminum / magnesium carbonate / calcium carbonate co-precipitated products.

Examples of crude drug-based antacids include cuttlefish bone, stone determination, volley, and scopolia extract.

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

Preferred examples include inorganic compound antacids and scopolia extracts, with inorganic compound antacids being more preferred. Among the above-mentioned inorganic compound-based antioxidants, magnesium carbonate, magnesium silicate aluminate, magnesium aluminometasilicate, magnesium hydroxide, sodium hydrogencarbonate, precipitated calcium carbonate, anhydrous calcium hydrogenphosphate, and synthetic hydrotalcite are particularly preferable. .. In the present invention, two or more of these antacids may be contained.

From the viewpoint of exerting the effect of the present invention more remarkably, the orally-administered composition of the present invention preferably has a daily dose of (C) antacid contained in the composition, preferably 10. It contains ~ 5000 mg, more preferably 100-3000 mg, still more preferably 800-2500 mg.

The content of the (C) antacid in the internal composition 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 internal composition. , More preferably 25 to 50 w / w%.

The composition for internal use of the present invention has a viewpoint of (A) exerting more remarkable effects 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 change. From the viewpoint of cost effectiveness, the (A) antacid is preferably 0.2 to 100 parts by mass, more preferably 1 to 50 parts by mass, still more preferably 3 with respect to 1 part by mass of teprenone. It contains ~ 30 parts by mass, particularly preferably 5 to 20 parts by mass.

From the viewpoint of high effect on diseases related to gastric mucosa and low side effects (eg, drowsiness, etc.), the oral composition of the present invention contains (A) teprene at 10 to 300 mg, (B) as the daily dose. ) It is preferable to contain 0.1 to 50 mg of monoterpene and 10 to 5000 mg of (C) antacid.
More preferably, it contains (A) 50-200 mg of teprenone, 0.5-30 mg of (B) monoterpene, and 100-3000 mg of (C) antacid.
It is more preferable to contain (A) 100 to 150 mg of teprenone, 1 to 15 mg of (B) monoterpene, and 1000 to 2500 mg of (C) antacid.

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 oral composition of the present invention for a single administration preferably contains the above-mentioned daily dose divided by the number of daily administrations.

By blending the above-mentioned components (A), (B) and (C) with a compound that imparts suppression of color tone change over time to the composition for internal use according to the present embodiment, the color tone of the composition is adjusted. It is possible to suppress the change more remarkably.

As long as the effects of the present invention are sufficiently exhibited, crude drugs of Koboku and / or Sojutsu or extracts thereof can be exemplified.

Koboku and Soujutsu may be known crude drugs that can be used by oral administration and are pharmaceutically, pharmacologically or physiologically acceptable. The crude drug includes the crude drug itself, a chopped product thereof (crushed product, powder, etc.), a crude drug extract (extract), and the like. The crude drug extract can be prepared from crude drugs using an extractant such as water, ethanol, or a mixed solution of water and ethanol according to a known technique, and is used as a dry extract, tincture, flow extract, soft extract, or the like. be able to.

As Koboku and / or Sojutsu 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 handling. Is preferable. That is, as Koboku, Koboku powder, Koboku water extract, and Koboku ethanol extract are preferable. As the sojutsu, powder of sojutsu, water extract of sojutsu, and ethanol extract of sojutsu are preferable. These can be obtained as commercial products or manufactured according to known methods. For example, Koboku, Koboku powder, Soushutsu, Soujutsu powder listed in the 16th revised Japanese Pharmacopoeia, and dried extracts, soft extracts, tinctures, etc. made from these as raw materials can be mentioned.

In addition, the total content of Koboku and / or Sojutsu 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, still more preferably 1000 as the crude drug equivalent amount thereof. ~ 1500 mg. In addition, in this specification, "herbal medicine conversion amount" means the amount of the crude drug (herbal medicine mixture) necessary for preparing the powder or extract of Koboku or Sojutsu.

The total content of (C) Koboku and / or Sojutsu with respect to 1 part by weight of (A) Teprenone in the composition for internal use of the present invention is preferably 1 to 90 parts by weight, preferably 1 to 35 parts by weight in terms of crude drug equivalent. Parts are more preferable, and 5 to 20 parts by weight are even more preferable.

The composition for internal use of the present invention has various components (pharmacology) in addition to the components (A), (B), and (C), if necessary, as long as the effects of the present invention are sufficiently exhibited. It may contain (active or bioactive ingredients) or may be used in combination with them. The type of such a component is not particularly limited, and examples thereof include a stomachic agent, a digestive agent, an intestinal regulator, an antidiarrheal agent, an analgesic and antispasmodic agent, a mucosal repair agent, and an antifoaming agent. In the present invention, the following components can be mentioned, but the present invention is not limited to these components. The blending amount of these components is appropriately selected according to the type of preparation, the type of active ingredient, and the like.

Stomach-healing agents: Anis fruit, Aloe, Uikyo, Ukon, Uyaku, Enmeisou, Ogon, Oubaku, Ouren, Processed ginger, Gajutsu, Cuckoo, Karamus root, Dry sardine, Chenpi, Kijitsu, Keihi, Gentiana, Kojin, Koboku, Goshuyu, Kosho , Colombo, Conzlango, Sansho, Yamana, Shisoshi, Shuksha, Shokyo, Cardamom, Aohide, Stone iris, Centaurium grass, Senburi, Soyo, Otsuka, Daiou, Chikusetsu carrot, Chouji, Chimpi, Togarashi, Tohi, Nigaki Herbal medicines such as nutmeg, carrot, gentian (including gentian), chenpi, chenpi, hop, homica extract, gentian leaf, mokko, yakuchi, ryutan, alpinia, and its extract, ginger oil , Cardamom oil, chow oil, peppermint oil, animal bile (including yutan), betaine hydrochloride, glutamate, carnitine chloride, betanecol chloride, dried yeast, etc.

Digestive agents: starch digestive enzyme, protein digestive enzyme, fat digestive enzyme, fibrin digestive enzyme, ursodesoxycholic acid, oxycholate salts, cholic acid, bile powder, bile extract (powder), dehydrocoric acid, animal bile (Including Yutan) etc.

Intestinal regulators: crude drugs such as Mallotus japonicus, Asenyaku, Ubai, Ketsumeishi, Geranium thunbergii, or extracts thereof, intestinal viable bacterial components, etc.

Antidiarrheals: herbal medicines such as Asenyaku, Ubai, Oubaku, Ouren, Kujin, Gennoshoko, Gobuko, Sanzashi, Senburi, Yobaihi, or extracts thereof, Acrinol, Berberine chloride, Guayacol, Cleosotes, phenyl salicylate, Guayacol carbonate, Berberine tannate Bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth hypophagoic acid, tannic acid, albumin tannate, methylenetimole tannin, kaolin, natural aluminum silicate, aluminum hydroxynaphthoate, pectin, medicinal charcoal, calcium lactate, etc.

Antispasmodic and antispasmodic: Raw medicines such as Engosaku, Kanzo, Shakuyaku, Belladonna or extracts thereof, Oxyphencyclimine hydrochloride, Dicyclomine hydrochloride, Methixene hydrochloride, Scopolamine hydrobromide, Methylatropine bromide, Methylanisotropine bromide, Methyl bromide Scopolamine, methyl-l-hyoscyamine bromide, methylbenactidium bromide, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, roto root total alkaloid citrate, papaverin hydrochloride, ethyl aminobenzoate, etc.

Mucosal repair agent: Raw medicine such as red bud kashiwa, engosaku, kanzo or its extract, sodium azulene sulfonate, aldioxa, glycyrrhizinic acid and its salts, L-glutamine, copper chlorophyllin potassium, copper chlorophyllin sodium, histidine hydrochloride, pig stomach wall pepsin decomposition product , Pig stomach wall acid hydrolyzate, methylmethionine sulfonium chloride, gefarnate, setraxate hydrochloride, sucralfate hydrate (sucrose sulfate aluminum salt), sofalcone, etc.

Defoamer: Dimethylpolysimexan, etc.

The composition for internal use of the present invention is preferably an orally administered composition. The dosage forms include tablets (including quick-disintegrating tablets in the oral cavity, chewable tablets, effervescent tablets, jelly-like drop agents, etc.), troches, granules, pills, dry syrups, and powders (including fine granules). ), Capsules (including hard capsules, soft capsules), liquids, suspensions, emulsions, syrups, elixirs, limonades, tinctures, extracts, jellies, gels Examples thereof include agents and liposome agents. Among them, a solid agent containing teprenone and monoterpene is preferable from the viewpoint of further exerting the effect of the present invention and versatility, and in particular, a solid agent prepared through granulation. You may. The solid preparation includes granules, tablets, troches, hard capsules, soft capsules, dry syrups and the like, and granules and tablets are particularly preferable.

Further, the composition for internal use of the present invention may contain an appropriate additive depending on its dosage form. Such additives include, in the case of solid preparations (eg, tablets, capsules, powders, etc.), excipients (eg, sucrose, lactose, crystalline cellulose, light anhydrous silicic acid, etc.), and lubricants (eg, sucrose anhydride). , Sucrose fatty acid esters, magnesium stearate, talc, etc.), disintegrants (eg, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, etc.), foaming agents (eg, sodium hydrogen carbonate, etc.), fluidizers (For example, sodium aluminate metasilicate, light anhydrous silicic acid, etc.), and the like. The pharmaceutical uses of these additives may be other than the above. In the case of liquid preparations (for example, syrups, liquids, suspending agents, soft capsule contents, hard capsule contents such as liquid ones), oil-based bases (for example, olive oil, corn oil, etc.) Vegetable oils such as soybean oil, sesame oil, cottonseed oil; medium chain fatty acid triglycerides, etc.), aqueous bases (eg, Macrogol 400, water), gel bases (eg, carboxyvinyl polymers, gums, etc.), surfactants (eg, carboxyvinyl polymers, gums, etc.) , Polysolvate 80, hardened castor oil, glycerin fatty acid ester, sorbitan sesquioleate, etc.), suspending agents (eg, sala mitsuro, various surfactants, soy lecithin, etc.), dispersants, emulsifiers, stabilizers, buffers , Dissolving aids, pH adjusters, preservatives (preservatives) and the like. In any case, antioxidants, sweeteners, acidulants, colorants, flavors, flavoring agents and the like may be appropriately added to these compositions.

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

Specifically, the composition for internal use of the present invention has actions such as protection of gastric mucosa, enhancement of gastric mucosa, enhancement of gastric mucosal blood flow, etc., enhances resistance to gastric acid, and has an amount of gastric acid. It exerts an excellent therapeutic and preventive effect on gastritis, gastric ulcer, and gastric roughness in combination with the regulating action of. In particular, the oral composition of the present invention is used for improvement of gastric ulcer, gastric mucosal lesion (erosion, bleeding, redness, edema), treatment of acute gastritis, acute exacerbation of chronic gastritis, and the like. In addition, leaning (stomach leaning), overeating (overeating), overdrinking (overdrinking), chest burning, loss of appetite (decreased appetite), stomach bloating (including those due to indigestion), abdominal bloating (indigestion) (Including those caused by), rash (upset stomach, upset stomach, upset sickness / sickness, nausea, nausea), vomiting, chest tightness, excessive stomach acid, heavy stomach, weak stomach, stomach pain, stomach discomfort, promotion of digestion , Digestion, abdominal pain, swelling (stomach, swelling), swelling, swelling, stomachache, diarrhea (including diarrhea due to indigestion and abdominal pain), per meal, It can be suitably used for applications such as water contact, intestinal regulation (adjusting bowel movements), loose stools, and constipation. Of these, the oral composition of the present invention alleviates the symptoms of stomach upset, heartburn, and gastric mucosal roughness by containing (A) teprenone, B) monoterpene, and (C) antacid. To do.

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

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

By containing (A) teprenone, B) monoterpene, and (C) antacid, the preparation of the above-mentioned oral composition enhances the gastric mucosa protective effect, and is remarkable for diseases and symptoms related to the gastric mucosa. It has a therapeutic and / or preventive effect. In particular, it is effective for stomach upset, heartburn, and rough gastric mucosa.

In the preparation of the above-mentioned oral composition, (A) a ratio of 0.005 to 0.5 parts by mass of (B) monoterpene and 0.5 to 0.5 parts by mass of an antioxidant are added to 1 part by mass of teprenone. It is preferably contained in a proportion of 60 parts by mass, particularly preferably (B) containing monoterpene in a proportion of 0.01 to 0.3 parts by mass, and (C) containing an antioxidant in a proportion of 5 to 20 parts by mass. It is preferable to do so.

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

The above-mentioned oral composition may contain 0.1 to 10 mg of (B) monoterpene per preparation.

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

[How to suppress the color change of Teprenone]
The present invention also relates to a method of suppressing a color change of (A) teprenone with (B) monoterpenes and (C) antacids. For example, the coexistence of (A) teprenone, (B) monoterpene and (C) antacid in the internal composition of the present invention imparts good suppression of color change to the internal composition. be able to. Here, "suppressing the color tone change" and "providing a good color tone change suppression" can be used in the same meaning, and (A) the color tone of the composition is more than that of 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 the color difference meter by the measuring method according to the embodiment is preferably 70% or less, more preferably 50%, and particularly preferably 40% or less. preferable.
Also in this method, the amount of (B) monoterpene, (A) amount of teprenone, the amount of optional component (C) antacid, and their component ratios are the same as in the case of the composition for internal use.

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

In the composition for internal use of the present invention, for example, the component (A), the component (B), the component (C), other components added as desired, and additives added as desired are commonly used in the art. It is produced by mixing and stirring according to the above method.

The device for mixing and stirring is not particularly limited, and for example, a high-speed stirrer such as a commercially available biomixer or homojetter or a high-speed crusher 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)
Comparative Examples 1-1 to 1-2 and Examples 1-1 to 1-5 were prepared based on the formulations shown in Table 1. Specifically, L-menthol was dissolved in anhydrous alcohol and mixed with light anhydrous silicic acid. For Comparative Example 1-1 containing no L-menthol, only anhydrous alcohol was double-mixed with light anhydrous silicic acid. It was placed in a mortar, all other ingredients were weighed and mixed. In addition, the preparation example shown in Table 1 is 562.5 mg of an antacid against 112.5 mg of teprenone when converted into a daily dose. The initial value of the color difference △ a of the prepared formulation was measured using a color difference meter SPECTROP HOTOMETER CM-5 (manufactured by Konica Minolta), the remaining amount was sealed in a glass standard bottle, and stored in a constant temperature bath at 60 ° C for 2 weeks. .. The color difference of the sample after 2 weeks 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 the initial product) x 100

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

By blending menthol and various antacids, it was possible to remarkably suppress the change in color tone (Examples 1-1 to 1-5).

(Test Example 2)
The test was carried out in the same manner as in Test Example 1 using the formulations shown in Table 2. The preparation examples shown in Table 2 are 112.5 mg of teprenone and 1125 mg of antacid when converted into daily doses. The results are shown in FIG.

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

(Test Example 3)
The test was carried out in the same manner as in Test Example 1 using the formulations shown in Table 3. The preparation examples shown in Table 3 are 112.5 mg of teprenone and 2250 mg of antacid when converted into daily doses. The results are shown in FIG.

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

(Test Example 4)
The test was carried out in the same manner as in Test Example 1 except that the formulations shown in Table 4 were stored in a constant temperature bath at 60 ° C. for 1 week. The color tone change rate of Example 4-1 was calculated according to Equation 2, and the same was calculated 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 the product after one week of Example 4-1-color difference of the initial product of Example 4-1) / (1 of Comparative Example 4-1) Color difference of weekly products-Color difference of initial products of Comparative Example 4-1) x 100

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

Formulation Examples 1-14 (tablets)
Tablets are produced using known techniques for the formulation examples shown in Tables 5 and 6.

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

Formulation Examples 29-42 (granule)
Granules (Formulation Examples 29 to 42) are produced using known techniques at the same components and proportions as in Formulation Examples 1 to 14 shown in Tables 5 and 6.

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

Claims (5)

An internal composition containing (A) teprenone, (B) monoterpene, and (C) an inorganic compound-based antacid, wherein (C) an inorganic compound is based on 1 part by mass of (A) teprenone . An internal composition containing 1 to 50 parts by mass of an antacid. (A) The composition for internal use according to claim 1, which contains 30 to 300 mg of teprenone as a daily dose. The composition for internal use according to claim 1 or 2, which is a solid agent. The composition for internal use according to any one of claims 1 to 3, wherein the content of (C) is 10 to 99 w / w% with respect to the total amount of the composition. A method for suppressing a change in color tone of the composition, which comprises coexisting (A) teprenone, (B) monoterpene, and (C) an inorganic compound-based antacid in the composition.
A method in which the ratio of (C) an inorganic compound-based antacid to 1 part by mass of the (A) teprenone is 1 to 50 parts by mass.