JP2023163350A - Chewable tablet or intraoral disintegrable tablet - Google Patents

Abstract

To provide a chewable tablet or an intraoral disintegrable tablet that achieves reduction in an unpleasant taste after storage, mainly caused by loperamide hydrochloride, even in the presence of at least one selected from turmeric and extract thereof.SOLUTION: The present invention provides a chewable tablet or an intraoral disintegrable tablet that contains an uncoated tablet containing component (A): loperamide hydrochloride, component (B): at least one selected from turmeric and extract thereof, component (C): menthol, and component (D): a sugar alcohol.SELECTED DRAWING: None

Description

The present invention relates to chewable or orally disintegrating tablets.

Diarrhea can be caused by a variety of factors, including overeating and drinking, eating too much, and stress, but no matter what the cause, antidiarrheal drugs must be fast-acting.
For example, if you have diarrhea due to overeating or drinking too much, it can cause complications such as indigestion due to decreased stomach and liver function. Therefore, it is desired to include not only an antidiarrheal component as an active ingredient, but also a herbal medicine that normalizes the functions of the stomach and liver, for example.

Turmeric is known as a herbal medicine ingredient that is effective in restoring liver function. Therefore, it is desired to use turmeric and antidiarrheal ingredients in combination.
On the other hand, loperamide hydrochloride, which is an antidiarrheal ingredient, has a unique unpleasant taste such as bitterness and astringency, and when it is mixed with turmeric, the unpleasant taste is enhanced. In particular, chewable tablets that are chewed and taken in the oral cavity and orally disintegrating tablets that disintegrate in the oral cavity tend to have a noticeable unpleasant taste.
Menthol is known as a component that improves unpleasant taste (see, for example, Patent Document 1).

Japanese Patent Application Publication No. 2000-95707

However, although the unpleasant taste characteristic of loperamide can be improved by adding menthol to loperamide hydrochloride alone, the combination of loperamide hydrochloride and at least one selected from turmeric and its extracts does not improve over time. There is a problem in that menthol sublimes and the bitter and astringent taste caused by loperamide hydrochloride is restored.
An object of the present invention is to provide a chewable tablet or orally disintegrating tablet that improves the unpleasant taste that occurs after storage, mainly due to loperamide hydrochloride, even in the presence of at least one selected from turmeric and its extract. shall be.

As a result of intensive studies, the present inventors found that the unpleasant taste that occurs after storage can be improved by using a sugar alcohol in combination with loperamide hydrochloride, at least one selected from turmeric and its extract, and menthol. We have discovered that this can be done, and have completed the present invention.

That is, the present invention has the following aspects.
[1] Component (A): loperamide hydrochloride,
(B) Component: at least one selected from turmeric and its extract;
(C) Ingredient: menthol,
(D) Component: sugar alcohol,
Chewable or orally disintegrating tablets containing plain tablets.
[2] The chewable tablet or orally disintegrating tablet of [1] above, wherein the mass ratio represented by the component (D)/component (B) is 0.05 to 6.
[3] The chewable tablet or orally disintegrating tablet of [1] or [2] above, wherein the mass ratio represented by the component (D)/component (C) is 40 to 500.
[4] The chewable tablet or orally disintegrating tablet according to any one of [1] to [3] above, wherein the component (D) is at least one selected from mannitol, erythritol, xylitol, sorbitol, and maltitol.
[5] The chewable tablet or orally disintegrating tablet according to any one of [1] to [4] above, wherein the average particle diameter of the component (C) is 1 to 200 μm.

According to the present invention, it is possible to provide a chewable tablet or an orally disintegrating tablet that improves the unpleasant taste that occurs after storage, mainly due to loperamide hydrochloride, even in the presence of at least one selected from turmeric and its extract.

[Chewable tablets and orally disintegrating tablets]
Chewable tablets and orally disintegrating tablets are solid preparations that can be taken without water.
Unlike general-purpose tablets that are taken with water, chewable tablets and orally disintegrating tablets can be taken without water, regardless of the situation, such as when going out, and are easier to swallow, even in patients with impaired swallowing function. It has a hardness that allows it to be chewed and disintegrated in the oral cavity. In general, chewable tablets and orally disintegrating tablets are solid preparations that have superior disintegration properties compared to tablets that are taken with water, and orally disintegrating tablets have even better disintegration properties than chewable tablets.
Specifically, chewable tablets are solid preparations that are taken by being disintegrated by chewing in the oral cavity.For example, when evaluating disintegration properties in the oral cavity, the disintegration time is 8. Preferably less than 5 minutes, more preferably less than 5 minutes.
An orally disintegrating tablet is a solid preparation that is taken by being disintegrated with saliva in the oral cavity.For example, when evaluating the disintegration property in the oral cavity, the disintegration time is less than 60 seconds without being chewed in the oral cavity. is preferred, less than 45 seconds is more preferred, and even more preferably less than 30 seconds.
In the case of tablets to be taken with water, the disintegration time when evaluating disintegration in the oral cavity, for example, without chewing in the oral cavity, is 10 minutes or more.
If the solid preparation contains a disintegrant, the disintegration time can be controlled by the type and amount of the disintegrant. Furthermore, when producing a solid preparation, the disintegration time can also be controlled by the tableting pressure during tabletting.
Here, evaluating disintegration in the oral cavity means measuring the disintegration time when one tablet is rolled on the tongue in the oral cavity without chewing, and the disintegration time is short. This means that the disintegration property is excellent.

Chewable tablets and orally disintegrating tablets of the present invention are solid preparations having uncoated tablets containing component (A), component (B), component (C), and component (D) shown below.
The uncoated tablet may contain ingredients other than (A), (B), (C), and (D) (hereinafter also referred to as "optional ingredients") as long as they do not impair the effects of the present invention. may further include.
The chewable tablet of the present invention may have a coating layer formed on the surface of the uncoated tablet, if necessary. That is, the chewable tablet may consist of only a plain tablet, or may have a plain tablet and a coating layer formed on the surface of the plain tablet.
The orally disintegrating tablet of the present invention may have a coating layer formed on the surface of the uncoated tablet, if necessary. That is, the orally disintegrating tablet may consist of only a plain tablet, or may have a plain tablet and a coating layer formed on the surface of the plain tablet. However, from the viewpoint of maintaining good disintegration properties in the oral cavity, it is preferable that the orally disintegrating tablet does not have a coating layer, that is, it consists of only a plain tablet.

"Uncoated tablet"
<(A) component>
Component (A) is loperamide hydrochloride.
Component (A) is an antidiarrheal component and has an antidiarrheal effect.

The content of component (A) is preferably 0.1 to 100 mg, more preferably 0.5 to 30 mg, and even more preferably 0.5 to 5 mg per dose. If the content of component (A) is equal to or higher than the above lower limit, the pharmacological effect of component (A) (especially in preventing diarrhea caused by drinking alcohol) will be improved. If the content of component (A) is below the above upper limit, bitterness will be suppressed and ease of administration will be improved.
In addition, when taking one chewable tablet or orally disintegrating tablet at a time, the one-time dose of each component corresponds to the content (mg) per plain tablet.

The content ratio of component (A) to the total mass of the uncoated tablet is preferably 0.01 to 1% by mass, more preferably 0.03 to 0.6% by mass, and even more preferably 0.05 to 0.3% by mass. . If the content ratio of the component (A) is equal to or higher than the above lower limit, the pharmacological effect of the component (A) (especially antidiarrhea caused by drinking) will be improved. If the content ratio of component (A) is below the above upper limit, bitterness will be suppressed and ease of administration will be improved.

<(B) component>
Component (B) is at least one selected from turmeric and its extract.
Ingredient (B) functions as a gastrointestinal drug that normalizes the functions of the stomach and liver.

Turmeric is a perennial herb belonging to the Zingiberaceae family, and has an egg-shaped or cylindrical rhizome with a diameter of 3 to 4 cm and a yellow inner surface with ring-shaped nodes. Turmeric prefers high temperature and humidity, and is widely cultivated in tropical and subtropical regions from India to Southeast Asia. In Japan, it is cultivated in Okinawa, Amami Oshima, and other areas, and its rhizomes are used for medicinal purposes, food, and dyes. The main pharmacological actions of turmeric include liver function improvement, antibacterial action, antioxidant action, and anti-inflammatory action.
Component (B) is not particularly limited, but includes turmeric powder; turmeric extracts such as turmeric soft extract, turmeric liquid extract, and turmeric dried extract. Turmeric powder is also listed in the 17th edition of the Japanese Pharmacopoeia. Among these, turmeric powder and dried turmeric extract are preferred from the viewpoints of ease of manufacturing chewable tablets and orally disintegrating tablets (hardness of tableting failure) and storage stability (hardness of caking between plain tablets). , turmeric dry extract is more preferred.
In addition, as the turmeric extract, one manufactured according to the method for manufacturing a crude drug-specific preparation "extract" described in the general rules for preparations listed in the 18th edition of the Japanese Pharmacopoeia may be used. Specifically, the above method involves weighing out a certain amount of appropriately sized crude drugs according to the prescription, adding 10 to 20 times the amount of water to the total amount, heating for a certain period of time, and separating solid and liquid by centrifugation. Examples include a method of concentrating or drying the obtained leachate using an appropriate method. The soft turmeric extract has a starch syrup-like consistency, and the dried turmeric extract has a crushable mass, granules, or powder.
One type of turmeric may be used alone, or two or more types may be used in combination.

The content of component (B) is preferably 10 to 3,000 mg, more preferably 10 to 2,000 mg, and even more preferably 10 to 900 mg in terms of the original herbal medicine for turmeric extract. The amount of turmeric powder is preferably 10 to 1000 mg, more preferably 10 to 300 mg.
If the content of component (B) is equal to or higher than the above lower limit, the effectiveness of component (B) will be improved. If the content of component (B) is below the above upper limit, sublimation of menthol, which is component (C), becomes difficult to occur over time. In addition, unpleasant taste is reduced and ease of administration is improved.

In the case of turmeric powder, the content ratio of component (B) to the total mass of the uncoated tablet is preferably 3 to 70% by mass, more preferably 10 to 50% by mass. In the case of turmeric extract, it is preferably 1 to 50% by mass, more preferably 5 to 40% by mass. In the case of turmeric soft extract, it is preferably 1 to 50% by mass, more preferably 5 to 40% by mass. In the case of turmeric dry extract, the amount is preferably 1 to 70% by weight, more preferably 4 to 50% by weight, and even more preferably 4 to 40% by weight.
If the content ratio of the component (B) is equal to or higher than the above lower limit, the effectiveness of the component (B) will be improved. If the content ratio of component (B) is below the above upper limit, sublimation of menthol, which is component (C), becomes difficult to occur over time. In addition, unpleasant taste is reduced and ease of administration is improved.

The mass ratio expressed by component (B)/component (A) (hereinafter also referred to as "B/A ratio"), which is the mass ratio of component (B) to component (A), is preferably 65 to 6000. , 100 to 2000 is more preferable. Details are as follows.
When component (B) is turmeric extract, the B/A ratio is preferably 200 to 6,000, more preferably 600 to 2,000. If the B/A ratio is equal to or higher than the above lower limit, in addition to the antidiarrheal effect, the effect of restoring gastric and liver function will be improved. When the B/A ratio is below the above upper limit, sublimation of menthol, which is the component (C), becomes less likely to occur over time, and unpleasant taste is reduced, so that ease of administration is improved.
When component (B) is turmeric powder, the B/A ratio is preferably 65 to 2,000, more preferably 100 to 670. The reasons for the lower limit and upper limit of the B/A ratio are the same as in the case of turmeric extract.
In addition, when the (B) component is a turmeric extract, the mass of the (B) component in the B/A ratio is calculated in terms of the crude drug. Moreover, when the (B) component is turmeric powder, the mass of the (B) component in the B/A ratio is the content of the turmeric powder.

<(C) component>
Component (C) is menthol.
Component (C) is a component that improves unpleasant tastes such as characteristic bitterness and astringent taste mainly caused by component (A).
Menthol may be in the d-form, l-form, or dl-form, but the l-form and dl-form are preferable, and the l-form is more preferable.

The average particle diameter of component (C) is preferably 1 to 200 μm, more preferably 1 to 150 μm, even more preferably 1 to 100 μm. If the average particle size of component (C) is equal to or larger than the above lower limit, sublimation of component (C) that occurs over time and unpleasant taste mainly caused by component (A), especially after taking it several minutes after taking it, can be prevented. It can be improved further. If the average particle diameter of component (C) is below the above upper limit, the handling of component (C) in the manufacturing process of chewable tablets or orally disintegrating tablets (for example, the crushing process of component (C) described below) will be improved. do. In addition, holes in the chewable tablet surface or orally disintegrating tablet surface (dropping of menthol particles, etc. from the tablet surface) are less likely to occur.
In addition, in the present invention, the "average particle diameter" is a volume average particle diameter (D50) measured according to a laser diffraction particle size distribution measuring method.

The content of component (C) is preferably 0.01 to 10 mg, more preferably 0.1 to 10 mg per dose. If the content of component (C) is equal to or higher than the above lower limit, the unpleasant taste mainly caused by component (A), especially the unpleasant taste several minutes after taking it, will be improved, and a refreshing feeling will be obtained. Ease of administration is improved. If the content of component (C) is below the above upper limit, the irritation and bitterness derived from component (C) will be small and ease of administration will be improved.

The content ratio of component (C) to the total mass of the uncoated tablet is preferably 0.01 to 5% by mass, more preferably 0.1 to 2% by mass, and even more preferably 0.1 to 1% by mass. If the content ratio of component (C) is equal to or higher than the above lower limit, the unpleasant taste mainly caused by component (A), especially the unpleasant taste several minutes after taking it, will be improved, and a refreshing feeling will be obtained. Ease of administration is improved. If the content ratio of component (C) is below the above-mentioned upper limit, the irritation and bitterness derived from component (C) will be small, and ease of administration will be improved.

<(D) component>
Component (D) is a sugar alcohol.
By containing component (D) in the uncoated tablet, it is possible to improve the unpleasant taste that occurs after storage, which is mainly caused by component (A).
Examples of sugar alcohols include mannitol, erythritol, xylitol, sorbitol, maltitol, and the like. Among these, mannitol and erythritol are preferred from the viewpoint of manufacturability (handling properties during powder mixing) and quality assurance over time (difficulty in causing delayed disintegration) of chewable tablets and orally disintegrating tablets.
One type of sugar alcohol may be used alone, or two or more types may be used in combination.

The content of component (D) is preferably 10 to 700 mg, more preferably 50 to 500 mg, and even more preferably 100 to 300 mg per dose. If the content of component (D) is equal to or higher than the above lower limit, the sublimation of component (C) that occurs over time and the unpleasant taste mainly caused by component (A) will be improved, especially the unpleasant taste several minutes after taking it. can. If the content of component (D) is below the above upper limit, the uncoated tablet will be difficult to increase in size and will be easier to take.

The content ratio of component (D) to the total mass of the uncoated tablet is preferably 10 to 80% by mass, more preferably 30 to 75% by mass, and even more preferably 40 to 70% by mass. If the content ratio of component (D) is equal to or higher than the above lower limit, the sublimation of component (C) that occurs over time and the unpleasant taste mainly caused by component (A) will be improved, especially the unpleasant taste several minutes after taking it. can. If the content ratio of component (D) is below the above-mentioned upper limit, and if the content of component (C) is below the above-mentioned upper limit, uncoated tablets are less likely to be enlarged and ease of administration is improved.

The mass ratio of component (D) to component (B), expressed as component (D)/component (B) (hereinafter also referred to as "D/B ratio"), is 0.05 to 6. is preferable, and 0.1 to 3 is more preferable. Details are as follows.
When component (B) is turmeric extract, the D/B ratio is preferably 0.05 to 2, more preferably 0.1 to 1. If the D/B ratio is at least the above lower limit, the sublimation of component (C) that occurs over time and the unpleasant taste mainly caused by component (A), especially the unpleasant taste several minutes after taking the drug, can be further improved. If the D/B ratio is below the above upper limit, it will be difficult to inhibit the aromatic action derived from herbal medicines.
When component (B) is turmeric powder, the D/B ratio is preferably 0.15 to 6, more preferably 0.3 to 3. The reasons for the lower limit and upper limit of the D/B ratio are the same as in the case of turmeric extract.
In addition, when the (B) component is a turmeric extract, the mass of the (B) component in the D/B ratio is calculated in terms of the crude drug. Moreover, when the (B) component is turmeric powder, the mass of the (B) component in the D/B ratio is the content of the turmeric powder.

The mass ratio expressed by component (D)/component (C) (hereinafter also referred to as "D/C ratio"), which is the mass ratio of component (D) to component (C), is preferably 40 to 500, More preferably 80-400. If the D/C ratio is at least the above lower limit, the sublimation of component (C) that occurs over time and the unpleasant taste mainly caused by component (A), especially the unpleasant taste several minutes after taking the drug, can be further improved. If the D/C ratio is below the above upper limit, the refreshing sensation of the component (C) will be felt easily and ease of administration will be improved.

<Optional ingredients>
Optional ingredients include physiologically active ingredients other than the components (A) and (B) (hereinafter also referred to as "other physiologically active ingredients"), and additives other than the components (C) and (D) (hereinafter referred to as "other physiologically active ingredients"). (Also referred to as "other additives.").
Other additives include, for example, binders, excipients, disintegrants, lubricants, colorants, acidulants, foaming agents, sweeteners, flavorings, and the like.
These optional components may be used alone or in combination of two or more.
The blending amount of these optional components can be appropriately set depending on the purpose within a range that does not impede the effects of the present invention.

Examples of other physiologically active ingredients include berberine tannate, rhoto extract, acrinol, phenyl salicylate, guaiacol, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth subgallate, berberine chloride, creosote, albumin tannate, Sodium azulene sulfonate, bile powder, bile extract, dehydrocholic acid, scutellariae, scutellariae, precipitated calcium carbonate, calcium lactate, calcium hydrogen phosphate, sodium azulene sulfonate, aldioxa, sucralfate hydrate, synthetic hydrotalcite, glycyrrhizic acid and its salts, ibuprofen, aspirin, acetaminophen, loxoprofen sodium hydrate, anhydrous caffeine, live bacterial ingredients, herbal medicines other than ingredient (B) and their extracts (peony, corydalis, licorice, azalea, ubai, gennoshoko, quintessence) , hawthorn, kujin, japonica, japonica japonica, kouboku, akamegashiwa), etc.
The method for extracting crude drugs is not particularly limited, and they can be used not only as raw powders, but also as processed raw materials such as liquid extracts, dry extracts, and tinctures.
Other physiologically active ingredients may be granulated using excipients, binders, disintegrants, lubricants, etc. to form active ingredient granules.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gum arabic, pregelatinized starch, sodium alginate, carboxyvinyl polymer, agar, and honey.
Among these, polyvinyl alcohol and hydroxypropylcellulose are preferred for chewable tablets, and hydroxypropylcellulose and hydroxypropylmethylcellulose are preferred for orally disintegrating tablets.
The content of the binder is preferably 0.01 to 30% by mass, more preferably 0.1 to 10% by mass, based on the total mass of the uncoated tablet.

Examples of excipients include crystalline cellulose, lactose, trehalose, methyl ethyl cellulose, dextrin, cyclodextrin, hydroxypropyl starch, corn starch, potato starch, and the like.
Among these, corn starch is preferred.

Examples of the disintegrant include low-substituted hydroxypropylcellulose, carmellose, carmellose sodium, carmellose calcium, crospovidone, croscarmellose sodium, partially pregelatinized starch, and sodium starch glycolate.
Among these, low-substituted hydroxypropylcellulose and carmellose are preferred for chewable tablets, and crospovidone, carmellose calcium, and croscarmellose sodium are preferred for orally disintegrating tablets.
The content of the disintegrant is preferably 0.1 to 30% by mass, more preferably 0.2 to 20% by mass, based on the total mass of the uncoated tablet.

Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, light anhydrous silicic acid, hydrated silicon dioxide, and talc.
The content of the lubricant is preferably 0.01 to 5% by mass, more preferably 0.05 to 2% by mass, based on the total mass of the uncoated tablet.

Examples of the coloring agent include titanium oxide, iron sesquioxide, yellow iron sesquioxide, Yellow No. 5, Yellow No. 4, and the like.
Examples of the acidulant include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof.
Examples of sweeteners include aspartame, sucralose, acesulfame potassium, stevia, refined white sugar, saccharin, and glycyrrhizin.
As the fragrance, a powdered fragrance can be suitably used, such as a powdered fragrance prepared by dispersing limonene and plant essential oils (lychee oil, orange oil, lemon oil, etc.) with gum arabic, dextrin, lactose, gelatin, etc. can do.

<Form of uncoated tablet>
The dimensions of the uncoated tablet are not particularly limited, but from the viewpoint of ease of handling and dosing of the uncoated tablet, the diameter φ of the uncoated tablet is preferably 5 to 14 mm, more preferably 6 to 13 mm, and even more preferably 7 to 12 mm. Furthermore, the mass of each uncoated tablet is preferably 100 to 1000 mg.
Further, the shape of the uncoated tablet is not particularly limited, but it is preferably a rounded square flat tablet, a rounded round flat tablet, a rounded R tablet, or a two-stage R tablet. In particular, orally disintegrating tablets are more preferably sumi-square tablets and sumi-round flat tablets.

The uncoated tablet may have a single-layer structure (single-layer tablet) or a laminated structure (multi-layer tablet).
When the uncoated tablet is a single-layer tablet, the uncoated tablet has a drug layer containing the above-mentioned components (A), (B), (C) and (D), and optionally one or more optional components. Consists of. On the other hand, when the uncoated tablet is a laminated tablet, the uncoated tablet is composed of the drug layer and a layer (arbitrary layer) other than the drug layer.
In addition, when a plain tablet is a laminated tablet, the number of layers may be two layers, and three or more layers may be sufficient as it.
In addition, when the uncoated tablet is a laminated tablet, the optional layer may contain any one or more of the components (A), (B), (C), and (D), or may contain none of them. It's okay. The presence or absence of inclusion of these components in the arbitrary layer, the content ratio, etc. can be appropriately selected in consideration of the dosage of these components per dose, the content ratio of these components in the uncoated tablet, etc. Further, the above-mentioned optional components may be contained only in the drug layer, only in the arbitrary layer, or in both the drug layer and the arbitrary layer. When the uncoated tablet is a single-layer tablet, optional ingredients are contained in the drug layer.

<Hardness of uncoated tablet>
The hardness of the uncoated tablet may be set according to the tablet size as a chewable tablet or an orally disintegrating tablet. For example, in the case of a two-step R chewable tablet with a diameter of 9.5 mm, the hardness is preferably 3 to 15 kgf, more preferably 4 to 14 kgf, even more preferably 6 to 14 kgf, and particularly preferably 8 to 14 kgf. In the case of an orally disintegrating tablet with a diameter of 9.5 mm and a two-stage R tablet, the hardness is preferably 3 to 12 kgf, more preferably 3 to 10 kgf, and even more preferably 3 to 8 kgf.
Note that the hardness can be measured using a tablet hardness meter (for example, product name "PTB111E" manufactured by PHARMATEST).

<Moisture content of uncoated tablet>
The moisture content of the uncoated tablet is preferably 0.5 to 10% by mass, more preferably 1 to 5% by mass, based on the total mass of the uncoated tablet. If the water content is equal to or higher than the above lower limit, the hardness and the like when made into chewable tablets or orally disintegrating tablets can be maintained, and shape retention can be easily ensured. If the water content is below the above upper limit, the sublimation of component (C) that occurs over time and the unpleasant taste mainly caused by component (A), especially the unpleasant taste several minutes after taking, can be further improved.
The moisture content of the uncoated tablet is a value measured using a Karl Fischer moisture meter (for example, manufactured by Kyoto Denshi Kogyo Co., Ltd., product name "MKC-210").

The moisture content of uncoated tablets can be adjusted by using powders of any of the ingredients themselves before mixing, or after making them into chewable tablets or orally disintegrating tablets, using a constant temperature bath, dryer, fluidized bed granulator, etc. It can be adjusted by humidifying and drying. In order to ensure the stability of the formulation, it is desirable to adjust some of the ingredients by spraying water using a fluidized bed granulator or the like or by drying them before mixing.

"Coating layer"
The coating layer is a layer formed on the surface of the uncoated tablet.
If the chewable tablet or orally disintegrating tablet further has a coating layer in addition to the plain tablet, the ease of administration and stability (suppression of decomposition of physiologically active ingredients, maintenance of physical properties of the chewable tablet or orally disintegrating tablet) will be improved. . In particular, if the chewable tablet further has a coating layer, chewiness can be imparted to the chewable tablet.
In addition, as mentioned above, from the viewpoint of maintaining good disintegration properties in the oral cavity, it is preferable that the orally disintegrating tablet does not have a coating layer, that is, it consists of only a plain tablet.
Furthermore, in this specification, chewable tablets or orally disintegrating tablets having a coating layer are also particularly referred to as "coated tablets."

The coating layer contains a coating agent.
As a coating agent, it is preferable to select one that does not significantly impair disintegration properties, and it is preferable that it contains at least one of a water-soluble polymer compound, a plasticizer, a coloring agent, and a flavoring agent. It is more preferable to contain a compound.
One type of coating agent may be used alone, or two or more types may be used in combination.
Further, as a coating agent, a commercially available premix product such as Opadry (manufactured by Nihon Colorcon LLC) may be used.

Examples of water-soluble polymer compounds include celluloses such as carmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, methylcellulose, and ethylcellulose; gum arabic, carboxyvinyl polymer, povidone, crospovidone, polyvinyl alcohol, polyacrylic acid, Examples include saccharides, polysaccharides higher than disaccharides, sugar alcohols, starch syrup, isomerized sugars, oligosaccharides, sucrose, and trehalose.
Examples of the plasticizer include macrogol, glycerin, triethyl citrate, triacetin, and sucrose fatty acid ester.
Examples of the colorant include titanium oxide, talc, iron sesquioxide, yellow iron sesquioxide, Yellow No. 5, Yellow No. 4 (or aluminum lake), and the like.
Examples of the flavoring agent include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof, aspartame, sucralose, acesulfame potassium, stevia, refined white sugar, saccharin, glycyrrhizin, and the like.
The water-soluble polymer compound, plasticizer, coloring agent, and flavoring agent may each be used singly or in combination of two or more.

The amount of coating agent used in the coated tablet (coating amount) is appropriately set within a range that does not impair the effects of the present invention. For example, it is preferably 0.1 to 10 parts by weight, more preferably 0.5 to 5 parts by weight, per 100 parts by weight of the uncoated tablet. If the amount of the coating agent used is at least the above lower limit, the ease of taking the coated tablet can be maintained. In addition, the sublimation of component (C) that occurs over time and the unpleasant taste mainly caused by component (A), especially the unpleasant taste several minutes after taking the drug, can be further improved. If the amount of the coating agent used is below the above upper limit, good disintegration properties can be maintained.
In the case of coated tablets, the form of the coated tablets, the hardness of the coated tablets, and the moisture content of the coated tablets are as explained in the respective sections for uncoated tablets.

"Manufacturing method for chewable tablets and orally disintegrating tablets"
The chewable tablets and orally disintegrating tablets of the present invention are obtained by mixing the above-mentioned components (A), (B), (C) and (D), respectively, and optional components as necessary. It can be obtained by tabletting a mixture (mixed powder). Each component may be obtained by a known manufacturing method, or commercially available products may be used. Further, each component may be used as a raw powder or may be granulated. In the present invention, each component can be mixed all at once or sequentially to form a mixed powder and then tableted. However, the unpleasant taste suppressing effect of component (A) (especially improvement of unpleasant taste several minutes after taking) In order to further improve the properties, it is preferable to co-pulverize component (C) and optional components and then mix them. Moreover, from the viewpoint of content uniformity in chewable tablets or orally disintegrating tablets, it is preferable to granulate the components (A) and (D) and then mix them.
Hereinafter, an example of a method for manufacturing chewable tablets will be explained step by step.

<Method for manufacturing chewable tablets>
An example of the method for manufacturing the chewable tablet of the present embodiment includes the following steps of pulverizing component (C), granulating component (A), mixing step, and tableting step. When the chewable tablet has a coating layer, it further includes a coating process shown below after the tableting process.

(Crushing step of component (C))
The step of pulverizing component (C) is a step of pulverizing component (C) to obtain a pulverized product.
Although component (C) may be used as a commercially available product in the mixing step described below, it is preferable to grind it in advance in order to further improve the unpleasant taste suppressing effect of component (A).
The pulverized product of component (C) may consist only of component (C), or may contain component (C) and components other than component (C). The combination of component (C) with component (C) suppresses adhesion of component (C) to equipment during the crushing process, and prevents holes from forming on the surface of chewable tablets or orally disintegrating tablets (dropping of menthol particles, etc. from the tablet surface). It is preferable to co-mill the optional components. Note that the pulverized product obtained by co-pulverizing component (C) and any optional component is also particularly referred to as a "co-pulverized product."

As a method for pulverizing the component (C), conventionally known pulverizing methods can be used, but preferably pulverizing methods using a fine pulverizer or a stirring granulator are used. More preferred are a pulverization method that applies shear force to the powder and a pulverization method that allows heating. For example, pulverization can be carried out using a fine pulverizer such as a stone mill (manufactured by West Co., Ltd.), a pin mill (manufactured by Powrec Co., Ltd.), or an atomizer (manufactured by Dalton Co., Ltd.), or a stirring granulator (made by external heating with a jacket, etc.). Examples include a method of pulverizing with a Vertical Granulator VG-25 (manufactured by Powrex Co., Ltd., product name: "Vertical Granulator VG-25").
When co-pulverizing component (C) and an optional component, the optional component may be added to component (C) and then crushed.
The particle size of the pulverized product or co-pulverized product may be adjusted by using a sieve or the like. The average particle size of the pulverized product and the co-pulverized product is preferably 10 to 200 μm, respectively.

((A) Component granulation step)
The step of granulating component (A) is a step of granulating component (A).
As for component (A), a commercially available product may be used as it is in the mixing step described below, but from the viewpoint of ensuring uniformity of mixing and uniformity of tableting, it is preferable to form it into a granulated product in advance.
The granulated product of component (A) may consist only of component (A), or may contain components other than component (A) and (A). From the viewpoint of content uniformity in the chewable tablet, it is preferable to use a granulated product containing component (A), component (D), and an excipient.

Methods for granulating component (A) include conventionally known methods, preferably fluidized bed granulation, stirring granulation, and extrusion granulation. For example, when granulating component (A) by fluidized bed granulation, component (A) and optionally (D) are added to a fluidized bed granulator (manufactured by Freund Sangyo Co., Ltd., product name "FLO-5"). After adding the ingredients and one or more excipients, fluidized bed granulation is performed by spraying a binding liquid (such as an aqueous solution of a binding agent such as polyvinyl alcohol), and drying is performed until the exhaust temperature reaches 65°C. Get grains. The particle size of the obtained granules may be adjusted by using a sieve or the like.

(Mixing process)
The mixing step is a step of mixing component (A), component (B), component (C), and component (D), and optional components if necessary, to obtain a mixed powder.
Each component used in the mixing step may be obtained by a known manufacturing method, or may be commercially available. Each component may be used as a raw powder or may be granulated. When using granulated products, known granulation methods such as fluidized bed granulation, agitation granulation, and extrusion granulation can be used. In particular, for the reasons mentioned above, it is preferable to use component (A) that has been granulated together with component (D) (granules). For the reasons mentioned above, it is preferable to use a pulverized component (a pulverized product or a co-pulverized product) as the component (C).

The mixing method in the mixing step includes conventionally known mixing methods, and a commonly used mixer can be used. Examples of the mixer include a Bohle container mixer (manufactured by Kotobuki Kogyo Co., Ltd.), a V-type mixer (manufactured by Dalton Co., Ltd.), and a ribbon mixer (manufactured by Dalton Co., Ltd.).
All the components can be put into a mixing container and mixed, or after some of the components have been mixed, other components can be sequentially added and mixed.

(Tableting process)
The tableting step is a step of tableting the mixed powder prepared in the above mixing step to obtain plain tablets.
In the tableting process, a known tableting machine can be used. Examples of the tablet press include a rotary tablet press (manufactured by Kikusui Seisakusho Co., Ltd., product name: "Libra 2").
Tableting conditions such as tableting pressure and rotating speed of the rotary disk are appropriately set. For example, the tableting pressure is preferably 8 to 15 kN (3 to 15 kgf as the hardness of a plain tablet), more preferably 9 to 15 kN, even more preferably 10 to 15 kN, and particularly preferably more than 10 kN and 15 kN or less.

As mentioned above, the chewable tablet may be a single-layer tablet having a single layer, or a multi-layer tablet having two or more layers. When the chewable tablet is a single-layer tablet, it can be manufactured by compressing a mixed powder containing the above-mentioned components. When producing a multilayer tablet, for example, one of the mixed powder containing components (A to (D)) and the powder of an optional component is used as the first layer, the other as the second layer, and the first layer and the second layer are combined. It can be manufactured by laminating two layers and then compression molding between an upper punch and a lower punch.
The uncoated tablets thus obtained may be made into chewable tablets as they are. When chewable tablets are made into coated tablets, the following coating step is further performed.

(Coating process)
The coating step is a step of forming a coating layer on the surface of the uncoated tablet.
Conventionally known methods can be used for the preparation method of the coating agent and the coating treatment method. Coating equipment can be used. Specifically, first, the coating agent described above is dispersed in a solvent such as water to obtain a coating liquid. Next, a coating liquid is applied by spraying or the like to cover the uncoated tablet. Next, the solvent component in the coating liquid is dried to form a coating layer on the surface of the uncoated tablet to obtain a coated tablet.

<Method for producing orally disintegrating tablets>
When manufacturing orally disintegrating tablets, the method for manufacturing chewable tablets differs in that disintegration in the oral cavity is ensured. Therefore, in the tableting process, the mixed powder is compressed at a lower pressure than chewable tablets to produce uncoated tablets, while appropriately checking disintegration in the oral cavity. When manufacturing orally disintegrating tablets, the tableting pressure is preferably 5 to 10 kN (3 to 12 kgf as the hardness of the uncoated tablet), more preferably 5 to 9 kN, even more preferably 5 to 8 kN, particularly 5 kN or more and less than 8 kN. preferable.
Orally disintegrating tablets can be manufactured by applying the same manufacturing method as chewable tablets except for the tableting pressure in the tableting process.

"effect"
According to the chewable tablets and orally disintegrating tablets of the present invention, a decrease in the content of menthol, which is the component (C), after storage is suppressed by incorporating the sugar alcohol, which is the component (D). Furthermore, the bitter taste characteristic of loperamide hydrochloride, which is the component (A), after taking the drug is suppressed. Therefore, the chewable tablets and orally disintegrating tablets of the present invention are free from the discomfort that occurs after storage, mainly due to the component (A), even in the presence of at least one selected from component (B), turmeric and its extract. It can improve the taste.
The reason for the above effect is that the volatilization of the (C) component promoted by the combination of the (A) component, the (B) component, and the (D) component. It is thought that this is suppressed by chemical and physical interactions derived from functional groups between the components.
In particular, by granulating components (A) and (D) in advance to obtain uniformity within the uncoated tablet, variations between individual tablets are reduced, and the volatilization of component (C) and component (A) are reduced. The peculiar aftertaste of discomfort is effectively suppressed.

EXAMPLES Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited to the following description.
The raw materials, tableting conditions, and evaluation methods used in each example are as follows.

"Raw materials used"
The compounds shown below were used as raw materials.
・Loperamide hydrochloride: Manufactured by Shiono Chemical Co., Ltd., product name "Loperamide Hydrochloride".
・Turmeric dried extract: Manufactured by Matsuura Pharmaceutical Co., Ltd., product name: "Turmeric dried extract".
・Turmeric powder: manufactured by Nippon Powder Yakuhin Co., Ltd., product name "Turmeric powder".
-L-Menthol: Manufactured by Nagaoka Jitsugyo Co., Ltd., product name "Super Menthol 3003".
- Erythritol: Manufactured by Bussan Food Science Co., Ltd., product name "Erythritol 50M".
・D-Mannitol: Manufactured by Rocket Japan Co., Ltd., product name "Pairitol 50C".
・Corn starch: Manufactured by Matsutani Chemical Industry Co., Ltd., product name: Pharmacopoeia Matsutani Cornstarch.
- Crystalline cellulose: manufactured by Asahi Kasei Corporation, product name "CEOLUS UF-711".
- Magnesium aluminate silicate: Manufactured by Fuji Chemical Industry Co., Ltd., product name: "Neusilin A AS".
- Polyvinyl alcohol: manufactured by Mitsubishi Chemical Corporation, product name "Gohsenol EG-05 (P)", partially saponified product.
- Crospovidone: Manufactured by BASF Japan Co., Ltd., product name "Koridon CL-SF".
・Magnesium stearate: Manufactured by Taihei Kagaku Sangyo Co., Ltd., product name: "Magnesium stearate (vegetable)".

[Examples 1 to 11, Comparative Examples 1 and 2]
<Production of co-pulverized product of component (C) and corn starch>
Component (C) and corn starch (co-pulverized) were put into a tabletop pulverizer (manufactured by Osaka Chemical Co., Ltd., product name: "WONDER CRUSHER WC-3") so that the quantity ratios shown in Tables 1 and 2 were achieved. , 20,000 rpm for arbitrary seconds until the mixture was granulated. The entire amount of the obtained mixture was passed through a sieve with an opening of 500 μm to obtain a co-pulverized product. The average particle diameter of the co-pulverized product was about 95 μm.

<Manufacture of granules of component (A) and component (D)>
For Examples 1 to 9 and 11, component (A), component (D), and crystalline cellulose or corn starch (granulated) were mixed in a fluidized bed granulator (manufactured by Freund Sangyo Co., Ltd., product name: "FLO-"). 5), while spraying 8% by mass binding liquid (polyvinyl alcohol aqueous solution) prepared in advance until the predetermined amount as shown in Tables 1 and 2 is reached, the supply air temperature is 90°C and the exhaust air volume is 2.0 m ³ / Fluidized bed granulation was performed in minutes. After the spraying was completed, it was dried until the exhaust temperature reached 65° C. to obtain a granular dry product. The entire amount of the obtained granular dried product was passed through a sieve with an opening of 850 μm to obtain a granulated product.
Regarding Comparative Examples 1 and 2, Examples 1 to 9 and 11 were used except that the component (A), crystalline cellulose, and corn starch (granulated) or magnesium aluminate silicate were charged into the fluidized bed granulator. Granules were obtained in the same manner as above.
For Example 10, component (A), component (D), and crystalline cellulose were charged into a fluidized bed granulator (manufactured by Freund Sangyo Co., Ltd., product name "FLO-5"), and then the pre-prepared 8 Fluidized bed granulation was performed at an air supply temperature of 90° C. and an exhaust air flow rate of 2.0 m ³ /min while spraying the mass% binding liquid (polyvinyl alcohol aqueous solution) to the predetermined amount shown in Table 2. After the spraying was completed, the mixture was dried until the exhaust temperature reached 55° C. to obtain dried granules. The entire amount of the obtained granular dried product was passed through a sieve with an opening of 850 μm to obtain a granulated product.

<Manufacture of chewable tablets>
Chewable tablets were manufactured according to the following procedure.
Granules of components (A) and (D), component (B), co-pulverized product of component (C) and corn starch, and stearic acid in the quantitative ratios shown in Tables 1 and 2. After mixing with magnesium, tablets were compressed using a single-shot tablet machine (manufactured by Kikusui Seisakusho Co., Ltd.) equipped with a mortar with a diameter of 9.5 mm to obtain uncoated tablets with a diameter of 9.5 mm. The tableting pressure was adjusted using a tablet hardness meter (manufactured by Yamato Scientific Co., Ltd.) so that the hardness of the uncoated tablet was about 8 kgf.
The obtained uncoated tablets were made into chewable tablets, and the moisture content was measured by the method shown below, and a storage test was conducted. The results are shown in Tables 1 and 2.

<Evaluation of chewable tablets>
"Measurement of water content"
The moisture content in the chewable tablets was measured using a Karl Fischer moisture meter (manufactured by Kyoto Electronics Industry Co., Ltd., product name "MKC-210") as follows.
The chewable tablets were ground in a mortar and used as measurement samples. 10 to 100 mg of the measurement sample was dissolved in Karl Fischer reagent at room temperature (25°C), and measurement was started according to a conventional method. Upon completion of the electrode reaction, the measurement was automatically stopped. The amount of sample input was input into a Karl Fischer moisture meter to calculate the amount of water in the chewable tablet.

"Storage test"
Approximately 100 chewable tablets were placed in a glass bottle (manufactured by Nichiden Rika Glass Co., Ltd., screw-top bottle, capacity 50 mL), sealed, and stored in a constant temperature bath at 35°C and 70% RH for 5 days, and then subjected to a short-term stress evaluation. was carried out.

(Measurement of initial content of menthol)
Based on the following measurement conditions, the menthol content in the chewable tablets before and after the storage test was determined by gas chromatography. Note that, before the measurement, a solution prepared by grinding chewable tablets in a mortar and dissolving them in methanol to a predetermined concentration was used as a measurement sample.
<<Measurement conditions>>
-Testing machine: Manufactured by Shimadzu Corporation, product name "GC-2050".
・Carrier gas: helium.
- Column: TC-1.
- Column temperature: 110°C.
- Injection volume of measurement sample: 0.5 μL.

The menthol content in the chewable tablets before the storage test is defined as the "initial content", and the menthol content in the chewable tablets after the storage test is defined as the "initial content" relative to the initial content, and the ratio is calculated using the following formula (1). The initial content was determined. If the initial content was 50% or more, it was considered to be a pass.
Initial content (%) = Menthol content after storage test / Menthol content before storage test x 100 (1)

(Evaluation of ease of administration)
Four panelists (healthy adult men and women) took one chewable tablet after the storage test by chewing it in the mouth, and felt an unpleasant taste 5 minutes after taking it (the bitter aftertaste characteristic of loperamide hydrochloride). ) were scored according to the evaluation criteria for unpleasant taste suppression effect shown below, and the average value of the four panelists was calculated. An average value of 3 points or more was considered a pass.
<<Evaluation criteria for unpleasant taste suppression effect>>
4 points: No or almost no unpleasant taste felt.
3 points: Slightly unpleasant taste felt.
2 points: I feel a strong unpleasant taste.
1 point: I feel the unpleasant taste very strongly.

[Example 12]
<Production of co-pulverized product of component (C) and corn starch>
Component (C) and corn starch (co-pulverized) were put into a table-top pulverizer (manufactured by Osaka Chemical Co., Ltd., product name "WONDER CRUSHER WC-3") in the amount ratio shown in Table 2, and the mixture was pulverized at 20,000 rpm. for arbitrary seconds until the mixture was granulated. The entire amount of the obtained mixture was passed through a sieve with an opening of 500 μm to obtain a co-pulverized product. The average particle diameter of the co-pulverized product was about 95 μm.

<Manufacture of granules of component (A) and component (D)>
After putting component (A), component (D), and crystalline cellulose into a fluidized bed granulator (manufactured by Freund Sangyo Co., Ltd., product name "FLO-5"), a pre-prepared 8% by mass binding solution (polyvinyl Fluidized bed granulation was performed at a supply air temperature of 90° C. and an exhaust air flow rate of 2.0 m ³ /min while spraying an alcohol aqueous solution until the predetermined amount shown in Table 2 was reached. After the spraying was completed, it was dried until the exhaust temperature reached 65° C. to obtain a granular dry product. The entire amount of the obtained granular dried product was passed through a sieve with an opening of 850 μm to obtain a granulated product.

<Manufacture of orally disintegrating tablets>
Orally disintegrating tablets were manufactured according to the following procedure.
Granules of component (A) and component (D), component (B), co-pulverized product of component (C) and corn starch, and crospovidone so as to have the quantitative ratios shown in Table 2, After mixing with magnesium stearate, tablets were compressed using a single-shot tablet machine (manufactured by Kikusui Seisakusho Co., Ltd.) equipped with a mortar with a diameter of 9.5 mm to obtain uncoated tablets with a diameter of 9.5 mm. The tableting pressure was adjusted using a tablet hardness meter (manufactured by Yamato Scientific Co., Ltd.) so that the hardness of the uncoated tablet was about 5 kgf.
The obtained uncoated tablet was made into an orally disintegrating tablet, and the moisture content was measured as follows, and a storage test was conducted. The results are shown in Table 2.

<Evaluation of orally disintegrating tablets>
The measurement of the water content and the storage test (measurement of the initial menthol content) in the orally disintegrating tablets were conducted in the same manner as for the chewable tablets.
The storage test (evaluation of ease of administration) was carried out in the same manner as for the chewable tablets, except that after the storage test, one orally disintegrating tablet was taken without being chewed in the oral cavity, and was allowed to disintegrate with saliva.

In the table, "B/A ratio" is the mass ratio represented by component (B)/component (A). "D/B ratio" is a mass ratio represented by (D) component/(B) component. "D/C ratio" is a mass ratio represented by component (D)/component (C). In addition, the mass of component (B) in "B/A ratio" and "D/B ratio" is equivalent to the original drug if component (B) is turmeric extract, and if component (B) is turmeric powder, it is equivalent to turmeric. This is the mass contained in the powder.
A blank column in the table indicates that the component is not included.

The chewable tablets and orally disintegrating tablets obtained in each example were able to improve the unpleasant taste that occurred after storage.
On the other hand, the chewable tablets obtained in Comparative Examples 1 and 2 that did not contain component (D) had a low initial menthol content in a storage test, and could not improve the unpleasant taste that occurred after storage.

Claims (5)

(A) Component: loperamide hydrochloride,
(B) Component: at least one selected from turmeric and its extract;
(C) Ingredient: menthol,
(D) Component: sugar alcohol,
Chewable or orally disintegrating tablets containing plain tablets. The chewable tablet or orally disintegrating tablet according to claim 1, wherein the mass ratio represented by the component (D)/component (B) is 0.05 to 6. The chewable tablet or orally disintegrating tablet according to claim 1 or 2, wherein the mass ratio represented by the component (D)/component (C) is 40 to 500. The chewable tablet or orally disintegrating tablet according to claim 1 or 2, wherein the component (D) is at least one selected from mannitol, erythritol, xylitol, sorbitol, and maltitol. The chewable tablet or orally disintegrating tablet according to claim 1 or 2, wherein the average particle size of the component (C) is 1 to 200 μm.