JP2010006747A - Granulated particle and preparation containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide granulated particles excellent in both the stability with time of clemastine fumarate and its dissolution. <P>SOLUTION: The granulated particles comprises (A) clemastine fumarate (A) and one or more kinds (B) selected from cellulose, a water-insoluble cellulose derivative, and a water-soluble cellulose derivative having viscosity of a 2 mass% aqueous solution at 20°C of not less than 6.0 mPa s, and the total content of the component (A) and the component (B) is 50-100 mass% and the mass ratio represented by (A)/(B) is 1/50 to 1/420. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to granulated particles containing clemastine fumarate, which is an antihistamine, and preparations containing the same.

  Clemastine fumarate is known for its antihistaminic, sedative, anticholinergic, antiserotonin, and antiadrenergic effects, including allergic skin diseases (urticaria, eczema, dermatitis, pruritus) Used for allergic rhinitis. However, there is a problem in the temporal stability particularly under high temperature and high humidity conditions.

  For the purpose of improving the temporal stability of a drug, a method of forming granulated particles using excipients such as sugars and starches is known. It has also been proposed to granulate clemastine fumarate using an excipient (see Patent Document 1: Japanese Patent Application Laid-Open No. 2005-330245). However, in this case, there is a problem that although the blending amount of the excipient is large and the stability over time is improved, the dissolution property of clemastine fumarate is delayed. On the other hand, if the amount of excipient is small, granulated particles cannot be produced, or even if they can be produced, the stability over time of clemastine fumarate is not improved, and it is difficult to achieve both stability over time and dissolution. there were.

JP 2005-330245 A

  The present invention has been made in view of the above circumstances, and an object of the present invention is to provide excellent granulated particles having both aging stability and dissolution properties of clemastine fumarate and a preparation containing the same.

  The inventors of the present invention diligently studied to achieve the above object, and in (A) the granulated particles containing clemastine fumarate, (B) viscosity at 20 ° C. of cellulose, a water-insoluble cellulose derivative and a 2 mass% aqueous solution. 1 or 2 or more types selected from water-soluble cellulose derivatives having a pH of 6.0 mPa · s or more as an excipient, and the total content of the component (A) and the component (B) is 50 to 100% by mass, and Knowing that the mass ratio represented by (A) / (B) is in the range of 1/50 to 1/420, the aging stability and dissolution of clemastine fumarate can be significantly improved. The invention has been completed.

Therefore, the present invention provides [1]. One or more selected from (A) clemastine fumarate, (B) cellulose, a water-insoluble cellulose derivative, and a water-soluble cellulose derivative whose viscosity at 20 ° C. of a 2 mass% aqueous solution is 6.0 mPa · s or more. The total content of the component (A) and the component (B) is 50 to 100% by mass, and the mass ratio represented by (A) / (B) is 1/50 to 1/420. Granulated particles,
[2]. Furthermore, (C) the granulated particles according to [1] containing a binder,
[3]. Furthermore, (D) the granulated particle according to [1] or [2], which contains a surfactant,
[4]. [1]-[3] granular internal preparation containing the granulated particles according to any one of
[5]. A solid internal preparation containing the granulated particles according to any one of [1] to [3] is provided.

  ADVANTAGE OF THE INVENTION According to this invention, the outstanding granulated particle | grains which satisfy | fill both aging stability and dissolution property of clemastine fumarate, and a formulation containing it can be provided.

  The granulated particles of the present invention are obtained from (A) clemastine fumarate, (B) cellulose, a water-insoluble cellulose derivative, and a water-soluble cellulose derivative having a viscosity at 20 ° C. of 2% by mass aqueous solution of 6.0 mPa · s or more. 1 type or 2 or more types selected, The total content of the said (A) component and (B) component is 50-100 mass%, and the mass ratio represented by (A) / (B) Is a granulated particle having a ratio of 1/50 to 1/420.

(A) Cremastine fumarate Antihistamine, sedation, anticholinergic, antiserotonin, antiadrenergic, etc. are known, and allergic skin diseases (urticaria, eczema, dermatitis, pruritus) Used for allergic rhinitis. The content of clemastine fumarate with respect to the total amount of the granulated particles is not particularly limited, but it is preferable to adjust and blend appropriately so that the amount is 1.34 mg / day, which is the standard amount for drug approval.

(B) One type or two or more types selected from cellulose, a water-insoluble cellulose derivative, and a water-soluble cellulose derivative having a 2 mass% aqueous solution having a viscosity at 20 ° C. of 6.0 mPa · s or more. The cellulose or the cellulose derivative is shaped. It is used as an agent. By using this cellulose or cellulose derivative, it is possible to achieve both stability over time and dissolution of clemastine fumarate. On the other hand, saccharides and starches that are conventionally used most frequently as excipients are difficult to achieve both.

  Examples of cellulose include crystalline cellulose, microcrystalline cellulose, and powdered cellulose. Crystalline cellulose and powdered cellulose mean those described in the 15th revised Japanese Pharmacopoeia, and microcrystalline cellulose is known as a food additive mainly composed of crystalline cellulose. In the present invention, the water-insoluble cellulose derivative is a water-soluble one that is below the standard of “almost insoluble (15th revised Japanese Pharmacopoeia)” or “swells and becomes a suspension when water is added”. The thing which has. Specific examples include low-substituted hydroxypropylcellulose, carboxymethylcellulose, croscarmellose, carboxymethylcellulose calcium, croscarmellose sodium, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and cellulose acetate phthalate. Further, in the present invention, the water-soluble cellulose derivative means one having a property of “swells when added with water to become a viscous liquid (15th revised Japanese Pharmacopoeia)”, hydroxypropylcellulose, Examples thereof include hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylcellulose. In the present invention, a 2% by weight aqueous solution having a viscosity at 20 ° C. of 6.0 mPa · s or more is used.

In the present invention, the viscosity (including examples) is a value determined under the following conditions.
Rotational viscometer: LVDVII + PRO (manufactured by BROOK FIELD: Single cylindrical rotational viscometer)
Spindle No. ULA
Measuring container: tall beaker 500mL
Measurement liquid volume: Approximately 450mL
Measurement temperature: 20 ° C
Rotation speed: 60rpm
Measurement time: 4 minutes

  (B) As cellulose or a cellulose derivative, a cellulose and a water-insoluble cellulose derivative are preferable, a cellulose and a low substituted hydroxypropyl cellulose are more preferable, and a crystalline cellulose and a microcrystalline cellulose are further more preferable. In the present invention, the low-substituted hydroxypropyl cellulose means one described in the 15th revised Japanese Pharmacopoeia, which is a low-substituted hydroxypropyl ether of cellulose, and has a hydroxypropoxy group when a dry product is quantified. A water-insoluble cellulose derivative containing 5.0 to 16.0% by mass.

  The total content of the component (A) and the component (B) with respect to the total amount of the granulated particles is 50 to 100% by mass, preferably 60 to 95% by mass, and more preferably 70 to 90% by mass. Moreover, mass ratio of (A) component content represented by (A) / (B) and (B) component content is 1/50-1/420, and 1/100-1/400 are preferable. 1/120 to 1/250 is more preferable. If the content of component (B) is less than 50 parts by mass relative to 1 part by mass of clemastine fumarate, the stabilizing effect of clemastine fumarate is not sufficient, and if it exceeds 420 parts by mass, the granulated particles are hard. It becomes too much, and the dissolution property of clemastine fumarate is inferior. In addition, in this invention, the quantity in the case of combining 2 or more types of each component is the total quantity.

  In addition to the above components (A) and (B), the granulated particles of the present invention preferably contain (C) a binder because it is easy to granulate and the particle diameter can be easily controlled. Examples of the binder include water-soluble polymer compounds such as gum arabic, carboxyvinyl polymer, povidone, polyvinyl alcohol, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyacrylic acid. These can be used individually by 1 type or in combination of 2 or more types. In the present invention, the water-soluble polymer compound has a property of “swells when added with water to become a viscous liquid (15th revised Japanese Pharmacopoeia)”. However, in the case of a cellulose derivative, the 2% by weight aqueous solution having a viscosity at 20 ° C. of less than 6.0 mPa · s is used as the (C) binder, and is distinguished from the component (B).

  (C) As the binder, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose (however, in the case of a cellulose derivative, the viscosity at 20 ° C. of a 2 mass% aqueous solution thereof is less than 6.0 mPa · s) is more preferable. . Further, the component (C) of the present invention preferably has a viscosity at 20 ° C. of a 2 mass% aqueous solution of less than 6.0 mPa · s, more preferably 1.0 to 5.5 mPa · s, Preferably it is 1.2-5.0 mPa * s, Most preferably, it is 1.5-4.0 mPa * s. Within this range, the effect of the present invention is particularly improved. The polyvinyl alcohol preferably has a saponification degree of 96 mol% or less. The viscosity measurement method is the same as described above.

  Content of (C) component with respect to granulated particle whole quantity is 0-50 mass% normally, Preferably it is 5-40 mass%, More preferably, it is 10-30 mass%.

  In addition to the above components, the granulated particles of the present invention preferably contain (D) a surfactant. As the surfactant, a surfactant such as a nonionic surfactant, an anionic surfactant, a cationic surfactant, and an amphoteric surfactant can be used. These can be used individually by 1 type or in combination of 2 or more types.

  Nonionic surfactants include polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene glycerin fatty acid ester, glycerin Fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sterol, hydrogenated sterol, polyethylene glycol fatty acid ester, polyoxyethylene lanolin, polyoxyethylene lanolin alcohol, polyoxyethylene beeswax derivative, Polyoxyethylene alkylamine, polyoxyethylene fatty acid amide, alkyldiethano Amines, alkyl glucosides, alkyl maltosides, alkyl polyglucosides, sucrose fatty acid esters, methyl glucoside esters, and the like methyl glucamide is.

Examples of anionic surfactants include alkyl ether carboxylates, N-acyl sarcosine salts, N-acyl glutamates, N-acyl amino acid salts such as N-acyl-N-methyl β-alanine salts, alkyl polyoxyethylene sulfates, Examples include α-olefin sulfonate, N-acyl-N-methyl taurate, alkyl sulfosuccinate, alkyl phosphate, polyoxyethylene alkyl ether phosphate, and the like.
Examples of the cationic surfactant include N-acylaminoethyl diethylamine salt and N-acylguanidine salt.

  Amphoteric surfactants include soy phospholipids, hydrogenated soybean phospholipids, egg yolk phospholipids, hydrogenated egg yolk phospholipids, lecithin derivatives such as phosphatidylcholine, N-alkyldimethylamine oxide, N-alkyl-β-iminodipropionic acid Examples thereof include salts, N-alkyldimethylbetaines, N-acyl-dimethylbetaines, N-acylamidopropyldimethylbetaines, 2-alkylimidazoline derivatives, N-alkylsulfobetaine glucamines, N-alkylcarboxybetaine glucamines and the like.

  Among these, nonionic surfactants, anionic surfactants, and amphoteric surfactants are preferable, and nonionic surfactants are more preferable from the viewpoint of internal use.

  Content of (D) component with respect to granulated particle whole quantity is 0.0001-1.0 mass% normally, and is [(A) + (B)] / (D) in the granulated particle of this invention. The expressed mass ratio of (A) clemastine fumarate and (B) cellulose or a derivative thereof to (D) the surfactant content is 1 / 0.001 to 1 / 0.0. 2 is preferable, and 1 / 0.005 to 1 / 0.05 is more preferable.

  In the granulated particles of the present invention, in addition to the above components, as optional components, additives such as a disintegrant, a fragrance, a sweetener, a sour agent, and other excipients may be used alone or in appropriate combination of two or more. Can be used. The amount can be blended within a range not impairing the effect of the present invention (usually 20% by mass, preferably 10% by mass as the upper limit for the total amount of granulated particles).

  As the disintegrant, for example, croscarmellose, crospovidone and the like can be used. As a fragrance | flavor, menthol, limonene, vegetable essential oils (mint oil, mint oil, lychee oil, orange oil, lemon oil etc.) etc. can be used, for example. As the sweetener, for example, saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like can be used. As the acidulant, for example, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or a salt thereof can be used.

  Examples of other excipients include sugars and starch powders. Specific examples of sugars include monosaccharides, polysaccharides higher than disaccharides (sugar (granulated sugar, etc.), lactose, maltose, xylose, isomerized lactose, etc.), sugar alcohols (palatinite, sorbitol, lactitol, erythritol, xylitol, reduced) Saccharified starch, maltitol, mannitol, etc.), starch syrup, isomerized saccharide, oligosaccharide, sucrose, trehalose, reduced starch saccharified product (reduced starch degradation product) and the like.

  Specific examples of starches include corn starch (corn starch), potato starch (potato starch), starch such as wheat starch and rice starch, starch derivatives such as hydroxypropyl starch and partially pregelatinized starch.

  The granulated particles of the present invention can be obtained, for example, by the following wet granulation method, and are preferably wet granulated particles. Examples of the wet granulation method in the present invention include spray granulation method, stirring granulation method, fluidized granulation method, tumbling granulation method, tumbling fluidized granulation method, etc., but fluidized granulation method is generated. The fluidized granulation method is particularly preferred because the particles tend to be porous and have particularly excellent elution properties.

  For example, the fluidized granulation contains the above components (A) and (B) and optional components as necessary, and then contains the component (C) and optionally the component (D) in the fluidized bed granulator. It can obtain by carrying out wet granulation, spraying the aqueous solution to do. (The content of the component (C) in the aqueous solution is preferably from 0.01 to 10% by mass. Examples of the fluidized bed granulator include the GPCG series, WSG / WST / WH series, and Freund Sangyo Co., Ltd. ) Flow coater, spira flow, etc. The drying method after granulation is not particularly limited, but, for example, in the case of fluidized granulation, drying is performed while blowing hot air of 40 to 100 ° C. in a fluidized tank. be able to.

  The granulated particles of the present invention can be made into a granular internal preparation as they are or by mixing with other components. In addition, the granulated particles can be tableted as they are or mixed with other components to form a solid internal preparation such as a tablet.

  Content of the granulated particle of this invention can be suitably adjusted according to the compounding quantity of clemastine fumarate in a pharmaceutical formulation composition, for example, 1-100 mass% of granular internal preparations are preferable, and 1 in solid internal preparations. -100 mass% is preferable.

  In the case of the above-mentioned granular internal preparation, the particle diameter of the granulated particles of the present invention is preferably adjusted as appropriate so as to be compatible with powders and granules defined by the Japanese Pharmacopoeia. When setting it as a solid internal use formulation, it is preferable that the particle diameter of the granulated particle of this invention has a particle size whose 150-600 micrometers (sieving: 100-28 mesh (Tyler)) are 70 mass% or more.

  In addition to the granulated particles of the present invention, other active ingredients, excipients, disintegrants, sweeteners, acidulants, lubricants are included in the granular internal preparation or solid internal preparation of the present invention. Film coating agents, pigments, fragrances and the like can be blended. These can be used individually by 1 type or in combination of 2 or more types.

Examples of other active ingredients include, but are not limited to, naproxen, ketoprofen, loxoprofen, isopropylantipyrine, bromhexine hydrochloride, noscapine hydrochloride, dextromethorphan hydrobromide, dihydrocodeine phosphate, mefenamic acid, aluminum flufenamic acid, ibuprofen, Acetaminophen, anhydrous caffeine, chlorpheniramine maleate, diprofylline, meclizine hydrochloride, methylephedrine hydrochloride, potassium guaiacolsulfonate, guaifenesin, vitamin A, vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , calcium ascorbate, oxaprozin , Fenbufen, aspirin, aspirin aluminum, ethenzamide, sazapyrine, salicylamide, sodium salicylate, lacti Phenetidine, cysteine, pseudoephedrine, ephedrine, dextromethorphan, clofedanol, carbetapentane, calamiphen, noscapine, diphenhydramine, menthol, hydrocodone, hydromorphone, terpine hydrate, N-acetylcysteine, bromhexine, ambroxol, triprolidine, Azatadine, doxylamine, tripelenamine, cyproheptadine, hydroxyzine, cetirizine, ebastine, rhodoxamide, levocabastine, cetastine, tadifyline, temelastine, terphenazine, terbutaline, epinephrine, isoprenaline, acetylsalicylic acid, fenoprofen, doxylamine, indoxypropanoline, , Glyceryl guaiacolate, cal Noxamine, phenindamine, bromodiphenhydramine, pyrilamine, acribastine, astemizole, azelastine, ketotifen, loratidine, oxatomide, atropine, aminophylline, isoprenaline, metaproterenol, bitoterol, theophylline, albuterol, benzocaine, hexylresorfenol, diclonin Biprofen, indomethacin, dextromethorphan HBr, doxylamine succinate, pseudoephedrine HCl, triprolidine HCl, carprofen, thiaprofenic acid, cycloprofen, ketorolac, etodolac, sulindac, diclofenac, piroxicam, nabumetone, phenylephrine, bacicine, carbocysteine , Sobre roll, Examples thereof include dimenhydrinate, belladonna total alkaloid, tranexamic acid, lysozyme chloride, dipotassium glycyrrhizinate, glycyrrhetinic acid, phenylephrine hydrochloride, and the like.

  Examples of the excipient include cellulose powder, saccharide powder, starch, silicon dioxide powder and the like. Specifically, the cellulose powder is preferably crystalline cellulose, powdered cellulose, carmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, ethylcellulose, etc., and low-substituted hydroxypropylcellulose. Crystalline cellulose is more preferable, and low-substituted hydroxypropylcellulose is more preferable.

  Specific examples of sugar powders include monosaccharides, polysaccharides higher than disaccharides (sugar (such as granulated sugar), lactose, maltose, xylose, isomerized lactose, etc.), sugar alcohols (paratinite, sorbitol, lactitol, erythritol, Xylitol, reduced starch saccharified product, maltitol, mannitol, etc.), starch syrup, isomerized sugar, oligosaccharide, sucrose, trehalose, reduced starch saccharified product (reduced starch decomposed product) and the like are preferable.

Specific examples of the starch powder include corn starch (corn starch), potato starch (potato starch), starch such as wheat starch and rice starch, and starch derivatives such as hydroxypropyl starch and partially pregelatinized starch. Starch (corn starch) is more preferred.
As the excipient, cellulose powder and starch powder are preferable, and cellulose powder is more preferable.

  As the disintegrant, for example, croscarmellose, crospovidone and the like can be used. As a fragrance | flavor, menthol, limonene, vegetable essential oils (mint oil, mint oil, lychee oil, orange oil, lemon oil etc.) etc. can be used, for example.

  As the sweetener, for example, saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like can be used.

  As the acidulant, for example, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or a salt thereof can be used. Examples of the lubricant include magnesium stearate and calcium stearate. Examples of the film coating agent include polymer compounds such as hydroxypropyl methyl phthalate, polyvinyl pyrrolidone, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, polyvinyl alcohol, gum arabic, shellac, polyoxyethylene polyoxypropylene glycol, and carboxyvinyl polymer. Can be used.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

[Examples 1-5, Comparative Examples 1-5]
After mixing (A), (B) and other excipients, (C) hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.), 20 ° C. in a fluid bed granulator. A 9 mass% aqueous solution (Example 4 is an aqueous solution containing hydroxypropylcellulose and (D) surfactant) having a viscosity of 2.5 mPa · s) was spray-granulated while sprayed as a binder and dried at 70 ° C. To obtain granulated particles. The following evaluation was performed about the obtained granulated particle. The results are also shown in the table.

[Stability of clemastine fumarate over time]
The granulated particles were sealed in a glass vial and stored at 50 ° C. and 75% RH for 2 months. Then, the content of clemastine fumarate was measured by HPLC, and the mass% of clemastine fumarate relative to the initial value was calculated. . A result is shown based on the following evaluation criteria.
<Evaluation criteria>
A: Content of clemastine fumarate 97% or more ○: Content of clemastine fumarate 94% or more and less than 97% Δ: Content of clemastine fumarate 90% or more and less than 94% ×: Content of clemastine fumarate 90% or less

[Elution properties]
The dissolution property of clemastine fumarate was measured according to the JP General Test Method, and the dissolution rate (mass%) at 30 minutes was calculated. A result is shown based on the following evaluation criteria.
<Evaluation criteria>
◎: Dissolution rate of clemastine fumarate 60% or more ○: Dissolution rate of clemastine fumarate 40% or more and less than 60% △: Dissolution rate of clemastine fumarate 20% or more and less than 40% ×: Dissolution rate of clemastine fumarate 20% or less

[Example 6]
General cold medicine (fine granules)
The following composition was mixed in a Boule type mixer.
(Parts by mass)
Granulated particles of Example 1 211.34
Ibuprofen 450
Bromhexine hydrochloride 12
dl-Methylephedrine hydrochloride 60
Dihydrocodeine phosphate 24
Anhydrous caffeine 75
Calcium ascorbate 500
Lactose 700

[Example 7]
General cold medicine (tablets)
A mixed powder having the following composition was mixed with a Boule type mixer, and then compression-molded with a tableting machine (Kikusui Seisakusho Libra tableting machine) to form a tablet of about 240 mg.
(Parts by mass)
Granulated particles of Example 2 241.34
Ibuprofen 450
Bromhexine hydrochloride 12
dl-Methylephedrine hydrochloride 60
Dihydrocodeine phosphate 24
Anhydrous caffeine 75
Calcium ascorbate 500
Lactose 600
Hydrous silicon dioxide 90
Croscarmellose sodium 100
Magnesium stearate 10

[Example 8]
Rhinitis medicine (tablets)
A mixed powder having the following composition was mixed with a Boule type mixer, and then compression-molded with a tableting machine (Kikusui Seisakusho Libra tableting machine) to obtain a tablet of about 250 mg.
(Parts by mass)
Granulated particles of Example 3 561.34
Phenylephrine hydrochloride 15
Belladonna Total Alkaloid 0.4
Glycyrrhetinic acid 200
Anhydrous caffeine 150
Cornstarch 520
Croscarmellose sodium 50
Magnesium stearate 10

[Example 9]
Rhinitis medicine (tablets)
A mixed powder having the following composition was mixed with a Boule type mixer, and then compression-molded with a tableting machine (Kikusui Seisakusho Libra tableting machine) to obtain a tablet of about 250 mg.
(Parts by mass)
Granulated particles of Example 4 381.34
Belladonna Total Alkaloid 0.4
Lysotium chloride 90
Dipotassium glycyrrhizinate 30
Anhydrous caffeine 75
Hydrous silicon dioxide 70
Crystalline cellulose 400
Cornstarch 450
Magnesium stearate 10

[Example 10]
Antiallergic drugs (tablets)
A mixed powder having the following composition was mixed with a Boule type mixer, and then compression-molded with a tableting machine (Kikusui Seisakusho Ribra tableting machine) to obtain a tablet of about 300 mg.
(Parts by mass)
Granulated particles of Example 1 211.34
Acetaminophen 900
dl-Methylephedrine hydrochloride 60
Potassium guaiacol sulfonate 250
Tranexamic acid 420
Anhydrous caffeine 75
Lactose 700
Croscarmellose sodium 50
Magnesium stearate 30

[Example 11]
Antitussive expectorant (tablets)
A mixed powder having the following composition was mixed with a Boule type mixer, and then compression-molded with a tableting machine (Kikusui Seisakusho Libra tableting machine) to obtain a tablet of about 250 mg.
(Parts by mass)
Granulated particles of Example 3 561.34
Ibuprofen 450
Dihydrocodeine phosphate 24
Noscapine hydrochloride 48
Guayphenesin 250
Anhydrous caffeine 75
Hydrous silicon dioxide 25
Crystalline cellulose 400
Cornstarch 400
Magnesium stearate 18
About Examples 6-11, when time-dependent stability and the elution property of clemastine fumarate were evaluated similarly to Examples 1-5, all were favorable.

The raw materials used in preparing the examples and comparative examples are shown below.

Claims (5)

  One or more selected from (A) clemastine fumarate, (B) cellulose, a water-insoluble cellulose derivative, and a water-soluble cellulose derivative whose viscosity at 20 ° C. of a 2 mass% aqueous solution is 6.0 mPa · s or more. The total content of the component (A) and the component (B) is 50 to 100% by mass, and the mass ratio represented by (A) / (B) is 1/50 to 1/420. Granulated particles that are   The granulated particle according to claim 1, further comprising (C) a binder.   The granulated particles according to claim 1 or 2, further comprising (D) a surfactant.   The granular internal preparation which contains the granulated particle of any one of Claims 1-3.   The solid internal preparation which contains the granulated particle of any one of Claims 1-3.