JP2008156258A - Oral solid composition having covered bitterness - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an oral solid composition with covered bitterness of a medicine exhibiting bitterness. <P>SOLUTION: The oral solid preparation is obtained by granulating a composition containing (A) a medicine exhibiting bitterness and (B) a hydrophilic polymer in the presence of water and drying the granule until its water content reaches ≤7.5 mass%. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an oral solid composition that masks the bitter taste of a drug that exhibits a bitter taste.

  When a patient takes a bitter-tasting drug, powders and granules cannot be taken as they are, so it is necessary to conceal the unpleasant taste in the mouth. Examples of such a method include a method of adding a sweetener having a high sweetness such as aspartame (Patent Document 1), a method of inclusion with an inclusion compound (Patent Document 2), a gastric polymer, an enteric polymer, water. Methods for coating with insoluble polymers, waxes, etc. have already been proposed (Patent Documents 3 and 4). When the drug is ibuprofen, anhydrous caffeine, chlorpheniramine maleate, diclofenac sodium, or allyl isopropyl acetylurea, the drug and a water-swellable substance (low-substituted hydroxypropyl cellulose, carmellose calcium, or croscarm Oral preparations obtained by wet granulation with water or hydrous alcohol containing 30% by weight or more of roast sodium) in the composition, without reducing the dissolution of the drug, the taste of the drug having an unpleasant taste It has been clarified that it can be concealed (Patent Documents 5 and 6).

However, in the method of adding a high-sweetness sweetener, it may not be possible to hide the bitterness depending on the properties of the drug. Furthermore, in the method of inclusion, the bioavailability may be reduced without the drug being re-released from the inclusion compound. In the method by coating, it is possible to conceal by increasing the amount of the coating according to the strength of the bitterness, etc., but there is a feeling of roughness when taking the coating, and the coating dissolves the drug. In addition to the cost of the coating agent, not only the cost of the coating agent but also the high cost of the coating process is a drawback. Methods using water swellable materials have not been shown to be compatible and effective with drugs other than ibuprofen, anhydrous caffeine, chlorpheniramine maleate, diclofenac sodium or allyl isopropyl acetyl urea.
JP-A-2-56416 JP-A-3-236316 JP-A-57-58631 Japanese Patent Laid-Open No. 3-130214 Japanese Patent Laid-Open No. 9-208458 JP 2004-189758 A

  Accordingly, an object of the present invention is to provide an oral solid preparation which does not have the above-mentioned problems, can prevent the bitterness of a drug having a bitter taste, and can be produced at a low cost by a simple production method.

  As a result of various studies on methods for preventing the bitter taste of drugs, the present inventors granulated a composition containing a drug exhibiting bitter taste and a hydrophilic polymer in the presence of water, and then contained a water content of 7.5% by mass. It was found that the solid composition obtained by drying to the following does not exhibit the bitterness of the drug, and the present invention was completed.

That is, the present invention granulates a composition containing (A) a bitter drug and (B) a hydrophilic polymer in the presence of water, and then dries until the water content is 7.5% by mass or less. It is an oral solid formulation obtained by this.
Further, the present invention provides (B) a hydrophilic polymer by adding water to a hydrophilic polymer, which is mixed with (A) a drug exhibiting a bitter taste, granulated, and then a water content of 7.5% by mass or less. It is an oral solid preparation obtained by drying until.

  The oral solid composition of the present invention can prevent the bitter taste of a drug when taken.

Hereinafter, the present invention will be described in detail. In the present invention, a drug that exhibits a bitter taste is a drug that feels a bitter taste on the tongue when taken, and specific examples include herbal extracts (peony, licorice, keihi, taiso, ginger, valerian, passiflora, Extracts such as butterfly, hops, carrots, etc., Chinese herbal extracts (Kakkonto, Kaifu Detoyu, Hibikifufumaru, Koshisaikoto, Shoseiryu, Suijinto, Tomisento, etc.) ), Biological extracts (Akamegashiwa, Asenyaku, Owaurushi, Eijitsu, Engosaku, Oubak, Ouren, Kashi, Oyster, Yeast, Ginkgo Leaves, Aloe, Fennel, Turmeric, Uyaku, Gadju, Citrus, etc.) Vitamin B ₁ group ( Thiamine, thiamine nitrate, bisbenchamine, octothiamine, benfotiamine, dibenzoylthiamine, thiamine Sulfide, bis Eve thiamine, hydrochloride dicethiamine), vitamin B ₂ group (flavin adenine dinucleotide sodium, riboflavin, riboflavin sodium phosphate, riboflavin butyrate and the like), vitamin B ₆ group (pyridoxine, pyridoxol, pyridoxamine and their hydrochloride or phosphate Salt), vitamin B ₁₂ group (cobalamin, cyanocobalamin, methylcobalamin, adenosylcobalamin, hydroxocobalamin), amino acids (glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, cystine, methionine, Proline, hydroxyproline, aspartic acid, asparagine, glutamic acid, glutamine, arginine, histidine, lysine, γ-aminobutyric acid, pyro Doncarboxylic acid, ε-aminocaproic acid, hydrolyzed elastin, hydrolyzed collagen, water-soluble collagen, casein, glutathione, wheat peptide, soybean peptide), gastrointestinal drugs (loperamide hydrochloride, cimetidine, pirenzepine hydrochloride), antihistamine (diphenhydramine) , Promethazine hydrochloride), antipyretic analgesics (aspirin, acetaminophen, etezamide, isopropylantipyrine), antitussive expectorant (ephedrine hydrochloride, methylephedrine hydrochloride, codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, theophylline, Guaifenesin) and the like.

  In the present invention, the drug exhibiting bitterness is preferably contained in an amount of 1 to 99% by mass, preferably 2 to 95% by mass, based on the total mass of the drug exhibiting bitterness and the hydrous hydrophilic polymer substance. Is more preferable.

In the present invention, first, a composition containing (A) a drug exhibiting a bitter taste and (B) a hydrophilic polymer is granulated in the presence of water, or
(B) Water is added to the hydrophilic polymer to form a hydrous hydrophilic polymer, which is mixed with (A) a drug exhibiting a bitter taste and granulated. The latter method is preferred.
The hydrophilic polymer used in the present invention contains a hydrophilic group in the molecule and can hold water having a mass equal to or more than that of the hydrophilic polymer itself, and is solid or semi-solid in the state of holding water. Although it is in a state, it is insoluble without dissolving in water, and it is necessary that the hydrophilic polymer itself does not exhibit an unpleasant taste. Examples of such hydrophilic polymers include low-substituted hydroxypropylcellulose, crystalline cellulose, croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose, and the like. Two or more kinds may be mixed and used. Among these, preferable hydrophilic polymers include one or more selected from low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, and crystalline cellulose. Further particularly preferred hydrophilic polymers include low-substituted hydroxypropylcellulose, which is desirably used in an amount of 50% by mass or more, particularly preferably 65% by mass or more of the entire hydrophilic polymer. .

  When low-substituted hydroxypropylcellulose is used as the hydrophilic polymer, the hydroxypropoxy group is 5.0 to 16.0% by mass from the viewpoint of manufacturability that it is easy to process into an oral solid composition having an excellent shape and particle size. In particular, 7.0 to 13.0, particularly 7.0 to 9.9% by mass is preferable. Examples of such low-substituted hydroxypropylcellulose include LH-31 (hydroxypropoxy group 10.0 to 12.9% by mass) and LH-32 (hydroxypropoxy group 7.0 to 9.9) manufactured by Shin-Etsu Chemical Co., Ltd. 9% by mass). Furthermore, the average particle size of the low-substituted hydroxypropyl cellulose is preferably about 60 μm or less, more preferably 45 μm or less, and even more preferably 25 μm or less.

  The hydrophilic polymer substance varies depending on the kind of drug exhibiting a bitter taste, but it is usually preferable to contain 0.05 part by mass or more of the hydrophilic polymer substance with respect to 1 part by mass of the drug exhibiting a bitter taste. The amount is more preferably 0.1 parts by weight or more, and particularly preferably 0.3 parts by weight or more.

  In the present invention, the water-containing hydrophilic polymer substance is a substance in which water is held in a hydrophilic polymer and has a solid or semi-solid property. The ratio of water to hydrophilic polymer in the hydrous hydrophilic polymer material changes with time depending on the type of hydrophilic polymer and the type and amount of drug exhibiting a bitter taste, but is approximately water: hydrophilic polymer = 1 to It is preferably in the range of 10: 1, more preferably 2 to 5: 1.

  In the water-containing hydrophilic polymer substance, the water to be retained in the hydrophilic polymer may be water alone, or may be added with a small amount of alcohol. When adding alcohol, it is preferable that alcohol is 50 mass% or less of the total mass of the water hold | maintained by mass ratio, 25 mass% or less is more preferable, and 15 mass% or less is the most preferable. As alcohol, ethyl alcohol is usually used. The temperature of water held in the hydrophilic polymer is preferably in the range of 2 to 40 ° C, more preferably in the range of 5 to 30 ° C.

  In the oral solid composition of the present invention, other pharmacologically active ingredients and ingredients usually used in pharmaceuticals and foods are appropriately blended according to the purpose in addition to the bitter-tasting drug and the hydrous hydrophilic polymer substance. Also good. For example, pharmacologically active ingredients include antipyretic analgesics, antihypnotics, sedatives, drowsiness preventives, antipruritics, pediatric analgesics, stomachic drugs, antacids, digestives, cardiotonic drugs, arrhythmic drugs, antihypertensive drugs, vasodilators Examples include pharmacologically active ingredients used for drugs, diuretics, anti-ulcer drugs, intestinal drugs, osteoporosis drugs, antitussive expectorants, anti-asthma drugs, antibacterial agents, frequent urination improvers, nourishing tonics, vitamins and the like. In addition, examples of components used in pharmaceuticals and foods include excipients (diluents), binders, disintegrants, sweeteners, flavoring agents / fragrances, and coloring agents. Examples of excipients include sugars such as lactose, purified sucrose, glucose and trehalose, and sugar alcohols such as D-mannitol, sorbitol, xylitol and erythritol. Examples of the binder include hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinyl pyrrolidone, dextrin, pregelatinized starch and the like. Examples of the disintegrant include starches such as corn starch, potato starch, rice starch, and wheat starch. Examples of the sweetener include saccharin sodium, aspartame, acesulfame potassium, sucralose, licorice extract, stevia extract and lacanka extract. Examples of flavoring agents / fragrances include citrus flavors such as orange and lemon, coffee flavors, milk flavors, plant essential oils such as peppermint oil, spearmint oil, and spice oil. Examples of the colorant include titanium dioxide, natural food colors, foodstuffs, and dyes suitable for use in medicine.

  The oral solid composition of the present invention can be prepared by removing water from a uniform mixture of a drug having a bitter taste and a hydrous hydrophilic polymer substance. At that time, it is preferable to remove moisture until it becomes 7.5% or less by measurement by loss on drying, for example, loss of drying at 50 ° C. for 10 minutes, more preferably 5% or less, and moisture to 2% or less. Is particularly preferred. Examples of the method for removing moisture include a method for removing moisture by heat drying or reduced pressure drying using a box dryer or a fluidized bed granulation dryer.

  For a uniform mixture of a bitter-tasting drug and a hydrous hydrophilic polymer substance, add water to the hydrophilic polymer to prepare a hydrous hydrophilic polymer substance, and then add a bitter-tasting drug and mix uniformly. Alternatively, it may be prepared by uniformly mixing a drug having a bitter taste and a hydrophilic polymer, and then gradually adding water and mixing uniformly. Of these, the former method is preferred. A composition obtained by simply mixing a drug exhibiting bitterness and a hydrophilic polymer, or a product obtained by dry granulation of a drug exhibiting bitterness and a hydrophilic polymer cannot provide a sufficient effect of masking the bitterness.

  In addition, a uniform mixture of a drug exhibiting bitterness and a hydrous hydrophilic polymer substance is a wet granulation method usually used in the fields of pharmaceuticals and foods such as stirring granulation, fluidized bed granulation and extrusion granulation. However, it can be easily prepared by combining the stirring granulation method and the extrusion granulation method, which is preferable. For example, a bitter-tasting drug, a hydrophilic polymer, and other additives as necessary are added, and after mixing with a mixer such as a stirring type mixer, such as a vertical granulator (manufactured by POWREC), purified water is added. Gradually add about 1 to 10 times the hydrophilic polymer and knead to obtain a uniform mixture of the drug exhibiting bitterness and the hydrous hydrophilic polymer substance. This mixture is granulated by an extruding granulator, such as a FineLuzer (Fuji Paudal Co., Ltd.) extruding granulator, so that a wet granular composition is uniformly formed of a drug exhibiting bitterness and a hydrous hydrophilic polymer substance. Can also be made. Furthermore, this mixture can be made into granules of a desired particle size using a sieve, and can be made into a wet granular composition by applying a spheroid treatment using a Malmerizer (produced by Fuji Powder Co., Ltd.). .

  Water is removed from the uniform mixture of the drug having a bitter taste and the hydrous hydrophilic polymer substance, and finally, a sieve is used to obtain granules of a desired particle size. In the present invention, the particle size of the granule may be any of powder, fine granule, and granule, and the obtained dry granule is further made up of sugar, polymer, etc. in consideration of the feeling of administration and drug stability. Coating may be performed. In the present invention, the average particle size of the granules obtained by drying is preferably 25 μm or more, more preferably 50 to 1500 μm, particularly preferably 100 to 1000 μm, when the particle size is measured by a sieving method. In the present invention, the particle diameter of the granules can be easily prepared by changing the screen diameter of the extrusion granulator.

  The oral solid composition thus produced has a granular shape, the bitterness of a drug exhibiting a bitter taste is suppressed, and the fluidity is good. Although it can be used as a fine granule, a granule, etc., it may be filled into a hard capsule or a soft capsule and used as a capsule, or a solid composition granule may be tableted and used as a tablet. Furthermore, these capsules and tablets may be coated with saccharides or polymers. In preparing these formulations, formulation additives usually used in pharmaceuticals and foods, such as stabilizers, stabilizers, surfactants, plasticizers, lubricants, lubricants, reducing agents, sweeteners, etc. Agents, diluents, adsorbents, flavoring agents, binders, antioxidants, brighteners, coating agents, fragrances, skins, fillers, antifoaming agents, cooling agents, chewing agents, coloring agents, flavoring agents , Sugar coating, foaming agent, excipient, disintegrant, disintegration aid, disintegration extender, fragrance, moisture-proofing agent, preservative, preservative, fluidizing agent, antistatic agent, extender, seasoning, acidulant , Sweeteners, colorants / coloring agents, flavoring agents, strengthening agents, swelling agents, preservatives, preservatives / fungicides, antioxidants / bleaching agents, thickening stabilizers, bittering agents, enzymes, brighteners, manufacturing An agent or the like may be blended in a timely manner. And the oral solid composition of this invention manufactured in this way and the formulation containing it are those which the bitterness of a drug is prevented and are easy to take.

  Next, although an example and a comparative example are shown and the present invention is explained still more concretely, the present invention is not limited to these.

Example 1
Licorice extract powder (manufactured by Nippon Flour Pharmaceutical Co., Ltd.) 100 g (700 g in terms of active ingredient) and 3118 g hydrous hydrophilic polymer substance [low-substituted hydroxypropyl cellulose ((hydroxypropoxy group 10.0 to 12.9% by mass) ) LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) 800 g and purified water 2318 g] were uniformly mixed with a vertical granulator VG-10 (Paurec Co., Ltd.), then Twin Dome Gran TDG-80 (not used) Extruded and granulated with a 0.8 mm screen (manufactured by Nipaudal Co., Ltd.) and subjected to spherical treatment using a Malmerizer (manufactured by Fuji Paudal Co., Ltd.). Next, it is dried with a fluidized bed drying apparatus FLO-5A / 2 (Freund Sangyo Co., Ltd.) to produce granules having an average particle size of about 0.65 mm, and the mass per package by a four-sided aluminum heat seal Was packaged to 300 mg. The loss on drying of this granule was 1.2% at 50 ° C. for 10 minutes.

Comparative Example 1
10 g of licorice extract powder (manufactured by Nippon Powder Chemical Co., Ltd.) and 80 g of low-substituted hydroxypropyl cellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) are mixed uniformly, and are mixed with a four-way aluminum heat seal. Packaged so that the mass per package was 300 mg.

Example 2
Kakkonto dry extract powder (manufactured by Nippon Powder Chemical Co., Ltd.) 357.1 g (3.571 kg in terms of crude drug) and 1755 g hydrous hydrophilic polymer (low substituted hydroxypropylcellulose (LHPC: LH-31: Shin-Etsu) A mixture of 200 g of Chemical Co., Ltd.), 300 g of Carmellose Calcium (manufactured by Gotoku Yakuhin Co., Ltd.) and 1255 g of purified water was uniformly mixed with a vertical granulator VG-10 (Paurec Co., Ltd.), then Twin Dome Gran TDG-80 (manufactured by Fuji Powder Co., Ltd.) was extruded and granulated with a 0.6 mm screen. Next, it is dried with a fluidized bed drying apparatus FLO-5A / 2 (Freund Sangyo Co., Ltd.) to produce granules having an average particle size of about 0.5 mm, and the mass per package by a four-sided aluminum heat seal Was packaged to 2g. The loss on drying of this granule was 1.5% at 50 ° C. for 10 minutes.

Comparative Example 2
50 g of Kakkonto dry extract powder (manufactured by Nippon Powder Chemical Co., Ltd.), 28 g of low-substituted hydroxypropyl cellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.), and carmellose calcium (manufactured by Gotoku Pharmaceutical Co., Ltd.) ) 42 g was mixed uniformly and packaged by a four-way aluminum heat seal so that the mass per package was 2 g.

Example 3
250 g of dried extract of walnut (Matsuura Pharmaceutical Co., Ltd.) (2 kg of crude drug equivalent), and 1235 g of hydrous hydrophilic polymer substance [low-substituted hydroxypropylcellulose LHPC: LH-32, manufactured by Shin-Etsu Chemical Co., Ltd. (hydroxy) A mixture of 280 g of propoxy group (7.0 to 9.9 mass%), 70 g of carmellose calcium (manufactured by Gotoku Pharmaceutical Co., Ltd.) and 885 g of purified water was uniformly mixed with a vertical granulator VG-10 (Paurec Co., Ltd.). After mixing, it was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) 0.6 mm screen. Next, it is dried with a fluidized bed drying apparatus FLO-5A / 2 (Freund Sangyo Co., Ltd.) to produce granules having an average particle size of about 0.5 mm, and the mass per package by a four-sided aluminum heat seal Was packaged to 1g. The loss on drying of this granule was 0.9% at 50 ° C. for 10 minutes.

Comparative Example 3
50 g of dried walnut extract (Matsuura Pharmaceutical Co., Ltd.), 56 g of low-substituted hydroxypropylcellulose (LHPC: LH-32: manufactured by Shin-Etsu Chemical Co., Ltd.), and 14 g of carmellose calcium (Gotoku Pharmaceutical Co., Ltd.) And packaged with a four-way aluminum heat seal so that the mass per package is 2 g.

Example 4
100 g of bisbenchamine (manufactured by Tanabe Seiyaku Co., Ltd.), 100 g of pyridoxine hydrochloride (manufactured by Daiichi Fine Chemical Co., Ltd.), 12 g of riboflavin (manufactured by Mitsubishi Pharma Corporation), 1 cyanocobalamin (manufactured by DSM Nutrition Japan Co., Ltd.) 1 0.5 g, Vitamin E succinate calcium (Eisai Co., Ltd.) 103.58 g, Nicotinamide (DSM Nutrition Japan Co., Ltd.) 60 g, and hydrous hydrophilic polymer substance 2032.92 g (low substitution) After mixing uniformly a mixture consisting of 522.92 g of hydroxypropylcellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) and 1510 g of purified water) with a vertical granulator VG-10 (Paurec Co., Ltd.), Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) 0.5mm screen Extruded and granulated. Next, it is dried with a fluidized bed drying apparatus FLO-5A / 2 (Freund Sangyo Co., Ltd.) to produce granules having an average particle size of about 0.4 mm, and the mass per package by a four-sided aluminum heat seal Was packaged to 300 mg. The loss on drying of this granule was 0.6% at 50 ° C. for 10 minutes.

Comparative Example 4
10 g of bisbenchamine (manufactured by Tanabe Seiyaku Co., Ltd.), 10 g of pyridoxine hydrochloride (manufactured by Daiichi Fine Chemical Co., Ltd.), 1.2 g of riboflavin (manufactured by Mitsubishi Pharma Corporation), cyanocobalamin (manufactured by DSM Nutrition Japan Co., Ltd.) ) 0.15 g, vitamin E calcium succinate (manufactured by Eisai Co., Ltd.) 10.358 g, nicotinic acid amide (manufactured by DSM Nutrition Japan Co., Ltd.) 6 g, and low-substituted hydroxypropyl cellulose (LHPC: LH) -31: manufactured by Shin-Etsu Chemical Co., Ltd.) 52.292 g was uniformly mixed and packaged with a four-sided aluminum heat seal so that the mass per package was 300 mg.

Example 5
60 g of L-valine (manufactured by Ajinomoto Co.), 90 g of L-leucine (manufactured by Kyowa Hakko Co., Ltd.), 60 g of L-isoleucine (manufactured by Kyowa Hakko Kogyo Co., Ltd.), 120 g of L-glutamine (manufactured by Ajinomoto Co., Inc.) 120 g of L-arginine (manufactured by Ajinomoto Co., Inc.), 120 g of L-lysine hydrochloride (manufactured by Kyowa Hakko Kogyo Co., Ltd.) and 1705 g of a hydrous hydrophilic polymer substance (low-substituted hydroxypropyl cellulose (LHPC: LH-31: Shin-Etsu Chemical) After mixing uniformly with a vertical granulator VG-10 (Paurec Co., Ltd.), Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) 0. Extrusion granulation was performed using an 8 mm screen, and spherical treatment was performed using a Malmerizer (manufactured by Fuji Powder Co., Ltd.). Next, it is dried with a fluidized bed drying apparatus FLO-5A / 2 (Freund Sangyo Co., Ltd.) to produce granules having an average particle size of about 0.6 mm, and the mass per package by a four-sided aluminum heat seal Was packaged to 1 g. The loss on drying of this granule was 0.9% at 50 ° C. for 10 minutes.

Comparative Example 5
6 g of L-valine (manufactured by Ajinomoto Co., Inc.), 9 g of L-leucine (manufactured by Kyowa Hakko Co., Ltd.), 6 g of L-isoleucine (manufactured by Kyowa Hakko Co., Ltd.), 12 g of L-glutamine (manufactured by Ajinomoto Co., Inc.) 12 g of L-arginine (manufactured by Ajinomoto Co., Inc.), 12 g of L-lysine hydrochloride (manufactured by Kyowa Hakko Kogyo Co., Ltd.) and 43 g of low-substituted hydroxypropylcellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) And packaged with a four-sided aluminum heat seal so that the mass per package is 1 g.

Example 6
A mixture of 10 g of loperamide hydrochloride (manufactured by ISFI) and 5000 g of hydrous hydrophilic polymer substance (990 g of low-substituted hydroxypropylcellulose (LHPC: LH-32: manufactured by Shin-Etsu Chemical Co., Ltd.) and 4010 g of purified water) The mixture was uniformly mixed with a VG-10 (Paurec Co., Ltd.), and then extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) 0.2 mm screen. Next, it is dried with a fluidized bed drying apparatus FLO-5A / 2 (Freund Sangyo Co., Ltd.) to produce a fine granule having an average particle diameter of about 0.15 mm, and a four-sided aluminum heat seal is used per package. It was packaged so that the mass was 500 mg. The loss on drying of this granule was 0.5% at 50 ° C. for 10 minutes.

Comparative Example 6
1 g of loperamide hydrochloride (manufactured by ISFI) and 99 g of low-substituted hydroxypropylcellulose (LHPC: LH-32: manufactured by Shin-Etsu Chemical Co., Ltd.) are uniformly mixed, and the mass per package is 500 mg using a four-way aluminum heat seal. Packaged to become.

Example 7
50 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.), 3955 g of a hydrous hydrophilic polymer substance (950 g of low-substituted hydroxypropylcellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) and 3005 g of purified water) The mixture was uniformly mixed with a vertical granulator VG-10 (Paurec Co., Ltd.), and then extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) 0.6 mm screen. Next, it is dried with a fluidized bed drying apparatus FLO-5A / 2 (Freund Sangyo Co., Ltd.) to produce granules having an average particle size of about 0.5 mm, and the mass per package by a four-sided aluminum heat seal Was packaged to 1g. The loss on drying of this granule was 0.8% at 50 ° C. for 10 minutes.

Comparative Example 7
5 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 95 g of low-substituted hydroxypropyl cellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) are uniformly mixed, and each pack is packed with a four-way aluminum heat seal This was packaged so that the mass of the product became 1 g.

Example 8
225 g of acetaminophen (manufactured by Yamamoto Chemical Co., Ltd.), 285 g of etenzamide (manufactured by Shizuoka Caffeine Industry Co., Ltd.), 1470 g of a hydrous hydrophilic polymer substance (low substituted hydroxypropylcellulose (LHPC: LH-31: Shin-Etsu) (Chemical Co., Ltd.) 390 g, purified water 864 g, Japanese Pharmacopoeia Ethanol (Wako Chemical Co., Ltd. 216 g) are mixed uniformly with a vertical granulator VG-10 (Paurec Co., Ltd.), then Twin Dome Granulation was performed using Gran TDG-80 (Fuji Paudal Co., Ltd.) 0.6 mm screen. Next, it is dried with a fluidized bed drying apparatus FLO-5A / 2 (Freund Sangyo Co., Ltd.) to produce granules having an average particle size of about 0.5 mm, and the mass per package by a four-sided aluminum heat seal Was packaged to 1.2 g. The loss on drying of this granule was 0.4% at 50 ° C. for 10 minutes.

Comparative Example 8
Acetaminophen (manufactured by Yamamoto Chemical Co., Ltd.) 22.5 g, etenzamide (manufactured by Shizuoka Caffeine Industry Co., Ltd.) 28.5 g, and low-substituted hydroxypropylcellulose (LHPC: LH-31: Shin-Etsu Chemical ( 39 g) was uniformly mixed and packaged by a four-sided aluminum heat seal so that the mass per package was 1.2 g.

Example 9
40 g of dextromethorphan hydrobromide (manufactured by Watanabe Chemical Co., Ltd.), 200 g of theophylline (Shiratori Pharmaceutical Co., Ltd.), 40 g of lysozyme chloride (Eisai Co., Ltd.), 2790 g of hydrous hydrophilic polymer (low substituted hydroxypropyl) A mixture of cellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) 720 g, purified water 2070 g) was uniformly mixed with a vertical granulator VG-10 (Paurec Co., Ltd.), and then Twin Dome Gran TDG-80 ( Extruded and granulated with a 0.4 mm screen. Next, it is dried with a fluidized bed drying apparatus FLO-5A / 2 (Freund Sangyo Co., Ltd.) to produce granules having an average particle size of about 0.3 mm, and the mass per package by a four-sided aluminum heat seal Was packaged to 500 mg. The loss on drying of this granule was 0.9% at 50 ° C. for 10 minutes.

Comparative Example 9
4 g of dextromethorphan hydrobromide (manufactured by Watanabe Chemical Co., Ltd.), 20 g of theophylline (Shiratori Pharmaceutical Co., Ltd.), 4 g of lysozyme chloride (Eisai Co., Ltd.), and low-substituted hydroxypropylcellulose (LHPC: LH- 31: manufactured by Shin-Etsu Chemical Co., Ltd.) was uniformly mixed and packaged with a four-sided aluminum heat seal so that the mass per package was 500 mg.

Test Example 1:
The results of a sensory test using 10 subjects are shown below. The dosage method included 1 pack of each of the preparations of Examples 1-9 and Comparative Examples 1-9 in the mouth for 10 seconds, then exhaled and compared the feeling of dosing. Evaluation was divided into five stages, and bitterness (very strong bitterness: 5 points, slightly strong bitterness: 4 points, bitterness: 3 points, slightly bitterness: 2 points, not bitterness: 1 point) was evaluated. The results are shown in Table 1.

  From the above table, it can be seen that each of the preparations of the present invention has a bitter taste much less than that of the comparative preparation and is excellent in taking feeling.

  The oral solid composition obtained by removing water from the drug exhibiting the bitter taste and the hydrous hydrophilic polymer substance of the present invention can prevent the bitter taste of the drug when taken. Since this oral solid composition has a granular shape and good fluidity, not only can the granules of the oral solid composition be used as powders, fine granules, granules, etc., but also capsules. It can be easily processed as a tablet or tablet and can be widely applied to pharmaceuticals, foods, and the like. Furthermore, since the oral solid composition of the present invention releases the drug immediately after taking it with a slight lag time while masking the bitter taste, it can be applied to many immediate-release preparations. Therefore, since the oral solid composition of the present invention is easy to take, it is a preparation that many patients can take for a long period of time and can exert the effects of various drugs steadily.

Claims (7)

  An oral solid obtained by granulating a composition containing (A) a bitter-tasting drug and (B) a hydrophilic polymer in the presence of water and then drying to a moisture content of 7.5% by mass or less Formulation.   (B) Water is added to the hydrophilic polymer to form a hydrous hydrophilic polymer, which is mixed with (A) a drug exhibiting bitterness, granulated, and then dried until the water content is 7.5% by mass or less. Oral solid preparation obtained by   The oral solid preparation according to claim 1 or 2, comprising 0.05 part by mass or more of (B) a hydrophilic polymer with respect to 1 part by mass of the drug (A) having a bitter taste.   The oral solid preparation according to claim 1, 2 or 3, wherein the water content at the time of granulation is 1 to 10 parts by mass with respect to 1 part by mass of the hydrophilic polymer (B).   It is a granule, a fine granule, a capsule, or a tablet, The composition in any one of Claims 1-4.   (B) The hydrophilic polymer is a low-substituted hydroxypropyl cellulose, The composition according to any one of claims 1 to 5.   The composition according to any one of claims 1 to 6, wherein the average particle size of the granules obtained by drying is 25 µm or more.