Composition for inhibiting peritoneal deterioration, kit for composition for inhibiting peritoneal deterioration, peritoneal dialysis solution, and kit for peritoneal dialysis solution

Abstract

Provided is a composition capable of suppressing peritoneal deterioration. The composition for inhibiting peritoneal deterioration of the present invention contains carbon monoxide.

Description

Technical Field

[0001] The present invention relates to a composition for inhibiting peritoneal deterioration, a kit for the composition for inhibiting peritoneal deterioration, a peritoneal dialysis fluid, and a kit for the peritoneal dialysis fluid. Background Art

[0002] Artificial dialysis has become a treatment method for patients with decreased renal function to supplement their renal function. As the above-mentioned artificial dialysis, there are hemodialysis and peritoneal dialysis. The above-mentioned hemodialysis is performed about 3 times a week, and each time takes 4 to 5 hours. On the other hand, the above-mentioned peritoneal dialysis can be handled by replacing the dialysate once a day during sleep, so it has the advantage of improving the patient's QOL (Non-Patent Document 1).

[0003] Prior art literature

[0004] Non-patent literature

[0005] Non-patent document 1: Qin Zhou et al., "Preventing peritoneal membrane fibrosisin peritoneal dialysis patients", Kidney International, Volume 90, Issue 3, 2016, Pages 515-524 Summary of the invention

[0006] Problem that the invention aims to solve

[0007] However, patients who undergo peritoneal dialysis have the following problem: as time goes by, the function of the peritoneum decreases, such as the function of dehydration decreases, and the peritoneal dialysis cannot be continued in the sixth to seventh year after the start of the peritoneal dialysis. In this case, the patient will stop the peritoneal dialysis and switch to the hemodialysis. Therefore, in order to maintain the peritoneal dialysis for a longer period of time, a composition that can inhibit the deterioration of the peritoneum is required.

[0008] Therefore, an object of the present invention is to provide a composition capable of suppressing deterioration of the peritoneum.

[0009] Solutions for solving problems

[0010] In order to achieve the above-mentioned object, the composition for inhibiting peritoneal deterioration of the present invention (hereinafter also referred to as "composition") contains carbon monoxide.

[0011] The composition kit for inhibiting peritoneal deterioration of the present invention (hereinafter also referred to as "composition kit") comprises a composition for inhibiting peritoneal deterioration and other components.

[0012] The composition for inhibiting peritoneal deterioration is arranged to be separated from the other components.

[0013] The above-mentioned composition for inhibiting peritoneal deterioration is the above-mentioned composition of the present invention.

[0014] The peritoneal dialysis solution of the present invention comprises the above-mentioned composition of the present invention.

[0015] The peritoneal dialysis fluid kit of the present invention comprises a composition and a peritoneal dialysis fluid.

[0016] The above composition is configured to be isolated from the above peritoneal dialysis fluid,

[0017] The above composition is the composition of the present invention described above.

[0018] The composition of the present invention is a pharmaceutical composition for preventing or suppressing a disease caused by peritoneal dialysis (hereinafter also referred to as a "pharmaceutical composition"), which contains carbon monoxide.

[0019] The composition kit of the present invention is a pharmaceutical composition kit for preventing or inhibiting diseases caused by peritoneal dialysis (hereinafter also referred to as "pharmaceutical kit" or "pharmaceutical composition kit").

[0020] It contains a composition and other ingredients,

[0021] The above composition is configured to be isolated from the above other components,

[0022] The above composition is the composition of the present invention described above.

[0023] Effects of the Invention

[0024] According to the composition of the present invention, deterioration of the peritoneum can be suppressed. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is a cross-sectional view showing an example of a multi-chamber container containing the composition of the present invention and other components.

[0026] Figure 2 Schematic diagram showing a device for producing fine bubbles in Example 1.

[0027] Figure 3 Graph showing the amount of liquid discharge in Example 1.

[0028] Figure 4 These are photographs showing peritoneal thickening in Example 1 by tissue staining.

[0029] Figure 5 This is a photograph showing inflammatory cells revealed by tissue staining in Example 1.

[0030] Figure 6The photographs show the results of CD68 (macrophage marker) staining by immunohistochemical staining in Example 1.

[0031] Figure 7 This is a graph showing the macrophage-positive area (%) in Example 1.

[0032] Figure 8 These are photographs showing the results of CD31 (vascular endothelial cell marker) staining by immunohistochemical staining in Example 1.

[0033] Fig. 9 This is a graph showing the vascular endothelial cell-positive area (%) in Example 1.

[0034] Fig.10 These are photographs showing the results of Lyve-1 (lymphatic vessel marker) staining by immunohistochemical staining in Example 1.

[0035] Fig.11 This is a graph showing the results of the lymphatic vessel-positive area (%) in Example 1.

[0036] Fig.12 This is a graph showing the expression level of each gene in Example 1.

[0037] Fig.13 This is a graph showing the amount of peritoneal water in Example 2.

[0038] Fig.14 This is a graph showing the thickness of the peritoneal surface (peritoneal thickness) in Example 2.

[0039] Fig.15 This is a graph showing the expression level of IL-6 gene in Example 3.

[0040] Fig.16 This is a graph showing the amount of peritoneal water in Example 4. Fig.16 (A) shows the results of CO-UFB. Fig.16 (B) shows the results for CO-UFB 1 / 4. Fig.16 (C) shows the results for CO-UFB 1 / 10. Fig.16 (D) shows the results of CO-UFB 1 / 50. Fig.16 (E) shows the results of CO-dis. Fig.16 (F) shows the results for CO-dis 1 / 4. Fig.16 (G) shows the results of CO-dis 1 / 10. Fig.16 (H) shows the result of CO-dis 1 / 50. DETAILED DESCRIPTION

[0041] <Definition>

[0042] In this specification, "peritoneum" refers to a membrane covering part or all of the abdominal organs. The peritoneum is composed of the parietal peritoneum and the visceral peritoneum (including the diaphragm). The peritoneum covers the outer surface under normal conditions and is composed of a mesothelial cell layer composed of mesothelial cells and a submesothelial layer composed of connective tissue.

[0043] In this specification, "peritoneal deterioration" refers to a decrease in peritoneal function and / or a change in peritoneal morphology. The above-mentioned peritoneal deterioration is preferably peritoneal deterioration that occurs during peritoneal dialysis. The above-mentioned "decreased peritoneal function" refers to a decrease or failure in the ultrafiltration function of the peritoneum, and / or hyperpermeability of the peritoneum. The above-mentioned "change in peritoneal morphology" refers to the fibrous thickening of the peritoneum and / or the sclerotic thickening of the peritoneum. The above-mentioned "peritoneal deterioration" can be evaluated by the peritoneal function and / or peritoneal morphology of the research subject. The above-mentioned peritoneal function can be evaluated, for example, by a peritoneal equilibration test (PET). The above-mentioned peritoneal function can be evaluated based on the water removal function according to Example 1 described later. The above-mentioned peritoneal morphology can be evaluated, for example, by biological tissue diagnosis of the peritoneum of the subject.

[0044] In this specification, "peritoneal fibrosis" refers to a state in which extracellular matrix such as collagen is deposited in the peritoneum.

[0045] In this specification, "inhibiting peritoneal deterioration" may refer to the prevention, inhibition, suppression or cessation of the decline in peritoneal function, the inhibition or cessation of the progression of the decline in peritoneal function, and / or the improvement or alleviation (relief) of peritoneal function. It may also refer to the prevention, inhibition, suppression or cessation of changes in peritoneal morphology, the inhibition or cessation of the progression of changes in peritoneal morphology, and / or the improvement or restoration of the changed peritoneal morphology to normal.

[0046] In this specification, "inhibiting peritoneal fibrosis" means significantly inhibiting the fibrosis of the peritoneum of the subject. The above-mentioned "inhibiting peritoneal fibrosis" can also be referred to as, for example, preventing, suppressing or stopping the peritoneal fibrosis of the subject, inhibiting or stopping the progression of peritoneal fibrosis, and / or improving or restoring the fibrotic peritoneum to normal. The above-mentioned "inhibiting peritoneal fibrosis" can be evaluated, for example, by whether fibrosis is significantly inhibited under conditions that can induce peritoneal fibrosis. As a specific example, regarding the above-mentioned "inhibiting peritoneal fibrosis", under the conditions of inducing the above-mentioned peritoneal fibrosis, when the test substance treatment group significantly inhibits fibrosis compared with the control group not treated with the above-mentioned test substance or the control group treated with a substance (control substance) that does not have the above-mentioned peritoneal fibrosis inhibition activity, it can be evaluated that the above-mentioned test substance has peritoneal fibrosis inhibition activity. The above-mentioned inhibition of peritoneal fibrosis can also be evaluated based on the peritoneal thickening in the peritoneal deterioration model induced by chlorhexidine gluconate solution according to Example 1 (4) described later.

[0047] In this specification, "suppressing peritoneal inflammation" means significantly suppressing inflammation of the peritoneum of the subject. The above-mentioned "suppressing peritoneal inflammation" can also be referred to as, for example, preventing, suppressing or stopping inflammation of the peritoneum of the subject, and / or suppressing or stopping the progression (aggravation) of inflammation of the peritoneum. The above-mentioned "suppressing peritoneal inflammation" can be evaluated, for example, by whether inflammation is significantly suppressed under the condition of inducing peritoneal inflammation. As a specific example, regarding the above-mentioned "suppressing peritoneal inflammation", under the condition of inducing the above-mentioned peritoneal inflammation, when the test substance treatment group significantly suppresses inflammation compared with the control group not treated with the above-mentioned test substance or the control group treated with a substance (control substance) that does not have the above-mentioned peritoneal inflammation suppressing activity, it can be evaluated that the above-mentioned test substance has peritoneal inflammation suppressing activity. The above-mentioned suppression of peritoneal inflammation can also be evaluated according to the macrophage infiltration in the peritoneum in the peritoneal deterioration model induced by chlorhexidine gluconate solution in Example 1 (5) described later and / or the expression level of inflammatory cytokines in the peritoneum of Example 1 (6).

[0048] In this specification, "inhibiting angiogenesis" means significantly inhibiting angiogenesis in the peritoneum. As a specific example, regarding the above "inhibiting angiogenesis", for example, under conditions of inducing peritoneal angiogenesis, when the test substance-treated group significantly inhibits angiogenesis compared to a control group not treated with the test substance or a control group treated with a substance that does not have the above peritoneal angiogenesis inhibitory activity (control substance), the test substance can be evaluated as having angiogenesis inhibitory activity. The above inhibition of peritoneal angiogenesis can be evaluated based on the positive area of ​​vascular endothelial cell markers in the peritoneum of the peritoneal deterioration model induced by chlorhexidine gluconate solution according to Example 1 (5) described later.

[0049] In this specification, "inhibiting lymphangiogenesis" means significantly inhibiting lymphangiogenesis in the peritoneum. As a specific example, regarding the above "inhibiting lymphangiogenesis", for example, under conditions of inducing peritoneal lymphangiogenesis, when the test substance-treated group significantly inhibits lymphangiogenesis compared to a control group not treated with the test substance or a control group treated with a substance that does not have the above peritoneal lymphangiogenesis inhibitory activity (control substance), the test substance can be evaluated as having lymphangiogenesis inhibitory activity. The above peritoneal lymphangiogenesis inhibition can also be evaluated based on the positive area of ​​lymphatic endothelial cell markers in the peritoneum of a peritoneal deterioration model induced by chlorhexidine gluconate solution according to Example 1 (5) described later. In the above evaluation of lymphangiogenesis, the above peritoneum is preferably the diaphragm.

[0050] In this specification, "positive (+)" means that a higher signal is detected by an analysis method such as immunohistochemical staining that utilizes an antigen-antibody reaction for detection, compared with a negative control reaction using negative control cells that do not express the above antigen or an antibody that does not react with the above antigen.

[0051] In the present specification, "negative (-)" means that a signal equal to or lower than that of a negative control reaction using negative control cells that do not express the antigen or an antibody that does not react with the antigen is detected.

[0052] In this specification, "microbubbles" refer to closed microscopic spaces formed by gas and surrounded by substances other than gas. The microbubbles may also be referred to as fine bubbles, for example. Examples of the microbubbles include fine bubbles. The microbubbles generally refer to microbubbles having a bubble diameter of less than 100 μm. The bubble diameter refers to the spherical equivalent diameter of the bubble. The bubble diameter may be the average diameter (arithmetic mean diameter) of the microbubbles obtained by the measurement method described later. The small bubbles (fine bubbles: FB) may be microbubbles (Micro bubbles) or ultrafine bubbles (UFB). The microbubbles generally refer to microbubbles having a bubble diameter of 1 μm or more and less than 100 μm. The ultrafine bubbles generally refer to microbubbles having a bubble diameter of less than 1 μm. The bubble diameter of the ultrafine bubbles may be, for example, 1 nm or more and less than 1000 nm, 1 to 750 nm, or 1 to 500 nm.

[0053] In this specification, "subject" refers to an animal or a cell, tissue or organ derived from an animal, and is particularly used to include humans. The above-mentioned animal refers to humans and non-human animals. The above-mentioned non-human animals include mammals such as mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, dolphins, sea lions, etc.

[0054] In this specification, "treatment" refers to therapeutic treatment and / or preventive treatment. In this specification, "treatment" refers to the treatment, cure, prevention, inhibition, alleviation, improvement of a disease, condition or disorder, or the cessation, inhibition, reduction or delay of the progression of a disease, condition or disorder. In this specification, "prevention" refers to reducing the likelihood of occurrence of a disease or condition or delaying the occurrence of a disease or condition. The above-mentioned "treatment" can be, for example, treatment of a patient with the target disease, or treatment of a model animal of the target disease.

[0055] The present invention is described below with examples, but the present invention is not limited by the following examples, etc., and can be implemented after arbitrary changes. In addition, each description in the present invention can be referenced to each other as long as there is no special statement. It should be noted that in this specification, when the expression "~" is used, it is used with the meaning of the numerical value or physical value before and after it. In addition, in this specification, the expression of "A and / or B" includes "only A", "only B", "both A and B".

[0056] <Composition for inhibiting peritoneal deterioration>

[0057] The present invention provides a composition for inhibiting peritoneal deterioration. The composition for inhibiting peritoneal deterioration of the present invention contains carbon monoxide. The composition of the present invention is characterized by containing the above-mentioned carbon monoxide (CO), and other compositions and conditions are not particularly limited. The composition of the present invention can inhibit peritoneal deterioration. The composition of the present invention contains CO, so it can be directly administered to the body of the subject, such as the peritoneum, the abdominal cavity, etc.

[0058] The carbon monoxide exists, for example, in a medium. The carbon monoxide may exist in the medium in a state separated from the medium or in an integrated state. When the carbon monoxide exists in a state separated from the medium, the carbon monoxide exists, for example, in a state that can be distinguished or differentiated from the medium. In this case, the carbon monoxide exists, for example, in a space surrounded by the medium, and as a specific example, exists in the form of bubbles. The bubbles may include, for example, tiny bubbles. When the carbon monoxide exists in a state integrated with the medium, the carbon monoxide exists, for example, in a state that cannot be distinguished or differentiated from the medium. In this case, the carbon monoxide is dissolved or dissolved in the medium. When the medium is a liquid solvent, the medium in which the carbon monoxide is dissolved or dissolved may also be referred to as a carbon monoxide solution or a carbon monoxide solution.

[0059] The medium may be, for example, a liquid or a solid. The liquid may be, for example, an aqueous solvent containing water, an oily solvent, or a mixed solvent thereof. In addition, the liquid includes a sol. The solid may be, for example, a solid obtained by solidifying the liquid. In addition, the solid includes a gel. The liquid may be, for example: physiological saline; buffers such as phosphate buffer; infusion fluids such as extracellular fluid and intracellular fluid; water such as distilled water and pure water; cell culture fluids such as DMEM and RPMI1640; organ preservation fluid; etc. The solid may be, for example, a solidified product of the liquid.

[0060] The microbubbles are dispersed in the medium. Therefore, it can be said that the gas components of the microbubbles are surrounded by the medium. The gas components in the microbubbles are preferably in direct contact with the medium. The microbubbles are dispersed in the whole or part of the medium. In the latter case, it can be said that the microbubbles are biased in a part of the medium.

[0061] The composition of the present invention contains carbon monoxide as a gas component. The composition of the present invention may contain only carbon monoxide (CO) as a gas (gas component), or may further contain other gases as gases (gas components). The above-mentioned CO may also be referred to as an effective ingredient in the composition of the present invention, for example. The above-mentioned other gases refer to biogas such as nitric oxide (NO), hydrogen sulfide (H2S), hydrogen (H2); rare gases such as helium (He), argon (Ar), krypton (Kr), and xenon (Xe); carbon dioxide (CO2), nitrous oxide (N2O), carbon dioxide (CO2), nitrogen (N2), methane (CH4), ethane (CH3CH3), propane (CH3CH2CH3), fluoromethane (CH3F), difluoromethane (CH2F2), carbon tetrafluoride (CF4), ethylene oxide (C2H4O), air, etc. In the present invention, "biogas" refers to a gas containing carbon monoxide (CO), nitric oxide (NO), hydrogen sulfide (H2S) or hydrogen (H2) or a mixed gas containing two or more of these. When the composition of the present invention contains two or more gas components, the gas components other than CO are preferably gas components that do not react with CO, such as the above-mentioned rare gases, nitrogen, etc. The above-mentioned carbon monoxide does not include a case where the gas is only air, for example. In the present invention, the above-mentioned "air" refers to, for example, the air (atmosphere) used when manufacturing the composition of the present invention. In the composition of the present invention, when carbon monoxide and the above-mentioned other gases are gases at a medical gas level, they are preferably gases derived from medical gases. For example, the above-mentioned other gas components may exist in the same state as CO in the above-mentioned medium, or may exist in a state different from CO. As a specific example, when the above-mentioned carbon monoxide forms bubbles in the above-mentioned medium, the above-mentioned other gas components may form bubbles together with the above-mentioned carbon monoxide in the above-mentioned medium or form bubbles separately, or may exist in a state dissolved or dissolved in the above-mentioned medium. When the carbon monoxide is present in a state of being dissolved or dissolved in the medium, the other gas components may form bubbles in the medium, or may be present in a state of being dissolved or dissolved in the medium in the same manner as the carbon monoxide.

[0062] In the composition of the present invention, the content of the above-mentioned carbon monoxide can be set, for example, according to the dosage to the administration subject described later. The lower limit of the content (concentration) of the above-mentioned carbon monoxide can be, for example, 0.01 μmol / l or more, 0.1 μmol / l or more, 1 μmol / l or more, 10 μmol / l or more, 15 μmol / l, 50 μmol / l or more, 75 μmol / l or more, 100 μmol / l or more. The upper limit of the content (concentration) of the above-mentioned carbon monoxide can be, for example, 5 mmol / l or less, 1 mmol / l or less, 0.75 mmol / l or less, 0.5 mmol / l or less, 0.25 mmol / l or less. The range of the content (concentration) of the above-mentioned carbon monoxide in the composition of the present invention is, for example, 0.01 μmol / l to 5 mmol / l, 0.1 μmol / l to 1 mmol / l, 1 μmol / l to 1 mmol / l, 10 μmol / l to 1 mmol / l, or 100 μmol / l to 1 mmol / l.

[0063] When the composition of the present invention contains carbon monoxide in the form of bubbles and / or microbubbles, the density of the bubbles and / or microbubbles refers to the number of bubbles and / or microbubbles relative to the volume of the medium. The above "density" may also be referred to as number concentration. The lower limit of the density of the bubbles and / or microbubbles is, for example, 5×10 5 / ml, 1×10 6 / ml, 5×10 6 / ml, 1×10 7 / ml, 5×10 7 / ml, 1×10 8 / ml, 5×10 8 / ml, 1×10 9 / ml, preferably 1×10 6 / ml, 5×10 6 / ml, 1×10 7 / ml, 5×10 7 / ml, 1×10 8 / ml, 5×10 8 The upper limit of the density of the bubbles and / or microbubbles is, for example, 1.5×10 9 / ml, 2×10 9 / ml, 3×10 9 / ml, 5×10 9 / ml, 7×10 9 / ml, 9×10 9 / ml, 1×10 10 / ml, 5×10 10 / ml, 1×1011 / ml, 5×10 11 / ml, 1×10 12 / ml, 5×10 12 The density of the bubbles and / or microbubbles is, for example, in the range of 5×10 5 / ml~5×10 12 / ml, 5×10 5 / ml~1×10 12 / ml, 5×10 5 / ml~5×10 11 / ml, 5×10 5 / ml~1×10 11 / ml, 5×10 5 / ml~5×10 10 / ml, 5×10 5 / ml~1×10 10 / ml, 1×10 6 / ml~9×10 9 / ml, 5×10 6 / ml~9×10 9 / ml, 1×10 7 / ml~7×10 9 / ml, 5×10 7 / ml~7×10 9 / ml, 1×10 8 / ml~5×10 9 / ml, 5×10 8 / ml~5×10 9 / ml, 1×10 9 / ml~3×10 9 / ml, 5×10 8 / ml~2×10 9 / ml, 5×10 8 / ml~1.5×10 9 Pieces / ml.

[0064] The density, bubble diameter and average diameter (hereinafter also referred to as "characteristics") of the bubbles and / or microbubbles can be appropriately measured according to the medium in which the bubbles and / or microbubbles are dispersed. When the bubbles and / or microbubbles are dispersed in a liquid medium, the characteristics of the bubbles and / or microbubbles can be calculated by analyzing the bubbles in the composition of the present invention using a particle trajectory analysis method. The particle trajectory analysis method can be implemented, for example, using NanoSight (registered trademark) NS300 (manufactured by Malvern Instrument Co., Ltd.) according to Example 1 described later. The characteristics of the bubbles and / or microbubbles can also be calculated by other analysis methods other than the particle trajectory analysis method. In this case, the characteristics of the bubbles and / or microbubbles obtained by other analysis methods satisfy the above-mentioned examples when converted into calculated values ​​obtained by the particle trajectory analysis method. When the above-mentioned bubbles and / or the above-mentioned microbubbles are dispersed in a solid medium, the characteristics of the above-mentioned bubbles and / or the above-mentioned microbubbles can be calculated based on the characteristics of the bubbles and / or the above-mentioned microbubbles in the liquid before the above-mentioned medium is solidified and the characteristics of the bubbles and / or the above-mentioned microbubbles in the liquid obtained by dissolving the solid medium.

[0065] The proportion of CO in the above-mentioned gas is, for example, more than 0% and less than 100%, 10-100%, 20-100%, 30-100%, 40-100%, 50-100%, 60-100%, 70-100%, 80-100%, 90-100%, 95-100%, 96-100%, 97-100%, 98-100%, 99-100%, and preferably 90-100%.

[0066] The composition of the present invention preferably exhibits any one, two, three or four of the following activities (1) to (4). The following activities (1) to (4) can be evaluated by the above-mentioned method.

[0067] (1) Peritoneal fibrosis inhibitory activity

[0068] (2) Peritoneal inflammation inhibitory activity

[0069] (3) Inhibitory activity of angiogenesis in the peritoneum

[0070] (4) Inhibitory activity of lymphangiogenesis in the peritoneum

[0071] Regarding the above (1), the composition of the present invention has, for example, the following activity: in an experiment using the above-mentioned peritoneal degeneration model, 9 or 16 days after inducing the above-mentioned peritoneal degeneration, the thickness is suppressed by more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90% or more than 95% based on the thickness of the peritoneum of the above-mentioned control group.

[0072] Regarding the above (2), the composition of the present invention has, for example, the following activity: in an experiment using the above-mentioned peritoneal degeneration model, 9 or 16 days after inducing the above-mentioned peritoneal degeneration, based on the expression level of inflammatory cytokines in the peritoneum of the above-mentioned control group, the group administered with the composition of the present invention suppresses the expression level of the above-mentioned inflammatory cytokines by more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90% or more than 95%.

[0073] Regarding the above (3), the composition of the present invention has, for example, the following activity: in an experiment using the above-mentioned peritoneal degeneration model, 9 or 16 days after inducing the above-mentioned peritoneal degeneration, the area of ​​the positive area of ​​the above-mentioned vascular endothelial cell marker in the peritoneum of the above-mentioned control group is suppressed by more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90% or more than 95%.

[0074] Regarding the above (4), the composition of the present invention has, for example, the following activity: in an experiment using the above-mentioned peritoneal degeneration model, 9 or 16 days after inducing the above-mentioned peritoneal degeneration, the area of ​​the positive area of ​​the above-mentioned lymphatic endothelial cell marker in the peritoneum of the above-mentioned control group is suppressed by 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more or 95% or more, based on the area of ​​the positive area of ​​the above-mentioned lymphatic endothelial cell marker in the peritoneum of the above-mentioned control group.

[0075] The composition of the present invention can be manufactured using a method for manufacturing a medium in which gas is dissolved or a method for manufacturing a medium containing bubbles, depending on the state of CO in the composition. In the composition of the present invention, when the CO is dissolved or dissolved in the medium, the composition of the present invention can be manufactured, for example, by sealing the medium such as physiological saline and the gas in a sealable container and then mixing them. The volume ratio of the medium to the gas can be set, for example, according to the content of the gas in the medium, for example, the volume ratio (S:G) of the medium (S) to the gas (G) is, for example, 1:0.01 to 100, 1:0.1 to 10, 1:0.5 to 5. The mixing time is, for example, 1 minute to 24 hours, 10 minutes to 12 hours, or 20 minutes to 1 hour. In addition, in the composition of the present invention, when the CO forms bubbles, the composition of the present invention can be manufactured, for example, using any gas through a method for manufacturing microbubbles such as small bubbles. Therefore, the method for manufacturing the composition of the present invention includes, for example, a bubble manufacturing step, which uses a gas containing CO and a medium to manufacture microbubbles. As a specific example, when the composition of the present invention is a liquid, the liquid composition can be manufactured, for example, using a gas containing CO and the above-mentioned medium and a swirl method, an ejector method, a Venturi method, a static mixer method, a micro-bubble manufacturing device of a pressurized dissolution method or an ultrasonic cavitation method. In addition, when the composition of the present invention is a solid, the solid composition can be manufactured by solidifying the liquid composition using a known method. When the above-mentioned solid is a gel, the gel composition can be manufactured, for example, by mixing the above-mentioned liquid composition with a gelling agent. At the beginning of the above-mentioned bubble manufacturing process, the state of the gas containing CO is gas, liquid or solid. The gas containing the above-mentioned gas may contain a plurality of gases. In this case, each gas can be supplied to the above-mentioned bubble manufacturing process one by one, or all or part of the gas containing CO can be supplied to the above-mentioned bubble manufacturing process at the same time. As a specific example, when the above-mentioned gas is a gas other than CO and CO, the above-mentioned CO and CO can be introduced at the same time or one by one.

[0076] The composition of the present invention can be used in vivo or in vitro. The composition of the present invention can be used as a research reagent or as a medicine. In the latter case, the composition of the present invention can also be referred to as a medicine or a pharmaceutical composition.

[0077] The administration object (object) of the composition of the present invention is not particularly limited. When the composition of the present invention is used in vivo, the administration object can refer to the description of the above-mentioned object, for example. When the composition of the present invention is used in vitro, the administration object can be, for example, cells, tissues, organs, etc., and the cells can be, for example, cells collected from organisms, cultured cells, etc., and the tissues or organs can be, for example, tissues (organism tissues) or organs collected from organisms, etc. The cells can be, for example, peritoneal endothelial cells, peritoneal mesothelial cells, etc.

[0078] The subject to which the composition of the present invention is administered is preferably a subject scheduled to undergo peritoneal dialysis, a subject currently undergoing peritoneal dialysis, a subject who has undergone peritoneal dialysis, and / or a subject suspected of having deteriorated peritoneal function due to peritoneal dialysis.

[0079] The use conditions (administration conditions) of the composition of the present invention are not particularly limited, and for example, the administration method, administration time, administration amount, etc. can be appropriately set according to the type of the administration subject, etc.

[0080] The dosage of the composition of the present invention is not particularly limited, and is, for example, a therapeutically effective amount. When the composition of the present invention is used in vivo, the dosage can be appropriately determined according to, for example, the type, symptoms, age, and method of administration of the subject. As a specific example, when the density of the microbubbles is 1×10 8 / ml (Carbon monoxide content: about 0.0002mm 3 / ml)~5×10 12 / ml (Carbon monoxide content: about 10mm 3 When a composition having a carbon monoxide content (concentration) of 0.01 μmol / l to 5 mmol / l is intraperitoneally or intravenously administered to mice or humans, the total amount of the composition administered per day is, for example, 1 to 80 ml / kg body weight or 20 to 80 ml / kg body weight. In this case, the number of administrations of the composition of the present invention per day is, for example, 1 to 5 times, 1 to 3 times, and preferably 1 time. The density of the microbubbles is 1×10 8 / ml~5×10 12 When a composition having a carbon monoxide content (concentration) of 0.01 μmol / l to 5 mmol / l is administered to the peritoneal cavity of a human in the form of a peritoneal dialysis solution, the dosage of the composition per day is, for example, 2 to 5 L per time. In addition, the total dosage per day is, for example, 2 to 30 L, 5 to 20 L, or 8 to 18 L. In this case, the number of times the composition of the present invention is administered per day is, for example, 1 to 15 times, 1 to 13 times, or 3 to 10 times. In addition, the density of the microbubbles is 1×10 8 / ml~5×10 12When a composition having a carbon monoxide content (concentration) of 0.01 μmol / l to 5 mmol / l is administered to mice or humans for preventive purposes, the dosage of the composition per day is, for example, 0.00001 to 500 ml / time. In this case, the number of administrations per day of the composition of the present invention is, for example, 1 to 5 times, 1 to 3 times, and preferably 1 time. The content of the gas component in the above composition is not particularly limited, for example, it can be appropriately set according to the above dosage per day. The composition of the present invention can be administered continuously or discontinuously. The above discontinuous administration can also be referred to as intermittent administration, for example. The composition of the present invention can be administered, for example, at specified intervals. The above specified intervals can be approximately equal intervals or equal intervals, or can be unequal intervals. The above specified intervals can include, for example, intervals of 8 to 12 hours, intervals of 1 day, etc.

[0081] There is no particular limitation on the mode of administration of the composition of the present invention. When the composition of the present invention is administered in vivo, it can be administered orally or parenterally. The parenterally administered method includes, for example, intravenous injection (intravenous administration), intramuscular injection (intramuscular administration), transdermal administration, subcutaneous administration, intradermal administration, enteral administration, rectal administration, vaginal administration, nasal administration, pulmonary administration, intraperitoneal administration, topical administration, etc. When the composition of the present invention is administered intraperitoneally, the composition administered into the peritoneal cavity can be recovered from the peritoneal cavity.

[0082] The dosage form of the composition of the present invention is not particularly limited, and can be appropriately determined according to the above-mentioned mode of administration, for example. The above-mentioned dosage form can be, for example, liquid or solid. As a specific example, the above-mentioned dosage form can be exemplified by release-modified preparations (enteric preparations, sustained-release preparations, etc.), capsules, oral liquid preparations (elixirs, suspensions, emulsions, aromatic water preparations, lemonade preparations, etc.), syrups (syrup preparations, etc.), granules (foaming granules, fine particles, etc.), powders, tablets (orally disintegrating tablets, chewable tablets, foaming tablets, dispersible tablets, dissolving agents, coated tablets, etc.), pills, oral gel preparations, etc.; oral tablets (gum preparations) Preparations for oral administration such as oral sprays, oral semisolids, and mouthwashes; preparations for injection such as injections (implant injections, continuous injections, infusions (drip preparations, etc.), freeze-dried injections, powder injections, prefilled injections, cartridges, etc.); preparations for dialysis such as dialysis preparations (peritoneal dialysis preparations, hemodialysis preparations); preparations for bronchial / pulmonary use such as inhalation preparations (inhalation aerosols, inhalation liquids, inhalation powders, etc.) ; preparations for eye administration such as eye ointments and eye drops; preparations for ear administration such as ear drops; preparations for nose application such as nasal drops (nasal liquid, nasal powder, etc.); rectal application preparations such as suppositories, rectal semisolids, enemas; vaginal application preparations such as vaginal suppositories and vaginal tablets; external liquids (alcohol, emollients, lotions, etc.), creams, gels, external solids (external powders, etc.), sprays (external aerosols, pump sprays, etc.), patches (tapes, papules, etc.), ointments, etc., for skin application; etc. When the composition of the present invention is administered orally, the above dosage form can include, for example, tablets, coated tablets, pills, fine particles, granules, powders, capsules, liquids, syrups, emulsions, suspensions, etc. When the composition of the present invention is administered parenterally, the above dosage form can include, for example, preparations for injection, preparations for drip, etc. When the composition of the present invention is administered percutaneously, the dosage form may be, for example, an external medicine such as a patch, a coating, an ointment, a cream, and a lotion.

[0083] The composition of the present invention may include additives as needed, and when the composition of the present invention is made into a medicine or a pharmaceutical composition and used, the additives preferably include pharmaceutically acceptable additives or pharmaceutically acceptable carriers. The additives are not particularly limited, and examples thereof include osmotic pressure regulators such as salts, base materials, excipients, colorants, lubricants, binders, disintegrants, stabilizers, coating agents, preservatives, pH adjusters, flavoring agents such as spices, etc. In the present invention, the amount of the additives is not particularly limited as long as it does not hinder the function of CO.

[0084] Examples of the excipients include sugar derivatives such as lactose, lactose hydrate, white sugar, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, α-starch, and dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium aluminum silicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; and inorganic excipients such as sulfates such as calcium sulfate. Examples of the colorant include yellow iron oxide. Examples of the lubricant include metal stearates such as stearic acid, calcium stearate, and magnesium stearate; talc; polyethylene glycol; silicon dioxide; hydrogenated vegetable oil, etc. Examples of the flavoring and smelling agents include spices such as cocoa powder, menthol, powdered ginger, peppermint oil, borneol, and cinnamon powder, sweeteners, and acidulants. Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, etc. Examples of the disintegrant include cellulose derivatives such as carboxymethyl cellulose and carboxymethyl cellulose calcium; chemically modified starches and chemically modified celluloses such as carboxymethyl starch, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, and sodium starch glycolate. Examples of the stabilizer include parabens such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; sorbic acid, etc. Examples of the coating agent include hydroxypropyl cellulose, polyethylene glycol such as polyethylene glycol 6000, talc, titanium oxide, etc.

[0085] The composition of the present invention can, for example, inhibit peritoneal deterioration of the subject to which the composition is administered. Therefore, the composition of the present invention can be suitably used as a composition for preventing or inhibiting peritoneal deterioration caused by peritoneal dialysis, peritoneal inflammation and / or peritoneal fibrosis caused by the above peritoneal deterioration, and encapsulated peritoneal sclerosis caused by the above peritoneal deterioration.

[0086] <Kit for inhibiting peritoneal deterioration composition>

[0087] In one embodiment, the present invention provides a kit for a composition for inhibiting peritoneal deterioration. The kit for the composition for inhibiting peritoneal deterioration of the present invention comprises the composition for inhibiting peritoneal deterioration of the present invention and other components as described above, the composition for inhibiting peritoneal deterioration of the present invention is configured to be isolated from the other components, and the composition for inhibiting peritoneal deterioration of the present invention is the composition for inhibiting peritoneal deterioration of the present invention. The composition kit of the present invention is characterized in that it comprises the composition of the present invention, and other configurations and conditions are not particularly limited. According to the composition kit of the present invention, the dosage of CO can be adjusted by adjusting the dosage of the composition. The composition kit of the present invention can refer to the description of the composition of the present invention.

[0088] The above-mentioned other ingredients are not particularly limited and can be appropriately determined according to the content of the above-mentioned composition and the purpose of administering to the subject. Examples thereof include the above-mentioned additives, drugs, nutrients, etc. Examples of the above-mentioned drugs include antibiotics, etc. When the osmotic pressure of the above-mentioned composition is not adjusted, the above-mentioned other ingredients preferably include an osmotic pressure adjuster (substance). Examples of the above-mentioned osmotic pressure adjusting substance include sugars such as glucose and icodextrin; salts (electrolytes) such as sodium chloride, sodium lactate, calcium chloride, calcium chloride, sodium bicarbonate, and magnesium chloride; amino acids; proteins, etc. Examples of the above-mentioned nutrients include sugars such as glucose, vitamins, etc. The above-mentioned other ingredients may be solid or liquid. In the former case, the above-mentioned other ingredients are preferably configured in a state where they are not dissolved in a solvent, etc., for example, they are configured in a manner that they are dissolved when mixed with the above-mentioned composition. In the latter case, the above-mentioned other ingredients are preferably dissolved in a solvent, for example.

[0089] In the composition kit of the present invention, the composition is isolated from the other components, that is, the composition and the other components are arranged in an unmixed state or in a non-contact state. Specifically, the composition and the other components are arranged at different positions in the container containing them.

[0090] In the composition kit of the present invention, the composition and the other components are preferably contained in a container. In this case, the container has a plurality of chambers, and the composition and the other components are contained in different chambers. That is, the container is preferably a multi-chamber container. The number of chambers in one container is not particularly limited, for example, it can be determined according to the number of components to be isolated and configured, as a specific example, 2 to 10 chambers, 2 to 5 chambers. As a specific example, the container has a first chamber for accommodating the composition and a second chamber for accommodating the other components. In the container, the first chamber and the second chamber can be independently constructed, that is, constructed in the form of independent containers, or can be an integrated construction, that is, constructed in the form of one container. When the first chamber and the second chamber are constructed in the form of one container, the container preferably has an isolation portion capable of isolating the first chamber and the second chamber. When the container has an isolation portion, the first chamber and the second chamber are, for example, configured across the isolation portion. When the composition and the other components are mixed and administered to a subject, the partition section is preferably configured to allow communication between the first chamber and the second chamber.

[0091] The container having the first chamber and the second chamber may be, for example, a multi-chamber container for medical use. The multi-chamber container may be, for example, a plastic double bag in which a plurality of chambers are formed by providing the partition portion in a plastic bag (e.g., Japanese Patent Laid-Open No. 2016-190646, Japanese Patent Laid-Open No. 2016-131577, etc.), a dissolving solution kit in which a container containing other components and a container containing a dissolving solution (corresponding to the above-mentioned composition) are connected and integrated (e.g., International Publication No. 96 / 25136, etc.), a dual-chamber prefilled syringe (e.g., Japanese Patent Laid-Open No. 2012-245086, etc.), etc.

[0092] use Figure 1 An example of the multi-chamber container containing the composition and the other components in the composition kit of the present invention will be described. Figure 1 2 is a cross-sectional view showing an example of the composition kit of the present invention. Figure 1 As shown, the composition kit comprises a container 10, a composition 11, and other components 21. The container 10 comprises: a first chamber 1 containing the composition 11, a second chamber 2 containing other components 21, and a partition 3 that isolates the first chamber 1 and the second chamber 2 and enables communication between the first chamber 1 and the second chamber 2. The container 10 further comprises a hanging portion 5 on which the container 10 can be hung.

[0093] like Figure 1 As shown, the container 10 is formed by the sheet 13 and the sheet 14 and the discharge portion (discharge port) 22. Figure 1 As shown, the sheets 13 and 14 are welded to the sheet 13 at the upper end of the sheet 14 to form the upper end 12 of the first chamber 1, and are connected to the discharge portion 22 at the lower end side of the sheets 13 and 14. In addition, the sheets 13 and 14 are welded at their central parts to form the isolation portion 3. The welding of the isolation portion 3 is peelable, and the welding of the sheets 13 and 14 at the isolation portion 3 can be released by applying pressure to the first chamber 1, so that the first chamber 1 and the second chamber 2 can be communicated. In the container 10, the first chamber 1 is a space from the upper end 12 of the sheets 13 and 14 to the isolation portion 3. In addition, in the container 10, the second chamber 2 is a space from the isolation portion 3 of the sheets 13 and 14 to the discharge portion 22.

[0094] Plastic sheets can be used for the sheets 13 and 14. The plastic sheets are preferably composed of multiple layers, for example, an inner surface layer, an outer surface layer, and an intermediate layer. As the inner surface layer and the outer surface layer, thermoplastic resins such as thermoplastic olefin resins, thermoplastic propylene resins, and thermoplastic polyethylene resins can be used. By using such thermoplastic resins and stacking the sheets 13 and 14 in a manner that they are opposite to each other and performing heat sealing, the outer periphery of the first chamber 1 and the second chamber 2, the upper end portion 12, and the isolation portion 3 can be easily formed, and the container 10 can be manufactured. The intermediate layer is preferably a resin with high flexibility, for example, and as a specific example, a thermoplastic olefin resin composition can be used.

[0095] The volumes and shapes of the first chamber 1 and the second chamber 2 are not particularly limited and can be appropriately set, for example, according to the dosage of the above-mentioned composition and other components.

[0096] The kit of the present invention can, for example, inhibit peritoneal deterioration of the subject to be administered. Therefore, the kit of the present invention can be preferably used, for example, as a kit for inhibiting peritoneal deterioration caused by peritoneal dialysis, peritoneal inflammation and / or peritoneal fibrosis caused by the peritoneal deterioration, and for preventing or inhibiting encapsulated peritoneal sclerosis caused by the peritoneal deterioration.

[0097] <Peritoneal Dialysate>

[0098] In another embodiment, the present invention provides a peritoneal dialysis fluid for inhibiting peritoneal deterioration. The peritoneal dialysis fluid of the present invention is characterized in that it contains the above-mentioned composition for inhibiting peritoneal deterioration of the present invention. According to the peritoneal dialysis fluid of the present invention, peritoneal deterioration during peritoneal dialysis can be inhibited. The peritoneal dialysis fluid of the present invention is characterized in that it contains the above-mentioned composition of the present invention, that is, CO as a gas component, and other configurations and conditions are not particularly limited. The peritoneal dialysis fluid of the present invention can inhibit peritoneal deterioration during peritoneal dialysis. Since the composition of the present invention contains CO, it can be directly administered to the body of the subject of administration, such as the peritoneum, the peritoneal cavity, etc.

[0099] The peritoneal dialysis solution of the present invention contains other components that can be contained in peritoneal dialysis solution in addition to the above-mentioned composition of the present invention. That is, the peritoneal dialysis solution of the present invention contains the composition of the present invention, i.e., CO as a gas component, in addition to the components contained in a normal peritoneal dialysis solution. Examples of the above-mentioned other components include osmotic pressure regulating substances; ions of metals such as calcium, sodium, magnesium, and chromium; alkalizing agents; organic acids; and the like.

[0100] Examples of the osmotic pressure regulating substance include sugars such as glucose and icodextrin; amino acids; proteins; and the like.

[0101] Examples of the alkali agent include lactate ions and bicarbonate ions.

[0102] Examples of the organic acid include propionic acid, malic acid, fumaric acid, succinic acid, oxalacetic acid, N-acetylglycine, N-acetyl-L-cysteine, glutaric acid, glucuronic acid, ascorbic acid, citric acid, isocitric acid, gluconic acid, N-acetyl-L-aspartic acid, N-acetyl-L-glutamic acid, N-acetyl-L-methionine, N-acetyl-L-proline, N-acetyl-L-valine, N-acetyl-L-glutamine, N-acetyl-L-arginine, N-acetyl-L-histidine, N-acetyl-L-leucine, N-acetyl-L-tryptophan, and salts thereof.

[0103] The concentration of the other components can be appropriately set according to the types of the other components.

[0104] The pH of the peritoneal dialysis solution of the present invention is, for example, about pH 5.0 to 7.5, and preferably about pH 6.5 to 7.5.

[0105] The osmotic pressure of the peritoneal dialysis solution of the present invention is, for example, about 300 to 500 mOsm / kg, preferably about 330 to 450 mOsm / kg.

[0106] The amount of the peritoneal dialysis solution of the present invention injected is, for example, 1.5 to 2 L per time when the subject is a human. In addition, the retention time of the peritoneal dialysis solution of the present invention is, for example, 4 to 8 hours per time. Furthermore, the peritoneal dialysis solution of the present invention is, for example, discharged after the retention. The peritoneal dialysis solution of the present invention is, for example, continuously operated 3 to 5 times per day, with these operations counted as one time.

[0107] The peritoneal dialysis solution of the present invention can be prepared, for example, by mixing the composition of the present invention with other components such as the osmotic pressure regulating substance. Therefore, the other components are preferably prepared as concentrated solutions and the concentrations of the other components are adjusted so as to achieve a desired concentration after mixing with the composition of the present invention. The composition of the present invention and the other components are preferably sterilized in advance.

[0108] The peritoneal dialysis solution of the present invention is preferably sealed in a soft plastic bag or a glass container.

[0109] <Peritoneal dialysis fluid kit>

[0110] In another embodiment, the present invention provides a peritoneal dialysis fluid kit for inhibiting peritoneal deterioration. The peritoneal dialysis fluid kit of the present invention is characterized in that it contains the composition of the present invention and a peritoneal dialysis fluid. According to the peritoneal dialysis fluid of the present invention, peritoneal deterioration during peritoneal dialysis can be inhibited. The peritoneal dialysis fluid of the present invention is characterized in that it contains the composition of the present invention, i.e., CO as a gas component, and other configurations and conditions are not particularly limited. The peritoneal dialysis fluid of the present invention can inhibit peritoneal deterioration. Since the composition of the present invention contains CO, it can be directly administered to the body of the subject of administration, such as the peritoneum, the peritoneal cavity, etc.

[0111] The peritoneal dialysis solution in the peritoneal dialysis kit of the present invention is mixed with the composition of the present invention to prepare a mixed solution and used. Therefore, the peritoneal dialysis solution is preferably, for example, a concentrated solution of a conventional peritoneal dialysis solution. The concentration of each component (other component) in the concentrated solution of the peritoneal dialysis solution can be set so as to achieve a desired concentration after mixing with the composition of the present invention.

[0112] In the peritoneal dialysis kit of the present invention, the composition and the other components are preferably contained in a container. The container may be, for example, the container described above in the composition kit.

[0113] <Drug Composition>

[0114] In another embodiment, the present invention provides a composition capable of treating a disease caused by peritoneal dialysis or peritoneal deterioration. The pharmaceutical composition for treating a disease caused by peritoneal dialysis or peritoneal deterioration of the present invention (hereinafter also referred to as a "pharmaceutical composition") comprises the above-mentioned composition for inhibiting peritoneal deterioration of the present invention. The pharmaceutical composition of the present invention is characterized in that it comprises the above-mentioned composition of the present invention, and other compositions and conditions are not particularly limited. The pharmaceutical composition of the present invention can inhibit peritoneal deterioration of the subject of administration. Therefore, the pharmaceutical composition of the present invention can be preferably used, for example, for inhibiting the above-mentioned peritoneal deterioration caused by peritoneal dialysis, the inflammation of the peritoneum and / or peritoneal fibrosis that occurs during the above-mentioned peritoneal deterioration, and the prevention or inhibition of encapsulated peritoneal sclerosis caused by the above-mentioned peritoneal deterioration. According to the pharmaceutical composition of the present invention, the dosage of CO can be adjusted by adjusting the dosage of the above-mentioned composition.

[0115] The pharmaceutical composition of the present invention may include, for example, the above-mentioned pharmaceutically acceptable additives or pharmaceutically acceptable carriers.

[0116] <Drug kit>

[0117] In another embodiment, the present invention provides a kit for a composition capable of treating a disease caused by peritoneal dialysis or peritoneal deterioration. The drug kit for treating a disease caused by peritoneal dialysis or peritoneal deterioration of the present invention (hereinafter also referred to as a "drug kit") comprises the above-mentioned composition kit for inhibiting peritoneal deterioration of the present invention, that is, comprises the composition for inhibiting peritoneal deterioration of the present invention and other components. The drug kit of the present invention is characterized in that it comprises the composition kit of the above-mentioned invention, and other structures and conditions are not particularly limited. The drug kit of the present invention can inhibit peritoneal deterioration of the subject of administration. Therefore, the drug kit of the present invention can be preferably used, for example, for the inhibition of peritoneal deterioration caused by peritoneal dialysis, the inflammation of the peritoneum and / or peritoneal fibrosis that occurs during the above-mentioned peritoneal deterioration, and the prevention or inhibition of encapsulated peritoneal sclerosis caused by the above-mentioned peritoneal deterioration. According to the drug kit of the present invention, the dosage of CO can be adjusted by adjusting the dosage of the above-mentioned composition.

[0118] <Suppression methods>

[0119] In another embodiment, the present invention provides a method for inhibiting peritoneal deterioration. The inhibition method of the present invention is a method for inhibiting peritoneal deterioration, using the composition for inhibiting peritoneal deterioration of the present invention or the composition kit for inhibiting peritoneal deterioration of the present invention. The inhibition method of the present invention is characterized in that the composition for inhibiting peritoneal deterioration of the present invention or the composition kit for inhibiting peritoneal deterioration of the present invention is used, and other steps and conditions are not particularly limited. According to the inhibition method of the present invention, peritoneal deterioration can be inhibited.

[0120] The inhibition method of the present invention includes, for example, a step of administering the composition or the composition kit to a subject. The administration is preferably intraperitoneal administration.

[0121] In the inhibition method of the present invention, the subject can refer to the above-mentioned description of the subject of administration, and as a specific example, it can be a subject scheduled to undergo peritoneal dialysis, a subject currently undergoing peritoneal dialysis, or a subject who has undergone peritoneal dialysis.

[0122] In the inhibition method of the present invention, the above-mentioned composition or composition kit may be used in vitro or in vivo.

[0123] In the inhibition method of the present invention, the targets of the above-mentioned peritoneal deterioration include, for example, peritoneal fibrosis and decreased peritoneal function.

[0124] <Dialysis method>

[0125] In another embodiment, the present invention provides a dialysis method for inhibiting peritoneal deterioration. The dialysis method of the present invention is a peritoneal dialysis method, using the peritoneal dialysis solution of the present invention or the peritoneal dialysis solution kit of the present invention. The dialysis method of the present invention is characterized in that the peritoneal dialysis solution of the present invention or the peritoneal dialysis solution kit of the present invention is used, and other steps and conditions are not particularly limited. According to the dialysis method of the present invention, peritoneal deterioration in peritoneal dialysis can be inhibited.

[0126] The dialysis method of the present invention includes, for example, the steps of injecting the peritoneal dialysis solution or the mixed solution of the peritoneal dialysis solution kit into the peritoneal cavity of the subject; the step of allowing the peritoneal dialysis solution or the mixed solution to remain; and the step of draining the peritoneal dialysis solution or the mixed solution. The dialysis conditions such as the injection amount and the retention time in each step can be referred to the above description.

[0127] <Disposal method>

[0128] In another embodiment, the present invention provides a method for treating a disease caused by peritoneal dialysis or peritoneal deterioration. The treatment method of the present invention (hereinafter also referred to as "treatment method") is a method for treating a disease caused by peritoneal dialysis or peritoneal deterioration, using the pharmaceutical composition of the present invention or the pharmaceutical composition kit of the present invention. The treatment method of the present invention is characterized in that the pharmaceutical composition of the present invention or the pharmaceutical composition kit of the present invention is used, and other steps and conditions are not particularly limited. According to the treatment method of the present invention, peritoneal deterioration in peritoneal dialysis of the subject of administration can be suppressed. Therefore, according to the treatment method of the present invention, for example, the inhibition of peritoneal deterioration caused by peritoneal dialysis, the inflammation of the peritoneum and / or peritoneal fibrosis that occurs during the process of the peritoneal deterioration, and the prevention or suppression of diseases such as encapsulated peritoneal sclerosis caused by the peritoneal deterioration can be carried out.

[0129] The treatment method of the present invention includes, for example, a step of administering the composition for inhibiting peritoneal deterioration of the present invention to a patient.

[0130] In the treatment method of the present invention, the above-mentioned pharmaceutical composition can be used as the above-mentioned composition. In addition, in the treatment method of the present invention, a composition kit or a pharmaceutical kit (hereinafter also collectively referred to as a "kit") can be used as the above-mentioned composition.

[0131] When the treatment method of the present invention uses the above-mentioned kit, the above-mentioned administration step may be to administer the above-mentioned composition and the above-mentioned other ingredients simultaneously or separately. When the above-mentioned composition and the above-mentioned other ingredients are administered simultaneously, the treatment method of the present invention preferably includes a mixing step of mixing the above-mentioned composition in the above-mentioned kit and the above-mentioned other ingredients before the above-mentioned administration step. In this case, in the above-mentioned administration step, the obtained mixture is administered to the patient.

[0132] The administration conditions in the above-mentioned administration step can refer to the above-mentioned description.

[0133] In the treatment method of the present invention, the patient is preferably diagnosed with a disease caused by the above-mentioned peritoneal deterioration, or a patient suspected of having the disease. In addition, the patient may be a patient with peritoneal fibrosis, or a patient suspected of having fibrosis, or a patient with peritoneal inflammation, or a patient suspected of having inflammation. The above-mentioned peritoneal deterioration can be evaluated, for example, by bio-tissue diagnosis of the peritoneum of the above-mentioned patient.

[0134] <Application>

[0135] In another embodiment, the present invention is a composition for use in the inhibition of peritoneal deterioration, peritoneal dialysis, or the treatment of a disease caused by peritoneal dialysis or peritoneal deterioration, wherein the composition contains carbon monoxide. In addition, the present invention is a composition kit for use in the inhibition of peritoneal deterioration, peritoneal dialysis, or the treatment of a disease caused by peritoneal dialysis or peritoneal deterioration, wherein the composition kit contains a composition and other components, wherein the composition is arranged in isolation from the other components, and the composition contains carbon monoxide.

[0136] Example

[0137] [Example 1]

[0138] The composition of the present invention was produced and confirmed to be able to alleviate peritoneal deterioration.

[0139] (1) Preparation of composition

[0140] The composition of the present invention is used Figure 2 The microbubbles are manufactured by the manufacturing device 100 shown in FIG. Figure 2 As shown, in the manufacturing device 100, syringes 32 and 33 are arranged on both sides of the three-way stopcock 31. In the manufacturing device 100, the syringes 32 and 33 are connected through the three-way stopcock 31. First, the syringe 32 is released from the three-way stopcock 31, and 20 ml of physiological saline is introduced into the inside. Next, the syringe 32 is connected to the three-way stopcock 31 again, and the gas in the three-way stopcock 31 is removed. After the above removal, the syringe 33 is released from the three-way stopcock 31, and 20 ml of medical carbon monoxide (manufactured by Taiyo Nippon Sanso Co., Ltd. or Taiyo Nippon Sanso JFP Co., Ltd., CO concentration: 99.95% or more (G1)) is introduced into the inside. Then, the syringe 33 is connected to the three-way stopcock 31 again. After the above connection, the plungers of the syringes 32 and 33 are continuously piston-moved in the outer cylinder for 10 minutes, thereby producing microbubbles containing CO as a gas component, thereby producing the composition of the present invention (the composition of Example 1).

[0141] The obtained composition was left to stand for about 1 hour, and the physical properties of the composition were measured using NanoSight (registered trademark) NS300 (manufactured by Malvern Instrument Co., Ltd.) using default parameters. It should be noted that the above measurement was performed at 25° C. As a result, the average diameter of the microbubbles in the above composition and the density of the microbubbles are as follows.

[0142] (Composition of Example 1 (CO-UFB))

[0143] Average diameter: 136.3±1.4nm, density: 1.54×10 9 ±1.87×10 7 Pieces / ml

[0144] (2) Preparation of mice with peritoneal degeneration model

[0145] The peritoneal deterioration model mice were prepared by intraperitoneally administering chlorhexidine gluconate solution (CG solution: Chlorhexidine Gluconate Solution) to mice (strain: C57BL / 6JJmsSlc, purchased from Japan SLC). The above CG solution was prepared as follows. First, 1.5 ml of 99.5% ethanol (manufactured by Wako, Cat No: 057-00456) and 50 μl of 20% CG (manufactured by Wako, Cat No: 034-10871) were added to 8.5 ml of normal saline and mixed thoroughly. The obtained mixed solution was sterilized and filtered with a 0.2 μm filter to prepare 0.1% CG solution. Next, 300 μl of 0.1% CG solution was intraperitoneally administered to the above mice. Two hours after the administration of the above CG solution, 1.0 ml of CO-UFB was intraperitoneally administered. The above administration was performed every other day for a total of 7 times (CG+CO-UFB, Example group). The control group (Control) was treated in the same manner except that an equal amount of saline was used instead of the 0.1% CG solution and the CO-UFB was replaced with saline. The reference group (CG) was treated in the same manner except that saline was used instead of the CO-UFB.

[0146] (3) Determination of peritoneal function

[0147] On the 16th day from the start of the administration, peritoneal function was measured to confirm that peritoneal deterioration had occurred. Specifically, a peritoneal equilibrium test (PET: Peritoneal Equilibration Test) was performed on mice in each group on the 16th day from the start of the administration. 2 ml of 4.25% (registered trademark) Dianeal was intraperitoneally administered to mice in each group, and fluid and blood were collected 2 hours after the administration to evaluate the amount of water removed and fluid discharged. The results are shown in Table 1 and Figure 3 .

[0148] [Table 1]

[0149] Control (n=13) CG (n=16) CG+C0-UFB(n=21) mortality rate(%) 0％ 30.4％ 12.5％ Discharge volume (ml) 1.634ml 1.120ml 1.741ml Water removal (ml) -0.366ml -0.880ml -0.259ml

[0150] Table 1 above shows the mortality rate, discharge volume and water removal volume. Figure 3 is a graph showing the amount of liquid discharged. Figure 3 In the table, the horizontal axis represents the type of sample and the vertical axis represents the amount of fluid discharged. As shown in Table 1 above, the mortality rate of the reference group (CG) increased to 30.4% due to the induction of peritoneal deterioration. In contrast, the mortality rate of the example group (CG+CO-UFB) was 12.5%, which was a decrease. In addition, as shown in Table 1 and Figure 3 As shown, the reference group showed a tendency of decreased fluid volume compared with the control group (control). In contrast, no significant difference was observed in the fluid volume of the example group (CG+CO-UFB) compared with the control group.

[0151] From the above results, it was found that the decrease in water removal function due to peritoneal deterioration was alleviated by administering CO-UFB, which is the composition of the present invention.

[0152] (4) Measurement of peritoneal thickening

[0153] On the 16th day after the start of administration of the CG solution of Example 1 (1) above, peritoneal thickening and inflammatory cell infiltration in the peritoneum, which are indicators of peritoneal deterioration, were studied. Specifically, on the 16th day after the administration of the above CG solution, the parietal peritoneum and diaphragm of each group of mice were collected and fixed with 10% neutral buffered formalin. After the above fixation, the parietal peritoneum and the above diaphragm were embedded in paraffin, and paraffin-embedded sections with a thickness of 3 μm were prepared. HE staining was performed on the obtained paraffin-embedded sections by conventional methods. After the above staining, the thickness of the basement membrane to the peritoneal surface (peritoneal surface layer) was measured for each section using an optical microscope (OLYMPUS BX50, manufactured by Olympus Corporation) and a camera (OLYMPUS DP22, manufactured by Olympus Corporation). In addition, the presence or absence of inflammatory cell infiltration was also studied for each section. These results are shown in Figure 4 and Figure 5 .

[0154] Figure 4 This is a photograph obtained by tissue staining showing peritoneal thickening. Figure 4 In the figure, the arrow indicates the area from the basement membrane to the peritoneal surface. Figure 2 As shown, the peritoneal thickness of the reference group (CG) was an average of 166.6 μm, while the peritoneal thickness of the control group (control) was an average of 54.4 μm, confirming that the administration of CG solution leads to peritoneal thickening. In contrast, the peritoneal thickness of the embodiment group (CG+CO-UFB) was an average of 109.9 μm. From these results, it can be seen that the peritoneal thickening that occurs when the peritoneum deteriorates can be reduced by administering CO-UFB, which is a composition of the present invention.

[0155] then, Figure 5 This is a photograph showing inflammatory cells by tissue staining. Figure 5 As shown, the control group (control) did not observe the infiltration of inflammatory cells into the above-mentioned peritoneal surface layer. On the other hand, the reference group (CG) confirmed the infiltration of inflammatory cells into the above-mentioned peritoneal surface layer in the portion indicated by the arrow compared with the control group. In contrast, the embodiment group (CG+CO-UFB) observed a decrease in the number of inflammatory cells infiltrating into the above-mentioned peritoneal surface layer in the portion indicated by the arrow compared with the reference group.

[0156] From the above results, it was found that the administration of CO-UFB, which is the composition of the present invention, can alleviate peritoneal thickening caused by peritoneal deterioration and inhibit the infiltration of inflammatory cells.

[0157] (5) Measurement of inflammatory response to peritoneal deterioration

[0158] On the 16th day after the administration of the CG solution in Example 1(1), the angiogenesis and lymphangiogenesis related to the infiltration and water removal ability of macrophages, which are inflammatory cells, as indicators of peritoneal deterioration were studied. First, paraffin-embedded sections were prepared in the same manner as in Example 1(4).

[0159] Next, the paraffin-embedded sections were reacted with a primary antibody and then with a secondary antibody and HRP label (HRP Rb, manufactured by CellSignaling Technology, reagent number: 8114S, lot number: 21). As the primary antibody, CD68 antibody (Rt×Mo CD68, manufactured by Bio-Rad, reagent number: MCA1957, lot number: 1807-14) was used for macrophage staining, CD31 antibody (Rt×Mo CD31, manufactured by Merck, reagent number: CBL1337, lot number: 3123230) was used for vascular endothelial cell staining, and Lyve-1 antibody (Rb×Mo / Rt Lyve-1, manufactured by Acris, reagent number: DP3513P, lot number: 1410R24) was used for lymphatic vessel staining. After the above reaction, DAB (3,3'-Diaminobenzidine) was used as a chromogenic substrate for staining. After the above staining, hematoxylin was used for contrast staining. Then, the area of ​​CD68-positive macrophage aggregation, the area occupied by CD31-positive vascular endothelial cells, and the area occupied by Lyve-1-positive lymphatic endothelial cells were counted using the above optical microscope, and the proportion of each area in one field of view was calculated. These results are shown in Figures 6 to 11 .

[0160] Figure 6 This is a photograph showing the results of CD68 (macrophage marker) staining by immunohistochemical staining. Figure 7 is a graph showing the macrophage-positive area (%). Figure 6 and Figure 7 As shown in the figure, no macrophage infiltration was observed in the control group (control). On the other hand, the macrophage marker-positive area increased in the reference group (CG) compared with the control group. In contrast, the macrophage marker-positive area decreased in the embodiment group (CG+CO-UFB) compared with the reference group, as shown by the arrow.

[0161] then, Figure 8 This is a photograph showing the results of CD31 (vascular endothelial cell marker) staining by immunohistochemical staining. Fig. 9 is a graph showing the vascular endothelial cell positive area (%). Figure 8 and Fig. 9 As shown, the reference group (CG) showed an increase in the positive area of ​​vascular endothelial cell markers as shown by the arrow compared with the control group (control). In contrast, the example group (CG+CO-UFB) showed a tendency to decrease the positive area of ​​vascular endothelial cell markers as shown by the arrow compared with the reference group.

[0162] then, Fig.10 This is a photograph showing the results of Lyve-1 (lymphatic vessel marker) staining by immunohistochemical staining. Fig.11 It is a graph showing the results of lymphatic vessel-positive area (%). Fig.10 The gaps are where lymphangiogenesis occurs. Fig.10 and Fig.11 As shown in the figure, the reference group (CG) showed an increase in the lymphatic vessel marker-positive area as shown by the arrow compared with the control group (Control). In contrast, the example group (CG+CO-UFB) showed a decrease in the lymphatic vessel marker-positive area as shown by the arrow compared with the reference group.

[0163] From these results, it can be seen that by administering the composition of the present invention, i.e., CO-UFB, in the peritoneal deterioration model, the infiltration of macrophages among inflammatory cells is suppressed and the formation of blood vessels and lymphatic vessels is suppressed. As described above, the peritoneal function such as the dehydration ability in the peritoneal deterioration model is reduced, but when CO-UFB is administered, the decline in peritoneal function is suppressed. It is speculated that this is because CO-UFB suppresses inflammatory reactions such as macrophage infiltration and the decline in dehydration function caused by the formation of blood vessels and lymphatic vessels that occur in peritoneal deterioration.

[0164] (6) Measurement of gene expression of peritoneal degeneration

[0165] On the 16th day after the administration of the CG solution of Example 1 (1) above, the expression of genes related to angiogenesis, lymphangiogenesis and inflammation was studied. Specifically, the parietal peritoneum and diaphragm of mice in each group were collected, and total RNA was extracted from each membrane according to conventional methods. The obtained RNA and reverse transcriptase (High Capacity cDNA Reverse Transcription Kit, manufactured by Applied Biosystems) and PCR device (Thermal Cycler Dice, manufactured by Takara) were used to synthesize cDNA. Then, the above cDNA and the following primer set and RT-PCR reagent (RTB Green (trademark) Premix (trademark) Taq (trademark) II, manufactured by Takara) and real-time PCR measurement device (Quant Studio3, manufactured by Applied Biosystems) were used to measure the gene expression levels of VEGF-A (vascular endothelial growth factor), VEGF-C (lymphangiogenesis factor), PECAM-1 (vascular endothelial cell adhesion molecule), LYVE-1 (lymphatic endothelial cell marker), and IL-6 (inflammatory cytokine). In addition, GAPDH was used as an internal standard gene, and the expression level of each gene was calculated as a relative expression level relative to the expression level of the internal standard gene. These results are shown in Fig.12 .

[0166] VEGF-A Primer Set

[0167] Forward primer (SEQ ID NO: 1)

[0168] 5'-caggctgctgtaacgatgaa-3'

[0169] Reverse primer (SEQ ID NO: 2)

[0170] 5'-gctttggtgaggtttgatcc-3'

[0171] VEGF-C Primer Set

[0172] Forward primer (SEQ ID NO: 3)

[0173] 5'-cagacaagttcattcaattattagacg-3'

[0174] Reverse primer (SEQ ID NO: 4)

[0175] 5'-catgtcttgttagctgcctga-3'

[0176] ·PECAM-1 Primer Set

[0177] Forward primer (SEQ ID NO: 5)

[0178] 5'-cggtgttcagcgagatcc-3'

[0179] Reverse primer (SEQ ID NO: 6)

[0180] 5'-actcgacaggatggaaatcac-3'

[0181] LYVE-1 Primer Set

[0182] Forward primer (SEQ ID NO: 7)

[0183] 5'-gaagcagctgggtttggag-3'

[0184] Reverse primer (SEQ ID NO: 8)

[0185] 5'-cgtagcaaacagccagcac-3'

[0186] IL-6 Primer Set

[0187] Forward primer (SEQ ID NO: 9)

[0188] 5'-gctaccaaactggatataatcagga-3'

[0189] Reverse primer (SEQ ID NO: 10)

[0190] 5'-ccaggtagctatggtactccagaa-3'

[0191] · Primer set for internal standard gene (GAPDH)

[0192] Forward primer (SEQ ID NO: 11)

[0193] 5'-tgtgtccgtcgtggatctga-3'

[0194] Reverse primer (SEQ ID NO: 12)

[0195] 5'-ttgctgttgaagtcgcaggag-3'

[0196] Fig.12 It is a graph showing the expression level of each gene. Fig.12 In the figure, the horizontal axis represents the type of sample, and the vertical axis represents the expression level of each gene. Fig.12 As shown, the reference group (CG) showed an increase in the gene expression of vascular endothelial growth factor, lymphangiogenesis factor, vascular endothelial cell adhesion molecule, lymphatic endothelial cell marker, and inflammatory cytokine compared with the control group (control). In contrast, the example group (CG+CO-UFB) showed a decrease in the gene expression of vascular endothelial growth factor, lymphangiogenesis factor, vascular endothelial cell adhesion molecule, lymphatic endothelial cell marker, and inflammatory cytokine compared with the reference group.

[0197] From these results, it can be seen that the expression of vascular endothelial growth factor, lymphangiogenesis factor, vascular endothelial cell adhesion molecule, lymphatic endothelial cell marker and inflammatory cytokine, which are enhanced in the peritoneal deterioration model, is suppressed by administering the composition of the present invention, i.e., CO-UFB. As described above, the peritoneal function such as the water removal ability in the peritoneal deterioration model is reduced, and when CO-UFB is administered, the reduction in peritoneal function is suppressed. It is speculated that this is because CO-UFB suppresses the inflammatory response such as macrophage infiltration that occurs in peritoneal deterioration and the enhanced expression of genes related to the reduction in water removal function caused by angiogenesis and lymphangiogenesis.

[0198] [Example 2]

[0199] The composition of the present invention was produced and confirmed to be able to alleviate peritoneal deterioration.

[0200] (1) Preparation of composition

[0201] A composition containing CO in the form of microbubbles was prepared in the same manner as in Example 1(1) (composition of Example 2(1)). The average diameter of the microbubbles and the density of the microbubbles in the composition of Example 2(1) were measured in the same manner as in Example 1(1). The results are as follows.

[0202] (Composition of Example 2 (1) (CO-UFB))

[0203] Average diameter: 155.2nm, density: 1.03×10 8 Pieces / ml

[0204] In addition, a composition in which CO is dissolved in physiological saline (composition of Example 2 (2)) was produced according to the following steps. Specifically, physiological saline and the above-mentioned medical carbon monoxide were sealed in a syringe at a volume ratio of 1:1, and then shaken and mixed for 30 minutes to dissolve the above-mentioned CO in the above-mentioned physiological saline, thereby producing the composition of Example 2 (2). The carbon monoxide concentration in the composition of Example 2 (2) was measured, and the results are as follows.

[0205] (Composition of Example 2 (2) (CO-Dissolve))

[0206] Concentration: 839 μM

[0207] (2) Preparation of mice with peritoneal degeneration model

[0208] In the above Example 1(2), peritoneal degeneration model mice were prepared in the same manner except that the composition of the above Example 2(1) and the composition of the above Example 2(2) were administered instead of CO-UFB.

[0209] (3) Determination of peritoneal function

[0210] Next, the peritoneal function test was performed 2 days after the 7th administration (9th day after the start of CG solution administration). The peritoneal function test was performed in the same manner as in Example 1 (3) above, and the amount of water in the peritoneal cavity of each mouse (peritoneal water volume) was calculated. The negative control was performed in the same manner except that no treatment was performed, and the control was performed in the same manner except that physiological saline was used instead of the composition of Example 2 (1) above and the composition of Example 2 (2) above. These results are shown in Fig.13 It should be noted that in the figure, * indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.001, and **** indicates p < 0.0001.

[0211] Fig.13 is a graph showing the amount of peritoneal water. Fig.13In the figure, the horizontal axis represents the type of sample, and the vertical axis represents the amount of peritoneal water (mL). Fig.13 As shown, the water removal amount of the control was significantly reduced compared with the negative control. In contrast, the water removal amount of the group administered with the composition (CO-UFB+CG) of Example 2(1) and the group administered with the composition (CO-Dissolve+CG) of Example 2(2) was significantly reduced compared with the control, indicating that the decrease in water removal function caused by peritoneal deterioration was alleviated.

[0212] (4) Measurement of peritoneal thickening

[0213] Next, based on the 7th administration day, 2 days later (9th day after the start of CG solution administration), the thickness of the peritoneal surface was measured as an indicator of peritoneal deterioration. The measurement of the peritoneal surface thickness was carried out in the same manner as in Example 1 (4). The results are shown in Fig.14 .

[0214] Fig.14 It is a graph showing the thickness of the peritoneal surface (peritoneal thickness). Fig.14 In the graph, the horizontal axis represents the type of sample, and the vertical axis represents the thickness of the peritoneal surface. Fig.14 As shown, the control showed a significant increase in peritoneal thickness compared to the negative control. In contrast, the group administered with the composition (CO-UFB+CG) of Example 2(1) and the group administered with the composition (CO-Dissolve+CG) of Example 2(2) showed a significantly reduced increase in peritoneal thickness compared to the control, indicating that the peritoneal thickening that occurs during peritoneal deterioration can be reduced. In addition, a trend toward a further reduction in the increase in peritoneal thickness was observed in the group administered with the composition of Example 2(1) compared to the group administered with the composition of Example 2(2).

[0215] [Example 3]

[0216] The composition of the present invention was produced and confirmed to be able to prevent peritoneal deterioration.

[0217] (1) Preparation of composition

[0218] A composition containing CO in the form of microbubbles and a composition containing CO dissolved in physiological saline were prepared in the same manner as the composition of Example 1(1) and the composition of Example 2(1) (respectively, the composition of Example 3(1) and the composition of Example 3(2)). For the composition of Example 3(1), the average diameter of the microbubbles and the density of the microbubbles in the composition were measured in the same manner as in Example 1(1), and the results are as follows. In addition, for the composition of Example 3(2), the carbon monoxide concentration in the composition was measured, and the results are as follows.

[0219] (Composition of Example 3 (1) (CO-UFB))

[0220] Average diameter: 155.2nm, density: 1.03×10 8 Pieces / ml

[0221] (Composition of Example 3(2) (CO-Dissolve))

[0222] CO concentration: 755 μM

[0223] (2) Prevention of peritoneal deterioration

[0224] Whether the composition of the present invention can prevent peritoneal deterioration was studied by administering the composition of each example before administering CG. Specifically, first, 1.0 mL of the composition of Example 3 (1) or the composition of Example 3 (2) was intraperitoneally administered to the above-mentioned mouse. One hour after the above-mentioned administration, 300 μl of 0.1% CG solution was intraperitoneally administered to the above-mentioned mouse. Next, 6 hours after the administration of the CG solution, the parietal peritoneum and diaphragm of each mouse were collected. Then, except for using the above-mentioned parietal peritoneum and the above-mentioned diaphragm, the relative expression level of the IL-6 gene was calculated in the same manner as in Example 1 (6). The negative control was carried out in the same manner except that no treatment was performed, and the control was carried out in the same manner except that physiological saline was used instead of the composition of Example 3 (1) and the composition of Example 3 (2). The results are shown in Fig.15 .

[0225] Fig.15 It is a graph showing the expression level of IL-6 gene. Fig.15 In the figure, the horizontal axis represents the type of sample, and the vertical axis represents the expression level of IL-6 gene. Fig.15As shown, the expression level of IL-6 gene in the control was significantly increased compared with the negative control. In contrast, the expression level of IL-6 gene in the group administered with the composition (CO-UFB+CG) of Example 3(1) and the group administered with the composition (CO-Dissolve+CG) of Example 3(2) was significantly reduced compared with the control, indicating that the inflammation generated before peritoneal deterioration can be reduced. In addition, a trend of further reduction in the increase in the expression level of IL-6 gene was observed in the group administered with the composition of Example 3(1) compared with the group administered with the composition of Example 3(2).

[0226] [Example 4]

[0227] A dilution series of the composition of the present invention was prepared to examine the effect of CO concentration on mitigation of peritoneal deterioration.

[0228] (1) Preparation of composition

[0229] A composition containing CO in the form of microbubbles was prepared in the same manner as the composition of Example 1(1) above, and then, as the composition of Example 4(1), a stock solution, a 4-fold dilution, a 10-fold dilution, and a 50-fold dilution (CO-UFB, CO-UFB 1 / 4, CO-UFB 1 / 10, and CO-UFB 1 / 50, respectively) were prepared. In addition, a composition in which CO was dissolved in saline was prepared in the same manner as the composition of Example 2(2) above, and then, as the composition of Example 4(2), a stock solution, a 4-fold dilution, a 10-fold dilution, and a 50-fold dilution (CO-dis, CO-dis 1 / 4, CO-dis 1 / 10, and CO-dis1 / 50, respectively) were prepared.

[0230] (2) Preparation of mice with peritoneal degeneration model

[0231] In the above Example 1(2), a peritoneal deterioration model mouse was prepared in the same manner except that the composition of the above Example 4(1) or the composition of the above Example 4(2) was administered instead of CO-UFB.

[0232] (3) Determination of peritoneal function

[0233] Regarding the measurement of peritoneal function, the peritoneal equilibrium test (PET: Peritoneal Equilibration Test) was performed in the same manner as in Example 1 (3) above, except that the peritoneal function was measured on the 14th day from the start of administration, and the amount of water in the peritoneal cavity (peritoneal water volume) of each mouse was calculated. For the control (Saline), the same procedure was performed except that physiological saline was used instead of the composition of Example 4 (1) or the composition of Example 4 (2). These results are shown in Fig.16 (A) to (H) of FIG. 1 . It should be noted that * in the figure indicates p<0.05.

[0234] Fig.16 is a graph showing the amount of peritoneal water. Fig.16 In (A) to (H), the horizontal axis represents the type of sample and the vertical axis represents the peritoneal water volume (mL). Regarding the peritoneal water volume, which represents the permeability of the peritoneal membrane, the group that received the composition of the example showed a value higher than that of the control (Saline). In particular, the groups that received the composition of the example (CO-UFB, CO-UFB 1 / 4, CO-UFB 1 / 10, CO-UFB 1 / 50) showed significantly more peritoneal water volume than the control (Saline). In addition, the group that received the composition of Example 4 (2) showed significantly higher peritoneal water volume than the control (Saline). Fig.16 In (E) and (G) (CO-dis and CO-dis 1 / 10), the amount of peritoneal water was significantly higher than that in the control (Saline). Fig.16 In (F) and (H) (CO-dis 1 / 4 and CO-dis 1 / 50), the average value of peritoneal water volume was higher than that of the control (Saline). From these results, it can be seen that the composition of the present invention can reduce the decrease in water removal function caused by peritoneal deterioration even when the CO concentration is low.

[0235] The present invention has been described above with reference to the embodiments and examples, but the present invention is not limited to the above-described embodiments and examples. The configuration and details of the present invention can be modified in various ways that can be understood by those skilled in the art within the scope of the present invention.

[0236] <Appendix>

[0237] A part or all of the above-mentioned embodiments and examples are as described in the following supplementary notes, but are not limited to the following.

[0238] <Composition for inhibiting peritoneal deterioration>

[0239] (Appendix 1)

[0240] A composition for inhibiting peritoneal deterioration,

[0241] It contains carbon monoxide.

[0242] (Appendix 2)

[0243] The composition according to Appendix 1, comprising microbubbles,

[0244] The fine bubbles contain carbon monoxide as a gas component.

[0245] (Appendix 3)

[0246] The composition according to Appendix 2, wherein the density of the microbubbles is 5×10 5 ~5×10 12 Pieces / ml.

[0247] (Appendix 4)

[0248] The composition according to Appendix 2 or 3, wherein the proportion of the carbon monoxide in the gas component is 80% or more.

[0249] (Appendix 5)

[0250] The composition according to any one of Appendices 2 to 4, wherein the gas component is surrounded by an aqueous solvent in the fine bubbles.

[0251] (Appendix 6)

[0252] A composition according to any one of Appendixes 2 to 5, further comprising a medium,

[0253] The medium is at least one of a liquid and a solid.

[0254] (Appendix 7)

[0255] The composition according to Appendix 1, comprising a medium,

[0256] The carbon monoxide is dissolved in the medium.

[0257] (Appendix 8)

[0258] The composition according to Appendix 7, wherein the content of the carbon monoxide dissolved in the medium is 0.01 μmol / l to 5 mmol / l.

[0259] (Appendix 9)

[0260] The composition according to any one of Appendixes 1 to 8, wherein the peritoneal deterioration is peritoneal fibrosis.

[0261] (Appendix 10)

[0262] The composition according to any one of Appendixes 1 to 9, wherein the peritoneal deterioration is a decrease in peritoneal function.

[0263] (Appendix 11)

[0264] A composition according to any one of Appendices 1 to 10, for intraperitoneal administration.

[0265] <Peritoneal membrane deterioration inhibitory composition kit>

[0266] (Appendix 12)

[0267] A composition kit for inhibiting peritoneal deterioration,

[0268] The composition kit comprises a composition and other components,

[0269] The above composition is configured to be isolated from the above other components,

[0270] The above composition is any one of the compositions described in Appendices 1 to 11.

[0271] (Appendix 13)

[0272] The composition kit according to Appendix 12, further comprising a container,

[0273] The container has a plurality of chambers and a partition for isolating the chambers.

[0274] The plurality of chambers at least include a first chamber and a second chamber,

[0275] The above composition is contained in the above first chamber,

[0276] The other components are contained in the second chamber.

[0277] The isolation portion isolates the first chamber from the second chamber and enables the first chamber to communicate with the second chamber.

[0278] (Appendix 14)

[0279] The composition kit according to Appendix 12 or 13, wherein the other components include an osmotic pressure regulating substance.

[0280] <Peritoneal Dialysate>

[0281] (Appendix 15)

[0282] A peritoneal dialysis fluid comprising the composition described in any one of Appendices 1 to 11.

[0283] <Peritoneal dialysis fluid kit>

[0284] (Appendix 16)

[0285] A peritoneal dialysis fluid kit comprising a composition and a peritoneal dialysis fluid,

[0286] The above composition is configured to be isolated from the above peritoneal dialysis fluid,

[0287] The above composition is any one of the compositions described in Appendices 1 to 11.

[0288] (Appendix 17)

[0289] The peritoneal dialysis fluid kit according to Appendix 16, further comprising a container,

[0290] The container has a plurality of chambers and a partition for isolating the chambers.

[0291] The plurality of chambers at least include a first chamber and a second chamber,

[0292] The above composition is contained in the above first chamber,

[0293] The peritoneal dialysis fluid is stored in the second chamber.

[0294] The isolation portion isolates the first chamber from the second chamber and enables the first chamber to communicate with the second chamber.

[0295] <Composition for treating diseases caused by peritoneal dialysis or peritoneal deterioration>

[0296] (Appendix 18)

[0297] A pharmaceutical composition for treating a disease caused by peritoneal dialysis or peritoneal deterioration,

[0298] The pharmaceutical composition comprises carbon monoxide.

[0299] (Appendix 19)

[0300] The pharmaceutical composition according to Appendix 18, comprising microbubbles,

[0301] The fine bubbles contain carbon monoxide as a gas component.

[0302] (Appendix 20)

[0303] The pharmaceutical composition according to Appendix 19, wherein the density of the microbubbles is 5×10 5 ~5×10 12 Pieces / ml.

[0304] (Appendix 21)

[0305] The pharmaceutical composition according to Appendix 19 or 20, wherein the proportion of the carbon monoxide in the gas component is 80% or more.

[0306] (Appendix 22)

[0307] A pharmaceutical composition according to any one of Appendices 19 to 21, wherein, in the microbubbles, the gas component is surrounded by an aqueous solvent.

[0308] (Appendix 23)

[0309] A pharmaceutical composition according to any one of Appendix 19 to 22, further comprising a medium,

[0310] The medium is at least one of a liquid and a solid.

[0311] (Appendix 24)

[0312] The pharmaceutical composition according to Appendix 18, comprising a medium,

[0313] The carbon monoxide is dissolved in the medium.

[0314] (Appendix 25)

[0315] The pharmaceutical composition according to any one of Appendixes 19 to 24, wherein the disease caused by peritoneal dialysis is peritoneal fibrosis, peritonitis and / or encapsulating peritoneal sclerosis.

[0316] (Appendix 26)

[0317] A pharmaceutical composition according to any one of Appendices 19 to 25, which is for intraperitoneal administration.

[0318] <Composition kit for treating diseases caused by peritoneal dialysis or peritoneal deterioration>

[0319] (Appendix 27)

[0320] A pharmaceutical composition kit for treating a disease caused by peritoneal dialysis or peritoneal deterioration,

[0321] The pharmaceutical composition kit comprises a composition and other ingredients,

[0322] The above composition is configured to be isolated from the above other components,

[0323] The above composition is any one of the compositions described in Appendices 1 to 11.

[0324] (Appendix 28)

[0325] The pharmaceutical composition kit according to Appendix 27, further comprising a container,

[0326] The container has a plurality of chambers and a partition for isolating the chambers.

[0327] The plurality of chambers at least include a first chamber and a second chamber,

[0328] The above composition is contained in the above first chamber,

[0329] The other components are contained in the second chamber.

[0330] The isolation portion isolates the first chamber from the second chamber and enables the first chamber to communicate with the second chamber.

[0331] (Appendix 29)

[0332] The pharmaceutical composition kit according to Appendix 27 or 28, wherein the other components include an osmotic pressure regulating substance.

[0333] <Method for inhibiting peritoneal deterioration>

[0334] (Appendix 30)

[0335] A method for inhibiting peritoneal deterioration,

[0336] Use the composition described in any one of Appendices 1 to 11 or the composition kit described in any one of Appendices 12 to 14.

[0337] (Appendix 31)

[0338] The inhibition method according to Appendix 30, which includes the step of administering the above-mentioned composition or the above-mentioned composition kit to a subject.

[0339] (Appendix 32)

[0340] The inhibition method according to Appendix 31, wherein the drug is administered intraperitoneally.

[0341] (Appendix 33)

[0342] The inhibition method according to Appendix 31 or 32, wherein the subject is a subject scheduled to undergo peritoneal dialysis, a subject currently undergoing peritoneal dialysis, or a subject who has undergone peritoneal dialysis.

[0343] (Appendix 34)

[0344] The inhibition method according to any one of Appendices 30 to 33, wherein the composition or composition kit is used in vitro or in vivo.

[0345] (Appendix 35)

[0346] The inhibition method according to any one of Appendices 30 to 34, wherein the peritoneal deterioration is peritoneal fibrosis.

[0347] (Appendix 36)

[0348] The inhibition method according to any one of Appendices 30 to 35, wherein the peritoneal deterioration is a decrease in peritoneal function.

[0349] <Peritoneal dialysis method>

[0350] (Appendix 37)

[0351] A peritoneal dialysis method,

[0352] Use the peritoneal dialysis fluid described in Appendix 15 or the peritoneal dialysis fluid kit described in Appendix 16 or 17.

[0353] (Appendix 38)

[0354] The dialysis method according to Appendix 37, comprising:

[0355] A step of injecting the peritoneal dialysis fluid or a mixed solution of the peritoneal dialysis fluid kit into the peritoneal cavity of the subject;

[0356] a step of allowing the peritoneal dialysis solution or the mixed solution to remain; and

[0357] The step of draining the peritoneal dialysis fluid or the mixed fluid.

[0358] <Treatment methods for diseases caused by peritoneal dialysis or peritoneal deterioration>

[0359] (Appendix 39)

[0360] A method for treating a disease caused by peritoneal dialysis or peritoneal deterioration,

[0361] Use the pharmaceutical composition described in any one of Appendices 18 to 26 or the pharmaceutical composition kit described in any one of Appendices 27 to 29.

[0362] (Appendix 40)

[0363] The treatment method according to Appendix 39, which includes the step of administering the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical composition kit to a subject.

[0364] (Appendix 41)

[0365] The treatment method according to Appendix 40, wherein the administration is performed into the peritoneal cavity.

[0366] (Appendix 42)

[0367] The treatment method according to Appendix 40 or 41, wherein the subject is a subject scheduled to undergo peritoneal dialysis, a subject currently undergoing peritoneal dialysis, or a subject who has undergone peritoneal dialysis.

[0368] (Appendix 43)

[0369] The treatment method according to any one of Appendices 39 to 42, wherein the above-mentioned composition or composition kit is used in vitro or in vivo.

[0370] (Appendix 44)

[0371] The treatment method according to any one of Appendices 39 to 43, wherein the peritoneal deterioration is peritoneal fibrosis.

[0372] (Appendix 45)

[0373] The treatment method according to any one of Appendices 39 to 44, wherein the peritoneal deterioration is a decrease in peritoneal function.

[0374] (Appendix 46)

[0375] The treatment method according to any one of Appendices 39 to 45, wherein the disease caused by peritoneal dialysis is peritoneal fibrosis, peritonitis and / or encapsulating peritoneal sclerosis.

[0376] (Appendix 47)

[0377] A method of treatment according to any one of Appendices 39 to 46, wherein the treatment is prevention or inhibition.

[0378] <Application>

[0379] (Appendix 48)

[0380] A composition for inhibiting peritoneal deterioration,

[0381] The above composition comprises the composition described in any one of Appendices 1 to 11.

[0382] (Appendix 49)

[0383] A composition kit for inhibiting peritoneal deterioration,

[0384] The above-mentioned composition kit comprises a composition and other components,

[0385] The above composition is configured to be isolated from the above other components,

[0386] The above composition comprises the composition described in any one of Appendices 1 to 11.

[0387] (Appendix 50)

[0388] A composition for peritoneal dialysis,

[0389] The above composition comprises the composition described in any one of Appendices 1 to 11.

[0390] (Appendix 51)

[0391] A composition kit for peritoneal dialysis,

[0392] The above-mentioned composition kit comprises a composition and other components,

[0393] The above composition is configured to be isolated from the above other components,

[0394] The above composition comprises the composition described in any one of Appendices 1 to 11.

[0395] (Appendix 52)

[0396] A composition for treating a disease caused by peritoneal dialysis or peritoneal deterioration,

[0397] The above composition comprises the composition described in any one of Appendices 1 to 11.

[0398] (Appendix 53)

[0399] A composition kit for treating a disease caused by peritoneal dialysis or peritoneal deterioration,

[0400] The above-mentioned composition kit comprises a composition and other components,

[0401] The above composition is configured to be isolated from the above other components,

[0402] The above composition comprises the composition described in any one of Appendices 1 to 11.

[0403] Industrial Applicability

[0404] As described above, according to the present invention, peritoneal deterioration can be suppressed. Therefore, according to the present invention, for example, peritoneal deterioration caused by peritoneal dialysis can be suppressed and encapsulated peritoneal sclerosis caused by the above peritoneal deterioration can be prevented or suppressed. Therefore, the present invention can be preferably used to treat diseases caused by peritoneal deterioration, and is extremely useful in the medical field, the pharmaceutical field, and the like.

[0405] This application claims priority based on Japanese patent application No. 2022-100790 filed on June 23, 2022, the disclosure of which is incorporated herein in its entirety.

[0406] Description of Reference Numerals

[0407] 1 Room 1

[0408] 10 Container

[0409] 11 Composition

[0410] 12 Upper end

[0411] 13, 14 pieces

[0412] 2 Room 2

[0413] 21 Other ingredients

[0414] 22 Discharge section

[0415] 3 Isolation

[0416] 5. Hanging part

Claims

1. A composition for inhibiting peritoneal deterioration, comprising carbon monoxide.

2. The composition according to claim 1, wherein Contains tiny bubbles, The minute bubbles contain carbon monoxide as a gas component.

3. The composition according to claim 2, wherein The density of the microbubbles is 5×10 5 ~5×10 12 Pieces / ml.

4. The composition according to claim 2 or 3, wherein The carbon monoxide accounts for 80% or more of the gas components.

5. The composition according to claim 2 or 3, wherein In the microbubbles, the gas component is surrounded by an aqueous solvent.

6. The composition according to claim 2 or 3, wherein Also includes medium, The medium is at least one of a liquid and a solid.

7. The composition according to claim 1, wherein Contains media, The carbon monoxide is dissolved in the medium.

8. The composition according to claim 7, wherein The content of the carbon monoxide dissolved in the medium is 0.01 μmol / l to 5 mmol / l.

9. The composition according to any one of claims 1, 2, 7 or 8, wherein The peritoneal deterioration is peritoneal fibrosis.

10. The composition according to any one of claims 1, 2, 7 or 8, wherein The peritoneal deterioration refers to a decrease in peritoneal function.

11. The composition according to any one of claims 1, 2, 7 or 8, which is for intraperitoneal administration.

12. A composition kit for inhibiting peritoneal deterioration, comprising a composition and other components, The composition is configured to be isolated from the other components, The composition is the composition according to any one of claims 1, 2, 7 or 8.

13. The composition kit according to claim 12, wherein: Also includes a container, The container has a plurality of chambers and a partition that isolates the chambers. The plurality of chambers include at least a first chamber and a second chamber, The composition is contained in the first chamber, The other components are contained in the second chamber, The isolation portion isolates the first chamber from the second chamber and enables communication between the first chamber and the second chamber.

14. The composition kit according to claim 12, wherein: The other ingredients include an osmotic pressure regulating substance.

15. A peritoneal dialysis fluid comprising the composition of any one of claims 1, 2, 7 or 8.

16. A peritoneal dialysis fluid kit comprising a composition and a peritoneal dialysis fluid, The composition is configured to be isolated from the peritoneal dialysis fluid, The composition is the composition according to any one of claims 1, 2, 7 or 8.

17. The peritoneal dialysis fluid kit according to claim 16, wherein: Also includes a container, The container has a plurality of chambers and a partition that isolates the chambers. The plurality of chambers include at least a first chamber and a second chamber, The composition is contained in the first chamber, The peritoneal dialysis fluid is stored in the second chamber. The isolation portion isolates the first chamber from the second chamber and enables communication between the first chamber and the second chamber.

18. A pharmaceutical composition for preventing or inhibiting a disease resulting from peritoneal dialysis, comprising carbon monoxide.

19. A pharmaceutical composition kit for preventing or inhibiting diseases caused by peritoneal dialysis, comprising a composition and other ingredients, The composition is configured to be isolated from the other components, The composition is the composition according to any one of claims 1, 2, 7 or 8.

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