JP5676834B2 - Oral solid composition with reduced irritation to the gastrointestinal tract - Google Patents

Description

  The present invention relates to an oral solid composition having reduced irritation of a drug having irritation to the digestive tract.

  Not limited to non-steroidal anti-inflammatory drugs, antibiotics, medical drugs such as potassium chloride, neuropsychiatric drugs, gastrointestinal drugs, cardiovascular / blood drugs, respiratory drugs, genitourinary tract and anal drugs, Even general drugs such as nutritional tonics, feminine drugs, allergy drugs, smoking cessation aids, Chinese herbal medicines and herbal medicines have some irritation to the digestive tract. Due to its irritation, side effects of gastrointestinal symptoms such as stomach discomfort, nausea / vomiting, and loss of appetite often appear when taking medicines. In addition, drugs that are particularly irritating to the gastrointestinal tract, such as nonsteroidal anti-inflammatory drugs, may cause side effects of severe gastrointestinal symptoms such as gastric mucosal bleeding and ulcer formation. For this reason, it has become difficult to continue taking medicines, and it has become impossible to treat the disease.

In order to reduce the irritation to the gastrointestinal tract of pharmaceuticals, measures such as taking after meals have been taken, but that alone is not sufficient in many cases. Magnesium carbonate (Patent Document 1), hydroxylation in the same preparation An antacid such as magnesium (patent document 2) and aminoacetic acid (patent document 3) is blended together, an H ₂ blocker (patent document 4) and a proton pump inhibitor (patent document 5) are blended together. It has been proposed to incorporate a gastrointestinal motility-inhibiting action inhibitor (Patent Document 6) such as tiquidium bromide or butyl scopolamine bromide, or to blend with Saikoukei-edo extract (Patent Document 7). In addition, as a formulation-like device that reduces irritation to the digestive tract, an enteric coating (Patent Documents 8 and 9) is applied to prevent irritation to the stomach.
JP 63-198620 A JP 2002-255802 A JP 2004-123712 A JP-A-5-246853 JP 2005-145894 A JP 2004-2454 A JP-A-8-208465 JP-A-6-293635 JP-A-8-109126

  However, the method of blending with other pharmaceutical ingredients such as antacids may cause blending changes, the effect may be insufficient, the cost will be high, the preparation itself will be large and difficult to take, etc. However, it is not versatile enough to be applied to various drugs. In addition, even if the enteric preparation can reduce the irritation to the stomach, the enteric coating material itself is not only expensive, but also has the disadvantage that the cost of the manufacturing process itself for coating the coating is high, Furthermore, the lag time until the drug dissolves and is absorbed and exerts its effect increases, and an immediate-release preparation that exhibits an effect immediately after taking cannot be obtained. For these reasons, it is difficult to apply an enteric coating in order to reduce the irritation to the stomach to obtain an enteric preparation, which is applied to most general ordinary immediate-release pharmaceuticals.

  Therefore, an object of the present invention is to provide an oral solid preparation with reduced irritation to the gastrointestinal tract that can be applied to immediate release preparations of various drugs and can be manufactured at low cost by a simple manufacturing method. .

  As a result of various studies on methods for preventing gastrointestinal irritation of drugs having irritation to the gastrointestinal tract, the present inventors have found that drugs having water irritation to the gastrointestinal tract and water-swellable polymers can be combined with water or hydrous alcohol. When the oral solid composition obtained by wet granulation was orally administered, it was unexpectedly found that irritation to the oral digestive tract such as the oral cavity, pharynx, esophagus and stomach was suppressed, and the present invention was completed.

  That is, the present invention is an oral solid composition containing a gastrointestinal stimulating drug and a water-swellable polymer and obtained by wet granulation with water or hydrous alcohol.

  The oral solid composition of the present invention can prevent irritation to the gastrointestinal tract by a drug having gastrointestinal irritation.

Hereinafter, the present invention will be described in detail.
The gastrointestinal irritant used in the present invention is a gastric pain, stomach discomfort, stomach fullness, abdominal pain, abdominal fullness, nausea / vomiting, anorexia etc. It is a drug that does. Gastrointestinal irritating drugs, for example, in the over-the-counter drugs, classified as cold medicine (internal use), antipyretic analgesics, hypnotic sedatives, drowsiness preventives, and neuropsychiatric drugs such as pediatric sedatives that contain diarrhea Drugs classified as digestive organ drugs such as anthelmintic drugs; Drugs classified as cardiovascular / blood drugs such as inotropic drugs, arteriosclerotic drugs, and anemia drugs; antitussive expectorant Drugs classified as respiratory drugs; Drugs classified as genitourinary tract and anal drugs such as internal medicine for hemorrhoids; Vitamin A main drug, vitamin D main drug, vitamin E main drug, vitamin B ₁ main drug , Vitamin B ₂ active ingredient, Vitamin B ₆ active ingredient, Vitamin C active ingredient, Vitamin AD active ingredient, Vitamin B ₂ B ₆ active ingredient, Vitamin EC active ingredient, Vitamin B ₁ B ₆ B ₁₂ active ingredient, Vitamin-containing health Drugs classified as nourishing tonic health drugs such as protein / amino acid main drug formulations and crude drug main drug formulations; drugs classified as female drugs such as women's drugs; classified as allergic drugs such as antihistamine active drug formulations Drugs, drugs classified as otolaryngology drugs such as oral rhinitis drugs, drugs classified as smoking cessation adjuvants such as smoking cessation adjuvants; , Kakkon Benka-yu, Kakkon-yu, Kakkon-yu Kagawa Yumi-Shi, Kami-Ongyu-yu, Kami-san, Kikkyo-to, Yuki-gai-to, Yumi-style blood drinks, Yumi-style blood drinks first, subjugation Flute Maru, Kaifu Detoxin, Tsurenren-yu, Katsueka Kayaku Daioyu, Katsushido Maru, Katsue Karasuma-ka Kajin-jin, Sakai detoxification, Koji-yu, Gotora-yu, Ushizura-Ken-maru , Goto detoxification powder, Gojosan, Saikoka Ryokubo oyster bath, Saiko katsura dry water, Saikohyokanto, Sankoshinshinto, Sanzenjinyu, Sanmono yellow or hot water, Shiin Hot water, Shiyinsuiho hot water, Shichimono fall hot water, Yotsumono hot spring, Tsukuda licorice hot water, beef hot spring hot water, Juzen hot spring hot water, Jun-in hot water, Kojoki hot water, Shoseiryu hot water, Koseiryu hot water plaster , Kosei Ryuyu, Goma Anzu Amushiyu, Shoufusan, Spicy Seifengyu, Sakaifufuyu, Mystic Hot Spring, Kiyokami Fuyuyu, Negoti Drinking, Kawayumi Tea Trimming, Senkin Chicken Sesan, Ryokan Live Blood Scatter , Daikokanzo-to, Daiko-peony-skin-yu, Dai-saiko-to, Ji-ji-wan Child, Tokisan, Tokiyakuyakusan, Dokoku Kakkonyu, Dokokuyu, Megami-san, Ninjin Yoeiyu, Dyuyusan, Dyuyuto, Bakumontoyu, Hachimijiomaru, Shiratorakakaedayu, Chinese medicines such as Shiratora Ginseng Hot Spring, Shiratora Hot Spring, Hakurei Houyu, Fufutsu Seisaku, Mao Amashiyu, Mao Mizamyu, Aso Jinmaru, Yi Jin Hot Spring, Ryu Gyoen Liver Hot Spring, Rokumi Maru Examples include drugs classified as crude drug preparations. Since these are known to cause side effects of digestive tract symptoms after taking them, they are gastrointestinal stimulating drugs, and are preferable drugs for applying the present invention.

  For ethical drugs, drugs for internal use, drugs for central nervous system, drugs for peripheral nerves, drugs for sensory organs such as drugs for nervous system and sensory organs, drugs for circulatory organs, drugs for respiratory organs, digestion Drugs classified as individual organ system drugs such as organ drugs, hormonal drugs, urogenital and anal drugs, drugs classified as metabolic drugs such as vitamins and nutritional tonics, cell stimulants, tumors Drugs classified as tissue cell functional drugs such as pharmaceuticals and allergic drugs, crude drugs, herbal medicines such as herbal medicines, drugs classified as pharmaceuticals based on Kampo prescriptions, antibiotic drugs, chemotherapeutic agents, parasitic animal drugs, etc. Since it is known that side effects of gastrointestinal symptoms appear in drugs classified as pharmaceuticals against pathogenic organisms, drugs classified in these are gastrointestinal stimulating drugs and are preferable drugs for applying the present invention. Is

  Among these, non-steroidal anti-inflammatory drugs have a direct gastrointestinal mucosal stimulating effect in addition to gastrointestinal disorders due to the anti-inflammatory action mechanism of prostaglandin synthesis inhibitory action. In particular, it is a drug that is very strong and preferable for the present invention in terms of a drug that can be obtained by many patients with the effects of the present invention. Specific drug names of such non-steroidal anti-inflammatory drugs include acetaminophen, phenacetin, flufenamic acid aluminum, mefenamic acid, aspirin, etenzamide, salicylamide, sodium salicylate, isopropylantipyrine, sulpyrine, migrenin, acemetacin, indomethacin , Indomethacin farnesyl, Progouritacin maleate, Ampenac sodium, Diclofenac sodium, Actarit, Aluminoprofen, Ampiroxicam, Ibuprofen, Etodolac, Pentazocine hydrochloride, Oxaprozin, Ketoprofen, Zaltoprofen, Sulindac, Thiaprofen, Tenoxicam, Nabumetone, Naproxen, Naproxen , Bucolome, Planoprofen, Flurbiprofen, Messi Acid Jimetokiajin, meloxicam, mofezolac, Loxoprofensodium, Ronzaritto disodium, Rorunokikamu and the like.

  Caffeine drugs and xanthine drugs, which are inotropic agents, bronchodilators, and sleepiness inhibitors, have strong direct gastrointestinal mucosal irritation effects, including cardiotonic agents, bronchodilators, and sleepiness inhibitors. As an antipyretic analgesic, rhinitis, general cold medicine, antitussive expectorant, antipruritic, cardiotonic, multivitamin, nourishing tonic, etc. It is a drug preferable for the present invention in that it is a drug that can provide the effects of the present invention to many patients. Examples of such caffeine drugs and xanthine drugs include caffeine, anhydrous caffeine, sodium benzoate caffeine, aminophylline, choline theophylline, theophylline, proxyphylline and the like.

In addition, antihistamines are frequently applied to antitussive expectorant, general cold, antipruritics, hypnotic sedatives, allergic drugs, rhinitis drugs, etc. The antihistamines are very frequently incorporated and the effects of the present invention are easy to obtain for many patients. Preferred drug for the invention. Among these antihistamines, especially those that are very gastrointestinal irritant include diphenhydramine hydrochloride, diphenhydramine tannate, doxylamine succinate, clemastine fumarate, alimemazine tartrate, promethazine hydrochloride, promethazine hibenzate, mequitazine, methylenedi Examples thereof include promethazine salicylate.
As the gastrointestinal stimulating drug used in the present invention, ibuprofen, aspirin, acetaminophen, ethenamide, salicylamide, diphenhydramine hydrochloride, sodium benzoate caffeine, anhydrous caffeine, and caffeine are particularly preferable.

  In the solid composition of the present invention, the gastrointestinal stimulating drug is preferably contained in an amount of 80% by mass or less, more preferably 70% by mass or less, and particularly preferably 0.01 to 60% by mass.

  In the present invention, the water-swellable polymer swells when water or hydrous alcohol is added, can swell while holding a large amount of water or hydrous alcohol, and has an insoluble property without dissolving in water. Say the substance. In addition, the water-swellable polymer in the present invention is preferably one that does not adhere to the mucous membrane or the like. Examples of the water-swellable polymer used in the present invention include low-substituted hydroxypropylcellulose, crystalline cellulose, croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose, and the like. May be used alone or in combination of two or more. Preferred water-swellable polymers in the present invention include one or more selected from low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, and crystalline cellulose. More preferable water-swellable polymers include low-substituted hydroxypropyl cellulose, and it is desirable to use 40% by mass or more, and particularly 60% by mass or more of the whole water-swellable polymer. preferable.

  When low-substituted hydroxypropylcellulose is used as the water-swellable polymer, the hydroxypropoxy group has a hydroxypropoxy group of 5.0 to 16 in terms of the irritation suppressing effect of the gastrointestinal stimulating drug and the ease of processing into an oral solid composition. What is 0.0 mass% is preferable, what is further 6.0-14.0 mass% is preferable, and what is especially 7.0-13.0 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). Further, the average particle size of the low-substituted hydroxypropyl cellulose is preferably about 60 μm or less, more preferably 45 μm or less, and further preferably 4 to 25 μm.

  In the oral solid composition of the present invention, the water-swellable polymer is preferably contained in an amount of 20% by mass or more, preferably 30% by mass or more from the viewpoint of the irritation suppressing effect of the gastrointestinal irritating drug and the dissolution property of the drug. Is more preferable, and 40 to 99.99% by mass is particularly preferable.

  In the oral solid composition of the present invention, it is preferable that the water-swellable polymer is blended in an amount of 0.2 parts by mass or more with respect to 1 part by mass of the gastrointestinal stimulating drug, from the viewpoint of the effect of suppressing the stimulation of the gastrointestinal stimulating drug. It is more preferable to set it as 0.4 mass part or more, and it is preferable to set it as 0.8-10000 mass part especially.

  In the oral solid composition of the present invention, in addition to the gastrointestinal stimulating drug and the water-swellable polymer, other pharmacologically active ingredients and ingredients usually used in pharmaceuticals and foods are appropriately blended according to the purpose. Also good. For example, as other pharmacologically active ingredients, pharmacologically active ingredients used for stomachic drugs, antacids, digestives, anti-ulcers, intestinals and the like can be mentioned. In addition, examples of components used in pharmaceuticals and foods include excipients (diluents), binders, disintegrants, sweeteners, colorants, and fragrances. 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 the colorant include titanium dioxide, natural food colors, foodstuffs, and dyes suitable for use in medicine.

  The oral solid composition of the present invention has the effect of suppressing the stimulation of the gastrointestinal stimulating drug by wet granulating the mixed powder obtained by mixing the gastrointestinal stimulating drug and the water-swellable polymer with a kneaded liquid. Demonstrated. Therefore, it suppresses the irritation of the gastrointestinal tract when a composition in which the gastrointestinal stimulating drug and the water-swellable polymer are simply mixed or when the gastrointestinal stimulating drug and the water-swellable polymer are dry-granulated. A sufficient effect cannot be obtained. The kneading liquid used in the present invention is water or hydrous alcohol, but when producing the composition of the present invention, it is preferable to use water or hydrous alcohol of 50% by mass or less, water or 25% by mass. It is more preferable to use the following hydrous alcohol, and it is even more preferable to use water or a 15% by mass or less hydrous alcohol. The alcohol in the hydrous alcohol used in the present invention includes pharmaceuticals such as ethyl alcohol, methyl alcohol, isopropyl alcohol, and alcohols that can be used in the production thereof. Ethyl alcohol should be used for oral administration. Is preferred. The addition amount of the kneading liquid is preferably 1 to 10 times by mass and particularly preferably 2 to 5 times by mass with respect to the water-swellable polymer.

  The wet granulation in producing the oral solid composition of the present invention may be a wet granulation method usually used in the fields of pharmaceuticals and foods such as stirring granulation, fluidized bed granulation and extrusion granulation. Although not particularly limited, a stirring granulation method and an extrusion granulation method are preferable.

  The oral solid composition of the present invention can be produced, for example, as follows. First, add gastrointestinal stimulating drug, water-swellable polymer and other additives as needed, and mix with a mixer such as a vertical granulator (Powrec Inc.) Water or a hydrous alcohol of 50% by weight or less is gradually added to about 1 to 5 times the water-swellable polymer and kneaded to bring the water-swellable polymer into a swollen state. The kneaded product is granulated by an extrusion granulator, for example, a fine rewether (Fuji Powder Co., Ltd.) extrusion granulator, to produce a wet granular composition, and a box dryer or fluidized bed granulation Dry in a dryer. It can also be made into granules of the desired particle size using a sieve, and after extruding and granulating with a marumerizer (Fuji Paudal Co., Ltd.), a box dryer or fluidized It is also possible to produce spherical granules of the desired particle size by drying with a layer dryer and finally using a sieve.

  Further, the kneaded product can be immediately dried with a box-type dryer or a fluidized bed granulating dryer, and finally granulated with a desired particle size using a sieve. The particle size of the granules can be adjusted by adjusting the amount of water or hydrous alcohol, or by changing the screen diameter during extrusion granulation in the range of 0.3 to 1.2 mm to obtain powders, fine granules and granules. it can. The obtained granules may be further coated with saccharides, polymers, etc. in consideration of ingestion and drug stability.

  In the present invention, the average particle size of the granule obtained by wet granulation is preferably 25 μm or more, more preferably 50 to 1500 μm, and more preferably 100 to 1000 μm, when the particle size is measured by a sieving method. Further preferred.

  The oral solid composition thus produced has a granular shape, the direct irritation of the gastrointestinal stimulating drug is suppressed, and the fluidity is good. The granule of the composition can be used as it is as a powder, fine granule, granule, etc., but it may be used as a capsule by filling it into a hard capsule or soft capsule, or the solid composition granule is compressed into a tablet May be used. Furthermore, these capsules and tablets may be coated with saccharides, polymers and the like. In preparing these preparations, preparation additives usually used in pharmaceuticals and foods are added as stabilizers, stabilizers, surfactants, plasticizers, lubricants, lubricants, reducing agents, sweeteners. , Diluents, adsorbents, flavoring agents, binders, antioxidants, brighteners, coating agents, fragrances, skins, fillers, antifoaming agents, cooling agents, chewing agents, coloring agents, flavoring agents, Dragees, foaming agents, excipients, disintegrating agents, disintegrating aids, disintegrating extenders, fragrances, moisture-proofing agents, preservatives, preservatives, fluidizing agents, antistatic agents, bulking agents, seasonings, acidulants, For sweeteners, colorants / coloring agents, flavoring agents, fortifiers, swelling agents, preservatives, preservatives / antifungal agents, antioxidants / bleaching agents, thickening stabilizers, bittering agents, enzymes, brighteners, for production You may mix | blend timely as an agent. In addition, the oral solid composition of the present invention thus produced and the preparation containing it can provide a preparation in which gastrointestinal irritation is prevented and safety is improved.

  Next, although an Example and a test example are given and this invention is demonstrated further more concretely, this invention is not limited to these.

Example 1
900 g of ibuprofen (manufactured by BASF Japan Ltd.) as a gastrointestinal stimulating drug and low-substituted hydroxypropylcellulose (LHPC: LH-31 (hydroxypropoxy group 10.0 to 12.9% by mass) as a water-swellable polymer ): Shin-Etsu Chemical Co., Ltd.) 1500 g was mixed with a vertical granulator VG-25 (Paurec Co., Ltd.), purified water 4537 g was added and kneaded, then Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) )) Extruded and granulated with a 0.6 mm screen, spheroidized with Malmerizer Q400 (Fuji Powdal Co., Ltd.), and then fluidized bed dryer FLO-5A / 2 (Freund Sangyo Co., Ltd.) ) To obtain a preparation of Example 1 as granules having an average particle size of about 500 m.

Comparative Example 1
45 g of ibuprofen (manufactured by BASF Japan) and 75 g of low-substituted hydroxypropylcellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) were uniformly mixed to obtain a preparation of Comparative Example 1.

Test example 1
The preparation of Example 1 of the present invention and the comparative preparation of Comparative Example 1 were dissolved according to the Japanese Pharmacopoeia Fifteenth Amendment / Dissolution Test Method. Use the second solution (pH 6.8 buffer) as the test solution, perform the elution test with the paddle method 50 rpm, measure the ibuprofen concentration in the eluate with a high-performance liquid chromatograph, and calculate the elution rate. The results are shown in FIG.
It can be seen that the preparation of the present invention does not change the dissolution of ibuprofen from the preparation of Comparative Example 1 in which the bulk powder is dispersed, ibuprofen is rapidly dissolved, and exhibits the dissolution characteristics of the immediate release preparation.

Test example 2
Rat gastric mucosal irritation test:
Test method: SD male rats (purchased from Charles River Japan Co., Ltd.) were subjected to preliminary breeding for 1 week. 10 mg / kg of ibuprofen was orally administered to animals (210 to 230 g) fasted for 24 hours before administration of a group of 10 test drugs. Four hours later, the animals were killed and the stomach removed by head beating and carotid bleeding. 10 mL of 1% formalin solution was injected into the stomach and lightly fixed in the same solution. Cut the stomach along the large vagina, observe the presence or absence of ulcers under a stereomicroscope (10x), determine the incidence of ulcers, measure and add the length of ulcers (mm), and add the ulcer coefficient per animal It was.
Results: As shown in Table 1, the formulation of Example 1 of the present invention did not develop ulcers, whereas the formulation of Comparative Example 1 had an ulcer rate of 40% for each drug, and the ulcer coefficient Was 0.9 ± 0.4 mm (mean ± standard deviation). This suggested that the preparation of the present invention reduced irritation to the gastrointestinal tract by ibuprofen and suppressed the occurrence of ulcers.

Example 2
Vertical granule containing 80 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) as a gastrointestinal stimulating drug and 720 g of low-substituted hydroxypropylcellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) as a water-swelling polymer After mixing with VG-10 (Paurec Co., Ltd.), 2026 g of 15% ethanol / purified water was added and kneaded, then extruded with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) 0.6 mm screen. Granulated and dried with a fluidized bed drying apparatus FLO-5A / 2 (Freund Sangyo Co., Ltd.) to obtain granules having an average particle size of about 500 μm.

Example 3
400 g of caffeine (manufactured by Shizuoka Caffeine Industry Co., Ltd.) and 20 g of thiamine nitrate (manufactured by BASF Japan Co., Ltd.) as a gastrointestinal stimulating drug, and low-substituted hydroxypropylcellulose (LHPC: LH) as a water-swellable polymer -31: Shin-Etsu Chemical Co., Ltd.) 380 g was mixed with a vertical granulator VG-10 (Paurec Co., Ltd.), purified water 1053 g was added and kneaded, then Twin Dome Gran TDG-80 (Fuji Paudal ( Manufactured by Co., Ltd.) Extruded and granulated with a 1.0 mm screen and spheroidized with Malmerizer Q400 (Fuji Powdal Co., Ltd.), then fluidized bed dryer FLO-5A / 2 (Freund Sangyo Co., Ltd.) To make spherical granules with an average particle size of about 800 μm, and fill these granules into hard capsules to 200 mg per capsule. Capsules were obtained by filling.

  The oral solid composition of the present invention containing a gastrointestinal stimulating drug can prevent gastrointestinal irritation by a drug having gastrointestinal irritation and can be adapted to various gastrointestinal stimulating drugs. it can. Further, since the oral solid composition of the present invention does not delay elution unlike an enteric preparation, it can be applied to immediate release preparations of various drugs. In addition, 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. It can be easily processed as a capsule or tablet and can be widely applied to pharmaceuticals, foods, and the like. Moreover, the oral solid composition of the present invention is not only inexpensively manufactured by a simple manufacturing method, but also reduces irritation to the gastrointestinal tract, leading to stomach discomfort, nausea / vomiting, appetite in many patients. It is a formulation that can reduce the side effects of gastrointestinal symptoms such as poor performance, and many patients can benefit from the therapeutic effects of drug therapy.

It is drawing which shows the elution rate of this invention product and a comparative product.

Claims (3)

With ibuprofen with water or aqueous alcohol Ru is wet granulation, containing as an active ingredient of low substituted hydroxypropylcellulose, reducing agents irritant to the stomach mucosa of ibuprofen.   The agent of Claim 1 which contains 0.8-10000 mass parts of low substituted hydroxypropyl cellulose with respect to 1 mass part of ibuprofen.   The agent according to claim 1 or 2, wherein the average particle size of granules obtained by wet granulation is 100 to 1000 µm.

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