JP2023012558A - Modifying agents for presence ratio of intestinal microflora - Google Patents

Abstract

To provide a novel medicament that helps altering the intestinal flora, particularly increasing the mucin layer, which can be expected to treat and/or prevent obesity, diabetes, etc.SOLUTION: The present invention provides a pharmaceutical composition for improving intestinal flora, comprising 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.SELECTED DRAWING: None

Description

The present invention provides therapeutic and/or preventive agents for diseases that improve intestinal flora and are expected to have therapeutic effects due to the improvement thereof, more specifically, therapeutic and/or therapeutic agents for obesity, diabetes, etc., containing quinolone compounds as active ingredients. Regarding prophylaxis.

In recent years, associations between intestinal bacteria and various diseases have been reported, among which Akkermansia muciniphila is being studied for association with obesity and diabetes. The genus Akkermansia is a new genus whose establishment was proposed in 2004 (Non-Patent Document 1). The fungal species belonging to this genus are one genus and one species, and the representative species is Akkermansia muciniphila. The bacterium is a Gram-negative, obligately anaerobic, non-motile, non-spore-forming, oval eubacterium. As a major feature, it is said to be a mucin-degrading bacterium, from which the name is derived, and it is said that it uses mucin as a carbon source, and it is said that there is a need for mucin in the culture conditions.

It is known that the abundance of Akkermansia muciniphila is decreased in diabetic and obese intestines. It has been reported that increasing Akkermansia muciniphila in the intestine of high-fat-fed mice to a normal level reduces body weight, fat percentage, and thickens the intestinal mucus layer (Non-Patent Documents 2 and 3). In addition, according to various documents, an increase in Akkermansia muciniphila is associated with thickening of the mucin layer, improvement of intestinal barrier function, inflammatory bowel disease (Non-Patent Documents 4 and 5), fatty liver, hepatitis, appendicitis (Non-Patent Document 6). ) and is known to be useful for diabetes (Non-Patent Document 7). In addition, the association with central system diseases such as epilepsy and amyotrophic lateral sclerosis (ALS) has been studied (Non-Patent Documents 8 and 9).

Patent Document 1 discloses specific quinolone antibacterial agents, and that these antibacterial agents exhibit antibacterial activity against Clostridioides difficile living in the intestinal tract.

WO2013/029548

M Derrien, M. International Journal of Systematic and Evolutionary Microbiology (2004). Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. lsson CL, et al. Obes (Silver Spring) (2012). Dao MC, et al. Gut (2016). Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Png CW, et al. Am J Gastroenterol (2010). Mucolytic bacteria with increased prevalence in IBD mucosa augmented in vitro utilization of mucin by other bacteria. Lyra A, et al. World J Gastroenterol (2012). Comparison of bacterial quantities in left and right colon biopsies and faeces. Swidsinski A, et al. Gut (2011). Zhang X, et al. PLoS One (2013). Human gut microbiota changes reveal the progression of glucose intolerance. Christine A. Olson,; Helen E. Vuong,; Jessica M. Yano,; Qingxing Y. Liang,; David J. Nusbaum,; Diet, Cell, 2018, 173 Eran Blacher,; Stavros Bashiardes,; Hagit Shapiro,; Daphna Rothschild,; Uria Mor,; Mally Dori-Bachash, et al.

An object of the present invention is to provide a new drug for treating and/or preventing obesity, diabetes, etc., which is expected by promoting changes in the intestinal flora, particularly increasing the intestinal mucin layer. to do.

As a result of intensive studies, the present inventors found that 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5, a known quinolone antibacterial agent -pyridyl)-4-oxo-3-quinoline carboxylic acid dramatically increases the occupancy of Akkermansia spp. The present inventors have found that it can be effective in the treatment of obesity, diabetes, and the like, and have completed the present invention.

That is, the present invention is as follows.
[Item 1] 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or its A pharmaceutical composition for improving intestinal flora, comprising a pharmaceutically acceptable salt as an active ingredient.

[Item 2] The pharmaceutical composition according to Item 1, which improves intestinal flora by increasing the intestinal occupancy of Akkermansia.

[Item 3] The pharmaceutical composition according to Item 1, which improves intestinal flora by increasing the intestinal mucin layer.

[Item 4] 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or its A drug for the treatment and/or prevention of a disease which can be expected to be improved by increasing the intestinal occupancy of Akkermansia, which contains a pharmaceutically acceptable salt as an active ingredient.

[Claim 5] 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or its A drug for the treatment and/or prevention of a disease which can be expected to be improved by increasing the intestinal mucin layer, which contains a pharmaceutically acceptable salt as an active ingredient.

[Item 6] The agent of item 4 or 5, wherein the disease is obesity and/or diabetes.

[Claim 7] 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or its A drug for treating and/or preventing obesity and/or diabetes, which contains a pharmaceutically acceptable salt as an active ingredient.

[Item 8] The drug according to any one of Items 4 to 7, which is an oral formulation.

[Item 9] The drug according to any one of Items 4 to 8, wherein the daily dose of the active ingredient is 0.1 mg to 30000 mg.

[Item 10] A therapeutically effective amount of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3 - A method of treating and/or preventing obesity and/or diabetes, which comprises administering a quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[Item 11] 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino -3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof.

[Claim 12] 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano for use in treating and/or preventing obesity and/or diabetes -5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof.

Oral administration of the compounds of the present invention rapidly and dramatically increases the occupancy of the genus Akkermansia, reconstituting the intestinal flora dominated by Akkermansia muciniphila and increasing mucins due to their proliferation. By improving these intestinal microflora, the present invention is expected as a therapeutic and prophylactic agent for obesity and diabetes.

3 shows the results of changes in the amount of mucin in Example 3. FIG. The results of body weight change in Example 5 are shown (**p<0.01, *p<0.05). The results of changes in blood glucose levels in Example 5 are shown (**p<0.01). The results of HbA1c change in Example 5 are shown (**p<0.01, *p<0.05).

1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid of the compound of the present invention is as follows. and is disclosed as Compound No. 2-18 in Patent Document 1, and its production method and antibacterial activity against Clostridioides difficile are also disclosed.

Since the compounds of the present invention may exist in the form of hydrates and/or solvates, these hydrates and/or solvates are also included in the compounds of the present invention.
Also included in the compounds of the present invention are deuterium conversion products obtained by converting ¹ H in any one or more of the compounds of the present invention to ² H(D).
The compound of the present invention obtained as a crystal and its pharmaceutically acceptable salt may have crystal polymorphs, and such crystal polymorphs are also included in the present invention.

"Pharmaceutically acceptable salt" means acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, inorganic acid salts such as phosphate, oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluene organic acid salts such as sulfonates and trifluoromethanesulfonates; and amino acid salts such as glutamates and aspartates. Examples of various bases and salts include alkali metal salts such as sodium salts and potassium salts; Examples thereof include alkaline earth metal salts such as salts, or ammonium salts.

In the present invention, the general term for bacteria inhabiting the intestines of humans and animals is "intestinal flora", and "intestinal flora" refers to the intestinal tracts of humans and animals, mainly living in the large intestine. It is a complex intestinal microbial ecosystem in which approximately 1,000 types and 100 trillion intestinal bacteria are closely related to each other and are in balance. The main improving effect is to increase the intestinal occupancy rate of the genus Akkermansia, where the representative species of the genus Akkermansia is Akkermansia muciniphila. The genus Akkermansia is a mucin-degrading bacterium, and by increasing the occupancy rate of the genus Akkermansia in the intestine, thickening of the mucin layer and improvement of the intestinal barrier function can be expected. appendicitis, diabetes, epilepsy, amyotrophic lateral sclerosis (ALS), autism, atopic dermatitis, etc., and anticancer effects (enhancement of immune checkpoint inhibitors such as PD1 antibodies) ), etc. are expected.

As the route of administration of the compound of the present invention, oral administration, direct administration to the intestinal tract (enema, suppository, etc.) and the like are selected. It varies depending on the administration method, symptoms and age of the patient. For example, in the case of oral administration, it is usually about 0.02 mg to 500 mg, preferably about 0.01 mg to 200 mg, more preferably about 1 mg to 10 mg, still more preferably about 2 mg to 20 mg per 1 kg body weight of a human or mammal. It can be administered in several doses, and specifically, the daily dose for humans is about 0.1 mg to 30000 mg, preferably about 5 mg to 12000 mg, more preferably about 50 mg to 6000 mg, still more preferably about 100 mg to about 100 mg. 1200 mg.

Dosage forms include tablets, capsules, granules, powders, liquids, syrups, suspensions, enemas, suppositories and the like. These formulations can be prepared according to a conventional method. Liquid preparations may be dissolved or suspended in water, a suitable aqueous solution, or other suitable medium at the time of use. Tablets and granules may also be coated by well-known methods. Formulations are manufactured by known methods using pharmaceutically acceptable additives.
Additives include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, coloring agents, solubilizers, solubilizers, thickeners, dispersants, and stabilizers, depending on the purpose. , sweeteners, flavors and the like can be used. Specifically, for example, lactose, mannitol, calcium hydrogen phosphate, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, crospovidone, sodium starch glycolate. , hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, ferric oxide, yellow ferric oxide, etc. mentioned.

When the compound of the invention is prepared in a single formulation, for example, but not limited to, the compound of the invention may comprise from 0.1 to 85% by weight of the total composition of the formulation. Preferably, the compound of the invention is 10-70% by weight of the total composition of the formulation.

Furthermore, the compounds of the present invention can be used in combination or in combination with other drugs for the purpose of enhancing their effects and/or reducing side effects.

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited thereto. The acquisition of the compound of the present invention (hereinafter referred to as "test substance") used here is shown below.
Test substance [1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid]: Otsuka Obtained from Pharmaceutical Co., Ltd.

Example 1. Effect of Test Substance on Intestinal Microflora of Normal Mice The test substance was administered to normal Balb/c mice for 21 days, and fecal analysis was performed to examine the effect on the intestinal microflora.
(Test method)
Blalb/c mice were orally administered 5% Gum Arabic as a vehicle or 10 mg/kg of the test substance once daily, and feces were collected on days 7 and 21. Collected stool was crushed and homogenized with EZ-beads (Promega) together with a buffer, and bacterial genomic DNA was isolated from the obtained supernatant using a Maxwell ^™ RSC automatic nucleic acid purifier (Promega) according to the instruction manual. Extracted.
The concentration of the obtained bacterial genomic DNA sample was measured using DropSense96 (SCRUM), and after adjusting to 5 ng/μL, the V4 region of the ribosomal RNA gene was concentrated by PCR to prepare an amplicon. Prepared amplicon 5 μL, Nextera Index 1 adapters (N7xx) 5 μL, Nextera Index 2 adapters (S5xx) 5 μL, 2×KAPA HiFi HS ReadyMix 25 μL, Nuclease free water 10 μL were mixed as a reaction solution, which was placed in a thermal cycler. 8 cycles of 95°C x 3 min, (95°C x 30 sec, 55°C x 30 sec, 72°C x 30 sec) were reacted in steps of 72°C x 5 min to prepare a library.
After purifying the resulting library with Agencourt AMPure XP, the concentration was measured with DropSense96, and the quality was confirmed with a 2100 Bioanalyzer Electrophoresis System (Agilent).
A library for each sample was prepared at a concentration of 1 nM and then mixed in equal amounts to obtain a library for analysis. After denaturing the library for analysis with 0.1 N NaOH and neutralizing the single-stranded ones, readjusting the concentration to about 1.5 pM, use the next-generation sequencer MiniSeq (Illumina) according to the instruction manual. manipulated and analyzed. After the MiniSeq analysis is completed, a sequence file (.fastq), which is base sequence data, is automatically created inside the sequencer. Analysis of bacterial flora analysis was performed.

(result)
The results of the intestinal flora analysis on the 7th and 21st days are shown in Tables 1 and 2 below. Although no change in the intestinal flora over time was observed due to the administration of the solvent, a clear change was observed 7 days after the administration of the test substance as compared with the solvent administration group. Administration of the test substance significantly increased the occupancy of Akkermansia spp. in the fecal intestinal flora to more than 50%. Twenty-one days after administration, the ratio decreased, but the ratio remained high compared to the solvent-administered group.

Example 2. Effect of test substance on intestinal flora of colitis model mice (test method)
Naive T cells (CD4+CD62L+CD44- cells) were isolated from the spleens of Balb/c mice using the Naive CD4+ T Cell Isolation Kit, Mouse (Miltenyi Biotec). 500 μL/body (5×10 5 cells/body) were transplanted into the cells to create a colitis model. On the 14th day after cell transplantation, grouping was performed using body weight as an index, and 5% Gum Arabic as a solvent or 10 mg/kg of the test substance was orally administered once daily for 21 consecutive days. Naive are SCID mice without cell transplantation. The collected feces were subjected to intestinal microflora analysis using a next-generation sequencer. Detailed measurement and analysis methods were performed in the same manner as in Example 1.

(result)
The results of the 21-day gut microbiota analysis are shown in Tables 3 to 5 below. No significant changes in the intestinal microflora over time were observed in the solvent-administered group or the untreated group, but clear changes were observed after administration of the test substance. The administration of the test substance markedly increased the occupancy of the genus Akkermansia from day 7 onwards.

Example 3. Analysis of fecal microbiota and measurement of fecal mucin content in rats by twice-daily administration of the test substance (100 mg/kg)
Vehicle (5% Gum Arabic) or test substance (100 mg/kg) was administered to normal SD rats twice a day, and feces were collected daily from each group to analyze the fecal flora and measure the amount of mucin. did
(Test method)
The solvent, 5% Gum Arabic or 100 mg/kg of the test substance was orally administered to SD rats twice a day, rat feces were collected daily, and the feces were crushed with EZ-beads (Promega) along with buffer. - After homogenization, bacterial genomic DNA was extracted from the supernatant using a Maxwell ^™ RSC automatic nucleic acid purifier (Promega) according to the instruction manual.
The concentration of the obtained bacterial genomic DNA sample was measured using DropSense96 (SCRUM), and after adjusting to 5 ng/μL, the V4 region of the ribosomal RNA gene was concentrated by PCR to prepare an amplicon. Prepared amplicon 5 μL, Nextera Index 1 adapters (N7xx) 5 μL, Nextera Index 2 adapters (S5xx) 5 μL, 2×KAPA HiFi HS ReadyMix 25 μL, Nuclease free water 10 μL were mixed as a reaction solution and placed in a thermal cycler. 8 cycles of 95°C x 3 min, (95°C x 30 sec, 55°C x 30 sec, 72°C x 30 sec) were reacted in steps of 72°C x 5 min to prepare a library.
After purifying the resulting library with Agencourt AMPure XP, the concentration was measured with DropSense96, and the quality was confirmed with a 2100 Bioanalyzer Electrophoresis System (Agilent).
A library for each sample was prepared at a concentration of 1 nM and then mixed in equal amounts to obtain a library for analysis. The library for analysis was denatured with 0.1N NaOH to neutralize the single-stranded ones. manipulated and analyzed. After the MiniSeq analysis is completed, a sequence file (.fastq), which is base sequence data, is automatically created inside the sequencer. Analysis of bacterial flora analysis was performed.
The amount of mucin in feces was measured by collecting rat feces daily, freeze-drying the sample, and using FecalMucin Assay kit (Cosmo Bio Co., Ltd.).

(result)
The results of the solvent control group and the test substance administration group are shown in Tables 6 and 7 below.
Various intestinal flora were confirmed in the fecal flora of the solvent control group, and no significant change was observed from day 0 to day 7. The occupancy of the genus Akkermansia was very low.
On the other hand, administration of the test substance (100 mg/kg) temporarily reduced the diversity and species of the intestinal flora. After 1 day, the occupancy rate of the genus Akkermansia increased remarkably, the genus Lactobacillus increased, and the genus Parabacteroides slightly increased. These three species accounted for 90%, and the diversity of the intestinal flora decreased. After 3 days, the occupancy of the genus Akkermansia increased further to about 40%, the genus Lactobacillus decreased significantly, and the genus Parabacteroides slightly increased. After 7 days, the occupancy rate of the genus Akkermansia decreased slightly, the occupancy rate of the genus Parabacteroides increased slightly, and the proportion of other bacterial species also increased, indicating a tendency of recovery of diversity.

Fig. 1 shows changes in the amount of mucin in the vehicle-administered group and the test substance-administered group of rats. No significant change was observed in the fecal mucin content of the solvent control group from day 0 to day 7. On the other hand, administration of the test substance (100 mg/kg) increased fecal mucin levels from day 1, reached a maximum after 3 days, and was maintained for 7 days.
It was shown that there was a significant and strong correlation (r=0.52, P<0.05) between the increased occupancy of Akkermansia spp. and the amount of intestinal mucin.

Example 4. Test articles (1, 3, 10 mg/kg), SASP (300 mg/kg), CPFX (500 mg/kg) twice daily, and DEX (1 mg/kg) once daily in DSS-induced rat colitis model Analysis of fecal microflora by single administration
Vehicle (5% Gum Arabic) and test substance (1, 3, 10 mg/kg) were administered twice daily to a rat colitis model induced by oral ingestion of dextran sulfate sodium (DSS) in rats. The feces of each group were collected daily, and the fecal flora was analyzed. SASP (Sulfasalazine), CPFX (Ciprofloxacin), and DEX (Dexamethasone) were also evaluated as comparators for this test article.
(Test method)
The rats were acclimatized with a water bottle from three days before, and then divided into groups. After grouping, the 3% DSS solution was placed in a water bottle, and the rats were allowed to ingest it freely (the intake start date was defined as day 0) to induce colitis. For the untreated group, water for injection was placed in a water bottle and freely ingested throughout the experimental period. From the day after grouping until the end of the study, 1 test article (1, 3, 10 mg/kg) or control article SASP (300 mg/kg), CPFX (500 mg/kg), and vehicle (5% Gum Arabic) Oral administration was performed twice a day using an intragastric tube. The control drug DEX (1 mg/kg) was orally administered once a day using an intragastric tube. Rat feces were collected daily and the intestinal flora was analyzed using a next-generation sequencer. Detailed measurement and analysis methods were performed in the same manner as in Example 3.

(result)
The results for each group are shown in Tables 8 to 15 below. Different fecal microbiota changes were observed in each group. Various intestinal flora were confirmed in the fecal flora of the untreated group, and no significant change was observed from day 0 to day 7. Bacteroides occupancy increased over time in the vehicle control group. On the other hand, administration of the test substance (1, 3, 10 mg/kg) markedly increased the occupancy rate of Akkermansia from day 1. The extent of the increase was found to be dose-dependent. In the SASP group and DEX group of the control drug administration group, changes in the bacterial flora were observed, but no significant change was observed in the occupancy rate of the genus Akkermansia. In the CPFX group, no significant change in the occupancy rate of Akkermansia species was observed until the 7th day, despite the extremely high dose of 500 mg/kg.

Example 5. Effect of the test substance in obesity model mice induced by high-fat diet In order to evaluate the efficacy of the test substance against obesity and diabetes, the test substance was orally administered to obesity model mice induced by high-fat diet, and blood glucose levels and hemoglobin Alc (HbA1c) were measured. evaluated.
(Test method)
C57BL/6J mice were divided into groups using body weight, blood sugar level and HbA1c as indices, and were given a high-fat diet from the day of grouping, and orally administered a solvent control and a test substance (10 mg/kg) once a day. Body weight and food consumption were measured twice weekly. Blood glucose levels were measured using blood from the tail vein once every two weeks from the first day of administration. HbA1c was measured by DCA bandage (Siemens Healthcare Diagnostics) using tail vein blood once every 4 weeks.

(result)
Untreated mice (on normal diet) gained only a small amount of weight until day 63, but the high-fat diet vehicle control group showed significant weight gain compared to the untreated group (after 63 days, p<0.01). The test substance-administered group on the high-fat diet significantly suppressed body weight gain compared with the vehicle control group (p<0.05 after 63 days).
As for blood glucose level, significant increase in blood glucose level was observed in the high-fat diet solvent control group compared with the untreated group (63 days later, p<0.01). The high-fat diet test substance-administered group significantly suppressed the increase in blood glucose level compared to the vehicle control group (p<0.01 after 63 days), and was at the same level as the untreated group.
As for HbA1c, a significant increase in HbA1c was also observed in the high-fat diet solvent control group compared to the untreated group (p<0.01 after 63 days). The high-fat diet test substance-administered group significantly suppressed the increase in HbA1c compared to the vehicle control group (p<0.05 after 63 days). Compared to the high-fat diet vehicle control group, administration of the test substance significantly inhibited body weight gain, significantly inhibited blood glucose level elevation, and significantly inhibited HbA1c elevation. Usefulness for obesity and diabetes was suggested.

Claims (12)

1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or pharmaceutically acceptable thereof A pharmaceutical composition for improving intestinal microflora, comprising as an active ingredient a salt of the present invention. 2. The pharmaceutical composition of claim 1, which improves intestinal flora by increasing intestinal occupancy of Akkermansia. 2. The pharmaceutical composition of claim 1, which improves intestinal flora by increasing the intestinal mucin layer. 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or pharmaceutically acceptable thereof A drug for the treatment and/or prevention of a disease that can be expected to be improved by increasing the intestinal occupancy of Akkermansia genus, comprising as an active ingredient a salt of the genus Akkermansia. 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or pharmaceutically acceptable thereof A drug for the treatment and/or prevention of a disease that can be expected to be improved by increasing the intestinal mucin layer, which contains a salt as an active ingredient. 6. Medicament according to claim 4 or 5, wherein the disease is obesity and/or diabetes. 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or pharmaceutically acceptable thereof A drug for the treatment and/or prevention of obesity and/or diabetes, containing as an active ingredient a salt of obesity and/or diabetes. The drug according to any one of claims 4 to 7, which is an oral drug. Medicament according to any one of claims 4 to 8, characterized in that the daily dose of active ingredient is between 0.1 mg and 30000 mg. A therapeutically effective amount of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid A method for treating and/or preventing obesity and/or diabetes, which comprises administering obesity and/or diabetes or a pharmaceutically acceptable salt thereof to a patient in need thereof. 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano) for the manufacture of a medicament for treating and/or preventing obesity and/or diabetes -5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof. [Claim 12] 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano for use in treating and/or preventing obesity and/or diabetes -5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof.

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