JP2006076956A - Compounding agent for treating/preventing gastritis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical preparation which enables administration of a more effective H2 blocker and a mucosa-protecting/reinforcing agent to a living body for treating and preventing gastrointestinal injuries such as chronic gastritis and acute gastritis. <P>SOLUTION: In the pharmaceutical preparation for treating or preventing chronic gastritis and acute gastritis, an ingredient containing the H2 blocker and an ingredient containing the mucosa-protecting/reinforcing agent are prepared so that they show different dissolution rates from each other. The pharmaceutical preparation is a granule containing the ingredient containing the H2 blocker and the ingredient containing the mucosa-protecting/reinforcing agent that show different dissolution rates, a nucleated tablet containing cores that show different dissolution rates, a multilayer tablet with different dissolution rates, etc. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a medicament for effective treatment or prevention of gastritis.

Currently, disorders of the stomach and duodenum due to stress, alcohol, drugs, etc. are frequent symptoms in adults. In particular, the symptoms of chronic gastritis include “stomach upset”, “heavy stomach”, and “muddy”, which are also referred to as indefinite complaints, and these symptoms may cause problems in daily life activities. Further, chronic gastritis is a pathological condition having a high transition rate to gastric cancer, and elimination of chronic gastritis is a pathological condition that needs to be treated in modern society in terms of improving the quality of daily life.
Acute gastritis is a pathological condition in which the stomach mucous membrane is damaged due to strong stimuli such as stress, drugs (especially antipyretic analgesics), heavy drinking and eating, coffee and spices. In extreme cases, acute gastric ulcers may cause fatal abdominal pain, vomiting, etc., and hospitalization is required.

  As a therapeutic agent for chronic gastritis or acute gastritis, a histamine receptor-2 antagonist (hereinafter referred to as “H2 blocker”) or the like is used as a drug that suppresses secretion of gastric acid. H2 blockers are drugs that block H2 receptors among histamine receptors. This blockade can exert a strong gastric acid secretion inhibitory effect. Currently, cimetidine, ranitidine, famotidine, nizatidine, roxatidine and the like are known as H2 blockers, and among these, famotidine is most frequently used. In addition, gastric inflammation is also relieved by protecting and enhancing the mucous membrane of the stomach and duodenum. Therefore, substrate protein protecting action (gastric mucosal protecting action) such as sucralfate, aldioxa, gefarnate, L-glutamine, gastric juice pepsin activity inhibiting action, control Mucosal protective / enhancing agents that have acid action, growth promotion / revascularization action of regenerating mucosa, or gastric / duodenal mucosal blood flow increase action are also widely used for the treatment of these gastritis. Moreover, the formulation which mix | blended these is already known (for example, refer patent document 1 and patent document 2).

  However, when a combination of the above-mentioned H2 blocker and mucosal protective / enhancing agent, which is highly effective in the treatment and prevention of gastritis, one drug (eg, mucosal protective / enhancing agent) is used as the other drug (eg, H2 blocker). ) Has been pointed out as a problem. In addition, for example, using various gastric mucosal disorder models, it is not always clear what the mechanism of action of the drug is, specifically how it is absorbed into the body to optimize the action on chronic gastritis and acute gastritis. (For example, refer to Patent Document 3 and Patent Document 4).

  In addition, as an animal model of the mucosal disorder of these gastric / duodenal ulcers, a model for creating a gastric mucosal lesion caused by water immersion restraint stress is known as a model showing an acute disorder, and as a model showing a chronic disorder A model for creating gastric mucosal lesions using acetic acid is known.

WO99 / 49872 WO99 / 00112 publication JP-A-8-333259 Japanese National Patent Publication No. 10-509180

It is not always clear what kind of gastrointestinal disorder is brought about by the absorption of the H2 blocker and the mucosal protective / enhancing agent into the living body depending on the conventional formulation techniques as described above.
An object of the present invention is to provide a pharmaceutical preparation that enables administration of a more effective H2 blocker and mucosal protective / enhancing agent in vivo for the treatment and prevention of gastrointestinal disorders such as chronic gastritis and acute gastritis. It is what.

  The present inventors diligently studied what effect can be obtained by the absorption of the living body in the combination of the H2 blocker and the mucosal protective / enhancing agent, and as a result, they have a certain time difference. It has been found that an optimal action can be obtained for each pathological condition of chronic gastritis and acute gastritis by being absorbed in the living body in a state, and the present invention has been completed. In other words, in the present invention, when using a combination of an H2 blocker and a mucosal protective / enhancing agent, in order to optimize the therapeutic and preventive effects, these two types of drugs have a certain time difference in vivo. The present invention relates to medicines and pharmaceutical preparations to be absorbed in the existing state.

That is, the gist of the present invention is as follows.
(1) A drug acting on the treatment or prevention of chronic gastritis and acute gastritis characterized by absorbing at least one absorption of at least one of H2 blockers and at least one of mucosal protective / enhancing agents.
(2) The pharmaceutical composition for treating or preventing chronic gastritis and acute gastritis according to claim 1, wherein the time difference between absorption of the H2 blocker and the mucosal protective / enhancing agent is 15 to 120 minutes.
(3) Treatment or prevention of chronic gastritis and acute gastritis characterized in that the component containing H2 blocker and the component containing mucosal protective / strengthening agent are prepared so that their dissolution rates are different from each other. Pharmaceutical formulation.
(4) The dissolution rate of the component containing the H2 blocker is 2 to 50 times the dissolution rate of the component containing the mucosal protective / strengthening agent, according to any one of the above (1) to (3) The pharmaceutical or pharmaceutical preparation for treatment or prevention of chronic gastritis and acute gastritis described.
(5) The dissolution rate of the component containing the mucosal protective / strengthening agent is 2 to 50 times the dissolution rate of the component containing the H2 blocker, according to any one of (1) to (3) above The pharmaceutical or pharmaceutical preparation for treatment or prevention of chronic gastritis and acute gastritis described.
(6) Any of the above (3) to (5), wherein the component containing the H2 blocker and the component containing the mucosal protective / strengthening agent are separately prepared granules having different dissolution rates. A pharmaceutical preparation for treating or preventing chronic gastritis and acute gastritis described in 1.
(7) The above-mentioned (3), wherein the component containing H2 blocker and the component containing mucosal protective / strengthening agent, which are separately prepared granules having different dissolution rates, are encapsulated. )-Pharmaceutical preparation for treatment or prevention of chronic gastritis and acute gastritis according to any one of (6).
(8) In a dry-coated tablet composed of an inner core and an outer shell, a component containing a H2 blocker in the outer shell is used, using a component having a low dissolution rate among components including an H2 blocker in the inner core and a component containing mucosal protective / strengthening agent. And a treatment for or prevention of chronic gastritis and acute gastritis according to any one of (3) to (5) above, wherein a component having a high dissolution rate is used among the components including a mucous membrane protecting / enhancing agent. Pharmaceutical formulation.
(9) A multilayer tablet comprising two layers or three or more layers, wherein a component containing an H2 blocker is used in one layer, and a component containing a mucosal protective / strengthening agent is used in the other layer, (3) A pharmaceutical preparation for treating or preventing chronic gastritis and acute gastritis according to any one of (5) to (5).
(10) Mucosal protective / enhancing agent protects substrate protein (gastric mucosa protective), suppresses gastric pepsin activity, antacid, promotes growth of regenerated mucosa, increases blood vessels, or increases gastric / duodenal mucosal blood flow The medicament or pharmaceutical preparation for treatment or prevention of chronic gastritis and acute gastritis according to any one of the above (1) to (9), wherein
(11) Any one of the above (1) to (9), wherein the mucosal protective / enhancing agent is one or more components selected from sucralfate, aldioxa, gefarnate, L-glutamine or derivatives thereof. The pharmaceutical or pharmaceutical preparation for treatment or prevention of chronic gastritis and acute gastritis described.
(12) The H2 blocker is one or more of cimetidine, famotidine, nizatidine, ranitidine, roxatidine or a pharmaceutically acceptable salt or derivative thereof, according to any one of (1) to (9) above Pharmaceuticals or pharmaceutical preparations for the treatment or prevention of chronic gastritis and acute gastritis.
(13) Chronic gastritis and acute as described in any one of (1) to (9) above, wherein a component containing aldioxa is used as a component having a high dissolution rate, and an H2 blocker is used as a component having a low dissolution rate. A pharmaceutical or pharmaceutical preparation for the treatment or prevention of gastritis.
(14) Chronic gastritis and acute as described in any of (1) to (9) above, wherein a component containing an H2 blocker is used as a component having a high dissolution rate, and sucralfate is used as a component having a low dissolution rate A pharmaceutical or pharmaceutical preparation for the treatment or prevention of gastritis.
(15) The pharmaceutical or pharmaceutical preparation for treating or preventing chronic gastritis and acute gastritis according to any one of (1) to (14) above, wherein the H2 blocker is famotidine or a derivative thereof.

  According to the present invention, H2 blocker and mucosal protective / enhancing agent can be absorbed in an optimal state by in vivo absorption for the treatment and prevention of acute gastritis, chronic gastritis, and eventually acute exacerbation of chronic gastritis. It has excellent effects in the treatment and prevention of chronic gastritis.

Hereinafter, the present invention will be described in detail.
The present invention is a pharmaceutical preparation for allowing a living body to absorb an H2 blocker and a mucosa protecting / enhancing agent in a state having a certain time difference. Various substances can be obtained by appropriately adjusting and selecting the solubility of the component containing the reinforcing agent, but generally the component containing the H2 blocker and the component containing the mucosal protective / enhancing agent are dissolved in vivo. The time difference may be 15 to 120 minutes, preferably 15 to 60 minutes, more preferably 20 to 50 minutes, and still more preferably 25 to 40 minutes. For example, in the case of famotidine and sucralfate or aldioxa, it is preferably 20 to 50 minutes, more preferably 25 to 40 minutes.

  The H2 blocker used in the present invention is not particularly limited as long as it has an action of blocking the H2 receptor among histamine receptors. For example, cimetidine, famotidine, nizatidine, ranitidine, roxatidine or a pharmaceutically acceptable salt thereof. Examples thereof include salts and derivatives. Of these, famotidine (chemical name: N- (1-Amino-3- {[2- (diamino methylene amino) -1,3-thiazol -4-yl] methylsulfanyl} propylidene) sulfamide) is most frequently used. The

  Further, the mucosal protective / enhancing agent used in the present invention is a substrate protein protective action (gastric mucosa protective action), gastric juice pepsin activity inhibitory action, antacid action, growth promotion / vascularization action of regenerating mucosa, or gastric / duodenal mucosa. It has an effect of increasing blood flow. Examples of such mucosal protective / enhancing agents include sucralfate, aldioxa, gefarnate, L-glutamine, and derivatives thereof.

  Among these mucosal protection / enhancement agents, with regard to mucosal protection / enhancement agents with relatively strong gastric mucosal protection, such as sucralfate, the formulation should be prepared so that the H2 blocker used is generally absorbed for 15 to 120 minutes ahead of time. In the case of a mucosal protective / enhancing agent having a relatively strong mucosal blood flow enhancing action, such as aldioxa, it is generally 15 to 120 minutes ahead of the H2 blocker. It is desirable to prepare and use the formulation for absorption.

  The pharmaceutical preparation of the present invention is prepared so that the component containing H2 blocker and the component containing mucosal protective / strengthening agent have different dissolution rates. Specifically, the H2 blocker and the mucosal protective / strengthening agent are separately molded together with an appropriate base, carrier, and additive to form granules having different solubility from each other. This is a capsule filled in a capsule. Alternatively, a nucleated tablet consisting of an inner core (core) and an outer shell, or a layered tablet of two or more layers, and a component containing an H2 blocker in one layer of the nucleated tablet or one of the layered tablets or Use one of the ingredients containing the mucosal protective / enhancing agent, and use the other ingredient in the outer shell of the nucleated tablet or the other layer of the layered tablet.

  In the case of granules and capsules, the dissolution rate and disintegration of one granule are increased by appropriately selecting the base, carrier, and additives used to prepare the granule, and the dissolution rate and disintegration of the other granule. What is necessary is just to make nature small. Similarly, in the case of tablets, by appropriately selecting a base, carrier, additive, and binder, the outer shell of the nucleated tablet and one layer of the layered tablet are increased in dissolution rate and disintegration. The dissolution rate and disintegration of the inner core and other layers of the layered tablet may be reduced.

  In the pharmaceutical preparation of the present invention, various bases, carriers, additives, and binders are appropriately selected and used according to the purpose in order to form granules and tablets and adjust their dissolution rate and disintegration property. Examples of such bases, carriers, additives, and binders include polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose. Acetate succinate, ethyl cellulose, aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer emulsion, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, partially pregelatinized starch, pregelatinized starch, hydroxypropyl starch , Stearic acid, stearate, hydrogenated oil, Fatty acid esters, cetyl alcohol, Kaunaubarou, higher fatty acids, paraffin wax or a combination thereof.

  Specifically, for example, in the case of a granule, a granule having a high dissolution rate can be obtained by producing the granule using a usual method. If necessary, after dissolving the water-soluble polymer and the active ingredient in a solvent, the speed of the active ingredient can be further increased by adhering or granulating it to some additive. A granule having a high elution rate of the active ingredient can also be obtained by adding a water-soluble polymer or the like to the solution in which the active ingredient is dissolved in some solvent and, if necessary, spray drying.

  Granules having a low dissolution rate can be obtained by coating granules produced by a usual method using a polymer base material that is insoluble or hardly soluble in water. Also, matrix type granules in which elution of the active ingredient is delayed can be obtained by kneading the waxy substance or polymer base material with the active ingredient. These granules are prepared and mixed to form granules. Moreover, a tablet and a capsule can also be manufactured using this granule.

  In the case of a nucleated tablet, the inner core (core) having a low dissolution rate is coated with a water-insoluble or hardly soluble polymer base material on a tablet produced by a conventional method to form an inner core having a low dissolution rate. Obtainable. It is also possible to obtain a matrix-type preparation by obtaining an uncoated tablet using a wax-like substance or a polymer base material. Granules produced by ordinary methods can be used for the outer shell portion having a high dissolution rate. If necessary, granules can be obtained by a method of granulating together with other additives using a solution in which an active ingredient is dissolved, or a method of spray drying this solution. If necessary, an additive such as a water-soluble polymer can be added to this solution.

  In the case of a multilayer tablet, the granule having the low dissolution rate of the granule shown above is used for the layer portion having a low dissolution rate, and the dissolution rate having the high dissolution rate described above is used for the other layer portion having a high dissolution rate What is necessary is just to prepare a multilayer tablet using a granule.

  Moreover, this invention is not limited to an oral solid preparation, The effect of this invention can be shown also with another type of oral preparation. For example, in the case of a syrup that is an oral liquid, for example, the active ingredient whose syrup environment is weakly basic and whose dissolution rate is to be increased is dissolved or suspended in the solution, and the active ingredient whose dissolution rate is to be decreased is indicated above. An oral solution can be prepared by coating granules having a low dissolution rate with a polymer that can be dissolved in the stomach.

  In the combination of the H2 blocker of the present invention and the mucosal protective / enhancing agent, the amount of the drug used varies depending on the drug used and the route of administration. Take 1 to 4 times. In particular, in the case of famotidine, 5 to 100 mg per day can be taken in 1 to 3 divided doses, but it is preferable to take 10 to 40 mg per day. The amount of the mucosal protective / enhancing agent varies depending on the drug used. For example, in the case of sucralfate, 500 to 4000 mg per day is taken in 1 to 3 times, but the dose can be appropriately increased or decreased depending on the patient's condition and the like. Aldioxa is also taken 100 to 500 mg a day in 1 to 3 divided doses, which can be appropriately increased or decreased depending on the patient's condition.

  Furthermore, in producing the pharmaceutical composition of the present invention, various additives generally used in the production of pharmaceutical compositions may be included as long as the effects of the present invention are not hindered. Such additives include adsorbents, preservatives, antioxidants, buffers, chelating agents, colorants, emulsifiers, flavoring / flavoring agents, surfactants, suspending agents, sweeteners, lubricants. , Binders, excipients, coating agents, disintegrating agents, fluidizing agents, brightening agents, tonicity agents and the like.

  Specifically, carmellose calcium, hydrous silicon dioxide, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, aluminum oxide, dextrin, silicon dioxide, magnesium metasilicate magnesium as the adsorbent Examples of the agent include benzoic acid or a salt thereof, phenol, sodium edetate, benzalkonium chloride, sodium sulfite, salicylic acid, sorbic acid, paraoxybenzoic acid or a salt thereof.

  Antioxidants include sodium nitrite, ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, soy lecithin, tocopherol, butylhydroxyanisole, benzotriazole, propyl gallate, and buffers include ascorbic acid, arginine, benzoic acid Acid or salt thereof, ammonium chloride, potassium chloride, sodium chloride, benzalkonium hydrochloride, arginine hydrochloride, glucosamine hydrochloride, sodium carbonate, hydrochloric acid, citric acid or salt thereof, glutamic acid, sodium hydrogen phosphate, acetic acid or salt thereof, tartaric acid, Examples thereof include sodium hydrogen carbonate, sodium carbonate, triethanolamine, lactic acid, boric acid, maleic acid, malic acid, phosphoric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate and the like.

  Coloring agents include indigo carmine, yellow iron oxide, yellow ferric oxide, carbon black, caramel, carotene, licorice extract, black iron oxide, titanium oxide, ferric oxide, disazo yellow, blue No. 1, yellow No. 4, etc. Examples include pigments, talc, copper chlorophyllin sodium, copper chlorophyll, phenol red, methylene blue, and riboflavin. Emulsifiers include carrageenan, glycerin, glycerin fatty acid ester, sucrose fatty acid ester, soybean lecithin, gelatin, polysorbate, and flavoring and flavoring agents. Various synthetic flavors, orange oil, orange essence, orange extract, caramel, licorice powder, camphor, cinnamon powder, cinnamon oil, sugar flavor, mint water, mint oil, vanilla flavor, vanillin, menthol, rose water It rose oil, aspartame, sweet hydrangea leaf, fennel, chlorella extract, saccharin, saffron, and the like.

  Surfactants include sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearyl ether, polyoxyethylene polyoxypropylene glycol, polysorbate, macrogol, sorbitan monooleate, glyceryl monostearate Sorbitan monolaurate, sodium lauryl sulfate, etc., as suspending agents, for example, sodium alginate, carmellose sodium, dry aluminum hydroxide gel, glycerin fatty acid ester, aluminum magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystals Cellulose / Carmellose sodium, Sucrose fatty acid ester, Propylene glycol fatty acid ester, Propylene glycol, Polysorbate, Macrogol, Ma Nitoru, like ethylene glycol monostearate.

  Examples of the lubricant include carnauba wax, glycerin fatty acid ester, hydrogenated oil, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, calcium stearate, talc and the like. Examples of binders include candy powder, gum arabic, pregelatinized starch, ethyl cellulose, carboxyvinyl polymer, carboxymethyl ethyl cellulose, carmellose sodium, agar, glycerin, vinyl acetate resin, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, Examples include hydroxypropylmethylcellulose, pullulan, pectin, povidone, macrogol, and water candy.

  Excipients include sugar powder such as candy powder, gum arabic, fructose, caramel, dry yeast, agar, xylitol, mannitol, erythritol, sorbitol, starches such as crystalline cellulose, wheat starch, corn starch, potato starch, silicic acid Calcium, magnesium silicate, magnesium oxide, refined sucrose, cetanol, ammonium carbonate, calcium carbonate, magnesium carbonate, dextran, tragacanth powder, silicon dioxide, lactose, sucrose, honey, glucose, powdered sugar, reduced maltose starch syrup, pectin, bentonite, For example, medicinal charcoal.

  Coating agents include ethyl acrylate / methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate polymer RS, gum arabic, ethyl cellulose, opadry, kaunalubaro, carboxyvinyl polymer, carboxymethylethylcellulose, triethyl citrate, glycerin, Glycerin fatty acid ester, wax, hard wax, cellulose acetate, vinyl acetate resin, cellulose acetate phthalate, honey beeswax, sucrose fatty acid ester, stearyl alcohol, stearic acid, calcium stearate, gelatin, shellac, purified white sugar, zein, cetanol, sorbitan Fatty acid ester, calcium lactate, honey, hydroxypropylcellulose, hydroxypropylmethyl cell Over scan, pullulan, macrogol, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, aluminum monostearate, liquid paraffin and the like.

  Examples of the disintegrant include alginic acid, carboxymethyl starch sodium, carmellose, carmellose calcium, crospovidone, starches, low-substituted carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, partially pregelatinized starch and the like. Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, and synthetic aluminum silicate. Further, as a matter of course, an additive that can be produced by these derivatives, or salts thereof, and combinations thereof are also included.

In the pharmaceutical preparation of the present invention, for the above-mentioned components that reduce the dissolution rate or disintegration property, in order to delay dissolution in vivo, the surface of the particles of the component is insoluble or slowly soluble polymer, for example, It can be coated with a film of an acrylic polymer such as an insoluble cellulose derivative such as ethyl cellulose or an ethyl acrylate / methyl methacrylate copolymer dispersion.
EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples. In the following examples, “%” is based on mass unless otherwise noted.

  In order to confirm the effectiveness of the pharmaceutical preparation in which the dissolution rate of the H2 blocker and the mucosal protective / enhancing agent of the present invention are different from each other, the following two types of evaluation methods for gastric mucosal lesions are used. The effect of improving gastric mucosal damage when H2 blocker and mucosal protective / enhancing agent were administered by various administration methods was evaluated.

i) Evaluation method :
Test method A (acetic acid ulcer model):
A stomach ulcer was created by opening a circular frame with a diameter of 7 mm at the stomach-pyloric boundary of a Wistar rat (male) weighing about 200 g, injecting 100% acetic acid into the frame, and rinsing acetic acid with physiological saline 60 seconds later. Was made. The drug is orally administered twice a day by the method described in the following administration method for 10 days from the next day after the operation, and the stomach is excised the day after the final administration, and the ulcer area (long diameter (mm × short diameter (mm) Was measured.

Test Method B (Water immersion restraint stress ulcer model):
Drugs were administered to Wistar rats (male) weighing about 100 g according to the method described below. After administration of the drug or 1 hour after the first drug administration, Wistar rats to which the drug was previously administered were immersed in a water bath at 23 ° C. until the xiphoid process. The Wistar rats were killed by anesthesia after 5 hours of water immersion, the stomach was removed, and the total length of the injured part (糜爛 index) was measured.

ii) Drug administration method :
The H2 blocker famotidine and the mucosal protective / enhancing agent sucralfate or aldioxa were administered by the methods of Tests 1 to 8 below.
Test 1: No drug is administered.
Test 2: Famotidine was orally administered at 10 mg / kg.
Test 3: Famotidine 10 mg / kg and sucralfate 100 mg / kg were orally administered simultaneously.
Test 4: Famotidine was orally administered at 10 mg / kg, and 30 minutes later, sucralfate at 100 mg / kg was orally administered.
Test 5: Sucralfate was orally administered at 100 mg / kg, and 30 minutes later, famotidine was orally administered at 10 mg / kg.
Test 6: Famotidine 10 mg / kg and aldioxa 100 mg / kg were orally administered simultaneously.
Test 7: Famotidine was orally administered at 10 mg / kg, and 30 minutes later, 100 mg / kg of aldioxa was orally administered.
Test 8: Aldioxa was orally administered at 100 mg / kg, and 30 minutes later, famotidine was orally administered at 10 mg / kg.

iii) Test results :
Tables 1 and 2 show the evaluation results by Test Method A (acetic acid ulcer model) for evaluating chronic gastric mucosal damage.

  When famotidine is used as an H2 blocker and sucralfate is used as a mucosal protective / enhancing agent, acetic acid ulcer, which is a model of chronic gastric mucosal damage, is effective even when administered simultaneously. It was confirmed that there was an even greater therapeutic effect when administered sucralfate followed by sucralfate.

  When famotidine is used as an H2 blocker and aldioxa is used as a mucosal protective / enhancing agent, it can be treated simultaneously with acetic acid ulcer, which is a model of chronic gastric mucosal damage, but aldioxa is first administered. It was confirmed that the administration of famotidine followed by famotidine had an even greater therapeutic effect.

  Next, Table 3 and Table 4 show the evaluation results by Test Method B (water immersion restraint stress ulcer model) for evaluating mucosal damage of acute gastric / duodenal ulcer.

  When famotidine is used as an H2 blocker and sucralfate is used as a mucosal protective / enhancing agent, even if these are administered simultaneously to a water immersion restraint stress ulcer, which is a model of acute gastric mucosal damage, there is a therapeutic effect. It was confirmed that when famotidine was administered first and sucralfate was administered thereafter, there was a greater therapeutic effect.

  When famotidine is used as an H2 blocker and aldioxa is used as a mucosal protective / enhancing agent, even if these are administered simultaneously against a water immersion restraint stress ulcer, which is a model of acute gastric mucosal damage, there is a therapeutic effect. It was confirmed that when aldioxa was administered first and then famotidine was administered, there was a greater therapeutic effect.

Famotidine-sucralfate formulation i) Production of famotidine granules 100 g of famotidine and 50 g of hydroxypropylmethylcellulose 2910 were dissolved in water. The previously prepared famotidine solution was added to 700 g of low-substituted hydroxypropylcellulose, and sprayed and granulated using a fluidized bed granulator.
ii) Production of sucralfate granules 1000 g of sucralfate, 200 g of lactose, 100 g of crystalline cellulose, and 100 g of low-substituted hydroxypropylcellulose were kneaded with a stirring granulator using water, and then pellets were prepared with an extrusion granulator. The pellet was rounded with a stirring granulator.
Using this granule, 413 g of an ethylcellulose aqueous dispersion, 104 g of triethyl citrate, and 52 g of hydroxypropylmethylcellulose 2910 were dispersed in 3400 g of purified water, and this solution was used to coat the previously produced granules.
iii) Production of capsules 45 g of the granules of i) above, 700 g of the granules of ii) and 5 g of hydrous silicon dioxide were mixed in a V-type mixer. The granules were filled into No. 1 capsules to give 300 mg of one capsule to prepare a famotidine-sucralfate formulation.

Famotidine-aldioxa compounding agent i) Production of famotidine tablets 1000 g of famotidine, 3200 g of lactose and 1400 g of corn starch were granulated with 2000 g of 10% hydroxypropylcellulose aqueous solution in a fluidized bed granulator. To 5220 g of the granules, 315 g of carmellose calcium and 45 g of magnesium stearate were added and mixed, and then compressed into tablets of 60 mg using a 6.0 mm diameter punch.
On the other hand, 2400 g of ethylcellulose aqueous dispersion, 160 g of triethyl citrate, and 2400 g of ethyl acrylate / methyl methacrylate copolymer emulsion were dispersed in 6400 g of purified water. Using this dispersion, 4800 g of the previously produced tablets were coated.
ii) Production of Aldioxa Granules 1000 g of aldioxa, 400 g of lactose, 190 g of crystalline cellulose, 60 g of croscarmellose sodium, and 20 g of hydroxypropyl cellulose were granulated with a stirred granulator using purified water. 20 g of magnesium stearate was added to the granules.
iii) Manufacture of tablets The tablet manufactured in i) is used as the inner core, and the tablet manufactured using a nucleated tableting machine so that the outer shell is 170 mg using the granules manufactured in ii) as the outer shell, and famotidine-aldioxa preparation Was prepared.

The pharmaceutical preparation of the present invention has a large therapeutic and preventive effect in acute gastritis, chronic gastritis, and acute exacerbation of chronic gastritis, and is useful as a therapeutic / preventive agent for gastritis.

Claims (15)

  A medicament for treating or preventing chronic gastritis and acute gastritis characterized by absorbing at least one absorption of one or more of H2 blockers and one or more of mucosal protective / enhancing agents with a time difference.   The pharmaceutical composition for treating or preventing chronic gastritis and acute gastritis according to claim 1, wherein the time difference between absorption of the H2 blocker and the mucosal protective / enhancing agent is 15 to 120 minutes.   A pharmaceutical preparation for the treatment or prevention of chronic gastritis and acute gastritis characterized in that the component containing H2 blocker and the component containing mucosal protective / strengthening agent are prepared so that their dissolution rates are different from each other .   The chronic gastritis and acute according to any one of claims 1 to 3, wherein the dissolution rate of the component containing H2 blocker is 2 to 50 times the dissolution rate of the component containing mucosal protective / enhancing agent. A pharmaceutical or pharmaceutical preparation for the treatment or prevention of gastritis.   The chronic gastritis and acute according to any one of claims 1 to 3, wherein the dissolution rate of the component containing the mucosal protective / enhancing agent is 2 to 50 times the dissolution rate of the component containing the H2 blocker. A pharmaceutical or pharmaceutical preparation for the treatment or prevention of gastritis.   The chronic gastritis according to any one of claims 3 to 5, wherein the component containing an H2 blocker and the component containing a mucosal protective / enhancing agent are separately prepared granules having different dissolution rates. A pharmaceutical preparation for the treatment or prevention of acute gastritis.   The component containing an H2 blocker and the component containing a mucosal protective / strengthening agent, each separately prepared granules having different dissolution rates, are encapsulated in capsules. A pharmaceutical preparation for treating or preventing chronic gastritis and acute gastritis according to any one of the above.   In the cored tablet consisting of the inner core and outer shell, the component containing the H2 blocker in the inner core and the component containing the mucosal protective / strengthening agent are used, and the component containing the H2 blocker in the outer shell is used to protect the mucous membrane. -The pharmaceutical preparation for treatment or prevention of chronic gastritis and acute gastritis according to any one of claims 3 to 5, wherein a component having a high dissolution rate is used among the components containing the reinforcing agent.   A multilayer tablet comprising two or more layers, wherein a component containing an H2 blocker is used in one layer, and a component containing a mucosal protective / strengthening agent is used in the other layer, 6. A pharmaceutical preparation for treatment or prevention of chronic gastritis and acute gastritis according to any one of 5.   Mucosal protective / enhancing agent has substrate protein protective action (gastric mucosal protective action), gastric juice pepsin activity inhibitory action, antacid action, growth promotion of regenerating mucosa, blood vessel increasing action, or gastric / duodenal mucosal blood flow increasing action The pharmaceutical or pharmaceutical preparation for treatment or prevention of chronic gastritis and acute gastritis according to any one of claims 1 to 9, wherein   The chronic gastritis and acute according to any one of claims 1 to 9, wherein the mucosal protective / enhancing agent is one or more components selected from sucralfate, aldioxa, gefarnate, L-glutamine or derivatives thereof. A pharmaceutical preparation for the treatment or prevention of gastritis.   The chronic gastritis and acute gastritis according to any one of claims 1 to 9, wherein the H2 blocker is one or more of cimetidine, famotidine, nizatidine, ranitidine, roxatidine or a pharmaceutically acceptable salt or derivative thereof. Or pharmaceutical preparations for the treatment or prevention of   A component containing aldioxa as a component having a high dissolution rate and an H2 blocker as a component having a low dissolution rate are used for the treatment or prevention of chronic gastritis and acute gastritis according to any one of claims 1 to 9 Pharmaceutical or pharmaceutical preparation.   The use of a component containing an H2 blocker as a component with a high dissolution rate and sucralfate as a component with a low dissolution rate, for the treatment or prevention of chronic gastritis and acute gastritis according to any one of claims 1 to 9 Pharmaceutical or pharmaceutical preparation. The medicament or pharmaceutical preparation for treating or preventing chronic gastritis and acute gastritis according to any one of claims 1 to 14, wherein the H2 blocker is famotidine or a derivative thereof.