JP5530716B2 - Crude drug-containing tablet and method for producing herbal medicine-bearing particles for herbal medicine-containing tablet - Google Patents

Description

  The present invention relates to a crude drug-containing tablet and a method for producing a crude drug-carrying particle for a crude drug-containing tablet.

Conventionally, herbal medicines are often taken as granules, but in recent years, they are increasingly taken as tablets for ease of taking.
Herbal medicine-containing tablets include those obtained by directly compressing powdered herbal medicines such as dry extracts of herbal medicines with disintegrants, etc., and powdered herbal medicines with disintegrants and the like as granulated particles (for example, patents) Documents 1-2) are proposed.

JP 2007-176861 A JP 2007-297313 A

However, a herbal medicine-containing tablet obtained by tableting a water-soluble herbal medicine dry extract such as a peony dry extract directly or as granulated particles has a significant delay in disintegration time compared to a tablet containing no water-soluble herbal extract. In addition, tablets are easily chipped and cracked after the friability test, and the impact resistance is low. Although the disintegration time is shortened by adding a disintegrant to the composition of the tablet containing the water-soluble crude drug extract, the impact resistance is not improved. Furthermore, the herbal medicine-containing tablet containing the dried water-soluble herbal medicine also has a problem that the herbal taste is felt strongly when taken. This is an important problem especially in the case of orally disintegrating tablets or chewable tablets.
The present invention has been made in view of the above circumstances, and is improved in both disintegration and impact resistance and improved in herbal taste, and production of herbal medicine-supporting particles useful for the herbal medicine-containing tablet It aims to provide a method.

The present invention for solving the above problems has the following aspects.
[1] A crude drug-containing tablet comprising crude drug-bearing particles comprising crospovidone and a water-soluble crude drug extract component adsorbed on the crospovidone .
[2] The crude drug-containing tablet according to [1], wherein the proportion of crospovidone in the crude drug-carrying particles is 10% by mass or more and 70% by mass or less with respect to the total amount of the crude drug-carrying particles.
[ 3 ] The herbal medicine-containing tablet according to [1] or [2] , further comprising a disintegrant.
[ 4 ] The herbal medicine-containing tablet according to any one of [1] to [3] , which is an orally disintegrating tablet or a chewable tablet.
[ 5 ] Any one of [1] to [4] , wherein the crude drug-carrying particles are obtained by impregnating crospovidone with a water-soluble herbal extract and / or a water-soluble herbal dry extract solution and drying. The herbal medicine-containing tablet according to 1.
[ 6 ] For a herbal medicine-containing tablet, comprising a step of adding a water-soluble herbal extract and / or a water-soluble herbal dry extract solution to crospovidone under a fluidized bed or stirring, impregnating and drying. Of manufacturing crude drug-carrying particles.

  INDUSTRIAL APPLICABILITY According to the present invention, a herbal medicine-containing tablet with improved disintegration and impact resistance and improved herbal taste and a method for producing herbal medicine-supporting particles useful for the herbal medicine-containing tablet can be provided.

  The crude drug-containing tablet (hereinafter referred to as tablet) of the present invention contains crude drug-carrying particles (hereinafter referred to as supported particles) in which a water-soluble crude drug extract component is adsorbed to crospovidone. By adsorbing the water-soluble crude drug extract component to crospovidone, the disintegration and impact resistance of the tablet containing the supported particles are improved, and the crude drug taste is also improved.

<Supported particles>
Here, the “water-soluble herbal extract” is an extract extracted from herbal medicine with water or an aqueous ethanol solution of 40% by volume or less, a concentrated extract obtained by concentrating the extract, and the extract is triturated in an excipient. Dilute extract (diluted product). Examples of the excipient include lactose, dextrin, corn starch, potato starch, and mixtures thereof.
The “water-soluble herbal extract component” indicates a pure content (extracted pure content excluding water and ethanol as extraction solvents) contained in the water-soluble herbal extract.
The crude drug is not particularly limited and can be appropriately selected from known crude drugs according to the purpose. Specifically, for example, red-crowned wrinkles, engosaku, awaku, auren, valerian, guarana, licorice, pygmy, keihi, gentiana, gennoshouko, kokuboku, peonies, ginger, senega, senna, suzutsu, touki, carrot, belladonna, wood incense, Examples include funnels and yokuinin. These herbal medicines may be used alone or in combination of two or more. In the present invention, among the above, at least one selected from peony, funnel, and engosaku is preferably contained, and peony is particularly preferred.
Water or an aqueous ethanol solution of 40% by volume or less is used as a solvent for the dilution of the water-soluble crude drug extract or the water-soluble crude drug dry extract solution.

  The proportion of the water-soluble crude drug extract component in the supported particles is preferably 10% by mass or more, more preferably 20% by mass or more, and particularly preferably 30% by mass or more based on the total mass of the supported particles. As the amount of the water-soluble crude drug extract component decreases, the amount of the supported particles for obtaining a prescribed amount of the crude drug extract increases. Therefore, depending on the prescription amount of the herbal medicine, the dose as a preparation increases, and there is a risk of lowering the dosage. The upper limit is preferably 90% by mass or less, more preferably 75% by mass or less, particularly preferably 70% by mass or less, and most preferably 60% by mass or less. In the following ranges, particularly good disintegration can be obtained.

Crospovidone, a carrier of water-soluble herbal extract components, is insoluble in water, absorbs water during the three-dimensional structure of the molecule, and swells (increases volume without changing its essence). It is a form and listed in the Pharmaceutical Additives Standard.
Since crospovidone has swellability, the supported particles obtained by adsorbing the water-soluble herbal extract component to crospovidone also have swellability, and the disintegration property of the tablet containing the supported particles is improved. In addition, by adsorbing the water-soluble herbal extract component to crospovidone, the moldability is improved and the impact resistance of the tablet is improved.

  In the present invention, crospovidone preferably has an adsorption capacity measured by the following measuring method of 2 mg / mg of adsorbent, more preferably 3 mg / mg of adsorbent, and even more preferably 4 mg / mg of adsorbent. The higher the adsorptive capacity, the more excellent the effect of the present invention, particularly the effect of improving the raw condiment. On the other hand, if the adsorptive capacity is low, the effects of the present invention may not be sufficiently obtained. In addition, the amount of liquid that can be added during stirring granulation decreases, and the amount of water that can be sprayed during fluidized bed granulation is small, making it difficult to set the manufacturing conditions. The upper limit of the adsorption capacity is not particularly limited.

(Measurement method of adsorption capacity)
As the adsorbing solution, the same water-soluble herbal extract and / or water-soluble herbal dry extract solution used for preparing the supported particles is prepared in advance. For example, a commercially available water-soluble herbal medicine dry extract and purified water are mixed at a predetermined ratio (for example, water-soluble herbal medicine dry extract: purified water = 1: 2 (mass ratio)) to prepare a water-soluble herbal medicine dry extract solution. Moreover, in the case of a crude drug for which a water-soluble crude drug dry extract is not commercially available, a commercially available water-soluble crude drug extract or a water-soluble crude drug extract prepared by a conventional method may be used. The water-soluble herbal extract may be used after dilution, but it is preferably used without dilution from the viewpoint of improving adsorption efficiency.
Next, 10 g of raw material powder (crospovidone) is placed in a mortar, and 1 g of the adsorbent is dropped into the mortar and mixed with a pestle. The operation from dripping to mixing is repeated, and the dripping amount (g) of the adsorbing liquid when the powder becomes a lump is taken as the adsorbing liquid amount. The above operation is performed within 3 minutes. If the adsorbing liquid is not adsorbed before the powder becomes a lump, the amount of dripping (g) 1 g before exuding is taken as the adsorbed liquid amount. From the amount of adsorbed liquid (the amount of adsorbed liquid adsorbed on 10 g of raw material powder (g)), the amount of adsorbed liquid adsorbed on 1 mg of raw material powder (mg) was determined, and the value was determined as the adsorbing capacity (mg / mg of adsorbent) And

The adsorptive capacity includes water absorption of crospovidone, types of water-soluble herbal extracts (dry extract / extract), concentrations of water-soluble herbal extracts in water-soluble herbal extracts and / or water-soluble herbal extracts, constituents It is affected by the type of (herbal medicine), the solvent composition of the water-soluble herbal extract and / or the water-soluble herbal dry extract solution, the lot difference and the like. For example, the higher the water absorption of crospovidone, the higher the adsorption ability. The water absorption of crospovidone varies depending on the product grade and is determined by the concentration of the water-soluble herbal extract component.
The water absorption of the crospovidone is an adsorption ability when the adsorbing liquid is water, preferably 2 mg / mg or more, more preferably 3 mg / mg or more, and further preferably 4 mg / mg or more. Examples of the water absorption amount of the commercially available product include a water absorption amount of 2.5 mg / mg of Kollidon CL (manufactured by BASF) and a water absorption amount of 4.0 mg / mg of Kollidon CL-SF (manufactured by BASF).

Here, the “water-soluble crude drug dried extract” is a powder obtained by drying a water-soluble crude drug extract.
As the water-soluble herbal dry extract and water-soluble herbal extract, those prepared by conventional methods may be used, respectively, or commercially available ones may be used. Moreover, you may use the trituration product of a water-soluble crude drug extract.
Specific examples of the water-soluble herbal dried extract include dried red-crowned wrinkle extract, dried engosac extract, dried duckweed extract, dried guarana extract, licorice extract powder, dried oyster extract, dried dried genoder extract, dried kakuboku extract, dried peonies extract, dried dried ginger. Examples include extracts, dried senna extracts, dried jujube extracts, dried toki extracts, and dried carrot extracts.
Specific examples of the water-soluble herbal extract include engosaku extract, oren extract, valerian extract, licorice extract, cinnamon extract, gentian extract, peonies extract, senegal extract, belladonna extract, incense extract, funnel extract, and yakuinin extract.
Examples of the water-soluble herbal extract powder include funnel extract powder and funnel extract triple powder.

A commercially available crospovidone is used. Examples of the commercially available products include Kollidon CL, Kollidon CL-SF manufactured by BASF, and Polyplastidone XL manufactured by ISP.
The average particle size of crospovidone is not particularly limited, and may be the same as that usually used as an excipient. Generally, about 5 to 200 μm is used.
In the present specification, the average particle diameter is a value measured by Beckman Coulter Co. LS13 320 type (dry measurement), volume-based median diameter; a _{(D 50} 50% volume diameter).

  The proportion of crospovidone in the supported particles depends on the water absorption capacity of crospovidone, but is preferably 10% by mass or more based on the total mass of the supported particles from the viewpoint of disintegration and impact resistance, % Or more is more preferable, 25% by mass or more is particularly preferable, and 30% by mass or more is most preferable. The upper limit is preferably 90% by mass or less, more preferably 75% by mass or less, particularly preferably 70% by mass or less, and most preferably 60% by mass or less.

  The supported particles may contain components other than the water-soluble herbal extract component and crospovidone as long as the effects of the present invention are not impaired. As this other component, the additive etc. which are mentioned later are mentioned as an arbitrary component which the tablet of this invention may contain, for example.

  Specifically, the supported particles are obtained by impregnating crospovidone with a water-soluble herbal extract and / or a water-soluble herbal dry extract solution and drying. When the water-soluble crude drug extract component is brought into contact with crospovidone as a solution, the solution is absorbed by crospovidone and held between the three-dimensional structures of the crospovidone molecules. By drying this, it can be set as the carrying | support particle | grains which the water-soluble crude drug extract component adsorbed. The supported particles can be produced by the production method shown below. However, the method for producing the supported particles of the present invention is not limited to this, and can be produced by methods known to those skilled in the art.

(Method for producing supported particles)
The supported particles are produced, for example, by adding a water-soluble herbal extract and / or a dry extract of a water-soluble herbal medicine to crospovidone under a fluidized bed or under stirring, impregnating, and drying to obtain supported particles. It can be manufactured by a method.
The water-soluble herbal medicine dry extract solution is obtained by dissolving a water-soluble herbal medicine dry extract in water or an aqueous ethanol solution of 40% by volume or less.
The impregnation and drying of the water-soluble herbal extract and / or water-soluble herbal dry extract solution (hereinafter collectively referred to as “herbal extract-containing solution”) may be performed in a fluidized bed or under stirring. Good. Since impregnation and drying can be performed simultaneously and it is not necessary to limit the amount of the herbal extract-containing solution added, it is preferably performed under a fluidized bed. When performing under stirring, it is necessary to adjust the addition amount of the herbal extract-containing solution to an amount that does not exceed the upper limit (maximum adsorption amount) of the herbal extract-containing solution that can be adsorbed to crospovidone. If the added amount of the crude drug extract-containing solution exceeds the maximum adsorption amount, the water-soluble crude drug extract component may not be adsorbed well, and a kneaded product may be formed.
The maximum adsorption amount (mg) is obtained by the following formula.
Maximum adsorption amount (mg) = adsorption capacity of raw material powder (crospovidone) (mg / mg of adsorbent) × mixing amount of raw material powder (mg)

  When the impregnation and drying are performed under a fluidized bed, the concentration of the water-soluble herbal extract component in the herbal extract-containing solution is preferably 1 to 70% by mass, and more preferably 10 to 40% by mass. If the concentration of the water-soluble herbal extract component is too high, atomization is not performed well during spraying, and uniform spraying cannot be performed, and disintegration may be reduced. This is presumably because the water-soluble herbal extract component is distributed on the particle surface by being dried before being sufficiently absorbed into crospovidone. On the other hand, if the concentration is too low, the spraying time becomes long, so the manufacturing time is long and the manufacturability may be affected.

Impregnation and drying under a fluidized bed can be performed using a fluidized bed apparatus (for example, a fluidized bed coating apparatus, a rolling fluidized coating apparatus, etc.) generally used for particle coating or granulation.
Specific examples of the fluidized bed apparatus include multiplex (product name, manufactured by POWREC Co., Ltd.).
The spray rate of the crude drug extract-containing solution varies depending on the scale and capacity of the manufacturing equipment, but it is preferable to carry out the conditions under which the powder flow does not stagnate during the impregnation and the adsorption amount is not saturated.
What is necessary is just to set drying conditions suitably according to the target water content, the apparatus to be used, and the component to mix | blend. For example, in the case of a multiplex, the exhaust temperature is preferably 40 to 75 ° C, and preferably 45 to 55 ° C.
Drying is preferably performed so that the water content is 0 to 10% by mass. The water content is determined by the 15th revised Japanese Pharmacopoeia General Test Method. Physical test methods Other physical test methods 41. According to the loss on drying test method, it is a value measured under conditions of 2 g, 105 ° C. for 4 hours.

When impregnation and drying are performed with stirring, the concentration of the water-soluble herbal extract component in the herbal extract-containing solution is not particularly limited. However, as described above, it is necessary to adjust the addition amount of the herbal extract-containing solution to an amount that does not exceed the maximum adsorption amount.
The amount of the crude drug extract-containing solution added is preferably such that the ratio to the maximum adsorption amount (addition amount of the crude drug extract-containing solution / maximum adsorption amount × 100) is less than 85% by mass, and more preferably less than 80% by mass. . When the ratio is 85% by mass or more, a kneaded product is produced during stirring, and there is a possibility that target supported particles cannot be obtained. The lower limit of the ratio is not particularly limited, but is preferably 25% by mass or more, and more preferably 30% by mass or more, considering that the impact resistance decreases as the ratio increases.

For the impregnation under stirring, a stirring device generally used for particle coating or granulation can be used. In the present invention, a high-speed stirring granulator is particularly preferable. The high-speed stirring granulator is a stirring device that mixes powders by rotating the stirring blades and adjusts the particle size by pulverizing blades, and includes, for example, a high-speed mixer (product name, manufactured by Fukae Pautech Co., Ltd.).
Stirring is performed by setting the number of revolutions so that it does not adhere to the wall surface (because of centrifugal force) at a speed higher than the mixing speed of the powder in consideration of the volume of the stirring device and the diameter of the stirring blade. As a specific example, when a high speed mixer LFS-2 (manufactured by Fukae Powtech Co., Ltd.) is used, the conditions of an agitator (stirring blade) rotation speed of 200 to 1000 rpm and a chopper (breaking blade) rotation speed of 1000 to 2500 rpm are preferable.
The crospovidone impregnated with the herbal extract-containing solution under stirring may be dried by any method usually used for drying. For example, a dryer such as a shelf dryer can be used.
What is necessary is just to set drying conditions suitably according to the target water content and the component to mix | blend. Usually, it is preferable to carry out at 60 to 80 ° C. so that the water content is 0 to 10% by mass.

After drying, the obtained particles may be used as support particles as they are, or may be appropriately subjected to a treatment such as sizing.
The sizing is preferably performed by combining a pulverization step using a pulverizer or the like and a sieving step. Grinding and sieving can be carried out by known methods.

In the present invention, the particle size of the supported particles is preferably 1000 μm or less from the viewpoint of uniform mixing with other components. The particle diameter is a value measured using a dry unit by LS13 320 type manufactured by Beckman Coulter, Inc., like the average particle diameter.
The average particle size of the supported particles is preferably 5 to 800 μm, and more preferably 10 to 500 μm.

  In the tablet of the present invention, the content of the supported particles can be set according to the prescription amount of the water-soluble crude drug to be used, but is preferably 30% by mass or less, and 25% by mass or less based on the total mass of the tablet. Is more preferable, and 20% by mass or less is particularly preferable. When there is too much this content, a moldability will fall and impact resistance will fall. The lower limit of the content of the supported particles varies depending on the type and ratio of the water-soluble crude drug extract component in the supported particles and is not particularly limited. From the viewpoint of disintegration, the content is preferably 1% by mass or more and more preferably 10% by mass or more with respect to the total mass of the tablet.

The tablet of this invention may be comprised only from the said support particle, and may contain other components other than the said support particle as an arbitrary component in the range which does not impair the effect of this invention. Examples of the other components include drugs and other various additives.
The drug is not particularly limited and can be used as a particulate raw material (drug particles: a single drug, a powdered drug particle, a drug particle supported on a supported particle, etc.). Specifically, for example, berberine tannate, aldioxa, berberine chloride, bismuth hyponitrite, pseudoephedrine hydrochloride, phenylephrine hydrochloride, chlorpheniramine maleate, chlorpheniramine maleate, belladonna total alkaloid, aspirin, acetaminophen , Etenzamide, isopropylantipyrine, ibuprofen, ketoprofen, naproxen, loxoprofen sodium, diphenhydramine hydrochloride, carbinoxamine maleate, dexttometrphan hydrobromide, anhydrous caffeine, sucralfate hydrate, synthetic hydrotalcite, albumin tannate, loperamide hydrochloride , Copper chlorophyllin potassium, glycyrrhizic acid and its salts, pseudoephedrine sulfate and the like. These can be used individually by 1 type or in combination of 2 or more types.

As additives, those generally blended into tablets can be used, and examples thereof include excipients, binders, disintegrants, lubricants and the like.
Examples of excipients include celluloses such as crystalline cellulose, low-substituted hydroxypropyl cellulose and derivatives thereof, corn starch, potato starch, starch and derivatives thereof such as hydroxypropyl starch, sugars and sugar alcohols such as lactose and mannitol, Examples thereof include magnesium aluminate metasilicate and synthetic hydrotalcite. These can be used individually by 1 type or in combination of 2 or more types.
Examples of the binder include water-soluble polymers, sugars, sugar alcohols and the like. Examples of water-soluble polymers include water-soluble cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, ethylcellulose, gum arabic, A starch etc. are mentioned. Examples of the sugar include glucose, fructose, sucrose, lactose, maltose, trehalose, maltotriose, oligosaccharide and the like. Examples of sugar alcohols include mannitol, sorbitol, maltitol, xylitol, erythritol and the like. These can be used individually by 1 type or in combination of 2 or more types.
Examples of the disintegrant include crospovidone, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl starch sodium, croscarmellose sodium, hydroxypropyl starch and the like. These can be used individually by 1 type or in combination of 2 or more types.

Moreover, a pigment | dye, a corrigent, a flavoring agent, a stabilizer, etc. are mentioned as another additive.
Examples of the dye include titanium oxide, iron sesquioxide, and edible yellow No. 5.
Examples of the stabilizer include sodium edetate and benzoic acid.
Examples of the corrigent include aspartame, sucralose, acesulfame potassium, saccharin, saccharin sodium, trehalose and the like as sweeteners, and citric acid, malic acid, tartaric acid, succinic acid, fumaric acid and the like as sour agents.
Examples of flavoring agents include monoterpenes such as menthol, camphor, borneol and limonene, and essential oils containing them.
Examples of the lubricant include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
Each of these may be used alone or in combination of two or more.

Each of the above-mentioned optional components may be blended in powder form with the support particles as it is, or may be blended as a solution. In addition, at least one of them may be blended with the carrier particles as tablet granules.
In the present specification, the tablet granule is a granulated particle obtained by granulating at least one of the above-mentioned optional components, and can be formed into an orally disintegrating tablet by mixing and tableting with the carrier particles. Show.

The granules for tablets are preferably those obtained by granulating a drug and / or excipient using a granulating liquid. Examples of the drug and excipient are the same as those described above, and each can be used alone or in combination of two or more. Examples of the granulating liquid include a binder aqueous solution in which a binder is dissolved in water. Examples of the binder include the same ones as described above, and can be used singly or in appropriate combination of two or more.
Granulation can be carried out by known granulation methods such as stirring granulation method, fluidized bed granulation method, extrusion granulation method, rolling granulation method, kneading and crushing granulation. After granulation, drying may be optionally performed, and a granulation treatment may be appropriately performed in order to adjust the particle size distribution.
The average particle size of the granules for tablets is preferably 3 to 1000 μm, more preferably 5 to 800 μm.
The tablet granule can be used alone or in combination of two or more.
In the tablet of the present invention, the content of the granule for tablet is preferably 40 to 99.9% by mass, and more preferably 70 to 90% by mass with respect to the total mass of the tablet.

The tablet of the present invention preferably further contains a disintegrating agent in addition to the above-mentioned supported particles or in addition to the supported particles and tablet granules. Thereby, disintegration improves further.
However, in the tablet of the present invention, the total amount of crospovidone contained in the supported particles and the disintegrant blended as an optional component other than the supported particles is 25% by mass or less based on the total mass of the tablet. Is preferable, and it is more preferable that it is 10-20 mass%. If the total amount exceeds 25% by mass, moldability may be reduced.

The tablet of the present invention can be obtained by tableting the mixture containing the supported particles and optional components.
Tableting can be performed using an apparatus generally used for tablet formation, such as a single tableting machine or a rotary tableting machine. At this time, tableting is performed so that the strength is in accordance with the tablet size. The tablet size is not particularly limited, and may be a tablet having a diameter based on a conventional powder amount in the pharmaceutical preparation field. The tablet strength can be measured by a tablet breaking strength measuring instrument TH203CP (manufactured by Toyama Sangyo Co., Ltd.).
The mass per tablet is not particularly limited, and may be set as appropriate according to the use, the method of taking, and the like. For example, in the case of an orally disintegrating tablet or a chewable tablet, it is preferably 100 to 2000 mg / tablet.
The dosage form of the tablet can be appropriately selected from known dosage forms such as a single-layer tablet, a laminated tablet, and a dry-coated tablet.
The tablet can be in any shape such as a round tablet, caplet tablet, donut tablet, oblong tablet and the like.
The tablet may be provided with a mark for identification, characters, and a dividing line for division.

The tablet of the present invention contains supported particles in which a water-soluble herbal extract component is adsorbed on crospovidone, so that disintegration and impact resistance are improved and herbal taste is also improved.
The reason for the above effect is not clear, but it is presumed that crospovidone constituting the supported particles adsorbs and retains the water-soluble herbal extract component between the three-dimensional structure (crosslinked network structure) of the crospovidone molecule. The For example, conventionally, when a herbal dry extract is directly compressed together with a disintegrant, the herbal dry extract remains in a solid state without adsorbing in other particles, which has an adverse effect on impact resistance, herbal taste, etc. I guess that. The same applies to tableting as granulated particles. In granulation, granulated particles having a large particle size are usually obtained by stirring or the like under conditions of relatively high moisture values. At that time, calcium silicate, disintegrant, etc. are mixed in advance with water for the purpose of preventing aggregation of the highly hygroscopic dried herbal extract and controlling granulation, and then the herbal dry extract is added thereto. It has been broken. In this case, in the granulated particles, most of the crude drug dry extract remains solid, for example, distributed outside the particles of the disintegrant, which is presumed to have adversely affected disintegration, impact resistance, crude drug taste, etc. The

The tablet of the present invention is useful as an orally disintegrating tablet or a chewable tablet because the raw drug taste is improved.
An orally disintegrating tablet refers to one that is disintegrated with saliva in the oral cavity and taken. Currently, there is no clear definition for the disintegration properties of orally disintegrating tablets, but it is generally preferable to disintegrate quickly in the oral cavity after taking the tablet, so the expected disintegration time is not to chew in the oral cavity. , Less than 60 seconds, preferably less than 45 seconds, more preferably less than 30 seconds.
A chewable tablet is one that is disintegrated by chewing in the oral cavity and taken.
Since the tablet of this invention is excellent in disintegration property, it is suitable as an orally disintegrating tablet.

The present invention will be described more specifically with reference to examples. However, the present invention is not limited to these.
The crude drug materials used in the following examples and comparative examples, the adsorbent adsorbed with the adsorbent during the production of the supported particles, and other raw materials are as follows.
[Herbal medicine materials]
Peonies dried extract: “Peonies dried extract” manufactured by Nippon Powder Chemical Co., Ltd.
Powder obtained by concentrating and drying extract extracted from peonies with water.
Peonies extract: “Peonies extract-A” (water content 25-35% by mass) manufactured by Nippon Powder Chemical Co., Ltd.
Rohto extract: “Rohto extract” manufactured by Alps Pharmaceutical Co., Ltd. (water content 30 to 40% by mass).

[Adsorbent]
The raw materials used as the adsorbent for adsorbing the adsorbent during the production of the supported particles are shown below.
Kollidon CL: product name, manufactured by BASF, crospovidone, average particle size 118 μm.
Kollidon CL-SF: product name, manufactured by BASF, crospovidone, average particle size 17 μm.
NS-300: product name, manufactured by Nichirin Chemical Industries, carmellose, average particle size 59 μm.
EXPLOTAB: Product name, manufactured by Kimura Sangyo Co., Ltd., sodium carboxymethyl starch, average particle size 46 μm.
Fluorite RE: Product name, manufactured by Eisai Food Chemical Co., Ltd., calcium silicate, average particle size 28 μm.

[Other raw materials]
L-HPC (low-substituted hydroxypropyl cellulose): “LH-31” manufactured by Shin-Etsu Chemical Co., Ltd.

<Test Example 1: Measurement of adsorption capacity>
For the adsorbent, the adsorbability (mg of adsorbed liquid (mg adsorbed) (mg of adsorbent (mg)) was used as the adsorbent in the above-described procedure when using an aqueous solution of peony dry extract: purified water = 1: 2 (mass ratio). )) Was measured. The results are shown in Table 1.
Moreover, when the adsorption ability of Kollidon CL-SF was measured using the funnel extract, it was 5.7 mg / mg adsorbent.

<Production Examples 1-2: Production of granules for tablets>
Granules for tablets (1) and (2) having the composition described in Table 2 were produced by the following procedure.
In advance, fructose was dissolved in purified water to prepare 1500 fructose aqueous solutions of the indicated composition. Ingredients other than fructose were put into a high-speed mixer LFS-2 (manufactured by Fukae Pautech Co., Ltd.) for 1000 tablets of the stated composition amount, and the rotational speed was set to 400 rpm agitator and 2000 rpm chopper and stirred. Under stirring, 1000 tablets of fructose aqueous solution were added dropwise over 2 minutes, and then the mixture was further stirred for 2 minutes. The obtained mixture was spread on a vat and dried by ventilation at 80 ° C. for 5 hours with a shelf dryer DN-93 (manufactured by Yamato Kagaku) to obtain granulated particles.
The granulated particles obtained by repeating the operations from preparation of fructose aqueous solution to drying are combined, and sieved with a sieve having an opening of 1000 μm, and granulated particles having an average particle diameter of 150 to 300 μm (granules for tablets (1), ( 2)) was obtained.

<Examples 1-14, Comparative Examples 1-6>
[1-1. Production of supported particles by stirring]
Supported particles having the compositions described in Tables 3 and 6 were produced by the following procedure.
In advance, the dried peony extract, peony extract or funnel extract described in the column of supported particles in Tables 3 and 6 was dissolved in purified water to prepare an adsorbate for 1500 tablets of the indicated composition amount. Ingredients other than the adsorbent described in the column for supported particles are put into a high-speed mixer LFS-2 (manufactured by Fukae Powtech Co., Ltd.) for 1000 tablets of the composition amount, and the rotational speed is set to agitator 400 rpm and chopper 2000 rpm. did. While stirring, 1000 tablets of the adsorbed solution were added dropwise over 2 minutes, and then stirred for another 2 minutes. The obtained mixture was spread on a vat and dried by ventilation with a shelf dryer DN-93 (manufactured by Yamato Kagaku) at 80 ° C. for 5 hours to obtain supported particles (water content 1.5% by mass).
The supported particles obtained by repeating the operations from preparation of the adsorbing liquid to drying were combined and sieved with a sieve having an opening of 1000 μm to obtain supported particles having an average particle size of 100 to 300 μm.

[1-2. Production of supported particles under fluidized bed]
Supported particles having the composition described in Table 4 were produced by the following procedure.
In advance, the dried peony extract described in the column of supported particles in Table 4 was dissolved in purified water to prepare an adsorbent for 1500 tablets of the indicated composition amount. Rotating fluidized coating apparatus MP-01 ((stock) of components other than the adsorbing liquid described in the supported particle column was preheated until the exhaust temperature reached 55 ° C. at an intake air temperature of 80 ° C. ) Made by POWREC), set to an intake air temperature of 80 ° C., an atomizing air pressure of 0.49 MPa, an atomizing air amount of 50 L / min [s], and spraying 1000 tablets of adsorbing liquid at a liquid speed of 20 mL / min. In the first 5 minutes, fluidized bed granulation was performed at an air volume of 0.3 Nm ³ / min. After 5 minutes, the air volume was increased to 0.4 Nm ³ / min and sprayed until the exhaust temperature reached 30 ° C. Thereafter, spraying was performed until the adsorbed liquid reached a predetermined amount with an air volume of 0.5 Nm ³ / min. After spraying, the air volume is dried at 0.5 Nm ³ / min. When the exhaust temperature reaches 35 ° C., the air volume is reduced to 0.35 Nm ³ / min, and when the exhaust temperature reaches 45 ° C., it stops and the supported particles Was recovered.
The supported particles obtained by repeating the operations from the preparation of the crude drug-containing solution to the collection of the supported particles were combined and sieved with a sieve having an opening of 1000 μm to obtain supported particles having an average particle size of 50 to 150 μm (water content 1 .5 to 4.0%).

[2. Production of tablets]
Of the compositions shown in Tables 3-6, 2000 tablets of ingredients other than magnesium stearate are taken in the prescribed ratios, placed in a plastic bag, mixed by shaking by hand about 20 times, and then added with magnesium stearate. Mixed twice. This mixed powder was tableted with an open feed shoe using a clean press 12HUK (manufactured by Kikusui Seisakusho) to obtain a round tablet with a diameter of 10.0 mm. At this time, the tableting pressure was adjusted with a tablet breaking strength measuring instrument TH-203CP (manufactured by Toyama Sangyo Co., Ltd.) so as to have a hardness of 3 to 5 kgf (rotation speed: 10 rpm, number of bottles: 12).
The following evaluation was performed about the obtained tablet. The results are also shown in the table.

[Evaluation of disintegration in the mouth]
The oral disintegration was evaluated by three adult men and one adult woman according to the following procedure.
The tablet was placed in the mouth, and the tablet was disintegrated while rolling with the tongue, and the time until the tablet was completely disintegrated was measured. From the average value of the disintegration time of 4 persons, the disintegration property in the mouth was evaluated based on the following evaluation criteria. △ or more is the allowable range.
(Evaluation criteria)
A: Less than 30 seconds, O: 30 seconds to less than 45 seconds, Δ: 45 seconds to less than 60 seconds, X: 60 seconds or more.

[Evaluation of impact resistance]
About 10 tablets, 15th revision Japanese Pharmacopoeia Reference information 12. The test was conducted according to the tablet friability test method. The state of the tablet after the test was visually confirmed, and the number of tablets in which cracking or chipping was observed was counted based on the following criteria.
(Criteria)
Tablets that fall into any one of the following items (1) and (2) are counted as missing tablets. Even if it does not apply to (1) to (2), a broken tablet is counted as “cracked”.
(1) The chip | tip over 1 mm or more has arisen in one place of the tablet.
(2) Chips of less than 1 mm are seen at 1/3 or more of the periphery of the tablet.

Based on the following criteria, impact resistance was evaluated from the number of tablets in which cracking or chipping was observed among 10 tablets subjected to the friability test. △ or more is the allowable range.
(Evaluation criteria)
A: The number of tablets in which chipping is recognized is 0.
○: The number of tablets in which chipping is observed is 1 to 2.
(Triangle | delta): The number of the tablets by which chipping is recognized is 3-4 pieces.
X: The number of tablets in which chipping is observed is 5 to 7, or the number of tablets in which cracking is observed is 1 to 2.
XX: The number of tablets in which chipping is observed is 8 to 10, or the number of tablets in which cracking is observed is 3 or more.

[Evaluation of oral condiment]
The raw condiment was evaluated by the following procedure by three adult men and one adult woman.
The tablet was put into the oral cavity, the tablet was disintegrated while rolling with the tongue, and the crude taste (bitterness peculiar to herbal medicine, sweetness) at the time when the disintegration was completed was determined according to the following criteria. However, those having a disintegration property in the mouth of 60 seconds or more were evaluated after being crushed and disintegrated.
(Criteria)
5 points: Not felt at all, 4 points: Slightly felt, 3 points: Slightly felt, 2 points: Prettyly felt, 1 point: Very felt.
From the average value of the determination results of four people, the raw condiment in the mouth was evaluated based on the following evaluation criteria. △ or more is the allowable range.
(Evaluation criteria)
○: 3.5 points or more, Δ: less than 3.5 points, 2 points or more, x: less than 2 points.

Tables 3 to 6 show the maximum adsorption amount (mg) of the adsorbent used in each example, the ratio of the adsorbed liquid to the maximum adsorption amount (%), the amount of crude drug extract component (%) in the supported particles, and the supported particles in the tablet. The ratio (%) and the ratio (%) of the disintegrant in the tablet are also shown.
“Maximum adsorption amount (mg)” is the amount of adsorbed liquid that can be adsorbed when the adsorption capacity is converted into each preparation, and the adsorption capacity (mg) determined in Test Example 1 of the adsorbent used in each example. / Adsorbent mg) and the value obtained from the following formula from the blending amount (mg) in one tablet.
Maximum adsorption amount (mg) = adsorption capacity (mg / adsorbent mg) x blending amount (mg)

“Ratio of adsorbed liquid to maximum adsorbed amount (%)” is the ratio (mass of blending amount per tablet of adsorbed liquid used at the time of producing the supported particles (mg) to “maximum adsorbed amount (mg)”. %).
“Amount of crude drug extract component (%) in supported particles” is the ratio of the amount of “herbal extract components” to the “mass of supported particles” (the total amount of all components excluding purified water used for the production of supported particles) ( Mass%). Here, as the amount of the herbal extract component, the blended amount of the peony dried extract was used as it was. Regarding the extract, moisture was measured by the Karl Fischer volumetric titration method, and it was confirmed that the peony extract contained 30% by mass of water, so that 70% by mass of the blended amount was taken as the dry weight, and this dry weight was used. Similarly, about the funnel extract confirmed to contain 35% of water, 65% by mass of the blending amount was taken as the dry weight, and this dry weight was used. The amount of purified water is an amount required at the time of production and evaporates at the time of drying, so it is not included in the mass of the supported particles.
“Ratio (%) of supported particles in tablet” is the ratio (mass%) of “mass of supported particles” to “tablet mass” (total amount of all components excluding purified water used in tablet production). It is. The amount of purified water is the amount required at the time of manufacture and evaporates when dried, so it is not included in the mass of the tablet and the supported particles.
The “ratio of disintegrant in tablet (%)” is the ratio (mass%) of “total amount of disintegrant contained in tablet” relative to “mass of tablet”. Here, the “disintegrant” indicates Kollidon CL, Kollidon CL-SF, NS-300, and EXPLOTAB.

As shown in the above results, all of the evaluation results of the tablets of Examples 1 to 14 in which the carrier particles were blended were in an acceptable range. Among these, the tablet of Examples 1-13 which mix | blended the disintegrating agent (Kollidon CL, L-HPC) with the support | carrier particle | grains had favorable disintegration, and was suitable as an orally disintegrating tablet.
On the other hand, the tablets of Comparative Examples 1 to 3 in which the components were directly mixed and compressed without blending the supported particles were poor in impact resistance and crude drug taste, and in particular, Comparative Example 1 with a small amount of crospovidone (Collidon CL). ~ 2 was also poorly disintegrating. In addition, Comparative Examples 4 to 6 using a material other than crospovidone as the adsorbent were poor in disintegration and impact resistance, and the raw condiment was also inferior to Examples 1 to 14 although it was in an acceptable range.

Claims (6)

A herbal medicine-containing tablet comprising herbal medicine-supporting particles comprising crospovidone and a water-soluble crude drug extract component adsorbed on the crospovidone . The crude drug-containing tablet according to claim 1, wherein a proportion of crospovidone in the crude drug-carrying particles is 10% by mass or more and 70% by mass or less with respect to a total mass of the crude drug-carrying particles. The herbal medicine-containing tablet according to claim 1 or 2 , further comprising a disintegrant. The herbal medicine-containing tablet according to any one of claims 1 to 3 , which is an orally disintegrating tablet or a chewable tablet. The crude drug-containing particles according to any one of claims 1 to 4 , wherein the crude drug-carrying particles are obtained by impregnating crospovidone with a water-soluble crude drug extract and / or a dried dry solution of a crude drug and drying. tablet.   A crude drug-carrying tablet for herbal medicine-containing tablets, characterized by having a step of adding a water-soluble crude drug extract and / or water-soluble crude drug dry extract solution to crospovidone under a fluidized bed or stirring and impregnating and drying. Particle production method.