Intestinal injury inhibitors

Abstract

To provide an intestinal injury inhibitor that can inhibit intestinal injury caused by a drug or the like.SOLUTION: An intestinal injury inhibitor contains at least one selected from the group consisting of aluminum hydroxide and magnesium oxide.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an agent for suppressing intestinal injury. [Background technology]

[0002] Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) in the arachidonic acid cascade, thereby suppressing the synthesis of prostaglandins and exerting analgesic, antipyretic, and anti-inflammatory effects. The above-mentioned NSAIDs, which are the first-choice analgesics, are known to induce gastric damage. Prostaglandin preparations, proton pump inhibitors, antacids, etc. are known as inhibitors of this gastric damage (Patent Document 1, Patent Document 2).

[0003] In recent years, it has become clear that NSAIDs cause not only stomach damage but also intestinal damage (see Non-Patent Document 1). The mechanisms of stomach damage and intestinal damage are different, and it has been reported that proton pump inhibitors, which are effective in suppressing stomach damage, exacerbate damage to the small intestine (Non-Patent Documents 2 and 3). Intestinal damage has few subjective symptoms, which can lead to delayed treatment, and an effective method for suppressing intestinal damage has not yet been established.

[0004] Aluminum hydroxide, magnesium oxide, magnesium aluminometasilicate, etc., which are known as antacids, are also included in the manufacturing and marketing approval standards for over-the-counter drugs as gastric mucosa protecting ingredients, and are known to have an effect of suppressing gastric damage (Patent Document 3, Patent Document 4), but their effect on intestinal damage is unknown. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2006-52210 A [Patent Document 2] JP 2013-136566 A [Patent Document 3] Japanese Patent Application Publication No. 198620 / 1983 [Patent Document 4] JP 2006-52210 A [Non-patent literature]

[0006] [Non-Patent Document 1] THE GI FOREFRONT Vol.10 No.1 2014.6 20-22 [Non-Patent Document 2] Clinical Rheumatology, 29:77-84, 2017 [Non-Patent Document 3] Clinical Gastroenterology and Hepatology 2016;14:809-815 Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an agent for suppressing intestinal injury caused by drugs or the like. [Means for solving the problem]

[0008] The present inventors conducted extensive research into compounds capable of suppressing intestinal damage caused by drugs and the like, and as a result discovered that aluminum hydroxide and magnesium oxide are effective against the intestinal damage, thereby completing the present invention.

[0009] The present invention has the following aspects. [1] An agent for suppressing intestinal damage, comprising at least one member selected from the group consisting of aluminum hydroxide and magnesium oxide. [2] The intestinal injury suppressant described in [1], wherein the intestinal injury is injury caused by drug administration. [3] The intestinal injury inhibitor according to [2], wherein the drug is a nonsteroidal anti-inflammatory drug. Effect of the Invention

[0010] According to the present invention, it is possible to provide an agent for suppressing intestinal injury caused by drugs or the like. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 is a schematic diagram showing eight sections of the rat small intestine. [Diagram 2] This figure shows the lesion area rate in the group administered loxoprofen (LOX), the group administered loxoprofen and dried aluminum hydroxide gel (LOX + dried aluminum hydroxide gel), the group administered loxoprofen and magnesium oxide (LOX + magnesium oxide), and the group administered loxoprofen and magnesium aluminometasilicate (LOX + magnesium aluminometasilicate). [Diagram 3] FIG. 1 shows the injury area rates in the ibuprofen-administered group (IBP), the ibuprofen and dried aluminum hydroxide gel-administered group (IBP+dried aluminum hydroxide gel), and the ibuprofen and magnesium oxide-administered group (IBP+magnesium oxide). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The intestinal injury inhibitor of the present invention contains at least one selected from the group consisting of aluminum hydroxide and magnesium oxide. At least one selected from the group consisting of aluminum hydroxide and magnesium oxide is preferably contained as an active ingredient of the intestinal injury inhibitor of the present invention. The intestinal injury inhibitor of the present invention only needs to contain at least one selected from the group consisting of aluminum hydroxide and magnesium oxide, and may contain aluminum hydroxide or magnesium oxide alone, or may contain both aluminum hydroxide and magnesium oxide.

[0013] The aluminum hydroxide contained in the intestinal injury inhibitor of the present invention may be, for example, aluminum hydroxide gel, dried aluminum hydroxide gel, aluminum hydroxide gel-sodium bicarbonate coprecipitate, aluminum hydroxide-magnesium carbonate mixed dried gel, aluminum hydroxide-magnesium carbonate-calcium carbonate coprecipitate, etc., with dried aluminum hydroxide gel being particularly preferred.

[0014] The intestine to which the intestinal injury inhibitor of the present invention is applied includes the small intestine and the large intestine. The small intestine includes the duodenum, jejunum, and ileum. The large intestine includes the cecum, colon, and rectum.

[0015] In the intestinal injury inhibitor of the present invention, the cause of intestinal injury is not particularly limited, and examples thereof include stress, drug administration, etc., but the intestinal injury inhibitor of the present invention is preferably applied to injury caused by drug administration. Note that the intestinal injury of the present invention is a state in which a decrease in mucus, erosion, ulcer, inflammation, bleeding, etc. are observed in the intestine.

[0016] The drug causing the intestinal injury is not particularly limited, and examples thereof include NSAIDs, such as diclofenac, indomethacin, etodolac, naproxen, meloxicam, ibuprofen, loxoprofen, celecoxib, ketoprofen, and pharma- ceutical acceptable salts thereof.

[0017] The administration route of the drug that causes injury includes oral administration, parenteral administration (intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, nasal administration, pulmonary administration, etc.), etc. Among these, the intestinal injury inhibitor of the present invention is preferably applied to intestinal injury caused by oral administration (ingestion).

[0018] When using the intestinal damage suppressant of the present invention, the single dose of aluminum hydroxide or magnesium oxide for an adult is preferably 1 to 2000 mg, more preferably 5 to 2000 mg, and even more preferably 10 to 1000 mg.

[0019] In using the intestinal injury suppressant of the present invention, the daily dose of aluminum hydroxide or magnesium oxide for adults is preferably 3 to 6000 mg, more preferably 15 to 6000 mg, and even more preferably 30 to 3000 mg. For example, when aluminum hydroxide gel is used, the daily dose can be 60 to 3000 mg, and when magnesium oxide is used, the daily dose can be 30 to 2000 mg.

[0020] The intestinal injury suppressant of the present invention may contain other drugs in addition to the aluminum hydroxide and magnesium oxide, if necessary (these drugs are called combination drugs). Examples of the other drugs include Antipyretics, analgesics and anti-inflammatory drugs (e.g., salicylic acid drugs such as acetylsalicylic acid, sodium salicylate, ethenzamide, salicylamide, sazapyrine, etc., propionic acid drugs such as ibuprofen and loxoprofen, fenamic acid drugs such as flufenamic acid and mefenamic acid, arylacetic acid drugs such as diclofenac sodium and indomethacin, pyrazolidine drugs such as phenylbutazone and oxyphenylbutazone, pyrimidine drugs such as bucolome, oxicam drugs such as piroxicam, pyrine drugs such as sulpyrine, isopropylantipyrine, acetaminophen, etc.); Antihistamines (e.g., diphenhydramine hydrochloride, chlorpheniramine maleate, clemastine fumarate, carbinoxamine maleate, etc.); Cough suppressants (e.g., dextromethorphan hydrobromide, dihydrocodeine phosphate, codeine phosphate, tipepidine hibenzate, cloperastine hydrochloride, benzonatate, etc.); Expectorants (e.g., noscapine hydrochloride, bromhexine hydrochloride, etc.); Mucolytics such as L-cysteine ​​hydrochloride, L-methylcysteine ​​hydrochloride, and acetylcysteine; mucus repair agents such as carbocysteine; Anti-inflammatory enzymes such as lysozyme chloride; Anti-inflammatory agents such as glycyrrhizic acid; Hypnotics and sedatives such as allylisopropylacetylurea; mucolubricants such as ambroxol hydrochloride; Antifungal agents such as terbinafine hydrochloride; Bronchodilators or asthma medications (e.g., beta2-adrenergic receptor stimulants such as pseudoephedrine, ephedrine hydrochloride, methylephedrine hydrochloride, terbutaline hydrochloride, isoproterenol, salbutamol, and terbutaline, xanthine drugs such as theophylline, aminophylline, and proxyphylline, cromoglycic acid, etc.); Examples include amino acids; herbal medicines; vitamins (fat-soluble vitamins such as vitamins A, D, E, K, and U; water-soluble vitamins such as vitamins B, C, and P); etc. These other drugs may be used alone or in combination. The content of the other drugs in the intestinal injury suppressant of the present invention is set at an appropriate prescribed amount depending on the intended use of the pharmaceutical preparation, taking into account efficacy and safety. The intestinal injury inhibitor of the present invention can inhibit intestinal injury caused by drug administration, and is therefore particularly useful and preferable in combination drugs containing antipyretic, analgesic and anti-inflammatory drugs (for example, propionic drugs such as ibuprofen, loxoprofen, etc., fenamic acid drugs such as flufenamic acid, mefenamic acid, etc., arylacetic acid drugs such as diclofenac sodium, indomethacin, etc., pyrazolidine drugs such as phenylbutazone, oxyphenylbutazone, etc., pyrimidine drugs such as bucolome, oxicam drugs such as piroxicam, pyrine drugs such as sulpyrine, isopropylantipyrine, etc.) among the other drugs mentioned above.

[0021] The intestinal injury inhibitor of the present invention may contain optional ingredients other than those described above, so long as the effects of the present invention are not impaired. The optional ingredients include binders, excipients, lubricants, flavors, flavorings (sweeteners, acidulants, etc.), colorants, stabilizers, coating agents, plasticizers, masking agents, etc., and may be used alone or in appropriate combinations of two or more in appropriate amounts. Examples of binders that can be used include starch, alpha-starch, sucrose, gelatin, powdered gum arabic, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, pullulan, and dextrin. Examples of excipients that can be used include low-substituted hydroxypropylcellulose, corn starch, lactose, talc, crystalline cellulose (such as Ceolus), powdered sugar, sugar alcohols such as mannitol, and light anhydrous silicic acid. Examples of lubricants include magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, sucrose fatty acid esters, sodium stearyl fumarate, etc. Examples of flavorings include menthol, limonene, plant essential oils (peppermint oil, mint oil, lychee oil, orange oil, lemon oil, etc.), etc. Examples of sweeteners include sodium saccharin, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, and sucralose. As the acidulant, for example, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or salts thereof can be used. Examples of coating agents that can be used include hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, carboxymethylcellulose, ethylcellulose, and Opadry (trade name) (manufactured by Nippon Colorcon LLC). As the plasticizer, for example, polyethylene glycol, triacetin, etc. can be used. As the masking agent, for example, titanium oxide, talc, etc. can be used.

[0022] The administration form of the intestinal injury inhibitor of the present invention is not particularly limited. For example, oral administration (e.g., oral administration, sublingual administration, etc.), parenteral administration (intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, nasal administration, pulmonary administration, etc.) and the like can be mentioned. Among these, the less invasive administration form is preferable, and oral administration (ingestion) is more preferable.

[0023] Examples of dosage forms of orally administered agents (internal preparations) or compositions for oral administration (internal compositions) include liquid (liquid), syrup (syrup), tablet (tablet, tablet), capsule (capsule), powder (granule, fine granule), soft capsule (soft capsule with gelatin base or the like), hard capsule (hard capsule), liquid (liquid), syrup (syrup), solid, semi-liquid, cream, and paste forms. The method of preparing the intestinal injury inhibitor of the present invention in a formulation is not particularly limited, and can be carried out by a conventional method depending on the formulation. For example, at least one selected from the group consisting of aluminum hydroxide and magnesium oxide, which are the active ingredients of the intestinal injury inhibitor of the present invention, can be mixed with other ingredients as is, or a part or all of the ingredients can be granulated or coated and then mixed to produce a granular mixture, which can be used as a granular agent (granules, fine granules, powder). The granular mixture can also be compressed into tablets and, if necessary, coated to form tablets. EXAMPLES

[0024] The present invention will be described in detail below with reference to examples, but the present invention is not limited to the following examples.

[0025] [Example 1] (1)Animals Eight-week-old male SD rats were pre-bred for at least four days, fasted for 18 hours (water was available ad libitum), fed, and then used for the test one hour later.

[0026] (2) Sample (suspension) The sample was prepared so that the dose of the sample for rats was 10 mL / kg, and the dose of loxoprofen (LOX) was 68.1 mg / kg. 5% gum arabic solution was used as the solvent. The amount of loxoprofen was the amount of dihydrate.

[0027] (3) Administration of samples Each sample was administered at 10mL / kg, and the dosage of each drug was prepared as shown in Table 1. Specifically, an amount of sample corresponding to the rat's weight (for example, 2mL if the rat's weight was 200g) was placed in a disposable syringe equipped with a rat oral administration probe and administered orally by force. Five rats were used for each example (n=5).

[0028] [Table 1]

[0029] (4) Evaluation of small intestinal toxicity Evans blue was administered to the tail vein 30 minutes before the small intestine was removed, and the small intestine was removed under isoflurane anesthesia 20 hours after administration of each sample. The removed small intestine was divided into eight sections as shown in Figure 1, and each section was spread on a filter paper and imaged. The damaged area was stained blue due to leakage of Evans blue, and the area of ​​the damaged area (Evans blue leakage site) was calculated using ImageJ. The areas of the lower part of the small intestine (sections 5 to 8) were then added together, and the percentage of the damaged area was calculated for each sample administration group according to the following formula. Injury area rate (%) = (Evans blue leakage area / total tissue area) x 100 The results are shown in Figure 2.

[0030] As shown in Figure 2, the small intestinal damage observed in the loxoprofen administration group (LOX) was suppressed by adding dried aluminum hydroxide gel or magnesium oxide to loxoprofen (LOX). On the other hand, the small intestinal damage was aggravated by adding magnesium aluminometasilicate to loxoprofen (LOX). These results demonstrate that dried aluminum hydroxide gel and magnesium oxide have the effect of suppressing small intestinal damage caused by loxoprofen.

[0031] [Example 2] The sample was prepared so that the dose of the sample to the rat was 10 mL / kg, and the dose of ibuprofen (IBP) was 200 mg / kg. Note that 5% gum arabic solution was used as the solvent.

[0032] Each sample was administered to rats at 10 mL / kg, and the dosage of each drug was prepared as shown in Table 2. Except for removing the small intestine 24 hours after administration of each sample, each sample was administered to rats in the same manner as in Example 1, and small intestinal injury was evaluated. The results are shown in Figure 3.

[0033] [Table 2]

[0034] As shown in Figure 3, the small intestinal damage observed in the ibuprofen-administered group (IBP) was suppressed by adding dried aluminum hydroxide gel or magnesium oxide to ibuprofen (IBP). This result demonstrated that dried aluminum hydroxide gel and magnesium oxide have the effect of suppressing small intestinal damage caused by ibuprofen.

Claims

[Claim 1] An agent for suppressing intestinal injury, comprising at least one selected from the group consisting of aluminum hydroxide and magnesium oxide, An agent for suppressing intestinal injury, wherein the intestinal injury is injury caused by administration of a nonsteroidal anti-inflammatory drug (excluding agents for suppressing small intestinal injury containing loxoprofen or a salt thereof and magnesium oxide).

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