HK1119589A1 - Solid composition - Google Patents

Abstract

The invention provides a solid composition which can be produced by a simple production method and prevents the formation of whiskers. This solid composition comprising a sublimable ingredient and a swelling agent, and obtained by wet-granulating the composition with water or a water-containing alcohol.

Description

Solid composition

Technical Field

The present invention relates to a solid composition in which precipitation of whiskers or generation of odor is prevented in a solid composition mixed with a sublimable or odorous component.

Background

When sublimation components such as menthol, caffeine, and ibuprofen are added to a solid composition such as a pharmaceutical product or a food product, the surface of the solid composition or the inside of a storage container such as a glass bottle often causes blurring of the bottle and deposition of whiskers due to sublimation. Therefore, the content changes during storage, the quality becomes uneven, the appearance changes, the quality at the time of production cannot be maintained for a long time, and the commercial value is often reduced. Further, if a component generating an odor is contained in a solid composition such as a drug or a food, the solid composition may not be taken or taken with a feeling of unpleasant sensation, may cause nausea when passing through the throat, may be difficult to take, may newly develop an odor during storage, may increase an odor, may not maintain the quality during production for a long time, and may fail to sufficiently exert the effect of a drug or may reduce the commercial value.

In order to prevent whisker precipitation due to sublimable components in a solid composition, a method of coating a solid composition with a coating film such as a sugar coating (patent documents 1 and 2) or a polymer film (patent document 3) has been proposed. Further, there have been proposed a method of allowing carbon, silicic anhydride and/or montmorillonite to coexist without mixing them with carbon, silicic anhydride and/or montmorillonite (patent document 4), a method of allowing carbon, silicic anhydride and/or montmorillonite to coexist with them (patent documents 5 and 6), a method of containing β -1, 4 glucan powder having a specific size and specific surface area (patent document 7), a method of incorporating an antacid (patent document 8), a method of incorporating hydrous silica (patent document 9), a method of storing one or two or more of polyvinylpyrrolidone, magnesium oxide and sodium hydrogencarbonate in a sealing system (patent document 10), a method of allowing a sublimable component and one or two or more of an antacid and hydrous silica to coexist (patent document 11), a method of storing a desiccant in a sealing system (patent document 12), a method of incorporating polyvinylpyrrolidone (patent document 13), a method of incorporating an adsorbent for whiskers, a substance for preventing whisker generation, or a method of allowing them to coexist, such as a method of incorporating anhydrous lactose by a dry method (patent document 14), a method of incorporating a yeast cell wall fraction (patent document 15), and a method of incorporating carboxymethylcellulose or a salt thereof (patent document 16).

In addition, in order to prevent unpleasant odor caused by odor-containing components in the solid composition, there have been tried a method of coating a solid preparation such as granules or tablets with a coating film such as a sugar coating film or a film, for example, a method of coating a sugar-coated tablet with a sugar coating film based on sucrose (patent document 17), a method of coating the tablet with 2 layers of an oil layer and a protein layer (patent document 18), a method of coating the tablet with 2 layers of a coating layer composed of an aminoalkyl methacrylate copolymer RS and a coating layer composed of only a hydrophobic substance and a water-insoluble inorganic substance (patent document 19), a method of coating amino acid particles with a film by containing pullulan and a surfactant (patent document 20), a method of coating the amino acid particles with a film by containing a water-soluble cellulose derivative (patent document 21), and a method of coating the tablet with a coating agent containing a water-soluble cellulose derivative (patent document 22), a method of coating with a polymer matrix such as an enteric coating matrix (patent document 23), a method of coating with a mixture of cyclosporine and sucrose fatty acid ester with a polymer compound (patent document 24), and the like. Further, as a method for containing a deodorizing or deodorizing component at the same time, there have been tried a method of containing a chlorine-based oxidizing agent or a peroxide-based oxidizing agent (patent document 25), a method of adding an extract of a plant tissue of the families Cunninghamiae, Cupressaceae, Pinaceae, Betulaceae, Urticaceae, Lauraceae, Fagaceae, Rutaceae, Ebenaceae, Labiatae, Cucurbitaceae, Compositae, Gramineae, and Liliaceae (patent document 26), a method of adding sucralose (patent document 27), a method of adding trehalose to a silk peptide and a silkworm enzyme degradation product (patent document 28), a method of adding cyclodextrin and/or a cyclodextrin derivative in addition to a sulfite (patent document 29), a method of adding palatinose (patent document 30), a method of adding a sulfite (patent document 31), a method of adding carboxymethylcellulose or a salt thereof (patent document 16), and the like, further, a method of sealing a solid deodorant together (patent document 32) and the like have also been performed.

[ patent document 1 ] Japanese patent laid-open No. 2002-179559

[ patent document 2] Japanese patent laid-open No. 2002-241275

[ patent document 3 ] Japanese patent laid-open No. Sho 61-129138

[ patent document 4 ] Japanese patent Japanese Kokoku No. 56-53525

[ patent document 5 ] Japanese patent application laid-open No. Sho 56-37970

[ patent document 6 ] Japanese patent Japanese Kokoku No. 56-53525

[ patent document 7 ] Japanese patent laid-open No. Sho 63-267733

[ patent document 8 ] Japanese patent laid-open No. Hei 2-85214

[ patent document 9 ] Japanese patent laid-open No. 5-339158

[ patent document 10 ] Japanese patent laid-open No. Hei 8-193027

[ patent document 11 ] Japanese patent laid-open No. 8-301764

[ patent document 12 ] Japanese patent laid-open No. 8-333247

[ patent document 13 ] Japanese patent laid-open No. 2000-247870

[ patent document 14 ] Japanese patent laid-open No. 2002-154960

[ patent document 15 ] Japanese patent laid-open No. 2003-95987

[ patent document 16 ] Japanese patent laid-open No. 2005-162619

[ patent document 17 ] Japanese patent laid-open No. Sho 61-257923

[ patent document 18 ] Japanese patent laid-open No. Hei 6-24963

[ patent document 19 ] Japanese patent laid-open No. 6-256170

[ patent document 20 ] Japanese patent laid-open No. 2002-12541

[ patent document 21 ] Japanese patent laid-open No. 2003-221326

[ patent document 22 ] No. W02005/000358

[ patent document 23 ] Japanese patent laid-open No. 2005-41818

[ patent document 24 ] Japanese patent laid-open No. 2005-289825

[ patent document 25 ] Japanese patent laid-open No. 6-157260

[ patent document 26 ] Japanese patent laid-open No. 9-275934

WO 00/24273 publication (patent document 27)

[ patent document 28 ] Japanese patent application laid-open No. 2002-187900

[ patent document 29 ] Japanese patent laid-open No. 2003-12439

[ patent document 30 ] Japanese patent laid-open No. 2004-

[ patent document 31 ] Japanese patent laid-open No. 2004-331524

[ patent document 32 ] Japanese patent laid-open No. 2004-315046

Disclosure of The Invention

However, the above-mentioned whisker precipitation preventing methods are insufficient in all effects, and have problems that the production process is complicated and the product cost is high.

In addition, among the above methods for preventing generation of odor, the method of applying a coating such as a sugar coating or a film and the method of enclosing a deodorizing agent have problems of complicated production process, high product cost, and insufficient continuation of the deodorizing effect with time. In addition, many methods of simultaneously containing a deodorizing component or a deodorizing component exhibit effectiveness against a specific component having an unpleasant odor, and if the component having an odor is different in type, the effect is reduced by half, and many methods are not deodorizing methods having versatility, and the deodorizing component or the deodorizing component itself may have unpleasant odor. Further, since unpleasant odor is greatly influenced by personal preference, it is preferable that the pharmaceutical preparation, health food, or other preparation taken in a daily life is free of odor regardless of the odor.

Accordingly, an object of the present invention is to provide a solid composition which can prevent the deposition of whiskers due to a sublimable component and the generation of an odor due to a component having an odor more easily than the conventional art.

The present inventors have studied various methods for preventing whisker precipitation from a solid composition having a sublimable component and a method for preventing odor from being released from a solid composition containing an odor component, and as a result, have unexpectedly found that a solid composition obtained by wet granulation with water or an aqueous alcohol, which contains a sublimable or odor component and a swelling agent, prevents whisker precipitation or releases odor from the odor component, and have completed the present invention.

That is, the present invention provides a solid composition obtained by wet granulation with water or a hydrous alcohol, which contains a sublimable or odorous component and a swelling agent.

The solid composition of the present invention can inhibit sublimation of a sublimable component, inhibit precipitation of whiskers, and blur a container, and can easily prevent an unpleasant odor caused by the component, which contains the component having an odor.

Best mode for carrying out the invention

The present invention is described in detail below.

In the present invention, the sublimable component is a substance which is sublimable by itself or a part of the component and/or the decomposition product is sublimable, and there is no particular limitation as long as such a substance is used. More specifically, examples of the sublimable component include ibuprofen, acetaminophen, ethenzamide, theophylline, carbamazepine, chlorpheniramine maleate, tipepidine, noscapine, pentoxyverine citrate, potassium guaiacolsulfonate, phenacetin, isopropylantipyrine, caffeine (1 hydrate), anhydrous caffeine, caffeine sodium benzoate, caffeine, camphor (l-camphor, d-camphor, dl-camphor, etc.), menthol (l-menthol, d-menthol, etc.), benzoic acid (isoamyl benzoate, estradiol benzoate, ethyl benzoate, phenyl benzoate, propyl benzoate, benzyl benzoate, methyl benzoate, sodium benzoate, caffeine sodium benzoate, etc.), salicylic acid (salicylic acid, aspirin, salicylic acid, isopropyl alcohol, isopropyl benzoate, ethyl benzoate, phenyl benzoate, propyl benzoate, benzyl benzoate, methyl benzoate, sodium benzoate, caffeine, etc, Isobutyl salicylate, sodium salicylate, physostigmine salicylate, methyl salicylate, etc.), crude drug extract (extract of herba Ephedrae, cortex Cinnamomi Japonici, Lumbricus, Ginseng radix, Glycyrrhrizae radix, calculus bovis, etc.), and Chinese medicinal extract (radix Puerariae decoction, XIAOZIHU decoction, XIAOQINGLONG decoction, ZIHUZHI decoction, etc.). Among them, ibuprofen, acetaminophen, theophylline, chlorpheniramine maleate, anhydrous caffeine, and l-menthol are particularly preferable.

In the present invention, the component having a malodor is not particularly limited if it is a substance having a malodor in itself or a part of the component and/or a decomposition product thereof, and is generally called a pharmaceutical material or a food material having a malodor to be orally taken, and may be not only a synthetic chemical product or a fermented product but also a natural product such as a crude drug extract or a chinese medicine extract or an extract thereof. More specifically, the component having an odor may be exemplified by extracts of Chinese herbs such as kudzu root decoction, wind-expelling and detoxifying decoction, rattlesnake whistle pill, bupleurum root decoction, parvallia decoction, zizyphi spinosa decoction, and shiwei toxin-vanquishing decoction, extracts of crude drugs or organisms such as aloe, fennel, turmeric, lindera root, zedoary, valerian root, zingiber, licorice, chrysanthemum, cassia bark, peony, ginger, jujube, uncaria, passion fruit, hop, garlic, ginseng, and earthworm, antiulcer drugs such as vitamin U, thiamine nitrate, thiamine hydrochloride, bisbenzoylthiamine, furathiamine, octylthiamine, benfotiamine, dibenzoylthioamine, bisisobutylthiamine, and cetothiamine hydrochloride, amino acids such as isoleucine, leucine, valine, antipyretic polysaccharides such as ibuprofen, analgesic, hyaluronic acid, dermatan sulfate, chondroitin sulfate, etc., ascorbic acid or its salt, isoascorbic acid or its salt, and vitamin C group, dl-alpha-tocopherol, natural vitamin E (d body), tocopherol acetate, tocopherol succinate, tocopherol calcium succinate, and tocopherol nicotinate. Especially preferred are radix Puerariae decoction, extract of crude drug or organism such as Ginseng radix, thiamine nitrate, leucine, and tocopherol succinate.

The solid composition of the present invention preferably contains 1 to 95% by mass of a sublimable component or an odorous component, more preferably 2 to 90% by mass, and particularly preferably 5 to 65% by mass.

The swelling agent used in the present invention is not particularly limited as long as it swells when water or aqueous alcohol is added and can hold a large amount of water or aqueous alcohol, but it is needless to say that a composition containing an odor component is preferably a non-odor swelling agent. More specific examples of the odorless swelling agent include low-substituted hydroxypropylcellulose, crystalline cellulose, croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium, and carboxymethylcellulose, and 1 kind thereof may be used or 2 or more kinds thereof may be mixed and used. Preferred examples of the swelling agent include 1 or 2 or more selected from the group consisting of low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium and crystalline cellulose. A more preferable swelling agent is low-substituted hydroxypropylcellulose, and it is preferable to use the low-substituted hydroxypropylcellulose in an amount of 40 mass% or more, particularly 60 mass% or more, based on the whole swelling agent.

When low-substituted hydroxypropylcellulose is used as the swelling agent, the hydroxypropoxyl group is preferably 5.0 to 16.0 mass%, more preferably 6.0 to 14.5 mass%, and particularly preferably 7.0 to 13.0 mass%, from the viewpoint of manufacturability. Examples of such low-substituted hydroxypropylcellulose include LH-31 (hydroxypropoxy group 10.0 to 12.9 mass%) and LH-32 (hydroxypropoxy group 7.0 to 9.9 mass%) manufactured by shin-Etsu chemical Co., Ltd. The average particle diameter of the low-substituted hydroxypropylcellulose is preferably 60 μm or less, more preferably 45 μm or less, still more preferably 25 μm or less, and particularly preferably 4 to 25 μm.

The solid composition of the present invention preferably contains 5 to 99 mass% of a swelling agent, more preferably 10 to 98 mass%, and particularly preferably 35 to 95 mass%.

In addition, the mass ratio of the sublimable or odorous component to the swelling agent is preferably 0.1 to 100 parts by mass, more preferably 0.2 to 90 parts by mass, and particularly preferably 0.5 to 80 parts by mass of the swelling agent to 1 part by mass of the component in terms of the effects of preventing whisker precipitation and preventing unpleasant odor.

In the solid composition of the present invention, other pharmacologically active ingredients, which are generally used in medicines or foods, may be appropriately incorporated depending on the purpose, in addition to the sublimable ingredient or the odor-bearing ingredient and the swelling agent. Examples of the pharmacologically active ingredient include those used as antipyretic, analgesic and anti-inflammatory agents, sedative and hypnotic agents, drowsiness preventing agents, anti-dizziness agents, pediatric analgesics, stomach-invigorating agents, antacids, digestive agents, heart-strengthening agents, arrhythmia agents, hypotensive agents, vasodilators, diuretics, antiulcer agents, intestinal tract regulating agents, osteoporosis treating agents, antitussive and expectorant agents, anti-asthma agents, antibacterial agents, urinary frequency improvers, anti-obesity agents, vitamin preparations and the like. Examples of the component to be used in the pharmaceutical and food products include excipients (diluents), binders, disintegrants, sweeteners, and colorants. Examples of the excipient include sugars such as lactose, purified white sugar, glucose, and trehalose, and sugar alcohols such as D-mannitol, sorbitol, xylitol, and erythritol. Examples of the binder include hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinylpyrrolidone, dextrin, and β -starch. Examples of the disintegrating agent include starches such as corn starch, potato starch, rice starch and wheat starch. Examples of the sweetening agent include saccharin sodium, aspartame, acesulfame potassium, sucralfate, licorice extract, stevia extract, and Momordica grosvenori extract. The coloring agent may, for example, be titanium dioxide, natural food coloring matters, dyes suitable for food and pharmaceutical applications, and the like.

The solid composition of the present invention may be added with a good smell by using an odorant or a perfume. In this case, the following method is preferably employed: wet granulating sublimable or odorous component and odorless swelling agent with water or aqueous alcohol to obtain wet granule composition, and adding perfume or perfume into the dried solid composition. Examples of the flavoring agent and flavor include citrus-based flavors such as orange and lemon, coffee-based flavors, milk-based flavors, plant essential oils such as peppermint oil, spearmint oil, and spice oil.

The solid composition of the present invention exhibits an effect of suppressing whisker precipitation and odor by adding a decoction to a composition containing a sublimable or odorous component and a swelling agent, decocting the mixture, and performing wet granulation. A composition obtained by mixing the component with a swelling agent alone or a case of dry granulating the component with a swelling agent cannot obtain a satisfactory effect. The cooking liquid used herein is preferably water or a hydrous alcohol of 50% by mass or less, more preferably water or a hydrous alcohol of 25% by mass or less, and still more preferably water or a hydrous alcohol of 15% by mass or less. In addition, the alcohol in the aqueous alcohol used in the present invention may be a reagent such as ethanol, methanol, or isopropanol, or an alcohol that can be used for the production thereof, and ethanol is preferably used as a preparation for oral administration. The amount of the boiled liquid to be added is preferably 1 to 10 times by mass, and particularly preferably 2 to 5 times by mass, based on the swelling agent.

As the wet granulation for producing the solid composition of the present invention, any wet granulation method may be used as long as it is generally used in the fields of medicines, foods and the like, such as agitation granulation, fluidized bed granulation, extrusion granulation, and the like, and the agitation granulation method and the extrusion granulation method are preferable.

The solid composition of the present invention can be produced, for example, as follows. First, sublimable or odorous components and a swelling agent, and if necessary, other additives are added, and mixed by using a mixer such as a vertical granulator (manufactured by paulix (パウレック), etc.), and then distilled water in an amount of about 1 to 10 times that of the swelling agent or an aqueous alcohol in an amount of 50% by weight or less is added thereto, followed by cooking to bring the swelling agent into a swollen state. The extract is granulated using an extrusion granulator such as a fine pulverizer (manufactured by nippon (パウダル) corporation) to prepare a wet granulated composition, and dried using a box dryer or a fluidized bed granulation dryer. Alternatively, the granules having a desired particle size may be obtained by using a sieve, followed by extrusion-granulating, subjecting to a spheronization treatment using a spheronizer (マルメライザ a) (manufactured by nippon corporation), drying the granules using a box dryer or a fluidized bed dryer, and finally obtaining spherical granules having a desired particle size by using a sieve.

Alternatively, the above cooked material may be dried directly in a box dryer or a fluidized bed granulation dryer, and finally granulated with a sieve to obtain granules of a desired particle size. The particle size can be adjusted by adjusting the amount of water or aqueous alcohol or changing the screen mesh diameter in extrusion granulation within the range of 0.3-1.2 mm, so as to obtain powder, fine granules and granules. The obtained granules may be coated with saccharides, polymers, etc. in consideration of the feeling of administration and stability of the drug.

In the present invention, when the particle size is measured by a sieving method, the average particle size of the wet-granulated particles is preferably 25 μm or more, more preferably 50 to 1500 μm, and still more preferably 100 to 1000 μm.

The solid composition thus obtained has a granular form, can suppress whisker precipitation due to sublimable components and odor due to odorous components, and has good fluidity, and therefore, the granules of the solid composition can be used as it is as a powder, a fine granule, a granule or the like, or can be filled into a hard capsule or a soft capsule to be used as a capsule, or can be used as a tablet by breaking the granules of the solid composition. These capsules and tablets may be coated with saccharides, polymers, or the like. In the preparation of these preparations, additives for pharmaceutical preparations and foods generally used in pharmaceutical preparations and foods may be used as stabilizers, surfactants, plasticizers, lubricants, reducing agents, sweeteners, diluents, adsorbents, flavoring agents, binders, antioxidants, glossing agents, coating agents, flavors, coatings, fillers, antifoaming agents, cooling agents, chewing agents, colorants, flavoring agents, sugar coating agents, foaming agents, excipients, disintegrants, disintegration aids, disintegration extenders, fragrances, moisture-proofing agents, preservatives, fluidizers, antistatic agents, extenders, seasonings, souring agents, sweeteners, colorants/developers, coloring agents, reinforcing agents, foaming agents, preservatives, mildewcides, antioxidants/bleaches, thickening stabilizers, bitters, enzymes, glossers, manufacturing agents, and the like are incorporated at appropriate times. Further, even when the thus-obtained solid composition of the present invention and a preparation containing the same are filled in a transparent airtight container such as a glass bottle or a transparent PTP package, the generation of odor is prevented without the occurrence of clouding of the container or the precipitation of crystals due to the precipitation of whiskers, and further, the generation of odor with time is prevented even when the composition is filled in an airtight container such as a glass bottle or a PTP package.

Examples

The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited thereto.

Example 1

300g of acetaminophen (manufactured by Shanghai chemical Co., Ltd.), 80g of anhydrous caffeine (manufactured by Jinggang caffeine Co., Ltd.) and 420g of low-substituted hydroxypropylcellulose (LHPC: LH-31: manufactured by shin-Etsu chemical Co., Ltd.) as a swelling agent were mixed with a vertical granulator VG-10 (manufactured by Paulinex Co., Ltd.), and 1622g of distilled water was added thereto to conduct cooking, and then extrusion-granulated with a 0.5mm mesh screen of wet extrusion granulator (ツインド - ムグラン) TDG-80 (manufactured by Bipamo Co., Ltd.), and dried with a fluidized bed dryer FLO-5A/2 (manufactured by Florindo フロイント Co., Ltd.) to obtain granules having an average particle diameter of about 420 μm. 10g of the pellets were put into a number 5 glass bottle of a transparent glass, and the bottle was sealed by plugging a stopper, and the appearance after 6 months of storage at room temperature was examined, whereby no whisker precipitation such as cloudiness of the bottle was observed.

Comparative example 1

30g of acetaminophen (manufactured by Shanben chemical industry Co., Ltd.), 8g of anhydrous caffeine (manufactured by Jinggang caffeine Co., Ltd.), and 42g of low-substituted hydroxypropylcellulose (LHPC: LH-31: manufactured by shin-Etsu chemical Co., Ltd.) were mixed. 10g of this mixture was put into a number 5 glass bottle of clear glass, and the bottle was sealed by plugging, and the appearance after 6 months of storage at room temperature was examined, as a result, blurring of the bottle was observed.

Example 2

200g of theophylline (manufactured by Bainiao pharmaceutical Co., Ltd.) as a sublimable component and 800g of low-substituted hydroxypropylcellulose (LHPC: LH-32: manufactured by shin-Etsu chemical Co., Ltd.) as a swelling agent were mixed with a vertical granulator VG-10 (manufactured by Paulinex Co., Ltd.), and 2406g of distilled water was added thereto to cook the mixture, followed by extrusion-granulation through a 0.6mm mesh screen using a wet extrusion granulator TDG-80 (manufactured by Bippaduo Co., Ltd.), and drying was carried out using a fluidized bed dryer FLO-5A/2 (manufactured by Florin Multi-Production Co., Ltd.), thereby obtaining granules having an average particle size of about 500. mu.m. 10g of the pellets were put into a number 5 glass bottle of a transparent glass, and the bottle was sealed by plugging, and the appearance after 6 months at room temperature was examined, and as a result, no whisker precipitation such as cloudiness of the bottle was observed.

Comparative example 2

Theophylline (manufactured by BAIYOUYAO corporation) 20g and low-substituted hydroxypropyl cellulose (LHPC: LH-32: manufactured by shin-Etsu chemical corporation) 80g were mixed. 10g of this mixture was put into a number 5 split bottle of clear glass, a stopper was inserted into the bottle to seal the bottle, and the appearance after 6 months of storage at room temperature was examined, as a result, blurring of the bottle was observed.

Example 3

300g of ibuprofen (manufactured by BASF Japan (ジヤパン) Co., Ltd.) as a sublimable component and 600g of low-substituted hydroxypropylcellulose (LHPC: LH-31) as a swelling agent were mixed by a vertical granulator VG-10 (manufactured by Paulex Co., Ltd.), then, 1895g of distilled water was added thereto and the mixture was boiled, and then, extrusion-granulated by a wet extrusion granulator TDG-80 (manufactured by Bipa Dow) 0.6mm mesh, and then, dried by a fluidized bed dryer FLO-5A/2 (manufactured by Florine industries, Ltd.), to obtain a granule having an average particle size of about 500. mu.m. 10g of the pellets were put into a number 5 glass bottle of clear glass, sealed with a stopper, and examined for appearance after 6 months of storage at room temperature, as a result that no blurring of the bottle was observed.

Comparative example 3

Ibuprofen (30 g, manufactured by BASF Japan) and low-substituted hydroxypropylcellulose (LHPC: LH-31, manufactured by shin-Etsu chemical Co., Ltd.) were added in an amount of 60 g. 10g of this mixture was put into a number 5 glass bottle of clear glass, a stopper was inserted into the bottle to seal the bottle, and the appearance after 6 months of storage at room temperature was examined, as a result, blurring of the bottle was observed.

Example 4

500g of anhydrous caffeine (Siloka caffeine industry Co., Ltd.) as a sublimable component, 45g of 1-menthol (high-sand flavor Co., Ltd.) and 955g of low-substituted hydroxypropylcellulose (LHPC: LH-32: shin-Chemie Co., Ltd.) as a swelling agent were mixed with a vertical granulator VG-25 (Paulex Co., Ltd.), and then distilled water 3031g was added thereto to conduct cooking, followed by extrusion granulation with a 0.6mm mesh screen of a wet extrusion granulator TDG-80 (Pakeda Dow Co., Ltd.), and then drying was conducted with a fluidized bed dryer FLO-5A/2 (Florine Multi-Production Co., Ltd.) to obtain granules having an average particle size of about 500. mu.m. 10g of the pellets were put into a number 5 glass bottle of a transparent glass, and the bottle was sealed by plugging the bottle stopper, and the appearance after 6 months of storage at room temperature was examined, whereby no whisker precipitation such as cloudiness of the bottle was observed.

Comparative example 4

50g of anhydrous caffeine (Jinggang caffeine industries, Ltd.), 4.5g of 1-menthol (Gaosha flavor, Ltd.), and 95.5g of low-substituted hydroxypropylcellulose (LHPC: LH-32: manufactured by shin Etsu chemical Co., Ltd.) as a swelling agent were mixed. 10g of the mixture was put into a number 5 glass bottle of clear glass, and the bottle was sealed by plugging, and the appearance after 6 months of storage at room temperature was examined, as a result, blurring of the bottle was observed.

Example 5

A method for producing a low-boiling-point compound for pharmaceutical preparations, which comprises mixing 450g of ibuprofen (BASF manufactured by Japan K.), 7.5g of chlorphenamine maleate (King Kong) and 75g of anhydrous caffeine (Jinggang caffeine industry K) as sublimable components, 1400g of low-substituted hypromellose (LHPC: LH-31: manufactured by shin-Etsu chemical Co., Ltd.) and 56.5g of carboxymethyl cellulose calcium (Penta Kasei K Co., Ltd.) as swelling agents, and in addition 24g of dihydrocodeine phosphate (Co., Ltd.), 24g of racemic methylcarbutine hydrochloride (Alps (アルプス)60g, 6g of isopropylammonium (Rice industry K Co., Ltd.), 300g of ascorbic acid (Wutian chemical industry K.K.), and 24g of thiamine nitrate (BASF K.K.) (BAS K.)) with a vertical granulator VG-25 (Paulex K.) and decocting the mixture with 4622g of distilled water, thereafter, the mixture was extruded through a 0.5mm sieve using a wet extrusion granulator TDG-80 (manufactured by Nepal Co., Ltd.), and then dried using a fluidized bed dryer FLO-5A/2 (manufactured by Florine industries, Ltd.), to obtain granules having an average particle diameter of about 420 μm. To 2162.7g of the granules were added 361.8g of crystalline cellulose (Asahi Kasei Chemicals (ケミカルズ) (Co.)), 108g of lactose (DMV Japan), 27g of talc (Kihara (キハラ) Kasei Co., Ltd.) and 13.5g of magnesium stearate (Taiping chemical industry Kasei Co., Ltd.) and mixed, and the mixture was tabletted into a tablet of 330 mg/tablet. The tablets were sprayed with a film-coating agent comprising hypromellose (shin-Etsu chemical Co., Ltd.), titanium oxide (Shiyu-Shiyu Co., Ltd.), distilled water and ethanol (7: 3: 20: 70) using a high-speed coater (ハイコ - タ I) (manufactured by Florin industries), to obtain 335 mg/tablet of film-coated tablets. The tablet 30 pieces were put into a number 5 glass bottle of clear glass, sealed with a stopper, and examined for appearance after 6 months of storage at room temperature, and as a result, no whisker precipitation such as cloudiness of the bottle was observed.

Example 6

50g of thiamine nitrate (manufactured by BASF Japan Co., Ltd.) as an unpleasant odor component and 850g of low-substituted hydroxypropylcellulose (LHPC: LH-31: manufactured by shin-Etsu chemical Co., Ltd.) as a swelling agent having no odor were mixed by a vertical granulator VG-10 (manufactured by Paulinex Co., Ltd.), added 2620g of distilled water and kneaded, then extrusion-granulated by a wet extrusion granulator TDG-80 (manufactured by Betapo Co., Ltd.) through a 0.6mm mesh, and then dried by a fluidized bed dryer FLO-5A/2 (manufactured by Florine industries Co., Ltd.) to obtain a granule having an average particle diameter of about 500. mu.m. 10g of the granules were put into a No. 5 subpackage bottle, sealed with a stopper, and tested for odor, with the result that no unpleasant odor was detected immediately after manufacture and after 6 months of storage at 40 ℃.

Comparative example 5

Thiamine nitrate (manufactured by BASF Japan) 5g and low-substituted hydroxypropylcellulose (LHPC: LH-31 manufactured by shin-Etsu chemical Co., Ltd.) 85g were mixed. 10g of this mixture was put into a No. 5 bottle, and the bottle was sealed with a stopper, and the odor was detected, and as a result, an unpleasant vitamin odor peculiar to thiamine was detected immediately after the manufacture and after 6 months of storage at 40 ℃.

Example 7

200g of leucine (manufactured by Aomobi corporation) as an unpleasant odor component and 800g of low-substituted hydroxypropylcellulose (LHPC: LH-32: manufactured by shin-Etsu chemical Co., Ltd.) as an odorless swelling agent were mixed with a vertical granulator VG-10 (manufactured by Parulix corporation), and then 15% ethanol/distilled water (2094 g) was added thereto to conduct cooking, followed by extrusion granulation with a 0.6mm mesh screen of a wet extrusion granulator TDG-80 (manufactured by Bipapao corporation), and then drying was conducted with a fluidized bed drying apparatus FLO-5A/2 (manufactured by Florin industries Co., Ltd.) to obtain granules having an average particle size of about 500 m. 10g of the pellets were put into a glass No. 5 bottle, sealed with a stopper, and odor was detected, and no unpleasant odor was observed immediately after the production and after 6 months of storage at 40 ℃.

Comparative example 6

20g of leucine (manufactured by Phlomycetin corporation) and 80g of low-substituted hydroxypropylcellulose (LHPC: LH-32, manufactured by shin-Etsu chemical corporation) were mixed. 10g of this mixture was put into a glass No. 5 bottle, and the bottle was sealed with a stopper, and odor was detected, and as a result, unpleasant odor peculiar to amino acid was detected immediately after manufacture and after 6 months of storage at 40 ℃.

Example 8

100g of d- α -tocopherol succinate (manufactured by registered trademark, エ - ザイ) as an unpleasant-odor component and 900g of low-substituted hydroxypropylcellulose (LHPC: LH-31) as an odorless swelling agent were mixed in a vertical granulator VG-10 (manufactured by Parulix corporation), 1902g of distilled water was added thereto, and then extrusion-granulated with a 0.6mm mesh screen using a wet extrusion granulator TDG-80 (manufactured by Domopoly corporation), and then dried in a fluidized bed dryer FLO-5A/2 (manufactured by Florine industries, Ltd.) to obtain granules having an average particle size of about 500 m. 10g of the pellets were put into a glass No. 5 bottle, and sealed with a stopper to detect an offensive odor, and as a result, no unpleasant odor was detected immediately after the production and after 6 months of storage at 40 ℃.

Comparative example 7

10g of d-alpha-tocopherol succinate (manufactured by Ware Co., Ltd.) and 90g of low-substituted hydroxypropylcellulose (LHPC: LH-31: manufactured by shin-Etsu chemical Co., Ltd.) were mixed. 10g of this mixture was put into a glass No. 5 bottle and the bottle stopper was sealed, and odor was detected, and as a result, peculiar unpleasant odor was detected immediately after manufacture and after 6 months of storage at 40 ℃.

Example 9

149.8g (1000 g as crude drug ginseng) of a dry extract of ginseng (manufactured by Nippon powder chemical Co., Ltd.) as an unpleasant odor component and 280g (LHPC: LH-32: manufactured by shin-Etsu chemical Co., Ltd.) of low-substituted hydroxypropylcellulose (LHPC: LH-32: manufactured by shin-Etsu chemical Co., Ltd.) as an odorless swelling agent were mixed with 50.2g of carboxymethylcellulose calcium (manufactured by Penta chemical Co., Ltd.) by a vertical granulator VG-10 (manufactured by Parulix Co., Ltd.), and then distilled water 952g was added thereto to conduct cooking, followed by extrusion granulation by a wet extrusion granulator TDG-80 (manufactured by Beta Doku corporation) 0.6mm mesh, followed by drying by a fluidized bed dryer FLO-5A/2 (manufactured by Florin industries Co., Ltd.), to obtain granules having an average particle diameter of about 500. mu.m. 10g of the granules were put into a glass No. 5 bottle and sealed with a stopper, and odor was detected, and as a result, no unpleasant odor was detected immediately after manufacture and after 6 months of storage at 40 ℃.

Comparative example 8

7.49g of a dried extract of ginseng (manufactured by Nippon powdered drug Co., Ltd.), 14g of low-substituted hydroxypropylcellulose (LHPC: LH-32 manufactured by shin-Etsu chemical Co., Ltd.) and 2.51g of carboxymethylcellulose calcium (Penta de chemical Co., Ltd.) were mixed. 10g of this mixture was put into a glass No. 5 bottle and the bottle stopper was sealed, and odor was detected, and as a result, peculiar unpleasant odor was detected immediately after manufacture and after 6 months of storage at 40 ℃.

Example 10

400g (2000 g as crude drug) of a dried extract of pueraria lobata decoction (Japanese powdered drug (manufactured by Kagaku Co., Ltd)) as an unpleasant-smelling component, 140g (LHPC: LH-31: manufactured by shin-Etsu chemical Co., Ltd.) of low-substituted hypromellose (LHPC: LH-31: manufactured by shin-Etsu chemical Co., Ltd.) as a swelling agent having no smell, and 210g of carboxymethylcellulose calcium (Penta chemical (manufactured by Kagaku Co., Ltd)) were mixed with a vertical granulator VG-10 (manufactured by Paulix corporation), and then 973g of distilled water was added thereto to conduct cooking, followed by extrusion-granulation through a 0.6mm mesh screen using a wet extrusion granulator TDG-80 (manufactured by Beauda Co., Ltd.), and then dried by a fluidized bed dryer FLO-5A/2 (manufactured by Florin Polyproductions Co., Ltd.), to obtain granules having an average particle size. 10g of the granules were put into a glass No. 5 bottle and sealed with a stopper, and odor was detected, with the result that no unpleasant odor was detected immediately after the production and after 6 months of storage at 40 ℃.

Comparative example 9

20g of a dried extract of Kudzuvine root decoction (Japanese powder medicine, Ltd.), 7g of low-substituted hypromellose (LHPC: LH-31, manufactured by shin-Etsu chemical Co., Ltd.) and 10.5g of carboxymethylcellulose calcium (Pengde medicine, Ltd.) were mixed. 10g of this mixture was put into a glass No. 5 bottle, and the bottle was sealed with a stopper, and odor was detected, with the result that a characteristic unpleasant odor was detected immediately after the manufacture and after 6 months of storage at 40 ℃.

Possibility of industrial utilization

[0102] The solid composition of the present invention, which contains a sublimable or odorous component and a swelling agent and is obtained by wet granulation, can suppress the precipitation of whiskers and the blurring of containers by suppressing the sublimation of the sublimable component, and can easily and effectively prevent an unpleasant odor caused by the odorous component. Further, since the solid composition of the present invention has a granular form and good fluidity, the granules of the solid composition can be directly prepared into powder, fine granules, etc., and can be easily processed into capsules and tablets, and thus, the solid composition can be widely used for medicines, foods, etc. Further, even when the solid composition of the present invention is stored in an airtight transparent container or the like for a long period of time, no blurring or crystal deposition of the storage container due to the deposition of whiskers of the sublimable component is observed, no unpleasant odor is observed, and stable quality can be maintained for a long period of time. The solid composition of the present invention is not only easy to take because of no unpleasant odor, but also is a preparation which is not unpleasant to take for a long time by consumers having various tastes.

Claims (3)

1. A solid composition characterized by comprising a sublimable or odorous component and a swelling agent, which is obtained by wet granulation with water or aqueous alcohol, wherein the swelling agent is low-substituted hydroxypropyl cellulose or a combination of low-substituted hydroxypropyl cellulose and calcium carboxymethylcellulose, and the swelling agent is contained in an amount of 0.1 to 100 parts by mass per 1 part by mass of the sublimable or odorous component,

the sublimable component is ibuprofen, acetaminophen, theophylline, chlorphenamine maleate, anhydrous caffeine and 1-menthol, and the odorous component is radix Puerariae decoction dry extract, Ginseng radix dry extract, thiamine nitrate, leucine and tocopherol succinate.

2. The solid composition of claim 1 wherein the swelling agent is free of odor.

3. The solid composition according to claim 1, wherein the average particle diameter of the granules obtained by wet granulation is 25 μm or more.