Oral compositions comprising inorganic porous bodies

Abstract

The oral composition according to the present invention contains an inorganic porous body, and when choline and primary / secondary / tertiary amine or ammonia, which are present as a mixture in an equal molar amount in an artificial intestinal juice, are mixed at a concentration of 2 g / L for 1 hour in an amount of 11.8 g per 1 mmol of choline, the adsorption rate of the primary / secondary / tertiary amine or ammonia is 60.0% or more, and the adsorption rate of choline is 40.0% or less. Alternatively, the oral composition according to the present invention contains a zeolite having an MFI structure and having a molar ratio of SiO2 to Al2O3 of 30.0 to 130000.0 (inclusive), or the zeolite having an FER structure and having a molar ratio of SiO2 to Al2O3 of 15.0 to 130000.0 (inclusive), or the oral composition according to the present invention contains a zeolite having an MFI structure and having a molar ratio of SiO2 to Al2O3 of 15.0 to 130000.0 (inclusive).

Description

Technical Field

[0001] This invention relates to an oral composition containing inorganic porous bodies, which is a composition formulated for selectively adsorbing primary / secondary / tertiary amines or ammonia compared to choline. Background Technology

[0002] Primary, secondary, and tertiary amines or ammonia include substances that exist as toxins in organisms, and their excessive presence in organisms can cause various diseases.

[0003] For example, in trimethylamineuria (fishy odor syndrome), due to genetic defects such as the trimethylamine-metabolizing enzyme FMO3, the level of trimethylamine (TMA) in bodily fluids becomes higher than in healthy individuals. As a volatile component, trimethylamine is excreted in sweat, breath, urine, and other bodily fluids, causing a fishy body odor, reducing the quality of life and social activities of patients with trimethylamineuria, and subsequently leading to mental symptoms such as depression. There is no fundamental cure; treatment mainly focuses on symptoms, such as limiting the consumption of foods containing high levels of choline, lecithin (phosphatidylcholine), carnitine, betaine (N,N,N-trimethylglycine), trimethylamine-N-oxide (TMAO), etc., which are precursors to trimethylamine, and / or using acidic soaps that effectively flush out the alkaline substance trimethylamine to wash the body.

[0004] In addition, TMAO, a metabolite of trimethylamine, has been reported as a pathogenic factor for atherosclerosis. It has also been reported to be associated with the following diseases: coronary heart disease, heart failure with preserved ejection fraction, ST-segment elevation myocardial infarction, atrial fibrillation, abdominal aortic aneurysm, ischemic stroke, post-stroke cognitive impairment, mild cognitive impairment, Alzheimer's disease, obesity, chronic kidney disease with type 2 diabetes, cardiovascular complications of chronic kidney disease, diabetic retinopathy, non-alcoholic steatohepatitis, polycystic ovary syndrome, Parkinson's disease, and colorectal cancer.

[0005] In addition, there are reports that excessive histamine production by intestinal bacteria leads to an increase in histamine concentration in the digestive tract, which activates H4 receptors and induces abdominal pain in patients with irritable bowel syndrome.

[0006] In addition, when liver detoxification from ammonia to urea becomes insufficient due to liver failure, cirrhosis, portosystemic shunt, urea cycle disorder, organic acidemia, etc., a state of excess ammonia in the circulating blood, namely hyperammonemia, is formed, which can lead to hepatic encephalopathy.

[0007] As in the examples above, it is believed that detoxification and / or treatment of disease can be achieved by adsorbing and removing excess primary / secondary / tertiary amines or ammonia, which are toxins or pathogens. However, the selectivity of choline, a basic organic molecule with similar properties and also a nutrient, remains a challenge. Choline is an essential nutrient for organisms, especially indispensable for development. It has been reported that choline deficiency can cause various diseases.

[0008] As materials (adsorbents) for adsorbing and removing alkaline compounds from biological fluids, and more broadly from water, known examples include activated carbon, cation exchange resins, clay minerals, inorganic porous materials, and metal-organic frameworks (MOFs). Choline, primary / secondary / tertiary amines, and ammonia are all alkaline compounds. When they exist in water in the same cationic form, it is difficult to distinguish and adsorb choline from primary / secondary / tertiary amines or ammonia; such adsorbents are currently unknown.

[0009] Patent document 1 discloses the use of zeolite to treat trimethylamineuria.

[0010] Primary, secondary, and tertiary amines, ammonia, or their metabolites include substances that exist as toxins in organisms, and their excessive presence can cause various diseases. It is believed that removing excessive primary, secondary, and tertiary amines or ammonia as toxins or pathogens through adsorption could be used to treat poisoning or disease. However, this also removes choline, a molecule with similar properties and a nutrient, posing a toxicity challenge for adsorbents. Therefore, selective adsorption and removal of primary, secondary, and tertiary amines or ammonia compared to choline is required.

[0011] Patent Document 1 does not specifically disclose an example of using zeolite to adsorb trimethylamine, nor does it disclose the specific characteristics of the zeolite used to selectively adsorb trimethylamine relative to choline. It completely fails to focus on the aforementioned adsorption selectivity.

[0012] Existing technical documents

[0013] Patent documents

[0014] Patent Document 1: U.S. Patent Application Publication No. 2018 / 0200291 Summary of the Invention

[0015] The problem the invention aims to solve

[0016] The present invention was made in view of the above circumstances, and provides an oral composition with good safety and capable of selectively adsorbing and removing primary / secondary / tertiary amines, ammonia or their metabolites.

[0017] Solution for solving the problem

[0018] To address the aforementioned issues, the inventors conducted in-depth research on adsorbents and discovered an oral composition containing inorganic porous bodies that selectively adsorbs primary / secondary / tertiary amines or ammonia compared to choline.

[0019] The present invention was completed based on the above insights.

[0020] That is, the main points of this invention include the following.

[0021] [1] An oral composition comprising an inorganic porous body,

[0022] When choline and primary / secondary / tertiary amines or ammonia present in an equimolar mixture in artificial intestinal fluid are mixed at a concentration of 2 g / L for 1 hour with the above-mentioned inorganic porous body containing 11.8 g of choline relative to 1 mmol, the adsorption rate of primary / secondary / tertiary amines or ammonia is 60.0% or more, and the adsorption rate of choline is 40.0% or less.

[0023] [1-1] According to the oral composition described above [1], when the inorganic porous body containing 11.8 g of choline in an equimolar mixture in artificial intestinal fluid is mixed at a concentration of 2 g / L for 1 hour, the adsorption rate of the primary / secondary / tertiary amine or ammonia is 70.0% or more, and the adsorption rate of choline is 40.0% or less.

[0024] [1-2] According to the oral composition described above [1] or above [1-1], when the inorganic porous body containing 11.8 g of choline in an equimolar mixture in artificial intestinal fluid is mixed at a concentration of 2 g / L for 1 hour, the adsorption rate of the primary / secondary / tertiary amine or ammonia is 80.0% or more, and the adsorption rate of choline is 40.0% or less.

[0025] [1-3] The oral composition according to any one of [1] to [1-2] above, wherein, for choline and primary / secondary / tertiary amines or ammonia present in an equimolar mixture in artificial intestinal fluid, when the above-mentioned inorganic porous body, which is 11.8 g relative to 1 mmol of choline, is mixed at a concentration of 2 g / L for 1 hour, the adsorption rate of primary / secondary / tertiary amines or ammonia is 90.0% or more, and the adsorption rate of choline is 40.0% or less.

[0026] [1-4] According to the oral composition described above [1] or above [1-1], when the inorganic porous body containing 11.8 g of choline in an equimolar mixture in artificial intestinal fluid is mixed at a concentration of 2 g / L for 1 hour, the adsorption rate of the primary / secondary / tertiary amine or ammonia is 70.0% or more, and the adsorption rate of choline is 30.0% or less.

[0027] [1-5] The oral composition according to any one of [1] to [1-2] above, wherein, for choline and primary / secondary / tertiary amines or ammonia present in an equimolar mixture in artificial intestinal fluid, when the above-mentioned inorganic porous body, which is 11.8 g relative to 1 mmol of choline, is mixed at a concentration of 2 g / L for 1 hour, the adsorption rate of primary / secondary / tertiary amines or ammonia is 80.0% or more, and the adsorption rate of choline is 20.0% or less.

[0028] [1-6] The oral composition according to any one of [1] to [1-3] above, wherein, for choline and primary / secondary / tertiary amines or ammonia present in an equimolar mixture in artificial intestinal fluid, when the above-mentioned inorganic porous body, which is 11.8 g relative to 1 mmol of choline, is mixed at a concentration of 2 g / L for 1 hour, the adsorption rate of primary / secondary / tertiary amines or ammonia is 90.0% or more, and the adsorption rate of choline is 10.0% or less.

[0029] [2] The oral composition according to any one of [1] to [1-6] above, wherein the adsorption rate of primary / secondary / tertiary amines or ammonia of the inorganic porous body is more than 2.00 times that of choline.

[0030] [2-1] According to the oral composition described in [2] above, the adsorption rate of primary / secondary / tertiary amines or ammonia by the inorganic porous body is more than 2.50 times that of choline.

[0031] [3] The oral composition according to any one of [1] to [2-1] above, wherein the inorganic porous body is aluminosilicate or silicate.

[0032] [4] The oral composition according to [3] above, wherein the aluminosilicate is a zeolite.

[0033] [5] According to the oral composition described in [4] above, the zeolite has a maximum number of rings of 10 and a maximum diameter of the diffuser spheres in the pores of 3.68 Å or more.

[0034] [5-1] According to the oral composition described above [5], the zeolite has a maximum number of rings of 10 and a maximum diameter of the diffuser spheres in the pores of 3.70 Å or more.

[0035] [5-2] The oral composition according to [5] or [5-1] above, wherein the zeolite has a maximum number of rings of 10 and a maximum diameter of the diffuser sphere in the pores of 3.75 Å or more.

[0036] [5-3] The oral composition according to any one of [5] to [5-2] above, wherein the zeolite has a maximum number of rings of 10 and a maximum diameter of the diffuser sphere in the pores of 4.22 Å or more.

[0037] [5-4] The oral composition according to any one of [5] to [5-3] above, wherein the zeolite has a maximum number of rings of 10 and a maximum diameter of the diffuser sphere in the pores of 4.50 Å or more.

[0038] [5-5] The oral composition according to any one of [5] to [5-4] above, wherein the zeolite has a maximum number of rings of 10 and a maximum diameter of the diffuser sphere in the pores of 4.65 Å or more.

[0039] [5-6] The oral composition according to any one of [5] to [5-5] above, wherein the zeolite has a maximum number of rings of 10 and a maximum diameter of the diffuser sphere in the pores of 4.69 Å or more.

[0040] [5-7] The oral composition according to any one of [5] to [5-6] above, wherein the maximum number of rings of the zeolite is 10 and the diameter of the maximum diffuser sphere in the pores is 4.91 Å or less.

[0041] [5-8] The oral composition according to any one of [5] to [5-7] above, wherein the maximum number of rings of the zeolite is 10 and the diameter of the maximum diffusion sphere in the pores is 4.90 Å or less.

[0042] [5-9] The oral composition according to any one of [5] to [5-8] above, wherein the maximum number of rings of the zeolite is 10 and the diameter of the maximum diffusion sphere in the pores is 4.85 Å or less.

[0043] [5-10] The oral composition according to any one of [5] to [5-9] above, wherein the maximum number of rings of the zeolite is 10 and the diameter of the maximum diffusion sphere in the pores is 4.80 Å or less.

[0044] [5-11] The oral composition according to any one of [5] to [5-10] above, wherein the maximum number of rings of the zeolite is 10 and the diameter of the maximum diffusion sphere in the micropore is 4.75 Å or less.

[0045] [5-12] The oral composition according to any one of [5] to [5-11] above, wherein the maximum number of rings of the zeolite is 10 and the diameter of the maximum diffusion sphere in the pores is 4.73 Å or less.

[0046] [5-13] The oral composition according to any one of [5] to [5-12] above, wherein the zeolite has a maximum number of rings of 10 and a maximum diameter of the diffuser sphere within the pores of 4.71 Å or less.

[0047] [6] The oral composition according to any one of [4] to [5-13] above, wherein the zeolite is an MFI structure or a FER structure.

[0048] [6-1] The oral composition according to [6] above, wherein the zeolite has an MFI structure.

[0049] [7] The oral composition according to any one of [4] to [6-1] above, wherein the zeolite is a zeolite in which the molar ratio of SiO2 to Al2O3 is 15.0 or more and 130,000 or less.

[0050] [7-1] According to the oral composition described above [7], the zeolite is a zeolite in which the molar ratio of SiO2 to Al2O3 is 18.0 or more and 129000.0 or less.

[0051] [7-2] The oral composition according to [7] or [7-1] above, wherein the zeolite is a zeolite in which the molar ratio of SiO2 to Al2O3 is 30.0 or more and 129000.0 or less.

[0052] [8] The oral composition according to any one of [7] to [7-2] above, wherein the zeolite is a zeolite in which the molar ratio of SiO2 to Al2O3 is 30.0 or more and 80.0 or less.

[0053] [9] The oral composition according to any one of [4] to [8] above, wherein the external surface area of ​​the zeolite is less than 33.0 m². 2 / g.

[0054] [9-1] The oral composition according to any one of [4] to [9] above, wherein the external surface area of ​​the zeolite is less than 30.0 m². 2 / g.

[0055] [9-2] The oral composition according to any one of [4] to [9-1] above, wherein the external surface area of ​​the zeolite is less than 26.0 m². 2 / g.

[0056] [9-3] The oral composition according to any one of [4] to [9-2] above, wherein the external surface area of ​​the zeolite is 20.0 m². 2 / g or less.

[0057] [9-4] The oral composition according to any one of [4] to [9-3] above, wherein the external surface area of ​​the zeolite is 15.0 m². 2 / g or less.

[0058] [9-5] The oral composition according to any one of [4] to [9-4] above, wherein the external surface area of ​​the zeolite is 13.3 m². 2 / g or less.

[0059] [9-6] The oral composition according to any one of [4] to [9-5] above, wherein the zeolite has an MFI structure and the half-width of the maximum peak in the range of 2θ = 7.9000° ± 0.5000° in the powder X-ray diffraction pattern measured by Cu-Kα rays is 0.0100° or more and 0.1800° or less.

[0060] [9-7] The oral composition according to any one of [4] to [9-6] above, wherein the zeolite has an MFI structure and the half-width of the maximum peak in the range of 2θ = 7.9000° ± 0.5000° in the powder X-ray diffraction pattern measured by Cu-Kα rays is 0.0100° or more and 0.1500° or less.

[0061] [9-8] The oral composition according to any one of [4] to [9-7] above, wherein the zeolite has an MFI structure and the half-width of the maximum peak in the range of 2θ = 7.9000° ± 0.5000° in the powder X-ray diffraction pattern measured by Cu-Kα rays is 0.0100° or more and 0.1300° or less.

[0062] [9-9] The oral composition according to any one of [4] to [9-8] above, wherein the median particle size of the zeolite is 5.5 μm or more.

[0063] [9-10] The oral composition according to any one of [4] to [9-9] above, wherein the median particle size of the zeolite is 10.0 μm or more.

[0064] [9-11] The oral composition according to any one of [4] to [9-10] above, wherein the median particle size of the zeolite is 11.7 μm or more.

[0065] [9-12] The oral composition according to any one of [4] to [9-11] above, wherein the cumulative frequency 10% particle size of the zeolite is 2.5 μm or more.

[0066] [9-13] The oral composition according to any one of [4] to [9-12] above, wherein the cumulative frequency 10% particle size of the zeolite is 5.0 μm or more.

[0067] [9-14] The oral composition according to any one of [4] to [9-13] above, wherein the cumulative frequency 10% particle size of the zeolite is 5.3 μm or more.

[0068] [9-15] The oral composition according to any one of [4] to [9-13] above, wherein the crystal shape of the zeolite is coffin-shaped.

[0069] [9-16] The oral composition according to any one of [1] to [9-15] above is a pharmaceutical composition, supplement, food or food additive.

[0070]

[10] The oral composition according to any one of [1] to [9-16] above is a pharmaceutical composition.

[0071]

[11] The oral composition according to

[10] above is used for the prevention, treatment or symptom relief of diseases caused by primary / secondary / tertiary amines, ammonia or their metabolites.

[0072]

[12] The oral composition according to

[11] above, wherein the primary / secondary / tertiary amine, ammonia or their metabolites comprise one or more selected from the group consisting of trimethylamine, dimethylamine, methylamine, histamine, ammonia and trimethylamine-N-oxide.

[0073]

[13] The oral composition according to

[12] above, wherein the primary / secondary / tertiary amine, ammonia or their metabolites are trimethylamine or trimethylamine-N-oxide.

[0074]

[14] The oral composition according to any one of

[11] to

[13] above, wherein the disease caused by primary / secondary / tertiary amines, ammonia or their metabolites is selected from the group consisting of: trimethylamineuria, cardiovascular disease, glaucoma, atherosclerosis, coronary heart disease, heart failure with preserved ejection fraction, ST-segment elevation myocardial infarction, atrial fibrillation, abdominal aortic aneurysm, ischemic stroke, post-stroke cognitive impairment, mild cognitive impairment, Alzheimer's disease, obesity, chronic kidney disease with type 2 diabetes, cardiovascular complications of chronic kidney disease, diabetic retinopathy, non-alcoholic steatohepatitis, polycystic ovary syndrome, Parkinson's disease, colorectal cancer, irritable bowel syndrome, hyperammonemia, urea cycle disorder, organic acidemia, hepatic encephalopathy and portosystemic shunt.

[0075]

[15] According to the oral composition described above

[14] , the above-mentioned disease is a disease caused by trimethylamine, and the above-mentioned disease is trimethylamineuria, cardiovascular disease or glaucoma.

[0076] [15-1] According to the oral composition described above

[15] , the above-mentioned disease is a disease caused by trimethylamine, and the above-mentioned disease is trimethylamineuria.

[0077]

[16] According to the oral composition described above

[14] , wherein the above-mentioned disease is a disease caused by trimethylamine-N-oxide, and the above-mentioned disease is atherosclerosis, coronary heart disease, heart failure with preserved ejection fraction, ST-segment elevation myocardial infarction, atrial fibrillation, abdominal aortic aneurysm, ischemic stroke, post-stroke cognitive impairment, mild cognitive impairment, Alzheimer's disease, obesity, chronic kidney disease with type 2 diabetes, cardiovascular complications of chronic kidney disease, diabetic retinopathy, non-alcoholic steatohepatitis, polycystic ovary syndrome, Parkinson's disease or colorectal cancer.

[0078] [16-1] According to the oral composition described above

[16] , the disease is caused by trimethylamine-N-oxide and the disease is atherosclerosis.

[0079]

[17] According to the oral composition described above

[14] , the disease is a histamine-induced disease, and the disease is irritable bowel syndrome.

[0080]

[18] According to the oral composition described above

[14] , wherein the above-mentioned disease is a disease caused by ammonia, and the above-mentioned disease is hyperammonemia, urea cycle disorder, organic acidemia, hepatic encephalopathy or portosystemic shunt.

[0081]

[19] The oral composition according to any one of

[10] to

[18] above contains zeolite as an active ingredient and is administered 1 to 5 times a day, wherein the dosage of the zeolite is 200 mg to 42000 mg per dose.

[0082]

[20] According to the oral composition described above

[19] , the dosage of the zeolite is 500 mg to 2000 mg per dose.

[0083]

[21] A method for manufacturing the oral composition described in any one of [4] to

[20] above, comprising obtaining zeolite by hydrothermal synthesis without the use of an organic structure directing agent.

[0084]

[22] According to the method described in

[21] above, sodium carbonate and / or sodium sulfate are used as raw materials.

[0085]

[23] The method described in

[21] or

[22] above includes conversion of an acid to a proton.

[0086]

[24] According to the method described in

[23] above, wherein the acid is sulfuric acid or nitric acid.

[0087]

[25] The method according to any one of

[20] to

[24] above, wherein the method further includes surface treatment of the hydrothermally synthesized zeolite in a solution containing a Si element source.

[0088]

[26] An oral composition for the treatment, prevention, or symptom relief of a disease selected from the group consisting of trimethylamineuria, atherosclerosis, irritable bowel syndrome, and hyperammonemia.

[0089] The oral composition contains zeolite.

[0090] The aforementioned zeolite possesses an MFI structure, and the molar ratio of SiO2 to Al2O3 is greater than 30.0 and less than 130,000.0, or...

[0091] The zeolite described above has a FER structure, and the molar ratio of SiO2 to Al2O3 is above 15.0 and below 130,000.0.

[0092] [26-1] According to the oral composition described in

[26] above, the zeolite has an MFI structure, and the molar ratio of SiO2 to Al2O3 is 30.0 or more and 80.0 or less.

[0093] The zeolite described above has a FER structure, and the molar ratio of SiO2 to Al2O3 is above 15.0 and below 130,000.0.

[0094]

[27] The oral composition according to

[26] or [26-1] above, wherein the zeolite is a zeolite in which the molar ratio of SiO2 to Al2O3 is 30.0 or more and 80.0 or less.

[0095]

[28] The oral composition according to any one of

[26] to

[27] above, wherein the external surface area of ​​the zeolite is less than 33.0 m². 2 / g.

[0096] [28-1] The oral composition according to any one of

[26] to

[28] above, wherein the external surface area of ​​the zeolite is less than 30.0 m². 2 / g.

[0097] [28-2] The oral composition according to any one of

[26] to [28-1] above, wherein the external surface area of ​​the zeolite is less than 26.0 m². 2 / g.

[0098] [28-3] The oral composition according to any one of

[26] to [28-2] above, wherein the external surface area of ​​the zeolite is 20.0 m². 2 / g or less.

[0099] [28-4] The oral composition according to any one of

[26] to [28-3] above, wherein the external surface area of ​​the zeolite is 15.0 m². 2 / g or less.

[0100] [28-5] The oral composition according to any one of

[26] to [28-4] above, wherein the external surface area of ​​the zeolite is 13.3 m². 2 / g or less.

[0101] [28-6] The oral composition according to any one of

[26] to [28-5] above, wherein the zeolite has an MFI structure and the half-width of the maximum peak in the range of 2θ = 7.9000° ± 0.5000° in the powder X-ray diffraction pattern measured by Cu-Kα rays is 0.0100° or more and 0.1800° or less.

[0102] [28-7] The oral composition according to any one of

[26] to [28-6] above, wherein the zeolite has an MFI structure and the half-width of the maximum peak in the range of 2θ = 7.9000° ± 0.5000° in the powder X-ray diffraction pattern measured by Cu-Kα rays is 0.0100° or more and 0.1500° or less.

[0103] [28-8] The oral composition according to any one of

[26] to [28-7] above, wherein the zeolite has an MFI structure and the half-width of the maximum peak in the range of 2θ = 7.9000° ± 0.5000° in the powder X-ray diffraction pattern measured by Cu-Kα rays is 0.0100° or more and 0.1300° or less.

[0104] [28-9] The oral composition according to any one of

[26] to [28-8] above, wherein the median particle size of the zeolite is 5.5 μm or more.

[0105] [28-10] The oral composition according to any one of

[26] to [28-9] above, wherein the median particle size of the zeolite is 10.0 μm or more.

[0106] [28-11] The oral composition according to any one of

[26] to [28-10] above, wherein the median particle size of the zeolite is 11.7 μm or more.

[0107] [28-12] The oral composition according to any one of

[26] to [28-11] above, wherein the cumulative frequency 10% particle size of the zeolite is 2.5 μm or more.

[0108] [28-13] The oral composition according to any one of

[26] to [28-12] above, wherein the cumulative frequency 10% particle size of the zeolite is 5.0 μm or more.

[0109] [28-14] The oral composition according to any one of

[26] to [28-13] above, wherein the cumulative frequency 10% particle size of the zeolite is 5.3 μm or more.

[0110] [28-15] The oral composition according to any one of

[26] to [28-14] above, wherein the crystal shape of the zeolite is coffin-shaped.

[0111]

[29] The oral composition according to any one of

[26] to [28-15] above is a pharmaceutical composition.

[0112]

[30] According to the oral composition described above

[29] , the zeolite is administered 1 to 5 times a day, and the dosage of the zeolite is 200 mg to 42000 mg per dose.

[0113]

[31] According to the oral composition described in

[30] above, the dosage of the zeolite is 500 mg to 2000 mg per dose.

[0114]

[32] A method for manufacturing an oral composition according to any one of

[26] to

[31] above, wherein zeolite is obtained by hydrothermal synthesis without the use of an organic structure directing agent.

[0115]

[33] According to the method described in

[32] above, sodium carbonate and / or sodium sulfate are used as raw materials.

[0116]

[34] The method described in

[32] or

[33] above includes conversion of an acid to a proton.

[0117]

[35] According to the method described in

[34] above, wherein the acid is sulfuric acid or nitric acid.

[0118]

[36] The method according to any one of

[32] to

[35] above, wherein the method further includes surface treatment of the hydrothermally synthesized zeolite in a solution containing a Si element source.

[0119]

[37] A method of treatment, prevention, or symptom relief for a disease selected from the group consisting of trimethylamineuria, atherosclerosis, irritable bowel syndrome, and hyperammonemia, comprising administering an amount of an orally administered composition containing zeolite as an active ingredient, effective for treatment, to a recipient who requires treatment, prevention, or symptom relief for a disease selected from the group consisting of trimethylamineuria, atherosclerosis, irritable bowel syndrome, and hyperammonemia.

[0120] The oral composition described above is any one of the oral compositions described above

[26] to

[31] .

[0121]

[38] Use of a zeolite for the manufacture of oral compositions for the treatment, prevention or symptom relief of diseases selected from the group consisting of trimethylamineuria, atherosclerosis, irritable bowel syndrome and hyperammonemia.

[0122] The oral composition described above is any one of the oral compositions described above

[26] to

[31] .

[0123]

[39] An oral composition comprising zeolite for the treatment, prevention or symptom relief of a disease selected from the group consisting of trimethylamineuria, atherosclerosis, irritable bowel syndrome and hyperammonemia.

[0124] The oral composition is any one of the oral compositions described in

[26] to

[31] above.

[0125] The effects of the invention

[0126] According to the present invention, by using an oral composition containing inorganic porous bodies, the essential nutrient choline is almost not removed, and primary / secondary / tertiary amines or ammonia that act as toxins or pathogens can be selectively removed, which is useful for the prevention, treatment or symptom relief of diseases caused by primary / secondary / tertiary amines, ammonia or their metabolites. Attached Figure Description

[0127] Figure 1 This is a histogram showing the distribution of the number of compounds with the half-value width of the maximum peak in the range of 2θ = 7.9000° ± 0.5000° of XRPD for MFI type zeolites with TMA adsorption rate less than 60% or choline adsorption rate greater than 40%, and MFI type zeolites with TMA adsorption rate greater than 60% and choline adsorption rate less than 40%.

[0128] Figure 2 It is a graph showing the results of particle size distribution of zeolites in Examples 26, 34, 6, and 22.

[0129] Figure 3 This is a graph showing the adsorption amounts of TMA (top), choline (middle), and arginine (bottom) over time for Examples 26, 34, and Comparative Example 6.

[0130] Figure 4 It is a graph showing the time-varying release of choline in Comparative Example 6, Comparative Example 22, Example 26 and Example 34.

[0131] Figure 5 It is a graph representing the energy shift during the process of TMA or choline adsorption along the thickness direction (z-axis) of the zeolite layer on the

[010] and

[100] planes, calculated using first-principles calculations based on density functional theory.

[0132] Figure 6-1 This diagram illustrates the cross-sectional structure of the zeolite layer at the energy reference point (z=11Å), the highest energy barrier point (z=7Å), and the internal adsorption point (z=0Å) when analyzing the adsorption process of TMA on the zeolite layer along the thickness direction (z-axis) of the

[010] plane using first-principles calculations based on density functional theory. It should be noted that for zeolite, the lattice is set to twice its original value in the z-axis direction for display.

[0133] Figure 6-2 This diagram illustrates the cross-sectional structure of the zeolite layer at the energy reference point (z=8Å), the highest energy barrier point (z=5Å), and the internal adsorption point (z=0Å) when analyzing the adsorption of choline on the zeolite layer along the thickness direction (z-axis) of the

[010] plane using first-principles calculations based on density functional theory. It should be noted that for zeolite, the lattice is set to twice its original value in the z-axis direction for display.

[0134] Figure 6-3 This diagram shows the cross-sectional structure of the zeolite layer at the energy reference point (z=9Å), the highest energy barrier point (z=5Å), and the internal adsorption point (z=0Å) when analyzing the adsorption process of TMA on the zeolite layer along the thickness direction (z-axis) of the

[100] plane using first-principles calculations based on density functional theory. It should be noted that for zeolite, the lattice is set to twice its original value in the z-axis direction for display.

[0135] Figure 6-4 This diagram shows the cross-sectional structure of the zeolite layer at the energy reference point (z=9Å), the highest energy barrier point (z=7Å), and the internal adsorption point (z=0Å) when analyzing the adsorption of choline on the zeolite layer along the thickness direction (z-axis) of the

[100] plane using first-principles calculations based on density functional theory. It should be noted that for zeolite, the lattice is set to twice its original value in the z-axis direction for display.

[0136] Figure 7 This is a diagram showing the structure of the highest energy barrier (z = 5~7 Å) when analyzing the adsorption of TMA or choline on the zeolite layer along the thickness direction (z-axis) of the

[010] plane using first-principles calculations based on density functional theory, viewed from the z-axis direction. It should be noted that for zeolite, the lattice is set to twice its original value in the z-axis direction for display.

[0137] Figure 8 The graph shows the plasma concentration of d9-TMA in mice under fasting cholinergic load after a large dose of the zeolite from Example 34 was administered over time (top) and its AUC (bottom). Results are expressed as mean ± standard error, and † indicates a significant difference relative to the vehicle group (Shirley-Williams test, P < 0.05).

[0138] Figure 9 This is a graph showing the plasma concentrations of d9-choline (top) and d9-TMA (bottom) in cholinergic-loaded mice under fasting after a large dose of zeolite from Comparative Example 6 was administered. Results are expressed as mean ± standard error.

[0139] Figure 10 This is a diagram showing the XRPD patterns of Example 34 (top) and Example 52 (bottom).

[0140] Figure 11 This is a conceptual diagram of the physiological pharmacokinetic (PBPK) model of d9-choline, d9-TMA, and d9-TMAO in mice after oral administration of d9-choline.

[0141] Figure 12-1This is a graph comparing the individual measured values ​​(dashed line) and the predicted values ​​(solid line) based on the PBPK model in the plasma concentrations of d9-choline (top), d9-TMA (middle), and d9-TMAO (bottom) in the choline-loaded mice under fasting over time.

[0142] Figure 12-2 This is a graph showing the time-lapse individual measured values ​​(dashed line) of plasma concentrations of d9-choline (top), d9-TMA (middle), and d9-TMAO (bottom) in fasted cholinergic-loaded mice when the zeolite of Example 34 was administered at a dose of 500 mg / kg, compared with the predicted values ​​(solid line) based on the PBPK model.

[0143] Figure 12-3 This is a graph showing the time-lapse individual measured values ​​(dashed line) of plasma concentrations of d9-choline (top), d9-TMA (middle), and d9-TMAO (bottom) in fasted cholinergic-loaded mice when the zeolite of Example 34 was administered at a dose of 1000 mg / kg, compared with the predicted values ​​(solid line) based on the PBPK model.

[0144] Figure 12-4 This is a graph showing the time-lapse individual measured values ​​(dashed line) of plasma concentrations of d9-choline (top), d9-TMA (middle), and d9-TMAO (bottom) in fasted cholinergic-loaded mice when the zeolite of Example 34 was administered at a dose of 2000 mg / kg, compared with the predicted values ​​(solid line) based on the PBPK model.

[0145] Figure 13 This is a graph showing the urinary excretion of d9-TMA and TMAO (top), native TMA and TMAO (middle), and d9-TMA, d9-TMAO, native TMA, and native TMAO (bottom) in mice subjected to high doses of the zeolite from Example 34 under cholinergic loading. Results are expressed as mean ± standard error, with # indicating a significant difference relative to the carrier group (Williams multiple comparison test, #: P < 0.025, ##: P < 0.005, ###: P < 0.0005). It should be noted that the urinary excretion of the zeolite from Example 70 at a dose of 1000 mg / kg is also included in the graph. Results are expressed as mean ± standard error, with * indicating a significant difference relative to the carrier group (Student's t-test, *: P < 0.05, **: P < 0.01). Detailed Implementation

[0146] The present invention will now be described in detail.

[0147] The oral composition of the present invention comprises an inorganic porous body.

[0148] When choline and primary / secondary / tertiary amines or ammonia present in an equimolar mixture in artificial intestinal fluid are mixed at a concentration of 2 g / L for 1 hour with the above-mentioned inorganic porous body containing 11.8 g of choline relative to 1 mmol, the adsorption rate of primary / secondary / tertiary amines or ammonia is 60.0% or more, and the adsorption rate of choline is 40.0% or less.

[0149] <Inorganic Porous Materials>

[0150] Inorganic porous materials refer to inorganic materials that have multiple pores inside, preferably inorganic materials that have a large number of fine pores with a diameter of less than 100 μm inside.

[0151] Inorganic materials are preferably silicates. Silicates are compounds that contain at least silicon (Si) and oxygen (O), and some of these atoms may be replaced by other atoms.

[0152] For example, as a silicate, it can also be an aluminosilicate in which some silicon atoms are replaced by aluminum atoms. That is, the inorganic material is preferably a silicate or an aluminosilicate.

[0153] Aluminosilicates are compounds containing at least aluminum (Al), silicon (Si), and oxygen (O), but some of these atoms may be further replaced by other atoms. The aluminosilicates in this invention comprise those containing isotopes (e.g., 2 H, 3 H, 17 O、 18 O、 29 Si、 30 Compounds labeled with Si, etc.

[0154] Examples of aluminosilicates include zeolite, mullite, kaolinite, illite, etc., with zeolite being the preferred choice.

[0155] As a zeolite, the zeolite as defined by the International Zeolite Association (IZA) can be used.

[0156] The molar ratio of SiO2 to Al2O3 in zeolite, i.e., the SiO2 / Al2O3 ratio, is typically 15.0 or more, preferably 18.0 or more, more preferably 20.0 or more, even more preferably 30.0 or more, and particularly preferably 31.0 or more. On the other hand, it is typically 130,000.0 or less, preferably 129,000.0 or less, more preferably 50,000.0 or less, even more preferably 10,000.0 or less, even more preferably 1,000.0 or less, even more preferably 500.0 or less, especially preferably 100.0 or less, and particularly preferably 80.0 or less.

[0157] By using zeolites with a specific range of SiO2 / Al2O3 molar ratios, the polarity of the zeolite can be controlled within a certain range, maintaining high selectivity for the adsorption of primary / secondary / tertiary amines or ammonia compared to choline.

[0158] It should be noted that the SiO2 / Al2O3 ratio refers to the ratio of SiO2 to Al2O3 when the molar ratio of Si to Al in zeolite is converted into the molar amounts of SiO2 and Al2O3, respectively. There are no particular limitations on the methods for determining their respective contents; for example, compositional analysis using ICP (inductively coupled plasma atomic emission spectrometry) and XRF (x-ray fluorescence spectrometry) can be cited.

[0159] It should be noted that the SiO2 / Al2O3 ratio of zeolite can be adjusted according to the reaction conditions of zeolite synthesis.

[0160] When representing the structure of zeolites using the codes specified by IZA, examples include ABW, ACO, AEI, AEN, AFI, AFT, AFX, ANA, ATN, ATT, ATV, AWO, AWW, BIK, CHA, DDR, DFT, EAB, EPI, ERI, ESV, GIS, GOO, ITE, JBW, KFI, LEV, LTA, MER, MON, MTF, OWE, PAU, PHI, RHO, RTE, RWR, SAS, SAT, SAV, SIV, TSC, UFI, VNI, YUG, AEL, AFO, AHT, DAC, FER, HEU, IMF, ITH, MEL, MFS, MWW, OBW, RRO, SFG, STI, SZR, TER, TON, TUN, WEI, MFI, MON, PAU, PHI, MOR, FAU, etc.

[0161] It should be noted that the structure of zeolite refers to the crystal structure of a crystalline structure in which four oxygen atoms are coordinated with cations, and the oxygen atoms at their vertices are shared and connected with the adjacent cations. For substances with a well-defined crystal structure, the IZA specifies the topology of its framework one by one through structural coding, and uses this symbol to represent the type of structure.

[0162] Zeolites with a fine-porous structure having a maximum ring number of 10 are particularly preferred. By controlling the pore size, the adsorption selectivity for primary / secondary / tertiary amines or ammonia compared to choline can be improved.

[0163] It should be noted that the so-called ring number refers to the number of oxygen atoms contained in the ring structure that constitutes the pore cross-section of zeolite. The maximum ring number indicates the largest number of oxygen atoms in the pores formed by oxygen and T elements (elements other than oxygen constituting the framework) that form the zeolite framework. For example, in the case of pores containing oxygen 10-membered rings and 8-membered rings, such as FER-type zeolite, it is considered a zeolite with oxygen 10-membered rings.

[0164] The maximum diameter of the diffusion sphere within the pores of the zeolite is preferably 3.68 Å or more, more preferably 3.70 Å or more, even more preferably 3.75 Å or more, even more preferably 4.22 Å or more, even more preferably 4.50 Å or more, particularly preferably 4.65 Å or more, and most preferably 4.69 Å or more. On the other hand, the upper limit of the maximum diffusion sphere diameter within the pores is preferably 4.91 Å or less, more preferably 4.90 Å or less, even more preferably 4.85 Å or less, even more preferably 4.80 Å or less, even more preferably 4.75 Å or less, particularly preferably 4.73 Å or less, and most preferably 4.71 Å or less.

[0165] By ensuring that the diameter of the maximum diffusion sphere within the micropores is within the aforementioned range, the adsorption selectivity for primary / secondary / tertiary amines or ammonia compared to choline can be further improved.

[0166] The maximum sphere diameter (Å) for diffusion within the pores can be found in the "Maximum diameter of a sphere that can diffuse along" section of the Zeolite Framework Types document from the Structure Commission of the International Zeolite Association (IZA-SC) (https: / / asia.iza-structure.org / IZA-SC / ftc_table.php). In cases where multiple values ​​exist for axes a, b, and c, the largest value should be used.

[0167] Examples of zeolites with a fine-pored structure having a maximum number of ring elements of 10 include AEL, AFO, AHT, CGF, CGS, DAC, EUO, FER, HEU, IMF, ITH, LAU, MEL, MFI, MFS, MTT, MWW, NES, OBW, PON, RRO, SFF, SFG, STF, STI, SZR, TER, TON, TUN, and WEI. Among these, zeolites with a fine-pored structure having a maximum number of ring elements of 10 and a maximum diameter of 3.68 Å or more for the diffusion spheres within the pores are preferred. FER or MFI are preferred among such zeolites, with MFI being more preferred.

[0168] As counter cations of zeolites, H can be listed as an example. + (proton), NH4 + Alkali metal ions (Li ＋ Na ＋ K ＋ 、Rb ＋ Cs ＋ (etc.), Group 2 element ions (Ca) 2＋ Mg 2＋ 、Sr 2＋ Ba 2＋ transition metal ions (Fe, etc.) 2+ Cu 2+ Zn 2+ (etc.) etc. Among them, protons and NH4 are preferred. + Li + Na + K + Plasma. As an ion suitable for oral administration, protons are preferred as they can prevent excessive uptake of various ions and can be safely used in organisms.

[0169] In addition, zeolite with an external surface area of ​​less than 33.0 m² is preferred. 2 / g of zeolite. More preferably less than 30.0m 2 / g, and more preferably less than 26.0m 2 / g, further preferably less than 25.8m 2 / g, more preferably 25.6m 2 / g or less, especially preferably 20.0m 2 / g or less, especially preferably 15.0m 2 Below / g, the optimal value is 13.3m. 2 Below / g. There is no specific lower limit, for example, 0.1m. 2 / g or more, 1.0m 2 / g or more, 3.0m 2 / g or more, 5.0m 2 / g or more, 6.5m 2 / g or more.

[0170] By setting the external surface area within a certain range, the selectivity for adsorption of primary / secondary / tertiary amines or ammonia can be improved compared to choline.

[0171] Here, external surface area refers to the value obtained by subtracting the internal surface area of ​​the pores per unit mass from the total surface area per unit mass of the solid. This value can be calculated from the slope and intercept of the plateau portion in a t-plot (standard isotherm: de-Bore form), which is obtained by measuring the nitrogen adsorption isotherm at liquid nitrogen temperature on a powder that has undergone heating degassing as a pretreatment.

[0172] Furthermore, MFI-type zeolites preferably use zeolites whose maximum peak width in the range of 2θ = 7.9000° ± 0.5000° in powder X-ray diffraction patterns measured using Cu-Kα rays is 0.1800° or less. More preferably, it is 0.1500° or less, and even more preferably, it is 0.1300° or less. There are no particular limitations on the lower limit, but for example, it is 0.0100° or more, 0.0300° or more, 0.0500° or more, 0.0700° or more, or 0.0900° or more.

[0173] By setting the half-width of the maximum peak in the range of 2θ = 7.9000° ± 0.5000° in the powder X-ray diffraction pattern measured using Cu-Kα rays to a certain range, the selectivity for adsorption of primary / secondary / tertiary amines or ammonia can be improved compared with choline.

[0174] Here, half-value width refers to the spectral width at half the value of the peak maximum.

[0175] Furthermore, the zeolite preferably used has a median particle size of 5.5 μm or more. More preferably, it has a median particle size of 10.0 μm or more, and even more preferably, it has a median particle size of 11.7 μm or more. There is no particular upper limit, for example, it can be 10.0 mm or less.

[0176] By setting the median particle size of the particle size distribution within a certain range, the selectivity for adsorption of primary / secondary / tertiary amines or ammonia can be improved compared to choline.

[0177] Furthermore, the zeolite preferably used has a particle size of 2.5 μm or more in the cumulative 10% frequency of its particle size distribution. More preferably, it has a particle size of 5.0 μm or more, and even more preferably, it has a particle size of 5.3 μm or more. There is no particular upper limit, for example, it can be 5.0 mm or less.

[0178] By setting the cumulative frequency of particle size distribution (10% diameter) within a certain range, the selectivity for adsorption of primary / secondary / tertiary amines or ammonia can be improved compared to choline.

[0179] Here, the median particle size and cumulative frequency 10% diameter of the particle size distribution refer to the particle sizes at the 50% and 10% cumulative values ​​in the particle size distribution, respectively, obtained by laser diffraction / scattering. These values ​​are obtained by using pure water as the dispersion medium, applying ultrasound, and circulating the mixture in a flow cell while measuring.

[0180] In addition, the crystal shape of MFI type zeolite is preferably coffin-shaped.

[0181] By setting the crystal shape of MFI-type zeolite to a certain shape, it is possible to achieve better selectivity for the adsorption of primary / secondary / tertiary amines or ammonia compared to choline.

[0182] Here, the term "coffin shape" refers to the shape dominated by the

[010] face when observed using a scanning electron microscope (SEM).

[0183] Furthermore, by selectively surface-treating the surfaces other than

[010] , the selectivity for adsorption of primary / secondary / tertiary amines or ammonia can be improved compared to choline.

[0184] Zeolite can be purchased commercially or synthesized through methods such as hydrothermal synthesis, as described later.

[0185] The oral composition of the present invention, when mixed with the above-mentioned inorganic porous body containing 11.8 g of choline in an equimolar mixture in artificial intestinal fluid at a concentration of 2 g / L for 1 hour, exhibits an adsorption rate of 60.0% or more for the primary / secondary / tertiary amine or ammonia and an adsorption rate of choline of 40.0% or less.

[0186] The adsorption rate of primary / secondary / tertiary amines or ammonia is typically 60.0% or higher, preferably 60.4%, more preferably 70.0% or higher, even more preferably 80.0%, and particularly preferably 90.0% or higher. On the other hand, the adsorption rate of primary / secondary / tertiary amines or ammonia can be, for example, set to 100.0% or lower.

[0187] Furthermore, the adsorption rate of choline is typically 40.0% or less, preferably 30.0% or less, more preferably 20.0% or less, and even more preferably 10.0% or less. On the other hand, the adsorption rate of choline can be, for example, 0.0% or more, 0.1% or more, or 0.2% or more.

[0188] Furthermore, the adsorption rate of primary / secondary / tertiary amines or ammonia is preferably 2.00 times or more than the adsorption rate of choline, more preferably 2.49 times or more, and even more preferably 2.50 times or more. On the other hand, no particular upper limit is specified; for example, the adsorption rate of primary / secondary / tertiary amines or ammonia may be 350.00 times or less, 342.00 times or less, or 341.70 times or less than the adsorption rate of choline.

[0189] Here, choline is a compound identified by CAS registry number 62-49-7, and is identified by (CH3)3N. + The quaternary ammonium cation represented by the formula (CH2)2OH.

[0190] Ammonia is a compound identified by CAS registry number 7664-41-7 and is represented by the stoichiometric formula NH3. It also includes ammonium cations (NH4+). + ).

[0191] Primary, secondary, and tertiary amines are compounds in which the hydrogen atoms of ammonia are replaced by hydrocarbon groups or aromatic groups. If there is one substitution, it is called a primary amine; if there are two substitutions, it is called a secondary amine; and if there are three substitutions, it is called a tertiary amine. For example, heterocyclic aromatic compounds such as imidazole and pyridine are also included in the category of amines. As primary, secondary, and tertiary amines, their conjugate acids are also included.

[0192] As an artificial intestinal fluid, fasting artificial intestinal fluid (FaSSIF; Fasted-state Simulated Small Intestine Fluid) is used.

[0193] Reference: Dissolution Technologies 20(3):44-50 "Comparison of theSolubility and Dissolution of Drugs in Fasted-State Biorelevant Media (FaSSIFand FaSSIF-V2)"

[0194] Specifically, FaSSIF (pH 6.5) with the following composition can be used.

[0195] 3.5mM sodium taurocholate, 0.75mM lecithin, 105.85mM sodium chloride, 10.5mM sodium hydroxide, 28.65mM sodium dihydrogen phosphate.

[0196] The adsorption rate is the value obtained by subtracting the concentration of the substance to be adsorbed onto the adsorbent in the solution after the adsorption operation from 1, and then dividing the concentration of the substance in the solution before the adsorption operation.

[0197] For example, equimolar amounts of choline and primary / secondary / tertiary amines or ammonia can be present in artificial intestinal fluid. Inorganic porous materials with a concentration of 2 g / L (11.8 g relative to 1 mmol of choline) are added to the fluid. After an adsorption reaction is carried out at room temperature for 1 hour, the adsorption rates of choline and primary / secondary / tertiary amines or ammonia are measured. It is confirmed that the adsorption rate of primary / secondary / tertiary amines or ammonia is above 60.0%, and the adsorption rate of choline is below 40.0%.

[0198] Room temperature refers to a temperature of 20℃±10℃.

[0199] Alternatively, for example, equimolar amounts of choline and TMA can be present in artificial intestinal fluid. The aforementioned inorganic porous body, which is 11.8 g relative to 1 mmol of choline, is added to the fluid at a concentration of 2 g / L. After an adsorption reaction is carried out for 1 hour, the adsorption rates of choline and TMA are measured. It is confirmed that the adsorption rate of TMA is above 60.0%, and the adsorption rate of choline is below 40.0%.

[0200] <Oral Composition>

[0201] An oral composition is a mixture of substances suitable for oral administration to an individual. For example, an oral composition may contain one or more inorganic porous bodies and oral carriers (excipients, binders, disintegrants, flavoring agents, odorants, emulsifiers, diluents, solubilizers, etc.).

[0202] As a carrier permitted for oral administration, it can be appropriately selected according to the dosage form. For example, excipients, lubricants, binders, and disintegrants in solid dosage forms, or solvents, solubilizers, emulsifiers, diluents, suspending agents, isotonic agents, buffers, and analgesics in liquid dosage forms can be listed. Furthermore, as needed, appropriate amounts of common preservatives, antioxidants, colorants, flavoring agents, odorants, wetting agents, and other additives can also be used.

[0203] Dosage forms of oral compositions can be listed as solid or liquid, specifically including tablets, coated tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, injections, lozenges, enteric-coated capsules, etc.

[0204] The oral composition of the present invention may also contain other therapeutically effective agents, such as inhibitors of TMA-producing enzymes such as cutC and cntAB, TMA-degrading enzymes such as trimethylamine dehydrogenase, riboflavin, and antibacterial agents. Additionally, anti-inflammatory agents, vitamins, amino acids, and other ingredients may be added as needed.

[0205] Oral compositions containing the inorganic porous body of the present invention can be used, for example, as pharmaceutical compositions, supplements, foods, or food additives.

[0206] It should be noted that supplements, foods, and food additives may also be supplements, foods, and food additives that are labeled with functions and / or uses such as adsorption of primary / secondary / tertiary amines or ammonia, adsorption and removal of primary / secondary / tertiary amines or ammonia, or prevention, treatment, or symptom relief of diseases caused by primary / secondary / tertiary amines, ammonia, or their metabolites.

[0207] Oral compositions containing the inorganic porous bodies of the present invention can preferably be used as pharmaceutical compositions, specifically for the treatment, prevention, or symptom relief of diseases caused by primary / secondary / tertiary amines, ammonia, or their metabolites.

[0208] The inorganic porous materials contained in the oral composition of the present invention are insoluble in water and exceed the particle size (100 nm) suitable for endocytosis, thus absorption in the body is negligible. Furthermore, the zeolite contained in the oral composition of the present invention is stably present in the stomach and other digestive tracts, and the dissolution of components including silicon and aluminum is minimal, thus ensuring high safety during administration.

[0209] One embodiment of the present invention is a pharmaceutical composition for the treatment, prevention, or symptom relief of diseases caused by primary / secondary / tertiary amines, ammonia, or their metabolites, comprising the inorganic porous body of the embodiments of the present invention described above, or an oral composition comprising the inorganic porous body.

[0210] One embodiment of the present invention is a method for treating, preventing, or alleviating symptoms of a disease caused by primary / secondary / tertiary amines, ammonia, or their metabolites, comprising the step of administering an effective amount of the inorganic porous body of the embodiments of the present invention described above, or an oral composition comprising the inorganic porous body, to a subject.

[0211] One embodiment of the present invention is the use of the inorganic porous body or oral composition comprising the inorganic porous body described in the above embodiments of the present invention for the manufacture of a medicament for the treatment, prevention or symptom relief of diseases caused by primary / secondary / tertiary amines, ammonia or their metabolites.

[0212] One embodiment of the present invention is an inorganic porous body or an oral composition comprising the inorganic porous body described above, used for the treatment, prevention or symptom relief of diseases caused by primary / secondary / tertiary amines, ammonia or their metabolites.

[0213] As a primary / secondary / tertiary amine, ammonia or their metabolites, it is preferably selected from one or more of the group consisting of trimethylamine, dimethylamine, methylamine, histamine, ammonia and trimethylamine-N-oxide, more preferably trimethylamine or trimethylamine-N-oxide.

[0214] Diseases caused by primary / secondary / tertiary amines, ammonia, or their metabolites are not particularly limited to any diseases and / or symptoms that may be caused by these substances. Diseases that can be treated, prevented, or whose symptoms can be alleviated by reducing or eliminating these substances can be listed.

[0215] Diseases caused by primary / secondary / tertiary amines or their metabolites, more specifically, include trimethylamineuria, cardiovascular disease, glaucoma, atherosclerosis, coronary heart disease, heart failure with preserved ejection fraction, ST-segment elevation myocardial infarction, atrial fibrillation, abdominal aortic aneurysm, ischemic stroke, post-stroke cognitive impairment, mild cognitive impairment, Alzheimer's disease, obesity, chronic kidney disease with type 2 diabetes, cardiovascular complications of chronic kidney disease, diabetic retinopathy, non-alcoholic steatohepatitis, polycystic ovary syndrome, Parkinson's disease, colorectal cancer, irritable bowel syndrome, hyperammonemia, urea cycle disorders, organic acidemia, hepatic encephalopathy, portosystemic shunt, etc.

[0216] For example, in cases where the causative agent of a disease is trimethylamine, diseases that can be treated, prevented, or have their symptoms alleviated by oral compositions containing the inorganic porous body of the present invention may include trimethylamineuria, cardiovascular disease, or glaucoma, preferably trimethylamineuria.

[0217] Trimethylaminuria is a disease in which trimethylamine, produced during the digestion and breakdown of food, is excreted in sweat, urine, and breath without being metabolized. Trimethylamine has a fishy odor, hence it is also known as fishy disease or fishy odor syndrome. It can be broadly classified into type 1 (primary trimethylaminuria), caused by congenital defects or low activity of the gene information for the trimethylamine oxidative metabolic enzyme, flavin monooxygenase 3 (FMO3), and type 2 (secondary trimethylaminuria), caused by renal and hepatic dysfunction, decreased renal and hepatic function, portosystemic shunting, intestinal flora imbalance (dysbiosis), or excessive intake of trimethylamine precursors, or a combination of these factors. In addition, there is an intermittent form, where FMO3 expression increases or decreases with the menstrual cycle due to the influence of steroid hormones, and a transient form, where FMO3 expression is decreased in infants and children. Sometimes, different types are mixed.

[0218] The relationship between trimethylamine and various diseases is documented in the following literature.

[0219] Trimethylamineuria: European Journal of Human Genetics, volume 23, page 1269 (2015)

[0220] Cardiovascular disease: Toxins 2019, 11(9), 490

[0221] Glaucoma: International Ophthalmology, volume 41, pages 341-347 (2021)

[0222] For example, in cases where the causative agent of the disease is trimethylamine-N-oxide, diseases that can be treated, prevented, or have their symptoms alleviated by the oral composition containing inorganic porous bodies of the present invention can include atherosclerosis, coronary heart disease, heart failure with preserved ejection fraction, ST-segment elevation myocardial infarction, atrial fibrillation, abdominal aortic aneurysm, ischemic stroke, post-stroke cognitive impairment, mild cognitive impairment, Alzheimer's disease, obesity, chronic kidney disease with type 2 diabetes, cardiovascular complications of chronic kidney disease, diabetic retinopathy, non-alcoholic steatohepatitis, polycystic ovary syndrome, Parkinson's disease, or colorectal cancer, preferably atherosclerosis.

[0223] Here, atherosclerosis refers to the formation of plaque-like intimal plaques (atherosclerotic plaques) that grow toward the lumen of medium and large arteries, thereby reducing and / or interrupting blood flow.

[0224] The relationship between trimethylamine-N-oxide and various diseases is documented in the following literature, for example.

[0225] Atherosclerosis: Nature Medicine, volume 19, pages 576-585 (2013)

[0226] Coronary artery disease: BMC Cardiovascular Disorders (2020) 20:7

[0227] Heart failure with preserved ejection fraction: BMC Cardiovascular Disorders (2020) 20:394

[0228] ST-segment elevation myocardial infarction: American Journal of Cardiology. 2019 Mar 15; 123(6): 894-898. Abdominal aortic aneurysm: Circulation Volume 147, Issue 14, 4 April 2023; Pages 1079-1096

[0229] Atrial fibrillation: International Journal of Cardiology, Volume 267, 15 September 2018, Pages 100-106

[0230] Ischemic stroke: Journal of Biochemical and Molecular Toxicology 2019 Feb; 33(2): e22246

[0231] Cognitive impairment after stroke: Neurological Sciences, volume 41, pages 57-63 (2020)

[0232] Mild cognitive impairment and Alzheimer's dementia: Alzheimer's Research & Therapy (2018) 10: 124

[0233] Obesity: Obesity Reviews. 2020; 21(5): e12993.

[0234] Chronic kidney disease complicated with type 2 diabetes: Journal of Clinical Medicine 2017, 6(9), 86

[0235] Cardiovascular complications of chronic kidney disease: Kidney International, Volume 92, Issue 4, October 2017, Pages 809-815

[0236] Diabetic retinopathy: Acta Diabetogica 58, 221-229 (2021)

[0237] Nonalcoholic steatohepatitis: Diabetes & Metabolism 47(2021)101183

[0238] Polycystic ovary syndrome: BMC Endocr Disord. 2020; 20:3.

[0239] Parkinson's Disease: Clinica Chimica Acta Volume 501, February 2020, Pages 165-173

[0240] Colorectal cancer: International Journal of Molecular Sciences 2020, 21, 6782

[0241] For example, in cases where the causative agent of the disease is histamine, the disease that can be treated, prevented, or whose symptoms can be alleviated using the oral composition containing inorganic porous bodies of the present invention may be irritable bowel syndrome.

[0242] Here, irritable bowel syndrome (IBS) refers to a syndrome that causes chronic bowel abnormalities such as diarrhea or constipation, as well as abdominal pain and bloating, even though there are no organic abnormalities such as ulcers or tumors in the large and small intestines.

[0243] The relationship between histamine and irritable bowel syndrome is documented in the following literature, for example.

[0244] Science Translational Medicine 14, eabj1895 (2022)

[0245] For example, when the causative substance of the disease is ammonia, the diseases that can be treated, prevented, or have their symptoms alleviated by the oral composition containing inorganic porous bodies of the present invention can be hyperammonemia, urea cycle disorder, organic acidemia, hepatic encephalopathy, or portosystemic shunt disease, preferably hyperammonemia.

[0246] Hyperammonemia, in this context, refers to a condition where the body is unable to metabolize ammonia, leading to its accumulation in the blood. Causes include impaired urea circulation due to conditions such as cirrhosis, fulminant hepatitis, and decreased liver function; portosystemic shunt syndrome; urea circulation disorders; organic acidemia; ammonia production associated with urease-producing bacteria; and drug-induced ammonia buildup (such as sodium valproate and neovalproic acid-containing antibiotics). Hyperammonemia can sometimes also lead to hepatic encephalopathy and hepatic coma.

[0247] The relationship between ammonia and hyperammonemia and related diseases is documented in the following literature.

[0248] Pediatric Nephrology volume 27, pages207-222 (2012)

[0249] Furthermore, the inventors have discovered that zeolites, particularly those selected from the group consisting of one or more types of zeolites with a SiO2 to Al2O3 molar ratio within a specific range and a maximum ring number of 10 and a maximum diffusion sphere diameter of 3.68 Å or more within the pores, exhibit superior selective adsorption of primary / secondary / tertiary amines or ammonia compared to choline in inorganic porous materials. This is useful for the treatment, prevention, or symptom relief of diseases caused by primary / secondary / tertiary amines, ammonia, or their metabolites.

[0250] Based on the above understanding, as one aspect of the oral composition of the present invention, an oral composition can be provided for the treatment, prevention, or symptom relief of one or more diseases selected from the group consisting of trimethylamineuria, atherosclerosis, irritable bowel syndrome, and hyperammonemia.

[0251] The oral composition contains zeolite.

[0252] The aforementioned zeolite possesses an MFI structure, and the molar ratio of SiO2 to Al2O3 is greater than 30.0 and less than 130,000.0, or...

[0253] The zeolite described above has a FER structure, and the molar ratio of SiO2 to Al2O3 is above 15.0 and below 130,000.0.

[0254] Alternatively, as a preferred embodiment of the oral composition of the present invention, an oral composition can be provided for the treatment, prevention, or symptom relief of one or more diseases selected from the group consisting of trimethylamineuria, atherosclerosis, irritable bowel syndrome, and hyperammonemia.

[0255] The oral composition contains zeolite.

[0256] The aforementioned zeolite possesses an MFI structure, and the molar ratio of SiO2 to Al2O3 is greater than 30.0 and less than 80.0, or...

[0257] The zeolite described above has a FER structure, and the molar ratio of SiO2 to Al2O3 is above 15.0 and below 130,000.0.

[0258] The oral composition or pharmaceutical composition containing inorganic porous bodies of the present invention can be administered to the recipient via oral administration.

[0259] The term "object" as the target of administration of the oral composition or pharmaceutical composition of the present invention includes humans or mammals other than humans (e.g., one or more of mice, guinea pigs, hamsters, rats, mice, rabbits, pigs, sheep, goats, cattle, horses, cats, dogs, marmosets, monkeys, or chimpanzees). The term "object" may be a patient diagnosed with a disease caused by primary / secondary / tertiary amines, ammonia, or their metabolites, or an individual at risk of developing a disease caused by primary / secondary / tertiary amines, ammonia, or their metabolites.

[0260] "Treatment" includes any treatment of diseases in mammals, especially humans, including: suppressing disease symptoms, that is, stopping their progression or causing the disease or symptoms to disappear; causing the disease or symptoms to subside or delaying the progression of symptoms.

[0261] "Symptom relief" includes reducing or alleviating the symptoms of the aforementioned diseases and decreasing the frequency of symptoms in mammals, especially humans.

[0262] "Prevention" includes preventing the occurrence of the above-mentioned diseases in mammals, especially humans.

[0263] The dosage of the oral composition or pharmaceutical composition comprising inorganic porous bodies of the present invention is determined by a physician based on various factors, such as the type of disease, the severity of symptoms, the patient's age, sex, weight, disease severity, pharmacological and toxicological characteristics, whether a drug delivery system is used, and whether it is administered as part of a combination of other drugs. Typically, for oral administration, the dosage for each adult (60 kg) can be 200 mg to 42,000 mg per dose, preferably 500 mg to 2,000 mg per dose. Administration can be once or multiple times daily, for example, 1 to 5 times daily.

[0264] <Methods for manufacturing zeolite>

[0265] One aspect of the present invention relates to a method for manufacturing zeolite. However, the zeolite contained in the oral compositions of the present invention is not limited to zeolite obtained by the method described below.

[0266] Hydrothermal synthesis refers to the synthesis and crystal growth of substances carried out in the presence of water at temperatures above 50°C.

[0267] In the method for manufacturing zeolites, hydrothermal synthesis is carried out in a reaction system containing a Si element source (a substance containing at least silicon (Si)), an Al element source (a substance containing at least aluminum (Al)), an alkali metal salt, and water, and also, if necessary, a structure-directing agent. Zeolite seed crystals may also be added to the reaction system.

[0268] Aluminum sources typically include aluminum sulfate, aluminum nitrate, aluminum hydroxide, sodium aluminate, boehmite, alumina sol, and aluminum isopropoxide. Alternatively, aluminum-containing zeolites such as FAU-type zeolites (e.g., Y-type zeolites) and CHA-type zeolites can also be used. Among these sources, aluminum sulfate, aluminum nitrate, aluminum hydroxide, or aluminum-containing zeolites are preferred in terms of reactivity, with aluminum hydroxide or aluminum-containing zeolites being more preferred.

[0269] From the viewpoint of ease of preparation and production efficiency of the aqueous gel obtained by pre-reaction mixture and / or aging of it, the amount of Al element source used, calculated as the molar ratio of aluminum (Al) in the Al element source to silicon (Si) contained in the raw material mixture excluding seed crystals added as needed, is generally 0.001 or more, preferably 0.005 or more, more preferably 0.01 or more, and even more preferably 0.02 or more. Furthermore, there is no particular upper limit, but from the viewpoint of ensuring uniform dissolution of the Al element source in the aqueous gel, it is generally 1 or less, preferably 0.5 or less, more preferably 0.25 or less, even more preferably 0.1 or less, particularly preferably 0.08 or less, and most preferably 0.06 or less.

[0270] There are no particular limitations on the Si element source; various known substances can be used, such as colloidal silica, amorphous silica, sodium silicate, trimethylethoxysilane, tetraethyl orthosilicate, aluminosilicate gel, etc., or zeolites containing Si atoms. One of these can be used alone, or two or more can be used in combination. Preferably, the form can be thoroughly and uniformly mixed with other components; water-soluble raw materials are particularly preferred, with colloidal silica, trimethylethoxysilane, tetraethyl orthosilicate, or aluminosilicate gel being preferred.

[0271] Alkali metal cations exist near aluminum anions to compensate for charge, and like structure-directing agents, they have the effect of assisting the crystal growth of the target structure.

[0272] Alkali metal salts include sodium and / or potassium salts, and may also contain other alkali metal atoms. There are no particular limitations on the other alkali metal atoms; known alkali metal atoms used in zeolite synthesis can be used, such as lithium, rubidium, and cesium, and combinations of two or more of these may be employed.

[0273] As alkali metal salts, inorganic acid salts such as hydroxides, oxides, carbonates, sulfates, nitrates, phosphates, chlorides, and bromides of the aforementioned alkali metal atoms, as well as organic acid salts such as acetates, oxalates, and citrates, can be used. Alkali metal salts can contain one or more types of alkali metals.

[0274] From the viewpoint of facilitating crystal formation, the amount of water used, in terms of the molar ratio of silicon (Si) contained in the raw material mixture excluding the seed crystal, is typically 5 or more, preferably 10 or more, more preferably 12 or more, further preferably 15 or more, and particularly preferably 17 or more. Within this range, crystal formation is easier and is preferred. Furthermore, to fully achieve the effect of reducing the cost required for wastewater treatment, the molar ratio of water used, in terms of the molar ratio of silicon (Si) contained in the raw material mixture excluding the seed crystal, is typically 100 or less, preferably 90 or less, more preferably 75 or less, and further preferably 50 or less.

[0275] Structure-directing agents are substances sometimes added as raw materials during zeolite synthesis to control the structure of the synthesized zeolite. There are no restrictions on the type of structure-directing agent, as long as the desired zeolite can be synthesized; any type can be used. Furthermore, a single structure-directing agent can be used, or two or more can be used in combination, or none of these structure-directing agents may be used.

[0276] Structure-directing agents are broadly classified into organic and inorganic types. Examples of common organic structure-directing agents include amines, quaternary ammonium salts, and primary alcohols. Examples of inorganic structure-directing agents include nitrates, sulfates, and carbonates, which convert cations into inorganic ions.

[0277] In the case of organic structure-directing agents, a calcination process is required to remove the structure-directing agent from the zeolite. However, it is considered that there are no approved pharmaceutical products requiring a calcination process, and there are no GMP-compliant calcination facilities for pharmaceutical manufacturing. Therefore, for the use of the oral composition of the present invention in pharmaceutical applications, it is preferable not to use organic structure-directing agents in the hydrothermal synthesis. That is, in a preferred embodiment, the method for manufacturing the oral pharmaceutical composition of the present invention includes a method for obtaining zeolite by hydrothermal synthesis without using organic structure-directing agents. Furthermore, from the viewpoint of obtaining zeolite of good quality, it is more preferable to use inorganic structure-directing agents in the hydrothermal synthesis. Moreover, when the target zeolite is of the MFI type, from the perspective of being an inorganic structure-directing agent and easily synthesizing MFI type zeolite, it is preferable to use an inorganic salt with a cation of Na, and from the perspective of having a greater effect on increasing particle size, it is even more preferable to use sodium carbonate and / or sodium sulfate.

[0278] In the method for manufacturing zeolites, seed crystals are further added as needed to a mixture obtained by mixing a Si element source, an Al element source, an alkali metal salt, water, and a desired structure directing agent, and the resulting pre-reaction mixture is subjected to hydrothermal synthesis.

[0279] There is no particular limitation on the mixing order of these raw materials. It is preferable to add the Si element source and the Al element source after preparing the alkaline solution. From the viewpoint of more uniform dissolution of the raw materials, it is preferable to add the Al element source, the Si element source, and the seed crystal as needed to the alkaline solution in sequence after preparing the alkaline solution by mixing water and alkali metal salt.

[0280] Zeolite is typically used as a seed crystal. If the zeolite being manufactured is an aluminosilicate, then an aluminosilicate zeolite is also preferred as a seed crystal. The seed crystal may contain an amorphous component as part of it. Furthermore, the zeolite used as a seed crystal may or may not contain an organic structure-directing agent. The method for manufacturing the zeolite used as a seed crystal is not particularly limited; it can be manufactured using the zeolite manufacturing method exemplified as the manufacturing method of the oral composition of the present invention, or it can be manufactured by other methods, such as using an autoclave in a general batch manner. The amount of seed crystal is preferred from the viewpoint that it easily acts as a seed crystal and exhibits a crystallization-promoting effect. On the other hand, a lower amount is preferred from the viewpoint that the seed crystal is easy to dissolve and easily functions as a seed crystal. Therefore, the amount of silicon dioxide (SiO2) contained in the raw material mixture other than the seed crystal contained in the raw material composition is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and even more preferably 1.0% by mass or more. In addition, on the other hand, it is preferred to be 30% by mass or less, more preferably 20% by mass or less, even more preferably 15% by mass or less, and particularly preferably 10% by mass or less.

[0281] It should be noted that, in addition to the Al element source, Si element source, alkali metal salt, water, and seed crystals as required, other additives such as reaction-promoting acid components, metal stabilizers such as polyamines, etc., can be added in any step as needed to prepare a pre-reaction mixture.

[0282] The pre-reaction mixture prepared as described above can be subjected to hydrothermal synthesis immediately after preparation. However, to obtain zeolite with high crystallinity, it is preferable to mature it for a certain period of time under specified temperature conditions. Especially when scaling up, the agitation deteriorates, and the mixing state of the raw materials easily becomes insufficient. Therefore, it is preferable to improve the raw materials to a more uniform state by maturing them while stirring them for a certain period of time. The maturation temperature is generally below 100°C, preferably below 95°C, more preferably below 90°C, and there is no particular lower limit, but it is generally above 0°C, preferably above 10°C. The maturation temperature can be constant during maturation or can be varied in stages or continuously. The maturation time is not particularly limited, but it is generally above 2 hours, preferably above 3 hours, more preferably above 5 hours, generally below 30 days, preferably below 10 days, and even more preferably below 4 days.

[0283] Hydrothermal synthesis is carried out for example as follows: the pre-reaction mixture prepared as described above and / or the aqueous gel obtained by aging it are placed in a pressure-resistant container and kept at a specified temperature under their own pressure or under gas pressure that does not impede crystallization, while being stirred, the container is rotated and / or shaken, or left to stand.

[0284] The reaction temperature during hydrothermal synthesis is typically above 100°C, typically below 230°C, preferably below 220°C, more preferably below 200°C, and even more preferably below 190°C. The reaction time is not particularly limited, but is typically 2 hours or more, preferably 3 hours or more, more preferably 5 hours or more, and particularly preferably 1 day or more. The upper limit is not particularly limited, but is typically 30 days or less, preferably 10 days or less, more preferably 7 days or less, and even more preferably 5 days or less. The reaction temperature can be constant during the reaction, or it can vary in stages or continuously.

[0285] Following the hydrothermal synthesis described above, the generated zeolite is separated from the hydrothermal synthesis reaction solution. There are no particular limitations on the method for separating zeolite from the hydrothermal synthesis reaction solution; methods such as filtration, decantation, or direct drying are commonly cited.

[0286] The zeolite recovered from the hydrothermal synthesis reaction solution is washed with water and dried as needed.

[0287] The drying temperature is typically 50°C or higher, preferably 80°C or higher, and more preferably 100°C or higher. On the other hand, the drying temperature is typically 200°C or lower, preferably 150°C or lower.

[0288] The drying time is not particularly limited as long as the zeolite is fully dried, but it is preferably 0.5 hours or more, more preferably 1 hour or more. There is no particular upper limit, but it is usually 200 hours or less, preferably 150 hours or less, and more preferably 100 hours or less.

[0289] In the case of using organic structure-directing agents in hydrothermal synthesis, the organic structure-directing agents are removed by calcination after drying.

[0290] The firing temperature is typically 350°C or higher, preferably 400°C or higher, more preferably 430°C or higher, and even more preferably 480°C or higher. On the other hand, the firing temperature is typically 900°C or lower, preferably 850°C or lower, more preferably 800°C or lower, and even more preferably 750°C or lower.

[0291] During firing, by firing at a temperature above the aforementioned lower limit, it is possible to prevent an increase in the proportion of residual organic structure-directing agents and suppress the adsorption hindrance caused by organic structure-directing agents remaining in the zeolite pores. Conversely, by heating the treatment temperature below the aforementioned upper limit, it is possible to prevent the loss of adsorption selectivity due to the destruction of the zeolite framework structure and the loss of the regular pore structure of the framework.

[0292] The heating time during firing is not particularly limited as long as it corresponds to the decomposition time of the organic structure directing agent, but it is preferably 0.5 hours or more, more preferably 1 hour or more. There is no particular upper limit, but it is generally 200 hours or less, preferably 150 hours or less, and more preferably 100 hours or less. The heat treatment can be carried out in an air atmosphere or in an atmosphere containing inert gases such as N2 and oxygen.

[0293] One method for manufacturing zeolite according to the present invention may further include exchanging cations via ion exchange. When synthesized using an organic structure-directing agent, ion exchange is typically performed after the removal of the organic structure-directing agent. Examples of ions that can be exchanged include H₂. + (proton), NH4 + Alkali metal ions (Li + Na + K + 、Rb + Cs + (etc.), Group 2 element ions (Ca) 2+ Mg 2+ 、Sr 2+ Ba 2+transition metal ions (Fe, etc.) 2+ Cu + Cu 2+ Zn 2+ (etc.) etc. Among them, protons and NH4 are preferred. + Li + Na + K + Plasma. As an ion suitable for oral administration, protons are preferred as they can prevent excessive uptake of various ions and can be safely used in organisms.

[0294] Ion exchange can be carried out by methods such as treating the zeolite with an aqueous solution containing nitrates such as NH4NO3 or KNO3, or the ions to be exchanged, or an acid such as hydrochloric acid as appropriate, at a temperature from room temperature to 100°C, followed by washing with water. Alternatively, it can be calcined at 100°C to 750°C as needed.

[0295] For the cations present inside the zeolite as part of the charge compensation of the atoms constituting the framework structure of the zeolite, more than 50% are protons (H). + Methods for producing proton-type zeolites include calcination after ion exchange to ammonium ions, and treatment by contact with acid. From the viewpoint of avoiding the calcination step during synthesis, acid treatment to convert to the proton-type form is preferred. Furthermore, examples of acids used include organic acids such as carboxylic acids and sulfonic acids, and inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, and hydrochloric acid; these can be used alone or in combination of two or more. Among these, sulfuric acid or nitric acid is preferred from the perspective of being a strong acid and efficiently promoting ion exchange.

[0296] One method of manufacturing zeolite according to the present invention may further include surface treatment of the hydrothermally synthesized zeolite in a solution containing a Si element source.

[0297] The solution used in this surface treatment is not particularly limited as long as it can handle the zeolite state under the surface treatment conditions. It can be a solution containing a solvent in a Si compound, a liquid without a solvent, or a sol or gel. Here, the solvent can be water or an organic solvent. In addition, substances that are liquid under pressure at temperatures above their boiling point are also included in the solvent. In this case, the pressure can be self-generated pressure or applied pressure. Furthermore, the liquid used for surface treatment only needs to contain at least a Si compound, and other element sources (compounds), such as Al compounds, can also be included as sources.

[0298] Examples of Si compounds that can be used include alkyl halides such as trichloroethylsilane, dichlorohexylmethylsilane, and chlorotrimethylsilane; alkylalkoxysilanes such as methyltriethoxysilane, 3-aminopropyltriethoxysilane, and 1,1,3,3-tetramethoxy-1,3-dimethylpropanedisiloxane; organosilicon compounds containing siloxanes such as hexamethyldisiloxane; organosilicon compounds containing silazanes such as hexamethyldisilazane; silicates such as tetramethoxysilane and tetraethoxysilane; silicate oligomers such as methyl silicate oligomers and ethyl silicate oligomers; amorphous silica; fumed silica; colloidal silica; silica gel; sodium silicate; and silica sol. These Si compounds can be used alone or in combination of two or more.

[0299] As a treatment method, zeolite can be impregnated with a liquid to form chemical bonds with Si compounds, or chemical bonds can be formed after impregnation, or chemical bonds can be formed both during and after impregnation. Alternatively, zeolite can be brought into contact with the gas phase of a liquid evaporated by heating or other methods to form chemical bonds, or chemical bonds can be formed after contact.

[0300] Example

[0301] The following examples illustrate the invention in more detail, but they do not limit the scope of the invention.

[0302] <In vitro adsorption test>

[0303] The following steps were used to evaluate the in vitro adsorption capacity of various zeolites for TMA, choline, etc. It should be noted that the various zeolites were synthesized or obtained according to the reference examples described below.

[0304] Test methods

[0305] [Adsorption Test]

[0306] Glycine, lysine, and histidine were added to fasted-state simulated small intestine fluid (hereinafter sometimes referred to as FaSSIF or artificial intestinal fluid) prepared according to the preparation method described in the literature (Dissolution Technologies 20(3):44-50) to prepare a reaction solvent. The concentrations of glycine, lysine, and histidine in the reaction solvent were 0.30, 0.42, and 0.21 mg / mL, respectively. 2050 mg of arginine, 120 mg of choline chloride, and 80 mg of TMA hydrochloride were accurately weighed into 50 mL of a 0.1 N hydrochloric acid aqueous solution prepared by diluting 1 N hydrochloric acid with purified water, and thoroughly shaken to dissolve them to prepare a standard solution. 10 mg of each zeolite was accurately weighed into a 25 mL tube, and 5 mL of the reaction solvent was added. A stir bar and 50 μL of the standard solution were added to the liquid. The liquid was stirred for 1 hour to prepare a reaction solution. In addition, 5 mL of the reaction solvent and 50 μL of the standard solution were added to a 25 mL tube as a blank stock solution. Two blank stock solutions were prepared to confirm any deviations in the preparation.

[0307] [Sample Preparation]

[0308] Remove the stir bar from the reaction solution and centrifuge at 3000 rpm for 5 minutes (unless otherwise specified, centrifugation is performed using a Hitachi Koki Himac CF 9RX at 3000 rpm for 5 minutes). Transfer 1.5 mL of the supernatant to a 2 mL tube and add 100 μL of 1N hydrochloric acid (pH = 1~2). Centrifuge the liquid at 10000 rpm for 10 minutes, then transfer 1 mL of the liquid to a 50 mL tube and add 9 mL of purified water as the sample solution.

[0309] Additionally, 1.5 mL of the blank stock solution was transferred to a 2 mL tube, and 100 μL of 1N hydrochloric acid (pH = 1~2) was added. This liquid was centrifuged at 10000 rpm for 10 minutes, and 1 mL of this liquid was transferred to a 50 mL tube, with 9 mL of purified water added to prepare the blank solution. Two blank solutions were prepared to confirm any deviations in the preparation.

[0310] Table 1 lists the reagents used in the experiment, and Table 2 lists the containers and equipment used in the experiment.

[0311] [Table 1]

[0312]

[0313] [Table 2]

[0314]

[0315] [Measurement Conditions]

[0316] The following ion chromatography conditions were performed using an Integrion RFIC system electrochemical detector manufactured by Thermo Fischer.

[0317] Column: CS17 (4×250mm)

[0318] Protective post: CG17 (4×250mm)

[0319] Detector: Conductivity detector

[0320] Flow rate: 1.0 mL / min

[0321] Eluent: Mesylic acid (eluent generator)

[0322] Gradient conditions: Table 3

[0323] [Table 3]

[0324]

[0325] Column oven: 30℃

[0326] Injection volume: 50μL

[0327] Suppressor: CERS500e (4mm)

[0328] Measurement time: 22 minutes

[0329] [Evaluation Method]

[0330] Based on a separately prepared standard curve (linearity) and the calculated detection / quantitation limits, the concentrations of TMA and choline in the sample solution are calculated, and the adsorption rates of each substance adsorbed on the zeolite and the adsorption rate ratio of TMA to choline are determined.

[0331] [Standard curve (linearity) and detection / quantitation limit]

[0332] Accurately weigh 2050 mg of arginine, 120 mg of choline chloride, and 80 mg of TMA hydrochloride, add approximately 25 mL of purified water, and stir thoroughly to dissolve. Then, add purified water to bring the volume to 50 mL. Using this liquid, prepare five solutions containing the concentrations of each substance added to the sample solution, and construct a standard curve (linearity). Furthermore, for liquids diluted to concentrations sufficient for detecting / quantitatively analyzing TMA and choline, confirm the relative standard deviations and linearity of each substance in six determinations, and calculate the detection / quantification limits.

[0333] The standard curve (linearity) and detection / quantitation limits are confirmed every 3 months, and the most recent result is used for evaluation.

[0334] Dynamic test methods

[0335] [Adsorption rate test of TMA / choline / arginine tri-component mixture]

[0336] Accurately weigh 13.53 mg of arginine, 10.84 mg of choline chloride, and 7.42 mg of TMA hydrochloride into 2.0 mL of a 0.1 N hydrochloric acid aqueous solution prepared by diluting 1 N hydrochloric acid with purified water. Shake thoroughly to dissolve the substances and prepare a standard solution.

[0337] Accurately weigh 10 mg of zeolite into a 25 mL tube and add 5 mL of FaSSIF. Add a stir bar and 50 μL of standard solution to this liquid. Sample only once for each solution, preparing the same number of reaction solutions as the sampled solutions using the same procedure. After stirring for the desired time (3 min, 10 min, 30 min, 1 h, 3 h, 6 h, 24 h, 48 h), sample again using the same procedure as for the [sample preparation] in the in vitro adsorption experiment. Calculate the time shift of adsorption for each component based on the concentrations of TMA, choline, and arginine in the supernatant at each time point. It should be noted that... Figure 3 The adsorption capacity (μg / mL) on the vertical axis refers to the value obtained by subtracting the concentration of each component in the sample solution from the concentration of each component in the blank solution.

[0338] [Cholinergic release rate confirmation test]

[0339] Weigh 12.38 g of sodium chloride, 8.94 g of sodium dihydrogen phosphate dihydrate, and 0.84 g of sodium hydroxide. Add approximately 1.8 L of purified water and stir thoroughly to dissolve. Adjust the pH to 6.5 with 1 mol / L sodium hydroxide aqueous solution or 1 mol / L hydrochloric acid. Add purified water to bring the volume to 2 L to obtain a phosphate buffer solution. Add 991.2 mg of choline chloride to 2 mL of the phosphate buffer solution to adjust the choline solution. Accurately weigh 70 mg of zeolite and add 5 mL of phosphate buffer solution and 50 μL of the above choline solution. Stir overnight at room temperature, filter the zeolite, and dry under reduced pressure at 40 °C for 30 minutes. For the filtrate, sample according to the same procedure as for the [sample preparation] of the in vitro adsorption test, and further dilute with purified water to 50 times for the determination of blank solution and sample solution.

[0340] Accurately weigh 10 mg of this zeolite powder and add 5 mL of phosphate buffer. Sample only once per solution, preparing the same number of reaction solutions as the sampled solutions using the same procedure. After stirring for the desired time (30 minutes, 1 hour, 3 hours, 8 hours, 24 hours), sample using the same procedure as for the [sample preparation] in the in vitro adsorption experiment. Calculate the time shift of choline release from the choline concentration in the supernatant at each time point. It should be noted that for... Figure 4The adsorption amount (μg / mL) on the vertical axis is obtained by multiplying the choline concentration in the sample solution during overnight choline adsorption by the choline concentration in the blank solution by 50 / 7 to get the adsorption amount at time point 0. The adsorption amount at each time point is obtained by subtracting the choline concentration in the sample solution at each time point of the release test from the choline concentration in the blank solution.

[0341] It should be noted that, from now on, each item in the table will represent the following content.

[0342] Maximum number of rings: The maximum number of rings of the zeolite used in this embodiment.

[0343] Skeleton Code: The skeleton codes of the zeolites used in this embodiment are based on the zeolite skeleton structure codes established by the IZA (International Zeolite Association). If the compound is not a zeolite, its name is recorded.

[0344] Maximum diffuse sphere diameter within pores (Å): The maximum diffuse sphere diameter within the pores of the zeolite used in this embodiment. The value of the maximum diffuse sphere diameter within pores is referenced from the Maximum diameter of asphere that can diffuse along in the zeolite Framework Types section of the Structure Commission of the International Zeolite Association (IZA-SC) (https: / / asia.iza-structure.org / IZA-SC / ftc_table.php). In cases where multiple values ​​exist for axes a, b, and c, the largest value is used.

[0345] Pore ​​dimensionality: The pore dimension of the zeolite used in this embodiment.

[0346] Counter cation: The counter cation of the zeolite used in this embodiment

[0347] SAR: The molar ratio of SiO2 to Al2O3 in the zeolite used in this embodiment; in Examples 70 and 78, the molar ratio of SiO2 to Al2O3 in the raw zeolite before surface treatment.

[0348] (In vitro) TMA adsorption rate: The TMA adsorption rate of the adsorption experiment performed in this example.

[0349] (In vitro) Choline adsorption rate: The choline adsorption rate of the adsorption experiment performed in this example.

[0350] (In vitro) TMA / choline: The value obtained by dividing the TMA adsorption rate by the choline adsorption rate in the adsorption experiment performed in this example.

[0351] XRPD half-width: The half-width (unit: °(2θ)) of the largest peak (hereinafter referred to as the 2θ=7.9° peak) in the range of 2θ=7.9000°±0.5000° of the powder X-ray diffraction (XRPD) of the MFI type zeolite used in this embodiment.

[0352] Zeolite before acid treatment: Example number of the zeolite before acid treatment implemented in this embodiment.

[0353] Acid: The reagent name of the acid used in this embodiment.

[0354] Acid treatment temperature: The acid treatment temperature implemented in this embodiment.

[0355] Acid treatment time: The acid treatment time implemented in this embodiment.

[0356] Na Residual Rate: The residual Na rate in the zeolite after acid treatment in this embodiment. The Na residual rate was calculated based on the Na / Al standard curve in XRF, with the zeolite of Example 48 before ion exchange set to 100%.

[0357] Raw material zeolite: The embodiment number of the zeolite used in the surface treatment reaction in this example.

[0358] SAR of raw material zeolite: The molar ratio of SiO2 to Al2O3 in the zeolite used in the surface treatment reaction in this embodiment.

[0359] Surface treatment reagent: The surface treatment reagent used in this embodiment

[0360] Reaction conditions: The reaction conditions for the surface treatment reaction implemented in this embodiment.

[0361] TMA AUC change rate: The d9-TMA AUC change rate of the zeolite-treated group relative to the carrier group in the choline loading test conducted under fasting conditions in this embodiment.

[0362] Choline AUC change rate: The d9-choline AUC change rate of the zeolite-treated group relative to the carrier group in the choline loading test under fasting conditions implemented in this example.

[0363] Post-treatment after hydrothermal synthesis: The post-treatment method implemented in this embodiment is as follows.

[0364] Features of the XRPD pattern: Features of the XRPD pattern of the zeolite used in this embodiment.

[0365] Surface area: The surface area of ​​the zeolite used in this embodiment.

[0366] SEM images: SEM images of the zeolite used in this embodiment.

[0367] Combination drugs: The classification and names of the combination drugs used in this embodiment based on their compound properties.

[0368] Free molecular weight: The free molecular weight of the combination drugs used in this embodiment.

[0369] pKa: The pKa of the combination drug used in this embodiment. Acidic compounds are described.

[0370] pKa of the conjugate acid: The pKa of the conjugate acid of the combination drug used in this embodiment. Basic compounds are described.

[0371] Zeolite adsorption rate (%): The adsorption rate (%) of the combined drug used in this example on the zeolite.

[0372] result

[0373] In vitro adsorption test

[0374] For Examples 1, 26 and 34, and Comparative Examples 1-5 and 7-21, the characteristics of the zeolite, such as the maximum number of rings and the framework, as well as the TMA adsorption rate and choline adsorption rate of the in vitro adsorption test, are summarized in Table 4.

[0375] It was concluded that in zeolites with a maximum ring number of 8, the pore diameter was smaller than that of TMA and choline molecules, and therefore no intrapore adsorption of TMA and choline occurred. Choline adsorption was observed in Comparative Example 16, but this was attributed to surface adsorption.

[0376] In the case of zeolites with a maximum ring number of 10, except for HEU-type zeolites, choline and TMA were adsorbed efficiently. MFI-type zeolites, in particular, also showed complete adsorption of TMA compounds in the system (Examples 26 and 34), preferentially adsorbing TMA compared to choline. In HEU-type zeolites, the pores of the 10-membered rings were crushed, and the diameter of the largest diffuse sphere within the pores was small (3.67 Å), therefore, it is considered that no TMA adsorption occurred within the pores.

[0377] In zeolites with a maximum ring number of 12, both choline and TMA are adsorbed, but not selectively for TMA. This is believed to be because the pore diameter is larger than that of TMA and choline, making it impossible to distinguish between them.

[0378] In activated carbon (Comparative Example 1), molecular sieve 4A (Comparative Examples 4 and 5), Lokelma (registered trademark), a potassium adsorbent used as a drug for hyperkalemia (Comparative Example 2), and clinoptilolite, used as a zeolite supplement in the United States (Comparative Example 3), almost no TMA adsorption occurred.

[0379] [Table 4]

[0380]

[0381] For the MFI-type zeolites (maximum ring number 10) of Examples 2-35 and 37-64, and Comparative Examples 6 and 22, the silica / alumina ratio (hereinafter referred to as SAR), counter cations, half-width of the 2θ=7.9° peak in XRPD, and in vitro adsorption test results are summarized in Tables 5-1 and 5-2.

[0382] When the SAR is less than 33.0, the TMA / choline selectivity varies within the range of 1 to 3. Between 33.0 and 79.4, the TMA / choline selectivity is generally high, and the TMA adsorption rate is also high. When the SAR exceeds 79.4, the TMA / choline selectivity is generally high, but a decreasing trend in TMA adsorption rate is observed compared to the range between 33.0 and 79.4.

[0383] [Table 5-1]

[0384]

[0385] [Table 5-2]

[0386]

[0387] For MFI-type zeolites with TMA adsorption rates less than 60.0% or choline adsorption rates exceeding 40.0%, and for MFI-type zeolites with TMA adsorption rates above 60.0% and choline adsorption rates below 40.0%, the distribution of the number of compounds with the half-width of the XRPD peak at 2θ=7.9° is recorded as a histogram. Figure 1 middle.

[0388] It is believed that in MFI-type zeolites, not only is the SAR related to TMA / choline selectivity, but crystal quality, i.e., the peak half-width (WWHM) of XRPD, is also related to TMA / choline selectivity. In compounds with TMA adsorption rates above 60.0% and choline adsorption rates below 40.0%, compounds with small WWHMs are more frequent, all below 0.15°. On the other hand, in compounds with TMA adsorption rates below 60.0% or choline adsorption rates above 40.0%, the WWHM exceeds 0.15°.

[0389] According to the Scherrer equation, the smaller the peak half-width, the larger the crystallite size of the zeolite. It is believed that zeolites with larger crystallite sizes are more affected by the diffusion rate within the crystal pores, and that TMA adsorption is preferential compared to choline.

[0390] Acid treatment

[0391] The stability of the framework under acidic conditions was confirmed using the zeolite of Example 50 (maximum number of rings: 10, framework code: MFI).

[0392] The results are summarized in Table 6. Under any conditions, the XRPD half-width did not change significantly, therefore the MFI framework structure was considered to be maintained. Acid treatment did not decrease the TMA adsorption rate, nor did it significantly change the choline adsorption rate.

[0393] [Table 6]

[0394]

[0395] Using the zeolite (maximum ring number: 10, framework code: MFI) from Example 48, which underwent only drying after hydrothermal synthesis, the effect of different protonation treatments on the Na / H exchange efficiency was confirmed (Table 7).

[0396] Considering the Na residue in the zeolites of Examples 68 and 69, it is believed that the Na / H cation exchange reaction roughly reaches equilibrium by stirring in a 1 mol / L nitric acid aqueous solution at room temperature for about 1 hour. The Na residue at this point is similar to that in the case of proton-type zeolites produced by ammonium ion exchange / calcination (Example 49).

[0397] [Table 7]

[0398]

[0399] Surface treatment

[0400] The changes in adsorption capacity caused by surface treatment of zeolite were confirmed.

[0401] The research results are summarized in Table 8.

[0402] Surface treatment improved the in vitro TMA / choline adsorption selectivity of any compound. Regarding low-molecular-weight surface treatment reagents (Comparative Example 23, Examples 70 and 72-76), the TMA adsorption rate of zeolites in Examples 74 and 76 treated with a surface treatment reagent containing octadecyl groups as long-chain alkyl chains decreased. One reason for this is that the internal pores may be blocked by the long alkyl chains. Regarding surface treatment reagents containing polymers (Examples 77-88), the change in choline adsorption rate was small when the reaction was carried out by the vapor (gas phase) method (Examples 77 and 80), therefore, the surface treatment reaction was considered insufficient in the vapor method. Whether toluene-2 ​​conditions or neat (solvent-free) conditions are better depends on the polymer surface treatment reagent.

[0403] [Table 8]

[0404]

[0405] Counter cations

[0406] Using zeolites (maximum ring number: 10, framework code: MFI) from Examples 34-36, 71 and 89 with the same hydrothermal synthesis conditions but different counter cations, the effect of different counter cations on adsorption capacity was confirmed (Table 9).

[0407] In transferring countercations from H + to become Li + Na + K + or NH4 + Under these conditions, the selectivity of TMA / choline adsorption in vitro did not decrease significantly. It should be noted that, for oral use, proton-type ions are preferred as they are less likely to cause adverse effects on the organism due to excessive ion uptake.

[0408] [Table 9]

[0409]

[0410] BET specific surface area, particle size distribution

[0411] For the zeolites (maximum number of rings: 10, framework code: MFI) of Examples 5, 11, 19, 26, 34, 38, 49, 52 and 53, and Comparative Examples 6 and 22, the results of the BET specific surface area and external surface area obtained by the BET surface adsorption test are recorded in Table 10.

[0412] External surface area exceeding 30m 2In compounds with a surface area of ​​ / g, the TMA adsorption selectivity relative to choline is low. It can be considered that in the adsorption using the fine pores inside the zeolite, the TMA adsorption selectivity relative to choline increases by recognizing differences in molecular size. However, in compounds with a large surface area, the adsorption contribution from the outer surface of the zeolite particles, which do not recognize differences in molecular size, becomes larger, thus reducing the selectivity.

[0413] [Table 10]

[0414]

[0415] Particle size distribution

[0416] For the zeolites of Examples 26 and 34 and Comparative Examples 6 and 22 (maximum ring number: 10, framework code: MFI), the particle size distribution results are recorded in Tables 11-1 and 12-1. Figure 2 .

[0417] In Comparative Examples 6 and 22, two frequency distribution peaks were observed, with the first peak below 1 μm. Consequently, the particle size at the 10% cumulative frequency was smaller (<2.5 μm). Conversely, in Examples 26 and 34, only one frequency distribution peak was observed, and the diameter at the 10% cumulative frequency was larger (>2.5 μm). Similarly, the median particle size in Examples 26 and 34 was larger than that in Comparative Examples 6 and 22. The larger external surface area in Comparative Examples 6 and 22 compared to Examples 26 and 34 is considered to reflect the difference in particle size. Furthermore, the smaller particle size is also associated with lower TMA adsorption selectivity relative to choline.

[0418] [Table 11-1]

[0419]

[0420] [In vitro adsorption test using low dosage of zeolite]

[0421] In vitro adsorption tests were conducted using zeolites from Examples 26 and 34 at low dosages. For the previous [adsorption tests], the zeolite dosage was changed from 10 mg to 3 mg or 1 mg, and the in vitro adsorption tests were performed using the same method. The results are shown in Table 11-2. It is believed that for zeolites with high TMA adsorption rates and TMA / choline selectivity, reducing the amount of zeolite added in the in vitro adsorption tests increases the TMA / choline adsorption ratio.

[0422] [Table 11-2]

[0423]

[0424] kinetic test

[0425] Regarding the zeolites (maximum ring number: 10, framework code: MFI) of Examples 26, 34, and Comparative Example 6, the adsorption amounts of TMA, choline, and arginine over time are shown in the figure. Figure 3 .

[0426] Regarding TMA, the adsorption of any compound reached a plateau within a short time. Regarding arginine, although it was adsorbed in Comparative Example 6, it was not adsorbed in Examples 26 and 34. In Comparative Example 6, the adsorption of choline reached a plateau within 3 minutes of the start of the adsorption test, but it did not reach a plateau in Examples 26 and 34.

[0427] As for the adsorption process of each component into the zeolite, it is believed that it proceeds in the order of (1) surface adsorption, (2) adsorption into the micropores of the surface layer, and (3) diffusion into the micropores of the deep layer. When (1) is rapid but (2) and (3) adsorption and diffusion into the micropores are slow, it becomes the rate-limiting process of adsorption. It is believed that the difference in adsorption rate between TMA and choline in Examples 26 and 34 reflects the difference in the rate of adsorption process in the micropores of (2) and (3). That is, choline, which has a larger molecular size than TMA, is slower than TMA in the adsorption and diffusion process in the micropores due to steric hindrance. In Comparative Example 6, choline, TMA and arginine are mainly adsorbed by surface adsorption, and no difference in adsorption rate is generated. However, in Examples 26 and 34 with large particle size, it is believed that the influence of the diffusion rate in the micropores is greater, and the adsorption rate of choline is significantly slower. In addition, arginine is a molecule larger than choline, and it was not adsorbed in Examples 26 and 34, which have small outer surface area and are mainly adsorbed in the micropores. It should be noted that, based on particle size distribution and external surface area, it was confirmed that the particle size in Examples 26 and 34 was larger than that in Comparative Example 6.

[0428] For Comparative Examples 6 and 22 and Examples 26 and 34, the time shift of choline release was recorded in Figure 4 In the release tests, Comparative Examples 6 and 22 showed higher choline release rates, with the release reaching a plateau within one hour. In contrast, Examples 26 and 34 showed lower choline release rates, and it took approximately eight hours to reach a plateau. In Comparative Examples 6 and 22, which have larger external surface areas, choline was primarily adsorbed on the outer surface; therefore, the contribution of choline diffusion within the pores was considered minimal, leading to rapid re-release.

[0429] <Calculation>

[0430] To support the reasoning for the adsorption rate difference between TMA and choline on MFI zeolite, and the TMA / choline selectivity, the adsorption process was analyzed by first-principles calculations based on density functional theory.

[0431] Calculation method

[0432] Application and version used: VASP (Vienna Ab initio Simulation Package) ver. 6.3.2 (Computation execution (Mitsubishi Chemical Corporation, Masayoshi Mikami))

[0433] Density functional theory: Exchange-correlation energy is generalized density gradient correction (GGA-PBE), and dispersion force correction is DFT+D3 (Grimm). PAW method (cutoff energy of plane wave basis set 400 eV). k-point sampling is the Γ-point, and the threshold calculated by SCF is 1.0 × 10⁻⁶. -6 eV, force threshold for structural optimization: 1.0 × 10⁻⁶ -5 eV / Å

[0434] Computational model

[0435] Periodic plate models corresponding to the

[010] surface and the

[100] surface of MFI zeolite were prepared in the form of data described in the paper (ACS Catalysis 2020 10, 3297-3312). Here, when TMA and choline were configured in the surface models, TMA was treated as a neutral molecule and choline was treated as a monovalent cation molecule. It should be noted that in the calculation of the monovalent cation state, in order to maintain the charge neutrality of the entire system, it is necessary to perform a uniform background charge distribution calculation with opposite signs. However, when the electron occupancy rate (NELECT) is adjusted in VASP and the calculation is performed in the state corresponding to the monovalent cation, the background charge distribution calculation can be performed automatically. Taking the middle position of the thickness direction (z-axis direction) of the zeolite layer of each surface model as the reference (set as z=0), the nitrogen atoms of TMA molecules or choline molecules were configured here. The stable configuration (internal adsorption) of the molecules was obtained by optimizing the atomic positions other than the z coordinate of the nitrogen atoms. Furthermore, the z-coordinate of nitrogen is shifted 1 Å towards the surface each time, and optimization calculations are performed on the atomic positions outside the z-coordinate of nitrogen each time. The point where the total energy of all molecules near the surface (z=8~11 Å) decreases is set as 0 kcal / mol, serving as the energy reference point. In addition, the point where the energy barrier is highest when penetrating the zeolite from the surface (z=5~7 Å) is set as the point of highest energy barrier.

[0436] Calculation results

[0437] The energy lines related to the adsorption process of TMA or choline from the

[010] and

[100] planes are plotted in the diagram. Figure 5 The energy reference point, the highest point of the energy barrier, and the zeolite layer profile during internal adsorption are shown in the figure. Figure 6-1 , Figure 6-2 , Figure 6-3 , Figure 6-4 The structure of the highest point of the energy barrier of the

[010] model from the z-axis perspective is shown in... Figure 7 .

[0438] The energy barrier for penetration into the zeolite from the

[100] facet is 5 kcal / mol for both TMA and choline molecules, indicating a similar adsorption rate (energy difference within 1 kcal / mol with quantum chemical precision). On the other hand, the energy barrier for penetration into the zeolite from the

[010] facet is approximately 10 kcal / mol for TMA molecules and approximately 15 kcal / mol for choline molecules, suggesting that the adsorption rate of choline molecules is slower than that of TMA. This calculation supports the experimental results that the

[010] facet is a crystal facet with high TMA / choline selectivity (see the results of "SEM images, external surface area, and efficacy of choline loading tests under fasting" described later). Figure 7 It can be observed that the tertiary amine TMA has a triangular pyramidal molecular structure with nitrogen as the vertex. The short and long axes of the molecule match the shape of the elliptical pore and can pass through. However, choline, as a quaternary ammonium ion, has a regular tetrahedral shape with nitrogen as the center, which does not match the elliptical shape and creates steric hindrance when it passes through.

[0439] The three-dimensional channels of MFI zeolite are formed by interconnecting linear

[010] channels and sinusoidal

[100] channels. By alternating between

[010] and

[100] channels, molecules gradually diffuse along the

[001] direction. It is speculated that the steric hindrance during choline intrusion into the

[010] surface also occurs when choline moves through the pores beyond the

[010] surface inside the crystal. Therefore, when diffusing in the

[010] and

[001] directions within the crystal, the diffusion rate of choline is slower than that of TMA. This is consistent with the experimental results of high TMA / choline selectivity in coffin-shaped crystals with long

[001] directions (results from "SEM images, external surface area and choline loading test efficacy under fasting" described later), and also consistent with the results of kinetic experiments showing slow choline adsorption rates in Examples 26 and 34 with large particle sizes (results from the previous "Kinetic Experiments").

[0440] <Cholelinergic Load Test Under Fasting>

[0441] Test methods

[0442] Seven-week-old male C57BL / 6 mice were fasted for 12 hours, and then simultaneously administered d9-choline chloride dissolved in distilled water (Toronto Research Chemicals Inc.) and zeolite suspended in sterile 0.5 w / v methylcellulose 400 solution (Fujifilm and Kojun Pharmaceutical Co., Ltd.) orally at doses of 78.78 mg / kg (60 mg / kg as d9-choline) and 500–2000 mg / kg, respectively. Blood samples were then collected from the tail vein at 1, 2, 4, 6, 8, and 10 hours, and the concentrations of d9-choline, d9-TMA, and d9-TMAO in plasma were determined by LC / MS / MS.

[0443] For d9-choline, d9-TMA, and d9-TMAO, plasma concentrations were plotted over time with plasma concentration on the ordinate and time after administration on the abscissa, and the area under the curve (AUC) was calculated up to 10 hours after administration. The pharmacological effects of the zeolites were confirmed by comparing them between the non-administered zeolite group (hereinafter referred to as the carrier group) and the administered zeolite group. Furthermore, the pharmacological effects of each zeolite were compared using the rate of change of AUC, which was standardized relative to the carrier group's AUC. The rate of change of AUC was calculated using the following formula.

[0444] [Number 1]

[0445]

[0446] result

[0447] Choline stress test under fasting

[0448] For the zeolites of Examples 1, 5, 9, 13, 15, 26, 34 and 55 and Comparative Examples 8, 6 and 22, the compound information and the results of the choline loading test under fasting are summarized in Table 12.

[0449] All compounds were tested at a dose of 500 mg / kg (unless otherwise specified, the results of the choline load test under fasting refer to the results when conducted at a dose of 500 mg / kg).

[0450] Compared to the support group, all compounds reduced the AUC of d9-TMA. In the zeolites of Comparative Examples 6, 8, and 22, which showed low TMA / choline selectivity in in vitro adsorption tests, the AUC reduction rate of d9-choline was the same as or greater than that of d9-TMA. In compounds with high TMA / choline selectivity and high TMA adsorption capacity in in vitro adsorption tests, the AUC reduction rate of d9-TMA was high, while the AUC reduction rate of d9-choline was low. Choline is a nutrient, and compounds that inhibit choline absorption are undesirable. It should be noted that "AUC reduction rate" refers to the value obtained by multiplying the "AUC change rate" by -1.

[0451] [Table 12]

[0452]

[0453] The time-dependent concentrations and AUCs of plasma d9-TMA in fasted cholinergic-loaded mice after administration of large doses of zeolite (Example 34) are shown in the figure. Figure 8 .

[0454] The zeolite in Example 34 dose-dependently reduced the plasma d9-TMA concentration and AUC, and at the maximum dose of 2000 mg / kg, it almost completely inhibited the rise of plasma d9-TMA. It is believed that at this dose, the zeolite in Example 34 adsorbed almost all of the d9-TMA in the digestive tract.

[0455] The time-shifted plasma concentrations of d9-choline and d9-TMA in mice subjected to large doses of zeolite in Comparative Example 6 under fasting cholinergic loading were shown in... Figure 9 .

[0456] In Comparative Example 6 zeolite with low TMA / choline selectivity, the peak time of d9-TMA at 600 mg / kg (hereinafter referred to as T) max Compared to the vector group delay, T max The decrease in plasma d9-TMA concentration subsequently slowed. Furthermore, in the 2000 mg / kg group, plasma d9-TMA concentration increased slowly over 4–10 hours. At any dosage, plasma choline concentration was consistently suppressed to a low level.

[0457] Based on these experimental results, it is believed that (1) the adsorption of choline by the compound in the upper digestive tract and small intestine leads to the inhibition of choline absorption in the digestive tract; (2) the compound releases choline in the large intestine; then (3) bacteria decompose choline into TMA; and (4) TMA is absorbed by the large intestine. That is, it is believed that the amount of TMA produced in the intestine increases due to the temporary adsorption of choline by the compound and its subsequent release in the large intestine. To fully eliminate the increased TMA absorption caused by choline delivery in the large intestine, it is believed that an in vitro TMA / choline adsorption selectivity of approximately 1 time is insufficient (Table 12; zeolites of Comparative Examples 6, 8, and 22). It should be noted that... Figure 4 The release rate over time confirmed that the zeolites in Comparative Examples 6 and 22 had a rapid choline release rate.

[0458] Zeolite counter-cation / post-treatment method and efficacy of choline loading test under fasting

[0459] For the zeolites of Examples 34, 35, and 68, the effects of differences in counter cations and post-treatment methods on choline loading tests under fasting were compared within the same experiment (Table 13). Example 35 was a Na-type zeolite without proton exchange, Example 34 was a proton-type zeolite obtained by calcining after ammonium ion exchange of the Na-type, and Example 68 was a proton-type zeolite obtained by treating the Na-type with nitric acid.

[0460] For each zeolite, the efficacy was confirmed by a choline loading test under fasting conditions. Compared with proton-type zeolites calcined after ammonium ion exchange, proton-type zeolites treated with nitric acid showed a higher reduction in the AUC of d9-TMA.

[0461] [Table 13]

[0462]

[0463] Zeolite surface treatment and choline loading test efficacy under fasting

[0464] To confirm the effect of zeolite surface treatment on pharmacological effects, the zeolites of Examples 34, 70, and 78 were administered to fasted choline-loaded mice for comparative pharmacological effects. Table 14 summarizes the compound information and the results of the fasted choline-loaded test.

[0465] The zeolites of Examples 70 and 78 were obtained by surface treatment of the zeolite of Example 34 or by the same synthesis method. Surface treatment resulted in a reduction rate of d9-TMA AUC equal to or greater than that before surface treatment, while preventing a reduction in d9-choline AUC. The effect of surface treatment in preventing choline adsorption was also confirmed in choline loading tests under fasting conditions.

[0466] [Table 14]

[0467]

[0468] The quartz contained in zeolite and its efficacy in choline loading tests under fasting conditions

[0469] For the zeolites of Examples 34 and 52, the compound conditions and AUC changes in the fasting choline loading test are shown in Table 15. Figure 10 The XRPD patterns of Example 34 (upper section) and Example 52 (lower section) are shown. The vertical axis represents intensity (cps), and the horizontal axis represents the diffraction angle 2θ (°).

[0470] It can be seen that, compared with Example 34, Example 52 contains more characteristic quartz peaks near 2θ=21° and 27°. In the zeolite of Example 52 with more quartz, the reduction rate of d9-TMA AUC in the fasting choline loading test is smaller (Table 15). It is believed that quartz does not have a fine porous structure and has no TMA adsorption effect. That is, it is believed that in Example 52 with more quartz, the content of MFI type zeolite per unit weight is reduced, and the efficacy (d9-TMA AUC reduction rate) in the fasting choline loading test is lower than that of Example 34.

[0471] [Table 15]

[0472]

[0473] SEM images, external surface area, and efficacy of the drug under fasting cholinergic loading test.

[0474] For zeolites used in in vitro adsorption tests and fasting choline loading tests, the correlation between efficacy, external surface area, and SEM images was confirmed (Tables 16-1 and 16-2).

[0475] Regarding the zeolites of Comparative Examples 6 and 22, whose d9-TMA AUC reduction rate and d9-choline AUC reduction rate were similar in the fasting choline loading test, SEM images confirmed that they were mostly composed of particles and aggregates smaller than 1-2 μm. On the other hand, for the zeolites (Examples 5, 26, 34, and 52) whose d9-TMA AUC reduction rate was greater than that of d9-choline AUC in the fasting choline loading test, it was confirmed that compared with Comparative Examples 6 and 22, the proportion of particles and aggregates smaller than 1-2 μm was less, and the crystals grew larger. For Examples 5, 26, and 34, which had high in vitro adsorption selectivity and a particularly large difference between the d9-TMA AUC reduction rate and the d9-choline AUC reduction rate, particle observation using SEM confirmed that the crystal shape was coffin-shaped with a wide crystal facet

[010] . The adsorption rates of choline and TMA are governed by the molecular intrusion rate from the medium into the zeolite pores and the molecular diffusion rate within the crystal pores. In the case of three-dimensional porous structures such as MFI-type zeolites, the difference in intrusion rate and diffusion rate along the three-dimensional coordinate axes of the crystal is attributed to the different crystal planes. In MFI-type zeolites, the TMA / choline selectivity is high when the

[010] plane is wide, therefore it is speculated that the

[010] plane is the crystal plane with particularly high TMA / choline selectivity. It should be noted that for MFI-type zeolites with a coffin-shaped crystal shape, the widest crystal plane has been identified as the

[010] plane in SCIENCE, 2003, Vol 300, Issue 5618, pp. 456-460. Furthermore, as reported in J. Am. Chem. Soc. 2023, 145, 9021-9028, it is speculated that selective surface treatment of surfaces other than the

[010] face, where choline is difficult to penetrate, could further improve selectivity. Additionally, since the crystal axis lengths of coffin-shaped crystals follow the order

[001] axis >

[100] axis >

[010] axis, it is also speculated that TMA / choline selectivity is obtained during diffusion into the crystal pores along the

[001] axis.

[0476] In SEM images, a tendency was confirmed that the more particles smaller than 1-2 μm, their aggregates (Comparative Examples 6 and 22), or scaly structures (Examples 19 and 53) were observed, the larger the external surface area. Furthermore, a correlation was confirmed between a larger external surface area and a higher reduction rate of d9-choline AUC in choline loading tests under fasting conditions.

[0477] Example 52, which was confirmed by XRPD data to contain a large amount of quartz, also showed more particles in its SEM image that were considered to be quartz and were different from MFI-type zeolite compared to Example 34.

[0478] [Table 16-1]

[0479]

[0480] [Table 16-2]

[0481]

[0482] <Single PK Trial and Construction of Physiological Pharmacokinetic (PBPK) Model>

[0483] PK trial of single intravenous administration of d9-TMA and d9-TMAO

[0484] In 7-9 week old male C57BL / 6 mice, d9-TMA or d9-TMAO were administered intravenously at doses of 11.5 mg / kg or 10 mg / kg, and blood samples were collected during menstruation. Additionally, in 7-week-old male C57BL / 6 mice, d9-TMA was administered intravenously at a dose of 10 mg / kg, and urine samples were collected 24 hours later. The concentrations of d9-TMA and d9-TMAO in plasma and urine were determined by LC-MS / MS.

[0485] Single oral pharmacokinetic study of d9-TMA

[0486] d9-TMA was orally administered at a dose of 34.6 mg / kg to 7-week-old male C57BL / 6 mice under fasting conditions, and blood samples were collected during menstruation. The concentrations of d9-TMA and d9-TMAO in plasma were determined by LC-MS / MS.

[0487] Construction of PBPK model

[0488] The report was adopted with reference to Shimizu et al. 1) Furthermore, a transport model was constructed that considered the transformation process of intestinal bacteria from d9-choline to d9-TMA in the large intestine and the transfer time from the upper digestive tract to the large intestine. A PBPK model was constructed for d9-choline, d9-TMA, and d9-TMAO when d9-choline was orally administered to mice. Figure 11 A conceptual diagram of the PBPK model is shown. In its construction, in vivo data from the previous "choline loading test under fasting" vector group and in vivo data from a single PK test were used.

[0489] 1) Shimizu, M. et al. Human plasma concentrations of trimethylamineN-oxide extrapolated using pharmacokinetic modeling based on metabolic profiles of deuterium-labeled trimethylamine in humanized-liver mice. J.Toxicol. Sci. 43, 387-393 (2018).

[0490] The following steps are applied to construct a PBPK model.

[0491] Assuming no interspecies differences in liver / plasma partition coefficients, blood cell / plasma partition coefficients, and unbound plasma proteins for d9-TMA and d9-TMAO, the reported values ​​by Shimizu et al. are cited. 1) .

[0492] • Liver volume and hepatic blood flow values ​​cited from Yamashita et al. 2) .

[0493] • PK parameters for d9-TMA and d9-TMAO were deduced using data from single-dose intravenous administration PK trials. Renal clearance was optimized to accurately reproduce the urinary excretion rate of d9-TMA.

[0494] • Using data from the carrier group in the fasting cholinergic loading test, absorption parameters of d9-TMA (including the transport rate constant from the upper gastrointestinal tract to the large intestine and the conversion rate from d9-choline to d9-TMA) were inferred. The conversion rate was calculated by dividing the dose-corrected AUC of d9-TMA in the carrier group of the fasting cholinergic loading test by the dose-corrected AUC of d9-TMA in the single intravenous PK test group, and then by the absorption rate of d9-TMA obtained from the PBPK model.

[0495] The reduction rate of AUC of d9-choline and d9-TMA is considered to reflect the rate of gastrointestinal absorption inhibition caused by zeolite adsorption (hereinafter, sometimes referred to as IR). pre IR and IR) were constructed respectively. pre The relationship between IR and zeolite dosage. For d9-choline, substituting the relationship between gastrointestinal absorption inhibition rate and zeolite dosage into E... maxThe model calculates a 50% effective dosage. Regarding d9-TMA, it is assumed that adsorption equilibrium is reached in the digestive tract, and the digestive tract absorption inhibition rate of d9-TMA is assumed to follow the formula: Theoretical acidity of unadsorbed zeolite / (Intestinal water volume × Dissociation constant + Theoretical acidity of unadsorbed zeolite). The dissociation constants of zeolite and d9-TMA are calculated. The intestinal water volume is taken from the value of SimCYP(V23) manufactured by Certara.

[0496] 2) Yamashita, M. et al. Human plasma concentrations of herbicidalcarbamate molinate extrapolated from the pharmacokinetics established in invivo experiments with chimeric mice with humanized liver and physiologicallybased pharmacokinetic modeling. Regulatory Toxicology and Pharmacology 70,214-221 (2014).

[0497] The parameters used in the PBPK model are shown in Table 16-3.

[0498] [Table 16-3]

[0499]

[0500] Simulation of plasma concentration shift and urinary excretion during administration of zeolite in Example 34

[0501] Figure 12 shows a graph comparing the measured plasma concentrations of d9-choline, d9-TMA, and d9-TMAO in fasted cholinergic-loaded mice after large-dose administration of the zeolite from Example 34 with the plasma concentration shifts predicted by the PBPK model. Table 16-4 shows the predicted 24-hour urinary excretion, also calculated by the PBPK model. The plasma concentration shifts of d9-choline, d9-TMA, and d9-TMAO simulated by the PBPK model largely reproduced the measured plasma concentration shifts.

[0502] [Table 16-4]

[0503]

[0504] <Cholelinergic Loading Test Under Ingestion>

[0505] Test methods

[0506] To induce acclimatization through diurnal reversal and restricted feeding, 10-week-old male C57BL / 6 mice fed a choline-free diet (A21122102) (EP Trading Co., Ltd.) were simultaneously orally administered d9-choline chloride dissolved in distilled water (Toronto Research Chemicals Inc.) and zeolite from Example 34 suspended in a sterile 0.5 w / v methylcellulose 400 solution (Fujifilm and Kojun Pharmaceutical Co., Ltd.) at doses of 78.78 mg / kg and 500–2000 mg / kg, respectively. Similarly, d9-choline chloride dissolved in distilled water and zeolite from Example 70 suspended in a sterile 0.5 w / v methylcellulose 400 solution were simultaneously orally administered at doses of 78.78 mg / kg and 1000 mg / kg, respectively. After oral administration, the animals were housed in metabolic cages, and urine was collected over 24 hours. The concentrations of d9-TMA, d9-TMAO, native TMA, and native TMAO in urine were determined by LC / MS / MS, and the 24-hour urinary excretion was calculated from the urine volume. Here, "native" refers to a molecule composed of isotopes with the highest isotopic abundance ratio.

[0507] The results are shown in Figure 13 It was confirmed that the total 24-hour urinary excretion (μmol) of d9-TMA and TMAO using the zeolite of Administration Example 34 was reduced in a dose-dependent manner compared to the carrier group. Similarly, the total 24-hour urinary excretion of native TMA and TMAO was also reduced in a dose-dependent manner. It was confirmed that the values ​​obtained by further summing these d9 and native forms were also reduced in a dose-dependent manner. Using the zeolite of Administration Example 70, the same degree of reduction in 24-hour urinary excretion of TMA and TMAO as that of the zeolite of Administration Example 34 was confirmed.

[0508] In a cholinergic loading test not under fasting conditions, but under conditions simulating human eating and loading d9-choline, the zeolite of Example 34 reduced the urinary excretion of d9-TMA and TMAO. This indicates that the zeolite of Example 34 specifically recognizes and adsorbs and removes TMA even under conditions where various impurities exist in the digestive tract during eating. This strongly suggests that efficacy can also be demonstrated in patients with TMAU through the use of zeolites with high selectivity for TMA.

[0509] <Clinical Dosage Prediction>

[0510] Based on the total excretion of d9-TMA and d9-TMAO in urine during the choline loading test, the gastrointestinal TMA absorption inhibition rate of the zeolite in Example 34 was calculated. The effective dosage was corrected by the ratio of gastrointestinal TMA levels in mice and humans, thereby estimating the clinically effective dosage of the zeolite in Example 34.

[0511] Calculation of TMA absorption inhibition rate in the digestive tract

[0512] Oral administration to humans and rats 14 With C-TMA, over 95% or 80% of the radioactivity is excreted in the urine within 24 hours after administration, with the majority being TMA and TMAO. 3, 4) Therefore, it is believed that the amount of TMA in the digestive tract can be inferred from the total excretion of TMA and TMAO in urine in mice.

[0513] 3) Al-Waiz M, Mitchell SC, Idle JR, Smith RL. The metabolism of 14 C-labelled trimethylamine and its N-oxide in man. Xenobiotica 1987; 17(5): 551-558

[0514] 4) Al-Waiz M, Mitchell SC. The fate of trimethylamine in the rat. Drug Metab and Drug Interact 1991; 9(1): 41-48

[0515] The total urinary excretion of d9-TMA and d9-TMAO when using the oral administration carrier or the zeolite of Example 34 with d9-choline was calculated using the following formula: the gastrointestinal TMA absorption inhibition rate of the zeolite of Example 34 in this experiment.

[0516] [Number 2]

[0517]

[0518] According to reports, the recommended daily intake of TMA in a typical Western diet is 50 mg / day. 5) The threshold for odorous urinary excretion in TMAU patients is 20 mg TMA / day. 6) Regarding the prevalence of TMAO in urine (as% of TMA+TMAO), the paper reported... 7)The rate was 9.5% in the most severe TMAU patients and 26.6% in the severe patients (n=13). Therefore, the gastrointestinal TMA absorption inhibition rate as a target for TMAU treatment was calculated in each patient group using the following formula.

[0519] [Number 3]

[0520]

[0521] 5) Fennema D, Phillips IR, Shephard EA. Trimethylamine andTrimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-MediatedHost-Microbiome Metabolic Axis Implicated in Health and Disease. Drug MetabDis 2016; 44:1839-1850

[0522] 6) Michell SC, Smith RL. Trimethylaminuria: The Fish MalodorSyndrome. Drug Metab Dis 2001; 29:517-521

[0523] 7) Shimizu M, Allerston CK, Shephard EA, Yamazaki H, Phillips IR. Relationships between flavin-containing mono-oxygenase 3 (FMO3) genotype and trimethylaminuria phenotype in a Japanese population. Br J Clin Pharmacol2013; 77(5): 839-851

[0524] Estimation of clinical dosage

[0525] The adsorption rate of zeolite is determined by the ratio of the target adsorbate to the zeolite. Based on this idea, when the TMA adsorption rate (gastrointestinal TMA absorption inhibition rate) in mice is equal to the clinically targeted TMA adsorption rate, the effective dosage in mice (mouse effective dosage) is estimated by correcting the dosage in mice with the ratio of standard gastrointestinal TMA amounts in mice to those in humans. The formula used for calculation is shown below.

[0526] [Number 4]

[0527]

[0528] *The total excretion (mol) of d9-TMA and d9-TMAO in the urine of the carrier group was divided by the urine recovery rate (0.9) and the bioavailability of TMA (assumed to be 0.8, the same as in rats) to convert it into the TMA weight value. It should be noted that the urine recovery rate (0.9) was calculated by dripping mouse urine into a metabolic cage and collecting it, and then calculating the amount of urine before and after collection.

[0529] Calculation of TMA absorption inhibition rate in the digestive tract

[0530] The gastrointestinal TMA absorption inhibition rates calculated according to the above formula are shown in Table 17, and the gastrointestinal TMA absorption inhibition rates used as targets in clinical practice are shown in Table 18. Regarding the gastrointestinal TMA absorption inhibition rates when mice were simultaneously administered the zeolite from Example 34 and 60 mg / kg of d9-choline, the rates were 42.8% at 500 mg / kg, 58.4% at 1000 mg / kg, and 90.4% at 2000 mg / kg.

[0531] Furthermore, regarding the target gastrointestinal absorption rate in clinical practice, it was calculated to be 42.6% in severely ill patients and 53.5% in the most severely ill patients reported in the paper. Based on the above results, it is concluded that the gastrointestinal TMA absorption inhibition rate of the zeolite from Example 34 administered to mice at 500 mg / kg and 1000 mg / kg is equivalent to the target inhibition rate envisioned for severely ill and most severely ill patients, respectively.

[0532] [Table 17]

[0533]

[0534] [Table 18]

[0535]

[0536] Estimated clinical dosage

[0537] The estimated clinically effective doses of the zeolite in Example 34, calculated according to the above formula, are shown in Table 19. Regarding the clinically effective dose for which therapeutic effects can be expected in severely ill patients, based on a 500 mg / kg equivalent in TMAU model mice, the estimated dose is 793 mg / man / meal. Similarly, based on a 1000 mg / kg equivalent in the same model mice, the estimated clinically effective dose for the most severely ill patients is 1595 mg / man / meal.

[0538] [Table 19]

[0539]

[0540] <Si and Al Dissolution Test>

[0541] Test Method & Results

[0542] Perform Si and Al dissolution tests on the zeolites of Examples 26 and 34. Precisely weigh 250 mg of the zeolite, add 5 mL of 1N hydrochloric acid, and stir at 37 °C for 3 hours. Centrifuge the liquid. Centrifuge 2 mL of the supernatant again to obtain a new supernatant (the first dissolution solution). Filter the remaining zeolite-containing liquid using filter paper (No. 5B) to filter out the zeolite. Add this zeolite to 5 mL of newly prepared 1N hydrochloric acid, and stir at 37 °C for 3 hours. Take 2 mL of the supernatant of this liquid and centrifuge it to obtain a new supernatant (the re-dissolution solution). Weigh 1000 mg each of the first and re-dissolution solutions, add 2 mL of 38% (12N) hydrochloric acid, and add purified water to make 25 mL. For these solutions, use ICP-AES to measure the Si and Al concentrations, and calculate the concentrations and dissolution rates of Si and Al in the dissolution solution (Table 20). It should be noted that the dissolution rate is the value obtained by dividing the weight of Si or Al present in the dissolution solution equivalent to 5 mL by the weight of Si or Al in the zeolite used in the test calculated assuming that the counter cations of the zeolite are protons and the zeolite does not contain water.

[0543] The dissolution rate of Al in the zeolite of Example 3 is 10% or less, and that of the zeolite of Example 26 is about 0.1%. In any of the compounds, the dissolution of Si is below 0.1%. In addition, when re-dissolving, the dissolution amounts of Si and Al are both reduced compared to the first dissolution. This is considered because the trace impurities other than the zeolite present during the first dissolution and the incomplete structure on the zeolite surface have disappeared during re-dissolution. It is considered that by increasing acid treatment as a post-treatment after zeolite synthesis, the dissolution amounts of Si and Al in the digestive tract when administered to organisms can be reduced.

[0544] It is envisaged that a small amount of Si and Al will dissolve in gastric acid when administered to organisms, so the impact on the body needs to be considered. Assuming that a person weighing 70 kg takes 3 g of the zeolites of Examples 26 and 34 per day, even if the dissolution in the digestive tract is at the same level as in this test, the dissolution amount of Al will not exceed the provisional tolerable weekly intake of Al (2 mg / kg body weight / week) set by the Joint FAO / WHO Expert Committee on Food Additives (JECFA), and it is considered that there is little concern about safety.

[0545] [Table 20]

[0546]

[0547] <Gastrointestinal Absorption Evaluation Test>

[0548] For the zeolites of Examples 26 and 34, the excretion rate in feces after a single oral administration to rats was calculated based on the concentrations of Si and Al in the feces, respectively. The results showed that for any given zeolite, almost all of the administered zeolite was excreted in the feces and was hardly absorbed by the digestive tract. This is illustrated in detail below.

[0549] Test methods

[0550] The zeolites of Example 26 or Example 34 were administered orally at a dose of 2000 mg / kg to 6-week-old male CR1:CD (SD) rats, and feces were collected within 48 hours after administration. Ultrapure water was added to the collected feces, and a homogenate was prepared using Polytron and freeze-dried. An appropriate amount of the dried feces was weighed and subjected to ashing, alkali-salt melting, and dilute acid dissolution. The soluble sample was analyzed by ICP emission spectroscopy to determine the concentrations of Si and Al in the feces. Additionally, feces obtained 24 hours before and immediately before administration of each zeolite were used as blank feces. The blank dried feces, homogenized and freeze-dried in the same manner as above, were supplemented with a specified amount of each zeolite, and the concentrations of Si and Al in the feces were determined using the same experimental procedures as above. A standard curve of Si and Al concentrations in the feces relative to the concentration of added zeolite was then constructed, and the fecal excretion rate of the zeolite was calculated.

[0551] result

[0552] The excretion rate of zeolite in feces in Example 26 was 99%~118% (Si concentration basis) and 98%~116% (Al concentration basis), while the excretion rate of zeolite in feces in Example 34 was 91%~104% (Si concentration basis) and 96%~109% (Al concentration basis).

[0553] <Safety Test>

[0554] Cytotoxicity tests, single-dose toxicity tests, one-week toxicity tests, and in vitro genotoxicity tests were conducted using various zeolites, and the results confirmed high safety in all tests. Details are shown below.

[0555] Cytotoxicity test

[0556] For each zeolite in Comparative Examples 6, 10, 12, 15, and 16, and Examples 9, 13, 25, 26, 58, 70, and 79, HepG2 cells were used to evaluate cytotoxicity based on the number of viable cells, using ATP levels, at a maximum dosage of 500 μg / mL. The results confirmed a 50% inhibitory concentration (IC50) for each zeolite. 50 All were above 500 μg / mL.

[0557] Single toxicity test

[0558] The zeolite of Example 34 was administered orally once to 6 or 7-week-old male CR1:CD (SD) rats at a maximum dose of 6000 mg / kg / day (2000 mg / kg, 3 times a day). Tolerance was evaluated based on general condition, body weight, food intake, and gross examination (exterior, thoracic and abdominal cavities and their internal organs / tissues). The results confirmed that tolerability was maintained up to the maximum dose.

[0559] One-week toxicity test

[0560] The zeolite from Example 34 was repeatedly administered orally to 6 or 7-week-old male CR1:CD (SD) rats at a maximum dose of 6000 mg / kg / day (2000 mg / kg, 3 times a day) for one week. General condition, body weight, food intake, ophthalmological examination, blood tests (red blood cell count, hemoglobin concentration, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin content, mean corpuscular hemoglobin concentration, red blood cell distribution width, reticulocytes, platelet count, mean platelet volume, white blood cell count, white blood cell differential, prothrombin time, activated partial thromboplastin time), and blood biochemistry tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, glutamate dehydrogenase, glucose, total bilirubin) were monitored. The following parameters were evaluated: direct bilirubin, indirect bilirubin, total bile acids, blood urea nitrogen, creatinine, total cholesterol, neutral fats, inorganic phosphorus, calcium, sodium, potassium, chloral, total protein, protein fraction, albumin / globulin ratio, organ weight (heart, thymus, spleen, lungs, liver, kidneys, pituitary gland, adrenal glands, testes, epididymis, prostate, brain), gross examination (external appearance, thoracic and abdominal cavities and their internal organs and tissues), histopathological examination (heart, sternum, sternal bone marrow, femur, knee joint, femoral bone marrow, thymus, spleen, mesenteric lymph nodes, bronchi, lungs, stomach, duodenum, jejunum, ileum, Peyer's lymph nodes, cecum, colon, rectum, liver, pancreas, kidneys, adrenal glands, testes, brain, sciatic nerve, eye, optic nerve, skeletal muscle), and bone marrow micronuclei. No toxicological changes were observed in any dosage group.

[0561] In vitro genotoxicity test

[0562] For the zeolite in Example 13, *Salmonella typhi* strains TA100, TA98, TA1537, and TA1535, and *Escherichia coli* strain WP2uvrA were used. The maximum dosage of 5000 μg / plate, as specified in the guidelines, was used. Mutagenicity was evaluated based on the number of revertant mutant colonies under two conditions (without and with the metabolic activation system). The results were negative. (Ames test)

[0563] For the zeolite in Example 13, using CHL / IU cells, the minimum precipitation dose of 0.5 μg / mL was taken as the maximum dose. Micronucleus induction was evaluated under three conditions (6 hours in the absence of the metabolic activation system, 6 hours in the presence of the metabolic activation system, and 24 hours in the absence of the metabolic activation system). The result was deemed negative. (In vitro micronucleus assay)

[0564] <Adsorption Selectivity Test>

[0565] For ions and compounds in organisms that may compete with the compounds to be removed when administered to humans, or that may cause problems due to adsorption, adsorption tests with zeolite are conducted to confirm adsorption selectivity.

[0566] Alkali metals / Alkali earth metals / Ammonia

[0567] Adsorption tests for alkali metals, alkaline earth metals, and ammonia were performed on each zeolite of Examples 5, 34, and 70, as well as Comparative Example 6. 3 mg of zeolite was accurately weighed and added to 10 mL of cationic mixed standard solution II (Kanto Chemical, Li...). + 0.5 mg / mL, Na + and NH4 + 2mg / mL, K + Mg 2+ and Ca 2+ (5 mg / mL), stirred at room temperature for 1 hour. The liquid was centrifuged, and the various components of the supernatant were determined by ion chromatography. The adsorption rate was calculated, and the results are shown in Table 21-1. Except for Example 5, which had a high SAR, the three compounds adsorbed NH4+. + and K + For Li + Na + Mg 2+ and Ca 2+ The adsorption rate of any one of the compounds is low.

[0568] Alkali metals / ammonia

[0569] Adsorption tests of alkali metals and ammonia were performed on the zeolite of Example 4. 3 mg of zeolite was accurately weighed and added to cationic mixed standard solution III (Kanto Chemical, Na...). + NH4 + and K + 0.5 mL of a solution containing 100 mg / mL sodium hydroxide and 9.5 mL of purified water were stirred at room temperature for 1 hour. The liquid was centrifuged, and the components of the supernatant were determined by ion chromatography. The adsorption rate was calculated, and the results are shown in Table 21-2. The zeolite in Example 4, with its high SAR, hardly adsorbed Na. + NH4 + and K + .

[0570] Alkali metal / ammonia (in the presence of TMA)

[0571] For each zeolite in Examples 34 and 70 and Comparative Example 6, adsorption tests of alkali metals and ammonia in the presence of TMA were performed. 80 mg of TMA hydrochloride was accurately weighed into 50 mL of a 0.1 N hydrochloric acid aqueous solution prepared by diluting 1 N hydrochloric acid, and thoroughly shaken to dissolve, thus preparing a TMA standard solution. 3 mg of zeolite was accurately weighed and added to cationic mixed standard solution III (Kanto Chemical, Na...). + NH4 + and K + 0.5 mL of 100 mg / mL TMA standard solution, 9.5 mL of purified water, and 50 μL of TMA standard solution were added and stirred at room temperature for 1 hour. The liquid was centrifuged, and the components of the supernatant were determined by ion chromatography. The adsorption rate was calculated, and the results are shown in Table 21-3. Any compound adsorbed all of the TMA in the presence of TMA, compared to the adsorption rate in the absence of TMA. + and K + The adsorption is reduced (see Table 21-1).

[0572] During the adsorption of various cations from water into the pores of zeolite, dehydration is required. The heat of hydration is Li. + Na + >K + ~NH4 + There is no stabilizing energy within the pores to compensate for the heat of hydration, therefore it is believed that Li + Na + The adsorption is relatively weak. Additionally, Mg... 2+ Ca 2+ As divalent cations, multiple acid sites are required within a unit pore for stabilization via electrostatic interactions within the zeolite micropores. It is considered that the zeolite used in this study has a low SAR ratio with multiple acid sites per unit pore, making it unsuitable for the adsorption of divalent cations. Furthermore, this study shows that... + and K + Compared to the adsorption of other substances, TMA has preferential adsorption (see Tables 21-1 and 21-3).

[0573] [Table 21-1]

[0574]

[0575] [Table 21-2]

[0576]

[0577] [Table 21-3]

[0578]

[0579] Essential metal elements

[0580] Adsorption tests of essential metal elements for humans were performed on each zeolite of Examples 5, 34, and 70, and Comparative Example 6. 3 mg of the compound was accurately weighed and added to 9.25 mL of 0.1 mol / L nitric acid aqueous solution, 0.15 mL of 0.1 mol / L cobalt(II) nitrate aqueous solution, 0.14 mL of 0.1 mol / L manganese(II) nitrate aqueous solution, 0.16 mL of 0.1 mol / L zinc(II) nitrate aqueous solution, 0.16 mL of 0.1 mol / L copper(II) nitrate aqueous solution, and 0.14 mL of 0.2 mol / L ferric(III) nitrate aqueous solution prepared by diluting 1 mol / L nitric acid aqueous solution 10 times with purified water. The mixture was stirred at room temperature for 1 hour. The liquid was centrifuged, and high-purity nitric acid (60%) was added to 1000 μL of the supernatant. The mixture was then diluted with purified water to a final volume of 50 mL (HNO3 2%). The adsorption rates of each component were determined by ICP-AES, and the results are shown in Table 22. The reagents used in the reaction are listed in Table 23.

[0581] [Table 22]

[0582]

[0583] [Table 23]

[0584]

[0585] amino acids

[0586] For each zeolite in Examples 5, 34 and Comparative Example 6, an amino acid adsorption test was conducted using the following two amino acid mixed solutions.

[0587] Amino acid mixed standard solution

[0588] Accurately weigh 3 mg of zeolite and add 1.0 mL of amino acid mixed standard solution AN type (high concentration, Fujifilm and Kodenpaku) and 1.0 mL of amino acid mixed standard solution B type (high concentration, Fujifilm and Kodenpaku), and 8 mL of phosphate buffer. Stir at room temperature for 1 hour. Centrifuge the liquid, ultrafilter the supernatant (MWCO=10,000), and use the membrane permeate for amino acid analysis.

[0589] It should be noted that the AN type (high concentration) amino acid mixed standard solution is a mixed standard solution containing 25 amino acids, including acidic and neutral amino acids. Regarding the concentration of each component, it contains 2.5 μmol / mL each of L-aspartic acid, L-threonine, L-serine, L-glutamic acid, glycine, L-alanine, L-citrulline, L-valine, L-cysteine, L-methionine, L-isoleucine, L-leucine, L-tyrosine, L-phenylalanine, β-alanine, DL-3-aminoisobutyric acid, L-hydroxyproline, and L-proline; 1.25 μmol / mL each of O-phospho-L-serine, taurine, O-phosphoethanolamine, DL-2-aminobutyric acid, and L-cystathionine; 6.25 μmol / mL of sarcosine; and 50 μmol / mL of urea. In addition, the amino acid mixed standard solution type B (high concentration type) is a mixed standard solution containing 12 amino acids, including 3 basic amino acids. It contains 2.5 μmol / mL each of 4-aminobutyric acid, ethanolamine, ammonium chloride, 5-hydroxy-DL-lysine, L-ornithine, L-lysine, 1-methyl-L-histidine, L-histidine, 3-methyl-L-histidine, L-chenosine, L-carnosine, and L-arginine.

[0590] Unstable amino acid mixture

[0591] Accurately weigh 3 mg of zeolite and add it to 10 mL of an amino acid mixture (each 1 mL of purified water contains 40.8 μg (0.20 μmol) L-tryptophan, 29.2 μg (0.20 μmol) L-glutamine, and 26.4 μg (0.20 μmol) L-asparagine). Stir at room temperature for 1 hour. Centrifuge the liquid, ultrafilter the supernatant (MWCO = 10,000), and use the membrane permeate for amino acid analysis. The reagents used are listed in Table 24.

[0592] [Table 24]

[0593]

[0594] Amino acid analysis was performed using a high-speed amino acid analyzer L-8900 (Hitachi High Technology) and the ninhydrin colorimetric method (post-label method). A standard curve was prepared by mixing 0.8 mL of amino acid mixed standard solution AN type and 0.8 mL of amino acid mixed standard solution B, and then diluting the volume with purified water to 10 mL. 10 μL of the above membrane permeate was then injected, and the concentrations of various amino acids in the membrane permeate were determined from the peak areas using a single-point standard curve. The adsorption rate was then calculated.

[0595] The adsorption rates of amino acids that constitute proteins and amino acids that do not constitute proteins are shown in Tables 25 and 26, respectively.

[0596] Regarding the silicalite of Example 5, it did not adsorb all protein-forming amino acids. The zeolite of Example 34 did not adsorb any protein-forming amino acids except for L-asparagine and L-glutamine. Regarding the zeolite of Comparative Example 6, adsorption of L-lysine and L-arginine, basic amino acids, was observed. Comparative Example 6 had a larger external surface area and lower SAR compared to Example 34, therefore it is believed to be more prone to adsorption of basic amino acids to acidic points on the outer surface. Regarding non-protein-forming amino acids, adsorption of 4-aminobutyric acid and ethanolamine was observed in Example 34. Both are primary amines containing straight-chain alkyl groups; considering the smallest molecular diameter, they can penetrate into the zeolite pores, therefore, there is a possibility of both surface and internal adsorption. Other non-protein-forming amino acids, regardless of molecular size, were almost completely adsorbed. These are considered to be highly water-soluble compounds, and their hydrated state is more stable compared to the hydrophobic zeolite pores. Urea, in particular, is a molecule abundant in the digestive tract of organisms and smaller than the pore size, thus potentially competitively inhibiting the adsorption of amines to zeolites; however, it was not adsorbed in this study. This confirms the important selectivity for the zeolites used in this study to exhibit pharmacological efficacy in vivo.

[0597] [Table 25]

[0598]

[0599] [Table 26]

[0600]

[0601] Vitamins

[0602] Vitamin adsorption tests were performed on each zeolite from Examples 34, 70, and Comparative Example 6. 3 mg of zeolite was accurately weighed and added to 10 mL of purified water. 100 μL of an aqueous solution containing 25 μmol of vitamin dissolved in 1.0 mL of purified water was added relative to the zeolite suspension, and the mixture was stirred at room temperature for 1 hour. The solution was centrifuged, and the vitamin concentration in the supernatant was determined using LC-UV (detection wavelength 210 nm). The results are shown in Table 27. The reagents used are recorded in Table 28. It should be noted that the vitamins were not mixed; adsorption tests and analyses were performed individually for each vitamin.

[0603] Of the fat-soluble vitamins (VA, VD3, VE, and VK1), the adsorption rate of VK1 was approximately 50%, while that of VA, VD3, and VE was less than 15%. Since fat-soluble vitamins have large molecular sizes, they are not expected to penetrate the micropores of the MFI-type zeolite; therefore, it is believed that the adsorption is due to surface adsorption. Compared to Comparative Example 6, Example 34 showed a higher SAR, indicating higher fat solubility on its outer surface. The fat solubility of the outer surface in Example 70 was further increased accordingly with the amount of surface treatment. It is evident that the adsorption rate of fat-soluble vitamins reflects the increased fat solubility of these outer surfaces.

[0604] Of the water-soluble vitamins (VB1, VB3, VB5, VB6, VB12, and VC), VB1, VB5, VB6 (3 types), and VB12 are almost not adsorbed into any zeolite (maximum adsorption is about 10%). On the other hand, about 10-30% of the water-soluble vitamin VC is adsorbed, and about 40-60% of VB3 (2 types) is adsorbed. VC has multiple hydroxyl groups, and it is assumed that surface adsorption occurs through multiple hydrogen bonds with silanols on the outer surface of the zeolite. It is believed that the adsorption rate of Comparative Example 6, which has a larger outer surface area, is higher than that of Example 34, which has a smaller outer surface area. In addition, VC is an acidic compound, so it is believed that surface adsorption is more likely to occur in Example 70, which has fewer acid spots on the outer surface due to surface treatment, compared to Example 34, which has residual acid spots on the outer surface. VB3 has a pyridine structure as a tertiary amine, and it is believed that it is easily stabilized within the pores of the zeolite with an anionic framework. VB6 also has a pyridine structure, but it has more substituents on the pyridine, and therefore does not adsorb into the pores in terms of size. It is believed that other water-soluble vitamins that are difficult to adsorb have larger molecular sizes than those that are easily adsorbed, thus preventing them from penetrating the micropores of zeolite. Furthermore, due to their high water solubility, they exist stably in a hydrated state. This demonstrates the potential of the zeolite used in the examples as a carrier for the adsorption / removal of heterocyclic amines such as VB3 (two types) with few or small substituents, as well as for sustained-release and controlled-release formulations.

[0605] [Table 27]

[0606]

[0607] [Table 28]

[0608]

[0609] Short-chain fatty acids

[0610] Adsorption tests for short-chain fatty acids were performed on the zeolites of Examples 5, 34, 70, and Comparative Example 6. 3 mg of zeolite was accurately weighed and added to 9.44 mL of purified water. Further, 0.143 mL, 0.187 mL, and 0.229 mL of acetic acid, propionic acid, and butyric acid were added, respectively, in amounts reaching 2.5 μmol. A stir bar was added to the liquid, and the mixture was stirred for 1 hour. After removing the stir bar, centrifugation was performed. Following centrifugation, the liquid diluted 10,000 times with purified water was analyzed using ion chromatography. The reagents used are listed in Table 29.

[0611] No short-chain fatty acids were adsorbed by any of the zeolites. It is believed that short-chain fatty acids, which dissociate in aqueous solution to produce conjugated basic anions, do not undergo stabilization due to electrostatic interactions with zeolites containing anionic frameworks, and therefore are not adsorbed into the zeolite. Short-chain fatty acids are mostly present in the digestive tract of organisms and are molecules of a size capable of entering the pores of zeolites; therefore, they may competitively inhibit the adsorption of amines into zeolites. In short, this study confirms an important selectivity for the pharmacological effects of zeolites in vivo.

[0612] [Table 29]

[0613]

[0614] Combination drugs

[0615] For the reagents that may be used in combination with the inorganic porous oral composition of this embodiment (hereinafter referred to as the combined reagents), adsorption tests were performed using the zeolites of Examples 34, 70, and 79. 3 mg of zeolite was accurately weighed and added to 9.9 mL of purified water. 100 μL of a DMSO solution containing 25 μmol of the combined reagent dissolved in 1.0 mL of DMSO was added relative to the zeolite suspension, and the mixture was stirred at room temperature for 1 hour. The liquid was centrifuged, and the concentration of the combined reagent in the supernatant was determined by LC-MS / MS. The adsorption rate was calculated (expressed as a percentage by subtracting the value obtained by dividing the concentration of the combined reagent in the supernatant by the initial concentration of 250 μmol / L from 1; a negative value is recorded as 0). The results are shown in Table 30. The reagents used are listed in Table 31. It should be noted that for carvedilol and miconazole, the solubility of carvedilol and miconazole, which are basic compounds, was increased by adding 10 μL of 1N hydrochloric acid after suspending zeolite in purified water (the pH of the solution immediately after adding the combined drugs in DMSO was 6-7). It should also be noted that the combined drugs were not mixed; adsorption tests and analyses were performed separately for each drug.

[0616] As a result, acidic compounds are hardly adsorbed in either case (adsorption rate <4%). MFI zeolite is known to adsorb p-xylene, but even acetaminophen and acetali, which also have para-substituted benzene structures and are molecularly sized for adsorption, show almost no adsorption from water. For the same reasons as with short-chain fatty acids, the adsorption of acidic compounds into the interior of the zeolite is considered unfavorable.

[0617] Neutral compounds pirfenidone and chloramphenicol were not adsorbed at all, and lactulose also showed a low adsorption rate. It is believed that neutral compounds do not have electrostatic interactions with surface acid points, and therefore are less prone to adsorption compared to basic compounds. Lactulose has multiple hydroxyl groups, therefore it is thought that surface adsorption, although weak, may occur through multiple hydrogen bonds with silanols on the zeolite outer surface.

[0618] For basic compounds, some were found to be weakly adsorbed. Metformin is a basic compound with a small molecular size, so it is believed that some of it would be adsorbed within the zeolite. In this case, compared with Example 34 without surface treatment, the adsorption rate of metformin in Examples 72 and 80, which were surface-treated, decreased. It is believed that surface treatment can partially prevent the adsorption of metformin to acid points on the outer surface. Regarding other combination drugs that were found to be weakly adsorbed (mirtazapine, ondansetron, lincomycin, oseltamivir, carvedilol), it is believed that the molecular size exceeds the pore diameter of the MFI zeolite, and therefore it is believed that the adsorption is based on the surface rather than the internal adsorption.

[0619] [Table 30]

[0620]

[0621] [Table 31]

[0622]

[0623] TMA precursor

[0624] Adsorption tests of TMA precursors were performed on each zeolite from Examples 34, 70, and Comparative Example 6. 3 mg of zeolite was accurately weighed and added to 10 mL of purified water. 100 μL of an aqueous solution containing 25 μmol of betaine (trimethylglycine) or carnitine dissolved in 1.0 mL of purified water was added relative to the zeolite suspension, and the mixture was stirred at room temperature for 1 hour. The liquid was centrifuged, and the concentration of betaine or carnitine in the supernatant was determined using LC-CAD (Charged Aerosol Detector). The results are shown in Table 32.

[0625] Regarding betaine, adsorption was observed in all zeolites, but carnitine was not adsorbed in Example 34. Betaine, being approximately the same molecular size as choline, is believed to have undergone internal adsorption. On the other hand, carnitine, with a larger molecular size than both betaine and choline, is considered less prone to internal adsorption. Comparative Example 6 showed greater adsorption of both betaine and carnitine compared to Examples 34 and 70. Comparative Example 6, with its larger external surface area and lower SAR compared to Examples 34 and 70, is considered to facilitate the adsorption of alkaline substances to its external surface. The reagents used are listed in Table 33.

[0626] Betaine and carnitine, like choline, are known precursors to TMA and are also nutrients. Since TMA is produced by bacterial decomposition in the digestive tract, the adsorption and release of these TMA precursors affect the amount of TMA absorbed. Similar to choline, zeolite may act as a coliform delivery medium for these TMA precursors, therefore, non-adsorption is preferred. In this experiment, regarding Examples 34 and 70, weak adsorption of betaine and carnitine was confirmed. Since the experiment was not conducted in the presence of TMA as in the in vitro adsorption experiment, it is believed that if the adsorption experiment were conducted in the presence of TMA, competition would occur, further reducing the adsorption rates of betaine and carnitine.

[0627] It should be noted that TMAO, which is also known as a precursor of TMA, does not have an alkaline structure like betaine and carnitine, and is highly hydrophilic. Therefore, it was assumed that it would not be adsorbed to zeolite in water, and no adsorption test was conducted.

[0628] [Table 32]

[0629]

[0630] [Table 33]

[0631]

[0632] serotonin

[0633] Serotonin adsorption tests were performed on each zeolite from Examples 34, 70, and Comparative Example 6. 3 mg of zeolite was accurately weighed and added to 10 mL of purified water. To the zeolite suspension, 100 μL of an aqueous solution containing 25 μmol of serotonin (5-hydroxytryptamin, Fujifilm and Kodenpaku) dissolved in 1.0 mL of purified water was added, and the mixture was stirred at room temperature for 1 hour. The solution was centrifuged, and the serotonin concentration in the supernatant was determined using LC-CAD. The results are shown in Table 34.

[0634] Only a small amount of adsorption was observed in Comparative Example 6. It is believed that serum underwent surface adsorption on Comparative Example 6, which has a large external surface area. Serotonin is a physiologically active substance present in the digestive tract; adsorption could potentially affect gastrointestinal motility and other serotonin-related biological responses. This experiment suggests that MFI-type zeolite hardly adsorbs serotonin.

[0635] [Table 34]

[0636]

[0637] <Reference Example>

[0638] The following describes the methods for obtaining and synthesizing zeolites used in the above-described examples and comparative examples for evaluation, as well as the methods for determining the physical properties of zeolites.

[0639] [Examples 1-3, Comparative Examples 1-14]

[0640] Table 35 records the sources of the compounds in Examples 1-3 and Comparative Examples 1-14. For Examples 1, 3, and Comparative Examples 1-14, commercially available products were purchased and used directly. For Example 2, the purchased zeolite was calcined at 500°C for 4 hours under air circulation, thereby converting it from the ammonia form to the proton form.

[0641] [Table 35]

[0642]

[0643] It should be noted that each item in Table 35 represents the following content.

[0644] Skeleton code: This is the skeleton code of the zeolite used in this embodiment, which is based on the skeleton structure coding of zeolites as specified by the IZA (International Zeolite Association).

[0645] Counter cation: The counter cation of the zeolite used in this embodiment

[0646] SAR: The molar ratio of SiO2 to Al2O3 in the zeolite used in this embodiment.

[0647] Product Name (Product Code): The product name of the compound used in this embodiment. The product code is indicated in parentheses.

[0648] Vendor: The vendor of the compounds used in this embodiment

[0649] [Synthesis method of Comparative Example 15]

[0650] [Hydrothermal Synthesis / Calcination of Organic Structure-Directing Agents]

[0651] In a container, 4.5 g of sodium hydroxide (NaOH) granules, 3.8 g of potassium hydroxide (KOH) granules, 66.6 g of a 25% (w / w) aqueous solution of N,N,N-trimethyl-1-adamantyl ammonium hydroxide (TMAdaOH) prepared by SACHEM as an Organic Structure Directing Agent (OSDA), 195 g of deionized water, 7.1 g of "KYOWAAD 200S" (alumina content 53.5% (w / w)) prepared by Kyowa Chemical Industry as aluminum hydroxide, and 225 g of colloidal silica "Cataloid SI-30" prepared by Nichibukai Catalyst Chemical Co., Ltd. as silica were added sequentially. The composition and molar ratio of the resulting mixture were SiO2:Al2O3:NaOH:KOH:TMAdaOH:H2O = 1.0:0.033:0.1:0.06:0.07:20. After thoroughly mixing these raw materials, the resulting mixture was placed in a pressure vessel and subjected to hydrothermal synthesis at 160°C for 48 hours under 100 rpm rotation. The resulting gel was filtered, washed with deionized water, and then dried by heating at 100°C for at least 8 hours (unless otherwise specified, drying operations will be performed under these conditions). The resulting powder was then calcined at 550°C for 6 hours under air circulation to remove OSDA from the powder.

[0652] [Ion exchange / sintering]

[0653] A 1 mol / L ammonium nitrate aqueous solution prepared from ammonium nitrate and demineralized water was used to disperse 10% by mass of OSDA-removed powder. The powder was then subjected to ammonium ion exchange at 80°C for 2 hours, filtered, and washed with demineralized water. This ion exchange and washing process was then repeated twice more. After drying the ion-exchanged powder, it was calcined at 500°C for 4 hours under air circulation to obtain proton-type zeolite.

[0654] [Comparative Example 16: Synthesis]

[0655] In a container, 1.0 g of sodium hydroxide granules, 8.7 g of an 18% (w / w) aqueous solution of 1,1'-(1,4-butadiyl)bis(1-azabicyclo[2.2.2]octane) dihydrogen phosphate (Dab-4) prepared by SACHEM of OSDA, 8 g of deionized water, 0.94 g of "KYOWAAD 200S" as aluminum hydroxide, 7.5 g of "SNOWTEX 40" as silicon dioxide, and 0.15 g of CHA-type zeolite synthesized in Comparative Example 15 as a seed crystal were added sequentially. The composition and molar ratio of the resulting mixture were SiO2:Al2O3:NaOH:Dab-4:H2O = 1.0:0.1:0.5:0.1:22. After thoroughly mixing these raw materials, the resulting mixture was placed in a pressure vessel and subjected to hydrothermal synthesis in an oven at 140°C for 120 hours under static conditions. The resulting gel was filtered, washed with deionized water, and then dried. The resulting powder was calcined at 550°C for 6 hours under air circulation to remove OSDA from the powder. Furthermore, the [ion exchange / calcination] operation of Comparative Example 15 was performed to obtain a proton-type zeolite.

[0656] [Comparative Example 17: Synthesis]

[0657] In a container, 0.772 g of sodium hydroxide granules, 2.262 g of 35% (w / w) aqueous solution of N,N-dimethyl-3,5-dimethylpiperidinium hydroxide (DMDMPIOH) prepared by SACHEM of OSDA, 9.9 g of demineralized water, 0.726 g of "KYOWAAD 200S" as aluminum hydroxide, 7.454 g of "SNOWTEX 40" as silica, and 0.300 g of CHA-type zeolite synthesized in Comparative Example 15 as seed crystals were added sequentially. The composition and molar ratio of the resulting mixture were SiO2:Al2O3:NaOH:DMDMPIOH:H2O = 1.0:0.013:0.4:0.1:17.5. After thoroughly mixing these raw materials, the resulting mixture was placed in a pressure-resistant container and subjected to hydrothermal synthesis in an oven at 180°C for 24 hours under a rotation of 15 rpm. The resulting gel was filtered, washed with demineralized water, and then dried. The obtained powder was calcined at 600°C for 6 hours under air circulation to remove OSDA from the powder. Then, the [ion exchange / calcination] operation of Comparative Example 15 was performed to obtain a proton-type zeolite.

[0658] [Synthesis method of Comparative Example 18]

[0659] 1.135 g of sodium hydroxide granules, 4.959 g of hexamethyleneimine (HMI) manufactured by Tokyo Chemical Industry Co., Ltd. as OSDA, 63.2 g of demineralized water, 0.944 g of "KYOWAAD 200S" as aluminum hydroxide, and 14.908 g of "SNOWTEX40" as silica were added sequentially to a container. The composition and molar ratio of the resulting mixture were SiO2:Al2O3:NaOH:HMI:H2O = 1.0:0.033:0.3:0.5:40. After thoroughly mixing these raw materials, the resulting mixture was placed in a pressure-resistant container and subjected to hydrothermal synthesis in an oven at 150°C for 144 hours under static conditions. The resulting gel was filtered, washed with demineralized water, and then dried. The resulting powder was calcined at 550°C for 6 hours under air circulation to remove OSDA from the powder. Then, the [ion exchange / calcination] operation of Comparative Example 15 was performed to obtain a proton-type zeolite.

[0660] [Synthesis method of Comparative Example 19]

[0661] In Comparative Example 19, the composition and molar ratio of the raw material mixture were changed to SiO2:Al2O3:NaOH:HMI:H2O=1.0:0.02:0.3:0.5:40. Otherwise, the zeolite was synthesized using the same steps as in Comparative Example 18.

[0662] [Synthesis method of Comparative Example 20]

[0663] 7.750 g of 1 mol / L sodium hydroxide aqueous solution, 6.487 g of 40% (w / w) tetrabutylammonium hydroxide (TBAOH) aqueous solution (as OSDA) manufactured by Tokyo Chemical Industry Co., Ltd., 15.9 g of demineralized water, 0.629 g of "KYOWAAD200S" (as aluminum hydroxide), and 14.908 g of "SNOWTEX40" (as silicon dioxide) were added sequentially to a container. The composition and molar ratio of the resulting mixture were SiO2:Al2O3:NaOH:TBAOH:H2O = 1.0:0.033:0.1:0.1:20. After thoroughly mixing these raw materials, the resulting mixture was placed in a pressure-resistant container and subjected to hydrothermal synthesis in an oven at 175°C for 72 hours under a rotation of 15 rpm. The resulting gel was filtered, washed with demineralized water, and then dried. The resulting powder was calcined at 550°C for 6 hours under air circulation to remove OSDA from the powder. Furthermore, by performing the [ion exchange / calcination] operation of Comparative Example 15, proton-type zeolite was obtained.

[0664] [Comparative Example 21: Synthesis]

[0665] In Comparative Example 21, the composition and molar ratio of the raw material mixture were changed to SiO2:Al2O3:NaOH:TBAOH:H2O=1.0:0.02:0.1:0.1:20. Otherwise, zeolite was synthesized through the same steps as in Comparative Example 20.

[0666] [Comparative Examples 15-21]

[0667] For the zeolites of Comparative Examples 15-21, the framework codes and SARs are summarized in Table 36. The zeolite framework was determined by confirming the XRPD diffraction pattern. The counter cation for any zeolite is a proton.

[0668] [Table 36]

[0669]

[0670] [Synthesis methods of Examples 4-64 and Comparative Example 22]

[0671] In Examples 4-34, Examples 37-64, and Comparative Example 22, the raw materials, feed amounts, hydrothermal synthesis conditions, stirring methods, and post-treatment were modified according to Tables 37-1, 37-2, and 37-3. Otherwise, the zeolites were synthesized following the same steps. Each zeolite was displayed as an MFI-type zeolite diffraction pattern in XRPD.

[0672] A 1 mol / L sodium hydroxide aqueous solution, 0-2 types of structure directing agent (SDA), demineralized water, an aluminum (Al) source, a silicon (Si) source, and seed crystals were added sequentially to a container. After thoroughly mixing these raw materials, the resulting mixture was placed in a pressure-resistant container for hydrothermal synthesis. The resulting gel was then filtered, thoroughly washed with demineralized water, and dried by heating at 100°C for at least 8 hours in air. The resulting zeolite powder underwent post-treatment.

[0673] [Table 37-1]

[0674]

[0675] [Table 37-2]

[0676]

[0677] [Table 37-3]

[0678]

[0679] The items in Tables 37-1, 37-2, and 37-3 represent the following contents respectively.

[0680] Si source: The type of Si source added in this embodiment

[0681] Si content: The amount of Si in the added Si source in this embodiment (unit: mol)

[0682] Al source: The type of Al source added in this embodiment

[0683] SAR (Specific SAR) refers to the molar ratio of SiO2 to Al2O3 in the raw material mixture (excluding seed crystals) added in this embodiment. The case where Al2O3 is not present is denoted as "∞".

[0684] Na content: The molar ratio of Na from the Si source and NaOH to Si in the raw material mixture (excluding seed crystals) added in this embodiment.

[0685] SDA1: The first type of SDA added in this embodiment.

[0686] SDA1 amount: The molar ratio of SDA1 to Si in the raw material mixture (excluding seed crystals) added in this embodiment.

[0687] SDA2: The second type of SDA added in this embodiment.

[0688] SDA2 amount: The molar ratio of SDA2 to Si in the raw material mixture (excluding seed crystals) added in this embodiment.

[0689] H2O amount: The molar ratio of H2O to Si in the raw material mixture (excluding seed crystals) added in this embodiment.

[0690] Seed crystals: The structure of the seed zeolite added in this embodiment

[0691] Seed SAR: The molar ratio of SiO2 to Al2O3 in the seed zeolite added in this embodiment.

[0692] Seed amount: The proportion (mass%) of the added seed relative to the amount of Si in the raw material mixture (excluding the seed) added in this embodiment, which is all converted to SiO2.

[0693] Hydrothermal synthesis temperature: The temperature at which hydrothermal synthesis was performed in this embodiment (unit: °C).

[0694] Hydrothermal synthesis time: The time (in hours) for hydrothermal synthesis in this embodiment.

[0695] Stirring rate: The stirring rate used for hydrothermal synthesis in this embodiment (unit: rpm. 0 indicates static conditions).

[0696] Container: The capacity (in L) of the pressure vessel used for hydrothermal synthesis in this embodiment.

[0697] Post-processing: This embodiment describes the post-processing method for the zeolite powder obtained through hydrothermal synthesis. The following combinations of [SDA removal], [ion exchange / calcination], or [acid treatment] are performed in the order listed in the table.

[0698] [SDA Removal]

[0699] The obtained zeolite powder was calcined at 550°C for 6 hours under air circulation to remove SDA from the powder.

[0700] [Ion exchange / sintering]

[0701] Zeolite powder was dispersed at 10% by mass in a 1 mol / L ammonium nitrate aqueous solution prepared using ammonium nitrate and demineralized water. Ammonium ion exchange was performed at 80°C for 2 hours, followed by filtration and washing with demineralized water. This process of ion exchange and washing was then repeated twice more. The ion-exchanged powder was then dried and calcined at 500°C for 4 hours under air circulation to obtain proton-type zeolite.

[0702] [Acid Treatment]

[0703] The obtained zeolite powder was added relative to 1 mol / L nitric acid aqueous solution at a mass ratio of 10%, stirred at room temperature for 1 hour, filtered, washed with demineralized water, and dried to obtain proton-type zeolite powder.

[0704] [Reagents used in the synthesis example]

[0705] The reagents used in the synthesis examples of Examples 4-35, Examples 37-64 and Comparative Examples 15-22 are summarized in Table 38.

[0706] [Table 38]

[0707]

[0708] Acid treatment

[0709] In Examples 65-67, the acid treatment of zeolite was carried out under the reaction conditions shown below, using nitric acid and temperature as shown in Table 39.

[0710] [Reaction Conditions]

[0711] To the exact weight of 100 mg of zeolite from Example 50, add 5 mL of a 1 mol / L nitric acid aqueous solution (1 mol / L nitric acid (1N)) or concentrated nitric acid (nitric acid 1.38) manufactured by Kanto Chemical. Stir the reaction solution at room temperature or 100°C for 5 hours using a stirrer, then filter the zeolite using a Kiriyama funnel. Wash the filtrate with purified water and dry under reduced pressure at 40°C for 2 hours.

[0712] [Table 39]

[0713]

[0714] In Example 68, acid treatment of zeolite was carried out under the reaction conditions shown below.

[0715] [Reaction Conditions]

[0716] For 1 g of precisely weighed zeolite from Example 48, 10 g of a 1 mol / L nitric acid aqueous solution prepared by KISHIDA CHEMICAL was added. After stirring the reaction solution at room temperature for 1 hour using a stirrer, the zeolite was filtered off using a Kiriyama funnel. The filtrate was washed with demineralized water and dried at 100°C for 12 hours in air.

[0717] In Example 69, the reaction time was changed to 2 hours, and the zeolite was otherwise treated with acid using the same steps as in Example 68.

[0718] Surface treatment

[0719] In Comparative Example 23 and Examples 70, 72-88, surface-treated zeolites were synthesized using the raw material zeolites and surface treatment reagents shown in Table 40 under any of the reaction conditions shown below. The surface treatment reagents used in the reaction are listed in Table 41.

[0720] [Reaction conditions: Neat (HMDS)]

[0721] For precisely weighed raw material zeolite, HMDS was added at a weight ratio of 10 g-HMDS / g-zeolite. The reaction solution was heated to 100°C in an oil bath while stirring under a nitrogen atmosphere for 5 hours. The resulting powder was filtered through a Kiriyama funnel. The filtrate was washed with acetone, air-dried in air for at least 8 hours, and then heated at 100°C in air for at least 8 hours to dry it.

[0722] [Reaction conditions: toluene-1]

[0723] For accurately weighed raw zeolite, add 20 mL / g toluene of zeolite. Add a surface treatment reagent at an equivalent ratio of 0.5 mmol / g zeolite, stir at room temperature for 5 hours, and filter the resulting powder using a Kiriyama funnel. Wash the filtrate with ethanol and dry under reduced pressure at 40°C overnight.

[0724] [Reaction conditions: vapor]

[0725] Place a glass bottle containing 100 mg of raw zeolite, an Eppendorf tube with 2 drops of purified water, and an Eppendorf tube with 2 drops of surface treatment reagent into a sealable container. Seal the container and place it in a chamber heated to 100°C for 5 hours. Then, dry the zeolite under reduced pressure at 40°C for 2 hours.

[0726] [Reaction conditions: neat]

[0727] Accurately weighed raw zeolite was placed in a constant temperature and humidity bath and allowed to absorb moisture overnight at 25°C / 75%RH. A surface treatment reagent was added at 20 mL / g zeolite, and the mixture was stirred at room temperature for 5 hours. The resulting powder was then filtered through a Kiriyama funnel. The filtrate was washed with ethanol and dried under reduced pressure at 40°C for 2 hours.

[0728] [Reaction conditions: toluene-2]

[0729] 100 mg of accurately weighed zeolite was added to 7 mL of toluene. Two drops of surface treatment reagent were added, and the mixture was stirred at room temperature for 5 hours. The resulting powder was then filtered through a Kiriyama funnel. The filtrate was washed with ethanol and dried under reduced pressure at 40 °C for 2 hours.

[0730] [Table 40]

[0731]

[0732] [Table 41]

[0733]

[0734] Cation exchange

[0735] In Examples 36, 71 and 89, the exchange of countercations was carried out using 1 mol / L aqueous nitrate solution prepared with the reagents and demineralized water corresponding to those in Table 42, under the reaction conditions shown below.

[0736] [Reaction Conditions]

[0737] The zeolite from Example 34 was dispersed at 10% by mass relative to a 1 mol / L ammonium nitrate aqueous solution and subjected to ammonium ion exchange at 80°C for 2 hours. The mixture was then filtered and washed with demineralized water. This process of ion exchange, filtration, and washing was repeated twice more. The resulting powder was dried to obtain ammonia-type zeolite (Example 89).

[0738] The zeolite from Example 89 was dispersed at 10% by mass relative to a 1 mol / L lithium nitrate or potassium nitrate aqueous solution, subjected to cation exchange at 80°C for 2 hours, filtered, and washed with demineralized water. This process of cation exchange, filtration, and washing was then repeated twice more. The resulting powder was dried to obtain lithium or potassium-type zeolites (Examples 36, 71).

[0739] [Table 42]

[0740]

[0741] <Determination of physical properties>

[0742] (Determination Method)

[0743] Analysis of zeolite composition

[0744] The following is an elemental analysis of silicon, aluminum, and sodium atoms in a zeolite standard sample.

[0745] The substance obtained by adding an alkali salt flux to a precisely weighed sample and heating it to dissolve is dissolved in warm water, then appropriately diluted with an acid-added solution. The content (wt%) of silicon, aluminum, and sodium atoms is determined using inductively coupled plasma atomic emission spectrometry (ICP-AES) through an acid concentration-matched standard curve method. Furthermore, the fluorescence X-ray intensity of the analytical elements in the zeolite standard sample is determined, and a standard curve is constructed comparing the intensity with the atomic concentrations determined by ICP-AES.

[0746] The content (wt%) of silicon, aluminum, and sodium atoms in the zeolite samples was determined by ICP-AES or by fluorescence X-ray analysis using a standard curve matched to ICP-AES. For samples with low aluminum content, the silicon was removed by adding hydrofluoric acid to a precisely weighed sample and heating it to volatilize it. The remaining ash was dissolved in the acid, and the aluminum content (wt%) was determined by ICP-AES using an acid concentration-matched standard curve. ICP-AES was performed using a ULTIMA2C manufactured by Horiba Corporation. Fluorescence X-ray analysis was performed using a Supermini200 manufactured by Rigaku.

[0747] Powder X-ray diffraction measurement

[0748] Measurements / data analysis were performed using an X'PertPro powder X-ray diffraction apparatus (manufactured by PANalytical B.V.) under the following conditions.

[0749] [Measurement Conditions]

[0750] X-ray generating apparatus: X-ray tube (cathode: copper, tube voltage: 45kV, tube current: 40mA)

[0751] Incident optical system: focusing condenser lens

[0752] Light-receiving optical system: High-speed semiconductor array detector (X-Celerator), extended light-receiving side arm

[0753] Sample stage: HTS sample stage (vibrates at an amplitude of 4mm in the X-axis direction)

[0754] Total number of attempts: 5 (with the incident angle changed to -2, -1, 0, 1, and 2° respectively).

[0755] Measurement range: 2θ = 3~40°

[0756] Scan rate: 0.668451° / second

[0757] Step size: 0.0167°

[0758] [Analysis Methods]

[0759] Software: High Score Plus

[0760] Peak Search

[0761] Minimum significance: 1.00

[0762] Minimum peak (°2Th.): 0.01

[0763] Maximum peak (°2Th.): 1.00

[0764] Peak base width (°2Th.): 2.00

[0765] <Curve Fitting> Performs 3 Default curve fittings

[0766] Determination of BET specific surface area and external surface area

[0767] (Preprocessing)

[0768] Before measuring the surface area, as a pretreatment, 30-80 mg of zeolite powder was filled into the measuring unit and subjected to degassing treatment at 350°C and reduced pressure for 5 hours using a pretreatment device (MasterPrep manufactured by Quantachrome Inc.).

[0769] (Determination of adsorption capacity)

[0770] For the pretreated zeolite powder, adsorption isotherms were determined. The measurements were performed using a constant-capacity gas adsorption apparatus (Quantachrome Inc. Autosorb iQ-XR-XR-XR or Autosorb iQ3-MP-XR), with nitrogen as the adsorbate, and the relative pressure was measured at liquid nitrogen temperature at 1 × 10⁻⁶. -5 Adsorption isotherms were obtained in the range of ~0.995. BET curves were constructed from the obtained adsorption isotherms, and the BET specific surface area was determined by multi-point analysis within a range with good linearity. Furthermore, a t-plot (standard isotherm: de-Bore type) was constructed, and the external surface area was calculated based on the slope and intercept of the plateau portion.

[0771] SEM

[0772] Platinum was deposited on the surface of the zeolite sample in an ion coating machine IB-3 manufactured by EIKO with a thickness of approximately 9 nm. The shape was then observed using a scanning electron microscope S-4500 manufactured by Hitachi High Technology Co., Ltd. or a JSM-6010LV manufactured by NEC.

[0773] <Particle Size Distribution>

[0774] Particle size distribution was measured using a laser diffraction / scattering particle size distribution measuring device LA-950V2 manufactured by Horiba Corporation. Pure water was used as the dispersion medium, and the measurement was performed in a flow cell with the refractive index of the sample set to 1.450-0.000i, the refractive index of the dispersion medium set to 1.333-0.000i, the circulation rate set to a range of 5, and the stirring rate set to a range of 2.

Claims

1. An oral composition comprising an inorganic porous body, When choline and primary / secondary / tertiary amines or ammonia are present in an equimolar mixture in artificial intestinal fluid, and the inorganic porous body, which contains 11.8 g of choline relative to 1 mmol, is mixed at a concentration of 2 g / L for 1 hour, the adsorption rate of primary / secondary / tertiary amines or ammonia is greater than 60.0%, and the adsorption rate of choline is less than 40.0%.

2. The oral composition according to claim 1, wherein, The adsorption rate of primary / secondary / tertiary amines or ammonia by the inorganic porous body is more than 2.00 times that of choline.

3. The oral composition according to claim 1, wherein, The inorganic porous body is an aluminosilicate or silicate.

4. The oral composition according to claim 3, wherein, The aluminosilicate is a zeolite.

5. The oral composition according to claim 4, wherein, The zeolite has a maximum number of ring elements of 10, and the diameter of the largest diffuse sphere within the pores is greater than 3.68 Å.

6. The oral composition according to claim 4, wherein, The zeolite has an MFI structure or a FER structure.

7. The oral composition according to claim 4, wherein, The zeolite is a zeolite in which the molar ratio of SiO2 to Al2O3 is greater than 15.0 and less than 130,000.

0.

8. The oral composition according to claim 7, wherein, The zeolite is a zeolite in which the molar ratio of SiO2 to Al2O3 is greater than 30.0 and less than 80.

0.

9. The oral composition according to claim 4, wherein, The zeolite has an external surface area of ​​33.0 m². 2 / g or less.

10. The oral composition according to claim 1, wherein it is a pharmaceutical composition.

11. The oral composition according to claim 10, for the prevention, treatment or symptom relief of diseases caused by primary / secondary / tertiary amines, ammonia or their metabolites.

12. The oral composition according to claim 11, wherein, Primary / secondary / tertiary amines, ammonia, or their metabolites include one or more of the group consisting of trimethylamine, dimethylamine, methylamine, histamine, ammonia, and trimethylamine-N-oxide.

13. The oral composition according to claim 11, wherein, Primary / secondary / tertiary amines, ammonia, or their metabolites are trimethylamine or trimethylamine-N-oxide.

14. The oral composition according to claim 11, wherein, Diseases caused by primary / secondary / tertiary amines, ammonia, or their metabolites are selected from the group consisting of the following diseases: trimethylamineuria, cardiovascular disease, glaucoma, atherosclerosis, coronary heart disease, heart failure with preserved ejection fraction, ST-segment elevation myocardial infarction, atrial fibrillation, abdominal aortic aneurysm, ischemic stroke, post-stroke cognitive impairment, mild cognitive impairment, Alzheimer's disease, obesity, chronic kidney disease with type 2 diabetes, cardiovascular complications of chronic kidney disease, diabetic retinopathy, non-alcoholic steatohepatitis, polycystic ovary syndrome, Parkinson's disease, colorectal cancer, irritable bowel syndrome, hyperammonemia, urea cycle disorders, organic acidemia, hepatic encephalopathy, and portosystemic shunt.

15. The oral composition according to claim 14, wherein, The disease is caused by trimethylamine, including trimethylamineuria, cardiovascular disease, or glaucoma.

16. The oral composition according to claim 14, wherein, The diseases described are caused by trimethylamine-N-oxide and include atherosclerosis, coronary heart disease, heart failure with preserved ejection fraction, ST-segment elevation myocardial infarction, atrial fibrillation, abdominal aortic aneurysm, ischemic stroke, post-stroke cognitive impairment, mild cognitive impairment, Alzheimer's disease, obesity, chronic kidney disease with type 2 diabetes, cardiovascular complications of chronic kidney disease, diabetic retinopathy, non-alcoholic steatohepatitis, polycystic ovary syndrome, Parkinson's disease, or colorectal cancer.

17. The oral composition according to claim 14, wherein, The disease is caused by histamine and is irritable bowel syndrome.

18. The oral composition according to claim 14, wherein, The disease is caused by ammonia and includes hyperammonemia, urea cycle disorder, organic acidemia, hepatic encephalopathy, or portosystemic shunt.

19. The oral composition according to claim 10, comprising zeolite as an active ingredient, administered 1 to 5 times a day, wherein the dosage of zeolite is 200 mg to 42000 mg per dose.

20. The oral composition according to claim 19, wherein, The dosage of the zeolite is 500mg to 2000mg per dose.

21. A method for manufacturing the oral composition of claim 4, comprising obtaining zeolite by hydrothermal synthesis without the use of an organic structure directing agent.

22. The method according to claim 21, wherein, Sodium carbonate and / or sodium sulfate are used as raw materials.

23. The method of claim 21, further comprising converting an acid to a protonated form.

24. The method according to claim 23, wherein, The acid is sulfuric acid or nitric acid.

25. The method according to claim 21, wherein, It also includes surface treatment of hydrothermally synthesized zeolites in a solution containing a Si element source.

26. An oral composition for the treatment, prevention, or symptom relief of a disease selected from the group consisting of trimethylamineuria, atherosclerosis, irritable bowel syndrome, and hyperammonemia. The oral composition contains zeolite. The zeolite has an MFI structure, and the molar ratio of SiO2 to Al2O3 is greater than 30.0 and less than 130,000.0, or... The zeolite has a FER structure, and the molar ratio of SiO2 to Al2O3 is greater than 15.0 and less than 130,000.

0.

27. The oral composition according to claim 26, wherein, The zeolite is a zeolite in which the molar ratio of SiO2 to Al2O3 is greater than 30.0 and less than 80.

0.

28. The oral composition according to claim 26, wherein, The external surface area of ​​zeolite is less than 33.0 m². 2 / g.

29. The oral composition according to claim 26, wherein it is a pharmaceutical composition.

30. The oral composition according to claim 29, wherein, The medication is administered 1 to 5 times a day, with each dose of the zeolite being 200 mg to 42,000 mg.

31. The oral composition according to claim 30, wherein, The dosage of the zeolite is 500mg to 2000mg per dose.

32. A method for manufacturing the oral composition of claim 26, wherein, Zeolites were obtained through hydrothermal synthesis without the use of organic structure-directing agents.

33. The method according to claim 32, wherein, Sodium carbonate and / or sodium sulfate are used as raw materials.

34. The method of claim 32, further comprising converting an acid to a protonated form.

35. The method according to claim 34, wherein, The acid is sulfuric acid or nitric acid.

36. The method of claim 32, further comprising surface treatment of the hydrothermally synthesized zeolite in a solution containing a Si element source.

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