Pharmaceutical composition for peritoneal disorders

Abstract

Provided are: a novel pharmaceutical composition for peritoneal disorders or peritoneal fibrosis accompanied by peritoneal inflammation; and a novel peritoneal dialysis fluid.　The present invention provides a pharmaceutical composition for peritoneal disorders accompanied by peritoneal inflammation, the composition containing, for example, a peptide compound represented by a general formula (I) (SEQ ID NO:1) as an active ingredient. (In the formula, [Mod] represents a modifying group, [Lin] represents a linking group, and [Pep] represents a peptide chain having an amino acid sequence comprising one amino acid residue or 2-15 amino acid residues.　t, s, and m each independently represent 0 or 1.　Xa1 represents Val etc., Xa2 represents Gln etc., Xa3 represents Phe etc., Xa4 represents Gly etc., Xa5 represents Val etc., Xa6 represents Arg etc., Xa7 represents Ser etc., and Xa8 represents Tyr etc.　Bq represents -SH HS- or -S-S-.)

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the interests of Japanese application No. 2022-20346, filed with the Japan Patent Office on 14 February 2022. The said Japanese application is incorporated herein by reference for all purposes as if its application documents (specification, claims, drawings, abstract) were expressly provided herein. The present invention belongs to the technical field of pharmaceutical compositions containing peptide derivatives. In that technical field, the present invention relates to adrenomedullin (hereinafter also referred to as "AM") or its derivatives or analogs. More specifically, the present invention relates to a pharmaceutical composition for peritoneal disorders or peritoneal fibrosis containing adrenomedullin or the like as an active ingredient. [Background technology]

[0002] Adrenomedullin is a bioactive peptide isolated and identified from human pheochromocytoma in 1993 (Non-Patent Literature 1). Initially, adrenomedullin was found to exert a potent vasodilatory antihypertensive effect, but subsequent research has revealed that it also exhibits a variety of effects, including cardiovascular protective effects, anti-inflammatory effects, angiogenic effects, and tissue repair promoting effects. In particular, its usefulness as a treatment for inflammatory bowel disease, peripheral vascular disease, acute myocardial infarction, and COVID-19 pneumonia is being anticipated, and physician-initiated clinical trials targeting inflammatory bowel disease and COVID-19 pneumonia are currently underway.

[0003] Regarding inflammatory bowel disease treatments containing adremedullin analogs as active ingredients, for example, they are disclosed in Patent Documents 1 and 2. Patent Document 1 discloses that adremedullin analogs are useful as prophylactic or therapeutic agents for nonbacterial inflammatory diseases. Patent Document 2 discloses that adremedullin analogs are useful as prophylactic or therapeutic agents for steroid-resistant or steroid-dependent refractory inflammatory bowel diseases.

[0004] By the way, when kidney function deteriorates and chronic renal failure develops, a kidney transplant or dialysis becomes necessary. In Japan, the number of organ transplants is low, and it is common for people to undergo dialysis for the rest of their lives. There are two types of artificial dialysis: hemodialysis (HD) and peritoneal dialysis (PD). Hemodialysis involves drawing a large amount of blood out of the body and passing it through a device equipped with a special filter to remove waste products and excess fluid. Patients visit the hospital about three times a week for 4-5 hours each time, undergoing intensive dialysis. Because the dialysis is performed intensively, physiological changes occur rapidly, placing a significant burden on the circulatory system. Peritoneal dialysis, on the other hand, is a dialysis method that uses the patient's own peritoneum, a biological membrane, as the dialysis membrane. Through a catheter surgically inserted into the peritoneum, old dialysis fluid containing waste products from the blood is drained from the body, and new dialysis fluid is injected into the peritoneum to remove waste products and excess fluid from the blood. Continuous ambulatory peritoneal dialysis (CAPD) is performed several times a day for about 30 minutes each time, while automated peritoneal dialysis (APD) is performed at night while the patient sleeps. Since it is basically performed at home, there are fewer physiological changes and the burden on the circulatory system is relatively small. Therefore, peritoneal dialysis can be said to be superior in terms of quality of life (QOL). [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2006-290777 [Patent Document 2] International Publication No. 2012 / 096411 Pamphlet [Non-patent literature]

[0006] [Non-Patent Document 1] Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun, April 30, 1993, Volume 192(2), pp. 553-560 [Overview of the project] [Problems that the invention aims to solve]

[0007] Peritoneal dialysis (PD) is an excellent renal replacement therapy that can be administered at home, with fewer impacts on hemodialysis (HD) and fewer time constraints. However, long-term use of peritoneal dialysis can lead to deterioration of the peritoneum used as the dialysis membrane, and in some cases, the development of peritonitis may necessitate discontinuing peritoneal dialysis. Fungal peritonitis, in particular, is difficult to treat, has a high mortality rate, and a poor prognosis. It has also been suggested to be associated with encapsulating peritoneal sclerosis (EPS), a fatal complication of peritoneal dialysis. Despite the importance of preventing peritoneal deterioration for long-term healthy peritoneal dialysis, the detailed mechanisms are not yet clear, and effective preventive and therapeutic methods have not been established. The present invention aims to provide novel pharmaceutical compositions and novel peritoneal dialysis solutions for peritoneal disorders or peritoneal fibrosis, particularly those involving inflammation of the peritoneum, including peritonitis. [Means for solving the problem]

[0008] As a result of diligent research, the inventors of this invention discovered that administering adrenomedullin or its analogs to animal models of peritonitis and peritoneal fibrosis, which are complications of peritoneal dialysis, can significantly suppress peritonitis, peritoneal fibrosis, and adhesions, thus completing the present invention.

[0009] Examples of the present invention include the following: A pharmaceutical composition for peritoneal disorders or peritoneal fibrosis accompanied by peritoneal inflammation, which contains, as an active ingredient, a peptide compound represented by the following general formula (I) (SEQ ID NO: 1) (hereinafter also referred to as "compound (I)") or a pharmaceutically acceptable salt thereof.

[0010]

Chemical formula

[0011] In the formula, [Mod] represents a modifying group, [Lin] represents a linking group, and [Pep] represents a peptide chain having one amino acid residue or an amino acid sequence consisting of 2 to 15 amino acid residues, respectively. t, s, and m each independently represent 0 or 1. Xa1 is Val (valine residue), Met (methionine residue), or Phe (phenylalanine residue), Xa2 is Gln (glutamine residue) or His (histidine residue), Xa3 is Phe (phenylalanine residue) or Leu (leucine residue), Xa4 is Gly (glycine residue) or Asn (asparagine residue), Xa5 is Val (valine residue), Ser (serine residue), or Met (methionine residue), Xa6 is Arg (arginine residue), D-Arg (D-type arginine residue), Lys (lysine residue), or Ala (alanine residue), Xa7 is Ser (serine residue) or Asn (asparagine residue), and Xa8 is Tyr (tyrosine residue), Tyr-NH2 (tyrosine residue-NH2), or Tyr-Gly (tyrosine residue-glycine residue), respectively. Bq represents -SH HS- or -S-S-. [2] The pharmaceutical composition according to [1] above, wherein the modifying group [Mod] in the compound (I) is selected from the group consisting of a C4-C 30 alkyl group, a C4-C 30 alkenyl group, or an organic group containing a polyethylene glycol group, the Fc region of an immunoglobulin, and serum albumin. [3] The pharmaceutical composition according to [1] or [2] above, wherein s in the compound (I) is 1, the modifying group [Mod] in the compound (I) is an organic group containing a polyethylene glycol group, and the linking group [Lin] in the compound (I) is a divalent linking group represented by the following general formula (a).

[0012]

Chemical formula

[0013] In the formula, q and u are the same or different and each represents an integer from 0 to 6. r, s, and t are the same or different and each represents an integer of 0 or 1. [4] The pharmaceutical composition according to any one of [1] to [3] above, wherein the organic group containing a polyethylene glycol group is any one of the following structural formulas (α), (β), and (γ).

[0014]

Chemical formula

[0015] [5] The pharmaceutical composition according to any one of [1] to [4] above, wherein the peritoneal disorder accompanied by peritoneal inflammation is peritonitis, acute peritonitis, chronic peritonitis, fungal peritonitis, bacterial peritonitis, or aseptic peritonitis. [6] The pharmaceutical composition for peritoneal disorder accompanied by peritoneal inflammation or peritoneal fibrosis according to any one of [1] to [5] above, for administration to peritoneal dialysis patients. [7] A peritoneal dialysis solution containing the compound (I) or a pharmaceutically acceptable salt thereof. [8] A first solution containing the compound (I) or a pharmaceutically acceptable salt thereof at a concentration in the range of 1 μg / L to 6 mg / L and a pH adjuster, with a pH in the range of 2.5 to 3.5, and a second solution containing a compound capable of releasing sodium ions, wherein the pH after mixing the first solution and the second solution is in the range of 6.0 to 7.5. The peritoneal dialysis solution according to [7] above.

[0016] [9] A composition for adding to peritoneal dialysis fluid, comprising the compound (I).

[10] A kit for preparing peritoneal dialysis fluid, comprising the composition described in [9] above and a diluent.

[11] The pharmaceutical composition according to any one of the above [1] to [6], wherein in compound (I), t is 0, s is 0, m is 1, and [Pep] is a peptide chain or amino acid residue having the amino acid sequence shown in the following formula (II), the peritoneal dialysis solution according to the above [7] or [8], the peritoneal dialysis solution additive composition according to the above [9], or the peritoneal dialysis solution preparation kit according to the above

[10] .

[0017] [ka]

[0018] In the formula, Xb1 represents Met (methionine residue) or Leu (leucine residue), Xb2 represents Leu (leucine residue), Pro (proline residue), or Ser (serine residue), and Xb3 represents Phe (phenylalanine residue) or Asn (asparagine residue). Each of m1 through m15 is independent; at least one of them is 1, and the others that are not 1 are 0. [Effects of the Invention]

[0019] According to the present invention, for example, it is possible to prevent or improve peritoneal disorders accompanied by inflammation of the peritoneum, such as peritonitis, and to suppress peritoneal fibrosis and adhesions. [Brief explanation of the drawing]

[0020] [Figure 1] The administration scheme is shown. The numbers represent days. The arrow labeled "MGO" indicates the day methylglyoxal is administered, the arrow labeled "PD fluid with Zymosan" indicates the day peritoneal dialysis fluid is administered, and the arrow labeled "Adrenomedullin or vehicle" indicates the day adrenomedullin or vehicle is administered. [Figure 2]These are anatomical photographs (gross visual evaluation results) of the rat peritoneum after administration. The two images on the left show the results for the adremedullin-administered group, and the two images on the right show the results for the non-adrenomedullin-administered group. [Figure 3] This graph shows the histological evaluation results of peritoneal thickness. The left graph shows the results for the lateral wall, and the right graph shows the results for the visceral wall. In each graph, the left side shows the results for the adremedullin group, and the right side shows the results for the non-adrenomedullin group. The vertical axis represents thickness (μm). [Figure 4] This graph shows the histological evaluation results of peritoneal thickness. The left graph shows the results for the lateral wall, and the right graph shows the results for the visceral wall. In each graph, the left side shows the results for the non-adrenomedullin administration group, the middle shows the results for the adremedullin administration group, and the right side shows the results for the non-adrenomedullin administration group (800 ng / kg / day). The vertical axis represents thickness (μm). [Figure 5] The results of C3 staining (left) and C5b9 staining (right) are shown. In each result, the two figures below are stained photographs. Furthermore, in each result, the left graph shows the results in the lateral wall, and the right graph shows the results in the visceral wall. In each graph, the left side shows the results for the adremedullin-treated group, and the right side shows the results for the non-adrenomedullin-treated group. The vertical axis of each graph shows the expression level (unit, score). [Figure 6] The results of CD68 staining (top left), esterase staining (top right), inducible nitric oxide synthase staining (bottom left), and CD163 staining (bottom right) are shown. In each result, the right-hand figure is the stained photograph. Furthermore, in each result, the left graph shows the results in the lateral wall, and the right graph shows the results in the visceral wall. In each graph, the left side shows the results for the adremedullin-treated group, and the right side shows the results for the non-adrenomedullin-treated group. The vertical axis of each graph shows the expression level (unit, score). [Figure 7]This graph shows the histological evaluation results of peritoneal thickness. The left graph shows the results for the lateral wall, and the right graph shows the results for the visceral wall. In each graph, the left side shows the results for the non-adrenomedullin administration group, and the right side shows the results for the adrenomedullin analog administration group. The vertical axis represents thickness (μm). [Modes for carrying out the invention]

[0021] The present invention will be described in detail below. Furthermore, matters other than those specifically mentioned herein (e.g., the primary structure and chain length of peptides) that are necessary for carrying out the present invention (e.g., general matters such as peptide synthesis, cell culture techniques, and the preparation of drug compositions containing peptides) can be understood as design matters for those skilled in the art based on prior art in fields such as cell engineering, medicine, pharmacy, organic chemistry, biochemistry, genetic engineering, protein engineering, molecular biology, and hygiene. The present invention can be carried out based on the contents disclosed herein and common technical knowledge in the art. In the following description, amino acids will be represented, as appropriate, by one-letter or three-letter notation in accordance with the amino acid nomenclature shown in the IUPAC-IUB guidelines. In amino acid sequences described herein, the left side is always the N-terminus and the right side is always the C-terminus.

[0022] Furthermore, "peptide" refers to an amino acid polymer having multiple peptide bonds. Unless otherwise specified, "amino acid residue" refers to each amino acid (-NH-C(R)(H)-CO-) contained in a peptide chain, and is a term that includes the N-terminal and C-terminal amino acids of the peptide chain. Unless otherwise specified, it refers to an L-type amino acid residue, but a D-type amino acid residue may also be used as long as it does not impair the effects of the present invention. All content of all references cited herein is incorporated herein by reference.

[0023] 1. Pharmaceutical composition according to the present invention The pharmaceutical composition for peritoneal disorders accompanied by peritoneal inflammation or for peritoneal fibrosis according to the present invention (hereinafter referred to as "the present invention composition") is characterized by containing a peptide compound represented by the following general formula (I) (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0024] [ka]

[0025] In the formula, [Mod], [Lin], [Pep], t, s, m, Xa1~Xa8, and Bq are equivalent to those defined above. A specific example of [Pep] is a peptide chain having the amino acid sequence shown in formula (II) below.

[0026] [ka]

[0027] In the formula, Xb1 to Xb3 and m1 to m15 are equivalent to those described above. Here, as described above, m1 to m15 are independent of each other; one of them is 1, and the others are 0. A "1" means that there is one amino acid residue in question, and a "0" means that there is no amino acid residue in question.

[0028] 1.1 About Compound (I) Compound (I) includes adrenomedullin (AM) and its derivatives or analogues. In compound (I), the compound with t=0 and s=0 is a peptide compound having the amino acid sequence of adrenomedullin (AM), or an adrenomedullin-like peptide compound (AM analogue) having physiological activity equivalent to that of adrenomedullin.

[0029] In compound (I), t=0, s=0, and m=1, and [Pep] is the peptide chain represented by formula (II), and m1~m 15If = 1, Bq is -SH HS-, and Xa1~Xa8 and Xb1~Xb3 are combinations shown in column (A1) of Table 1 below, then compound (I) is a peptide compound having the amino acid sequence of human adrenomedullin (SEQ ID NO: 2).

[0030] In compound (I), t=0, s=0, and m=1, and [Pep] is the peptide chain represented by formula (II), and m1~m 15 If = 1, Bq is -SH HS-, and Xa1~Xa8 and Xb1~Xb3 are combinations shown in column (B) of Table 1 below, then compound (I) is a peptide compound having the amino acid sequence of porcine adrenomedullin (SEQ ID NO: 3).

[0031] In compound (I), t=0, s=0, and m=1, and [Pep] is the peptide chain represented by formula (II), and m1~m 15 If = 1, Bq is -SH HS-, and Xa1~Xa8 and Xb1~Xb3 are combinations shown in column (C) of Table 1 below, then compound (I) is a peptide compound having the amino acid sequence of canine adrenomedullin (SEQ ID NO: 4).

[0032] In equation (I), t=0, s=0, and m=1, and [Pep] is the peptide chain shown in equation (II), and m1~m 15 If = 1, Bq is -SH HS-, and Xa1~Xa8 and Xb1~Xb3 are combinations shown in column (D) of Table 1 below, then compound (I) is a peptide compound having the amino acid sequence of bovine adrenomedullin (SEQ ID NO: 5).

[0033] In compound (I), t=0, s=0, m=1, and [Pep] is the peptide chain represented by formula (II), with m1~m6=1 、 m7, m8 = 0, m9 ~ m 15When t = 1, Bq is -SH HS-, and Xa1 to Xa8 and Xb1 to Xb3 are the combinations shown in column (E) of Table 1 below, compound (I) is a peptide compound having the amino acid sequence of rat adrenomedullin (SEQ ID NO: 6).

[0034] In compound (I), t = 0, s = 0, m = 1, [Pep] is a peptide chain represented by formula (II), and m1 to m6 = 1 、 m7, m8 = 0, m9 to m 15 When t = 1, Bq is -SH HS-, and Xa1 to Xa8 and Xb1 to Xb3 are the combinations shown in column (F) of Table 1 below, compound (I) is a peptide compound having the amino acid sequence of mouse adrenomedullin (SEQ ID NO: 7).

[0035] Peptide compounds having the amino acid sequence of human-derived adrenomedullin and peptide compounds having the amino acid sequence of non-human-derived adrenomedullin are collectively referred to as "adrenomedullin".

[0036] Natural adrenomedullin purified from human pheochromocytoma and binding to a specific receptor on the platelet membrane to induce an increase in intracellular cAMP has one intramolecular disulfide bond, and the C-terminal Tyr is amidated. In compound (I), t = 0, s = 0, m = 1, and m1 to m 15 When t = 1, Bq is -S-S-, and Xa1 to Xa8 and Xb1 to Xb3 are the combinations shown in column (A2) of Table 1 below, compound (I) is native human adrenomedullin (SEQ ID NO: 8).

[0037] In compound (I), the two cysteine residues easily form a disulfide bond under oxidizing conditions. When the mercapto group (-SH) exists in the free state in the two cysteine residues, in general formula (I), Bq is -SH HS-, and when a disulfide bond is formed, Bq is -S-S-.

[0038] In compound (I), if Xa8 is Tyr-Gly, Xa8 is converted to Tyr-NH2 by the action of the C-terminal amidase. For example, in compound (I), t=0, s=0, m=1, and m1~m 15 Peptide compounds (SEQ ID NOs: 9, 10) where = 1, Bq is -SH HS- or -SS-, and Xa1~Xa8 and Xb1~Xb3 are combinations shown in column (A3) of Table 1 below are converted to native human adrenomedullin (SEQ ID NO: 8) in environments where C-terminal amidases are present, such as in vivo.

[0039] [Table 1]

[0040] Natural human adrenomedullin has the structure shown in formula 7 below. Hereafter, natural human adrenomedullin will also be referred to as "hAM(1-52)" (Sequence ID 8).

[0041] [ka]

[0042] Adrenomedullin is known to have a site at positions 16-52 that binds to a receptor and leads to an increase in intercellular cAMP (Satoru Eguchi et al., Structure-Activity Relationship of Adrenomedullin, a Novel Vasodilatory Peptide, in Cultured Rat Vascular Smooth Muscle Cells, The Endocrine Society 1994 Vol. 135 No.6 p2454-2458, etc.). Therefore, peptide compounds in compound (I) with t=0, s=0, and m=0 are thought to have pharmacological activity similar to that of adrenomedullin.

[0043] AM or AM analogues can be extracted and purified from cell tissues by known and conventional methods, or produced using conventional peptide synthesizers. For example, they can be produced according to the method described in Adrenomedullin: A Novel Hypotensive Peptide Isolated From Human Pheochromocytoma (Kazuo Kitamura et, al. Biochemical and Biophysical Research Communications 1993 Vol.192 No.2 P553-560). They can also be produced according to the descriptions in the international publications listed below.

[0044] Examples of AM analogs include the adrenomedullin analogs disclosed in the specification of International Publication No. 2021 / 201271, etc. Specifically, in compound (I), t=0, s=0, m=1, and m1~m 12 =0, m 13 ~m 15 Examples of peptide compounds where = 1, Bq is -SH HS- (SEQ ID NOs. 11, 13, 15) or -SS- (SEQ ID NOs. 12, 14, 16), and Xa1-Xa8 and Xb3 are combinations shown in Table 2 below.

[0045] [Table 2]

[0046] These AM analogs maintain a similar level of physiological activity as AM, but are more stable in serum and have higher bioavailability when administered subcutaneously.

[0047] The biological half-life of AM or AM analogues can be extended by conferring appropriate modifying groups. The peptide compound with t=1 in compound (I) has a modifying group attached to the N-terminal α-amino group of AM or AM analogue, either via a linking group or not. Hereinafter, the compound with t=1 in compound (I) may be referred to as an "AM derivative".

[0048] AM derivatives, in which a modifying group is attached to the N-terminal α-amino group of AM or an AM analogue with or without a linking group, exhibit physiological activity equivalent to AM or AM analogues, and have a longer plasma half-life compared to AM or AM analogues.

[0049] In compound (I), the modifying group Mod is C4-C 30 Alkyl alkyl group, C4-C 30 Alkenyl group, C4-C 30 The modifying group may be selected from the group consisting of an organic group containing an alkanoyl group or polyethylene glycol (PEG) group, the Fc region of immunoglobulin, and serum albumin. Alternatively, it may be a modifying group selected from the group consisting of a sugar group such as a monovalent group derived from monosaccharides, disaccharides, oligosaccharides, or polysaccharides (e.g., a glycosyl group); and a peptide group such as a monovalent group derived from polyglycine, polyglutamic acid, polylysine, or polyasparagine (e.g., a monovalent group that forms a bond via an N-terminal amino group, a C-terminal carboxyl group, or a side chain group).

[0050] Said C4-C 30 Alkyl alkyl groups are linear or branched alkyl groups having 4 to 30 carbon atoms. Preferably, they have 14 to 22 carbon atoms (C 14 -C 22 ) is a linear or branched alkyl group. Examples of such alkyl groups include butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, myristyl, pentadecyl, palmityl, stearyl, isostearyl, and eicosyl.

[0051] Said C4-C 30 The alkenyl group is a linear or branched alkenyl group having 4 to 30 carbon atoms. Preferably, it has 14 to 22 carbon atoms (C 14 -C 22) are linear or branched alkenyl groups. Specifically, examples of such alkenyl groups include butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, palmitrail, elaidyl, oleyl, linoleyl, and elusyl. Furthermore, the organic group in question is a C4-C group such as butanoyl group, palmitoyl group, stearoyl group, myristoyl group, and oleoyl group. 30 It may also be an organic group containing an alkanoyl group.

[0052] If the modifying group Mod is an organic group containing a polyethylene glycol group, the linking group Lin may be a divalent linking group represented by the following general formula (a).

[0053] [ka]

[0054] [In the formula, q and u represent integers from 0 to 6, either identical or distinct. r, s, and t represent integers of 0 or 1, either identical or distinct.]

[0055] The organic group containing polyethylene glycol (PEG) groups contains one or more PEG groups. The configuration of the organic group containing one or more PEG groups is not particularly limited. For example, one or more PEG groups may be located at the terminal end of the organic group containing PEG groups, or they may be located inside the organic group containing PEG groups. The organic group containing PEG groups usually has a weight-average molecular weight in the range of 1 to 2000 kDa, for example, in the range of 1 to 1000 kDa, preferably in the range of 1 to 100 kDa, more preferably in the range of 5 to 80 kDa, even more preferably in the range of 10 to 80 kDa, and particularly preferably in the range of 20 to 80 kDa or 30 to 60 kDa.

[0056] In one embodiment, the organic group containing the PEG group has a structure represented by any of the following formulas (α) to (γ).

[0057] [ka]

[0058] In addition to the foregoing, the organic group containing the PEG group may be any group known in the art as a linear or branched group containing the PEG group. Known groups that can be used as an organic group containing the PEG group include, but are not limited to, the groups disclosed in International Publication No. 1995 / 11924, International Publication No. 2006 / 084089, International Publication No. 98 / 41562, International Publication No. 2005 / 079838, International Publication No. 2002 / 060978, International Publication No. 2001 / 048052, International Publication No. 1998 / 055500, International Publication No. 1996 / 021469, International Publication No. 2003 / 040211, and Japanese Patent Publication No. 04-108827, etc.

[0059] In one embodiment, in general formula (a), u may be an integer 0. In this case, the combination of q~t may be such that q is an integer from 0 to 6, s and r are integers of 0 or 1, t is an integer 0, and u is an integer 0. Alternatively, q may be an integer from 1 to 6, r, t and u may be integers 0, and s may be an integer 1. Specific examples of compound (I) in which an organic group containing a polyethylene glycol group is bonded via such a linking group are amide-linked, long-acting adrenomedullin derivatives disclosed in the specification of International Publication No. 2015 / 141819, etc.

[0060] In one embodiment, in general formula (a), u may be an integer from 1 to 6. In this case, the combination of q to u may be such that q and u are the same or different integers from 1 to 6, and r, s, and t are the same or different integers from 0 or 1. Alternatively, in general formula (a), the combination of q to u may be such that q is an integer 0, u is an integer from 1 to 6, and r, s, and t are integers 1. Specific examples of compounds (I) in which an organic group containing a polyethylene glycol group is bonded via such a linking group are alkylamine-linked, long-acting adrenomedullin derivatives disclosed in the specification of International Publication No. 2017 / 047788, etc.

[0061] In one embodiment, in general formula (a), q may be an integer between 0 and 6, r and s may be integers of 1, and t and u may be integers of 0. A specific example of compound (I) in which an organic group containing a polyethylene glycol group is bonded via such a linking group is a urethane-linked, long-acting adrenomedullin derivative disclosed in the specification of International Publication No. 2017 / 047788, etc.

[0062] In compound (I), if the modifying group Mod is the Fc region of an immunoglobulin, the linking group Lin may be a linking group consisting of a peptide having any amino acid sequence. The modifying group Mod is preferably the Fc region of immunoglobulin G1 (IgG1) or the Fc region of immunoglobulin G4 (IgG4). In compound (I), the mammal from which the immunoglobulin Fc region used as the modifying group Mod originates can be appropriately selected based on the target to which the pharmaceuticals, etc. of this embodiment are applied, as described below. The modifying group Mod is preferably the Fc region of an immunoglobulin derived from a human or non-human mammal (for example, a warm-blooded animal such as a pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, baboon, or chimpanzee), and more preferably the Fc region of an immunoglobulin derived from the same human or non-human mammal as the target to which the pharmaceuticals, etc. of this embodiment are applied.

[0063] A linking group Lin consisting of a peptide having any amino acid sequence is, for example, a linking group having the following amino acid sequences, where n is the number of repetitions: (GGGS)n (SEQ ID NO: 17) (n is an integer in the range of 2 to 10, preferably an integer in the range of 4 to 6), (GGGGS)n (SEQ ID NO: 18) (n is an integer in the range of 2 to 6, preferably 3), (GGGS)n + GGGK (SEQ ID NOs: 17 and 19) (n is an integer in the range of 1 to 9, preferably an integer in the range of 2 to 6), or (GGGGS)n + GGGGK (SEQ ID NOs: 18 and 20) (n is an integer in the range of 1 to 6, preferably an integer in the range of 2 to 5). In one embodiment, the linking group Lin consisting of a peptide is as follows:

[0064] GGGGSGGGGSGGGGS (Sequence No. 21); or GGGGSGGGGSGGGGK(Sequence 22);

[0065] The linking group may consist of a peptide having the amino acid sequence. Compound (I) of this embodiment has the structure of a protein or polypeptide as a whole. Specific examples of compounds in which the modifying group is an Fc region and the linking group is a peptide linking group include the immunoglobulin Fc region-linked, long-acting adrenomedullin derivatives disclosed in the specification of International Publication No. 2018 / 181638, etc.

[0066] A specific example of compound (I) in which the modifying group Mod is serum albumin is the serum albumin-conjugated, long-acting adrenomedullin derivative disclosed in the specification of PCT / JP2021 / 29112 prior to publication.

[0067] Compound (I) may be a salt with a pharmaceutically acceptable counterion. Such a counterion is not particularly limited as long as it is a pharmaceutically acceptable ion, but examples include sodium ions, potassium ions, calcium ions, magnesium ions, or cations such as substituted or unsubstituted ammonium ions, and chloride ions, bromide ions, iodide ions, phosphate ions, nitrate ions, sulfate ions, carbonate ions, bicarbonate ions, perchlorate ions, formate ions, acetate ions, trifluoroacetate ions, propionate ions, lactate ions, maleate ions, hydroxymaleate ions, methylmaleate ions, fumarate ions, adipicate ions, benzoate ions, 2-acetoxybenzoate ions, and p-aminobenzoic acid ions. Examples of anions include ions, nicotinate ions, cinnamate ions, ascorbic acid ions, pamoate ions, succinate ions, salicylate ions, bismethylenesalicylate ions, oxalate ions, tartrate ions, malate ions, citrate ions, gluconate ions, aspartate ions, stearate ions, palmitate ions, itaconic acid ions, glycolate ions, glutamate ions, benzenesulfonate ions, cyclohexylsulfamate ions, methanesulfonate ions, ethanesulfonate ions, isethionate ions, benzenesulfonate ions, p-toluenesulfonate ions, or naphthalenesulfonate ions. Among these, acetate ions and citrate ions are preferred.

[0068] Compound (I) and its pharmaceutically acceptable salts may also be in the form of solvates. The solvent in such solvates is not particularly limited as long as it is pharmaceutically acceptable, but examples include water and organic solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol), dimethyl sulfoxide (DMSO), acetic acid, ethanolamine, acetonitrile, or ethyl acetate. Compound (I), its pharmaceutically acceptable salts, and solvates are collectively referred to below as "Compound (I), etc."

[0069] Compound (I), etc., may also have protecting groups introduced to one or more of its functional groups (e.g., amino groups on the side chains of lysine residues). Such “protecting groups” are groups introduced to specific functional groups to prevent the progress of undesirable reactions, and are quantitatively removed under specific reaction conditions and are substantially stable, i.e., reaction-inactive, under other reaction conditions. The protecting group is not particularly limited as long as it can perform that role, but examples include t-butoxycarbonyl (Boc), 2-bromobenzyloxycarbonyl (BrZ), 9-fluorenylmethoxycarbonyl (Fmoc), p-toluenesulfonyl (Tos), benzyl (Bzl), 4-methylbenzyl (4-MeBzl), 2-chlorobenzyloxycarbonyl (ClZ), cyclohexyl (cHex), and phenacyl (Pac); other protecting groups for the amino group include benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzhydryloxycarbonyl, 2-(p-biphenyl)isopropyloxycarbonyl, 2-(3,5-dimethoxyphenyl)isopropyloxycarbonyl, p-phenylazobenzyloxycarbonyl, and triphe Nylphosphonoethyloxycarbonyl, 9-Fluorenylmethyloxycarbonyl, t-Amyloxyoxycarbonyl, Diisopropylmethyloxycarbonyl, Isopropyloxycarbonyl, Ethyloxycarbonyl, Allyloxycarbonyl, 2-Methylsulfonylethyloxycarbonyl, 2,2,2-Trichloroethyloxycarbonyl, Cyclopentyloxycarbonyl, Cyclohexyloxycarbonyl, Adamantyloxycarbonyl, Isobornyloxycarbonyl, Benzesulfonyl, Mesitylenesulfonyl, Methoxytrimethylphenylsulfonyl, 2-Nitrobenzenesulfonyl, 2-Nitrobenzenesulfenyl, 4-Nitrobenzenesulfonyl, and 4-Nitrobenzenesulfenyl; Other protecting groups for the carboxyl group: Methyl esters, ethyl esters, t-butyl esters, p-methoxybenzyl esters, and p-nitrobenzyl esters;Other protecting groups for Arg include 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, and 2-methoxybenzenesulfonyl; other protecting groups for Tyr include 2,6-dichlorobenzyl, t-butyl, and cyclohexyl; other protecting groups for Cys include 4-methoxybenzyl, t-butyl, trityl, acetamidomethyl, and 3-nitro-2-pyridinesulfenyl; other protecting groups for His include benzyloxymethyl, p-methoxybenzyloxymethyl, t-butoxymethyl, trityl, and 2,4-dinitrophenyl; and other protecting groups for Ser and Thr include t-butyl, etc.

[0070] Furthermore, compound (I), etc., also includes individual enantiomers and diastereomers of the compound, as well as mixtures of stereoisomers of the compound, such as racemates.

[0071] 1.2 Regarding Uses In the present invention, "for peritoneal disorders" refers to the use of the composition for the treatment or prevention of peritoneal disorders. "For peritoneal fibrosis" refers to the use of the composition for the treatment or prevention of peritoneal fibrosis. The composition of the present invention is useful for the treatment or prevention of peritoneal disorders or peritoneal fibrosis accompanied by inflammation of the peritoneum. Therefore, the composition of the present invention can be used for the prevention or treatment of subjects exhibiting or at risk of exhibiting inflammation of the peritoneum or peritoneal fibrosis. Such subjects may include humans or non-human mammals (for example, warm-blooded animals such as pigs, dogs, cattle, rats, mice, guinea pigs, rabbits, chickens, sheep, cats, monkeys, baboons, or chimpanzees). It is preferable that the subject is a human patient. Here, "accompanied by inflammation of the peritoneum" refers to a condition in which inflammation develops or occurs concurrently in the peritoneum. This inflammation includes both acute and chronic inflammation. In particular, the composition of the present invention can be preferably applied in the treatment or prevention of peritoneal disorders or peritoneal fibrosis accompanied by acute inflammation of the peritoneum.

[0072] Diseases that can present with inflammatory conditions of the peritoneum (peritoneal disorders) include, for example, peritonitis (bacterial peritonitis, fungal peritonitis, cancerous peritonitis, etc.), as well as ileus (adhesive ileus, etc.), gastrointestinal ulcers, appendicitis, and female reproductive organ diseases. Multiple of these diseases may occur concurrently or as complications.

[0073] The peritoneum is a membrane that covers the outer and inner walls of abdominal organs such as the liver, stomach, small intestine, and large intestine, as well as the diaphragm and pelvic floor. The peritoneum is normally sterile, but inflammation of the peritoneum for any reason is called peritonitis. Causes include, for example, irritation from gastrointestinal perforation, bacterial or fungal infection, and viral infection. Peritonitis caused by bacterial infection is called bacterial peritonitis, peritonitis caused by fungal infection is called fungal peritonitis, and peritonitis caused by viral infection is called sterile peritonitis. When inflammation of the peritoneum occurs and peritonitis develops, symptoms of peritoneal damage appear, such as shedding of mesothelial cells, fibrosis and hardening of the submesothelial stroma, and increased blood vessels.

[0074] Peritonitis can be classified into acute peritonitis, chronic peritonitis, and cancerous peritonitis. Furthermore, peritonitis can be idiopathic (such as idiopathic bacterial peritonitis) or secondary. Most secondary peritonitis cases present as acute peritonitis accompanied by bacterial infection. In recent years, with the increase in continuous ambulatory peritoneal dialysis (CAPD), peritonitis due to CAPD has also increased, but this type of peritonitis often presents as chronic peritonitis. Some cases are described as refractory, recurrent, exacerbating, or recurrent.

[0075] The composition of the present invention can be used for the prevention or treatment of peritoneal damage caused by any type of peritonitis. In particular, it can be used for the prevention or treatment of peritoneal damage caused by peritonitis that occurs during peritoneal dialysis (PD), such as continuous ambulatory peritoneal dialysis (CAPD).

[0076] Peritoneal fibrosis is a phenomenon in which connective tissue in the peritoneal tissue abnormally proliferates, and is caused by the excessive deposition of extracellular matrix such as collagen produced by fibroblasts in the peritoneal tissue. Peritoneal fibrosis can also occur as a complication of peritoneal dialysis. When the peritoneum becomes fibrotic, it eventually becomes dysfunctional.

[0077] The composition of the present invention can be used to suppress peritoneal fibrosis. It can be used to suppress peritoneal fibrosis caused by peritoneal dialysis (PD), such as continuous ambulatory peritoneal dialysis (CAPD).

[0078] Here, "prevention" means substantially preventing the occurrence (onset or manifestation) of the symptom, disease, or disorder in question. "Treatment" means suppressing (e.g., slowing its progression), alleviating, restoring, or curing the symptom, disease, or disorder that has occurred (onset or manifestation).

[0079] Compound (I), etc., may be used alone or in combination with one or more pharmaceutically acceptable components. The compositions of the present invention can be formulated into various dosage forms commonly used in the art, depending on the desired method of administration. Therefore, the compositions of the present invention can also be provided in a form containing Compound (I), etc., and one or more pharmaceutically acceptable carriers. In addition to the components, the compositions of the present invention may contain one or more pharmaceutically acceptable media (e.g., a solvent such as sterile water or a solution such as physiological saline), excipients, binders, vehicles, solubilizers, preservatives, stabilizers, disintegrants, disintegration inhibitors, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (e.g., vegetable oils), suspending agents, buffers, analgesics, antioxidants, sweeteners, and flavoring agents.

[0080] The dosage form of the composition of the present invention is not particularly limited and may be a formulation for parenteral administration, a formulation for administration via mucosal channels (e.g., nasal, sublingual, or oral mucosa), intravenous, dermal, rectal (enema), or vaginal, or a formulation for oral administration. Furthermore, the dosage form of the composition of the present invention may be a formulation in single dose form or a formulation in multiple dose forms.

[0081] Preparations for parenteral administration include, for example, injectable preparations such as sterile solutions or suspensions with water or other pharmaceutically acceptable liquids. Additives that can be mixed with the injectable preparation include, but are not limited to, vehicles such as isotonic solutions containing physiological saline, glucose or other adjuvants (e.g., D-sorbitol, D-mannitol, or sodium chloride), solubilizers such as alcohols (e.g., ethanol or benzyl alcohol), esters (e.g., benzyl benzoate), polyalcohols (e.g., propylene glycol or polyethylene glycol), nonionic surfactants such as polysorbate 80 or polyoxyethylene hydrogenated castor oil, oily solutions such as sesame oil or soybean oil, buffers such as phosphate buffer or sodium acetate buffer, analgesics such as benzalkonium chloride or procaine hydrochloride, stabilizers such as human serum albumin or polyethylene glycol, preservatives, and antioxidants. The prepared injectable preparation is usually filled into a suitable container (e.g., vial or ampoule) and stored in a suitable environment until use.

[0082] Examples of additives included in formulations for transmucosal administration include media, emulsifiers, suspending agents, antibacterial agents (e.g., chlorobutanol), isotonic agents (e.g., sodium chloride), pH adjusters, and penetrating agents. Examples of additives included in formulations for transdermal administration include media, antipruritic agents, antifoaming agents, mitigating agents, surfactants, emulsifiers, thickeners, suspending agents, buffers, viscosity enhancers, humectants, antioxidants, chemical stabilizers, colorants, and decolorizing agents. Examples of additives included in formulations for transanal administration include media, emulsifiers, and solid fat bases. Examples of additives included in formulations for transvaginal administration include media, buffers, oily liquids, suspending agents, wetting agents, surfactants, antioxidants, antibacterial agents, and isotonic agents.

[0083] The composition of the present invention may be in the form of a lyophilized formulation, for example, as described in Japanese Patent Publication No. 2017-178866. Such a lyophilized formulation is usually reconstituted by adding water for injection or the like before use.

[0084] In manufacturing the freeze-dried formulation, a peptide solution containing compound (I), etc., is prepared prior to freeze-drying. It is preferable to prepare the peptide solution using an aqueous solution that substantially does not contain buffering components such as phosphates to maintain or control the pH within a predetermined range, so as not to cause salting-out. Furthermore, only D-mannitol, which is an isotonic agent, is added to the aqueous solution for dissolving compound (I), etc., and while there are no particular restrictions on pH adjustment as needed, it is preferable to do so with sodium hydroxide or hydrochloric acid. The amount of D-mannitol added is in the range of 1 mg to 2500 mg of D-mannitol per 1 mg of compound (I), etc., preferably in the range of 50 to 200 mg of D-mannitol, and more preferably in the range of 100 mg of D-mannitol. The pH of the peptide solution is preferably in the range of 3.0 to 9.0, and more preferably in the range of 4.0 to 7.0.

[0085] The peptide solution may, if necessary, be formulated with an appropriate amount of pharmaceutically acceptable additives. Examples of such additives include suspending agents (benzalkonium chloride, sodium lauryl sulfate, laurylaminopropionic acid, glyceryl monostearate, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, etc.), dispersants (sodium citrate, light aluminum oxide, polysorbate, macrogol, dextrin, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, etc.), emulsifiers (ricerin, propylene glycol, cetanol, lecithin, lanolin, sodium lauryl sulfate, etc.), surfactants (cetanol, polyoxyethylene cetyl ether, lauromacrogol, etc.), isotonic agents (glucose, D-sorbitol, D-mannitol, glycerin, sodium chloride, etc.), analgesics (creatinine, benzyl alcohol, etc.), and stabilizers (taurine, amino acids, parahydroxybenzoic acid esters, benzyl alcohol, crystalline cellulose, macrogol, etc.). These additives may be used individually or in combination of any two or more.

[0086] The obtained peptide solution is generally sterilized and filtered using a sterilization filter. Typically, a sterile filter with a pore size of 0.22 μm or less, or a filter with at least equivalent microbial capture capacity, is used. The peptide solution is then injected into vials or ampoules and moved to the next lyophilization step. Specifically, freeze-drying is carried out through three processes: a freezing process in which the solute is cooled and frozen under atmospheric pressure; a primary drying (sublimation) process in which free water not constrained by the solute is sublimated and dried under reduced pressure; and a secondary drying (dehumidification) process in which adsorbed water and crystal water specific to the solute are removed. The appropriate temperatures for each process are -60°C to -40°C for the freezing process, -50°C to 0°C for the primary drying process, and 4°C to 40°C for the secondary drying process. The temperature for the freezing process may be an extremely low temperature lower than -60°C, such as -85°C or -80°C. The vacuum pressure for the primary drying process is preferably controlled to 0.1 to 50 Pa, and more preferably to 1 to 20 Pa. The vacuum pressure for the secondary drying process is preferably controlled to a higher vacuum. As an example, it is preferably carried out under a high vacuum state of 0.01 to 10 Pa.

[0087] After completing the above processes, the drying chamber is repressurized. The preferred method of repressurization is to introduce sterile air or an inert gas (e.g., sterile nitrogen gas, sterile helium gas, etc.) into the chamber to bring it to a primary pressure of approximately 60-90 kPa, and then, if necessary, to further repressurize it (secondary repressurization). It is preferable to cap the vials after the primary repressurization. As described above, a freeze-dried formulation according to the composition of the present invention can be manufactured.

[0088] The composition of the present invention can also be formulated as a depot formulation. In this case, the composition of the present invention in depot formulation form can be administered, for example, by subcutaneous or intramuscular implantation, or by intramuscular injection. By applying the composition of the present invention to a depot formulation, the adrenomedullin activity of compound (I), etc., can be sustained over a long period of time.

[0089] The composition of the present invention is preferably formulated as a single-dose formulation, and more preferably as a single-dose subcutaneous formulation.

[0090] Compound (I), etc., can be used in combination with one or more other pharmaceuticals. In this case, it may be provided as a single composition of the present invention comprising Compound (I), etc., and one or more other pharmaceuticals, or it may be provided in the form of a pharmaceutical combination or kit containing multiple formulations in which Compound (I), etc., and one or more other pharmaceuticals are separately formulated. In the form of a pharmaceutical combination or kit, each formulation can be administered simultaneously or separately (for example, sequentially).

[0091] When administering the composition of the present invention to a subject, particularly a human, the precise dosage and administration should be determined by the attending physician, taking into account many factors such as the subject's age, sex, the exact state (e.g., severity) of the symptoms, disease, and / or disorder to be prevented or treated, and the route of administration. Therefore, in the composition of the present invention, the active ingredient compound (I), etc., is administered to the subject in a therapeutically effective dosage and administration manner (e.g., dosage, frequency of administration, and route of administration). For example, when administering the composition of the present invention to a human, the dosage of compound (I), etc., used as the active ingredient is usually in the range of 0.005 to 1000 μg / kg body weight / day, preferably in the range of 0.01 to 250 μg / kg body weight / day, and more preferably in the range of 0.05 to 100 μg / kg body weight / day.

[0092] The composition of the present invention can be administered by any number of doses and route of administration. It is preferable that the composition of the present invention be administered as a single dose. Furthermore, it is preferable that the composition of the present invention be administered by parenteral routes such as intravenous administration, enema administration, subcutaneous administration, intramuscular administration, or intraperitoneal administration.

[0093] 2. Peritoneal dialysis solution, compositions for adding to peritoneal dialysis solution, etc. Compound (I) and others according to the present invention can be administered in combination with so-called peritoneal dialysis fluid. This makes it possible to prevent or treat peritoneal disorders and peritoneal fibrosis accompanied by inflammation of the peritoneum while performing peritoneal dialysis.

[0094] Methods for combining compound (I), etc. with peritoneal dialysis fluid include, for example, pre-containing compound (I), etc. in the peritoneal dialysis fluid, or containing compound (I), etc. in a separate composition added to the peritoneal dialysis fluid when administering it to a patient.

[0095] The present invention also includes a peritoneal dialysis solution containing compound (I), etc. (hereinafter referred to as "the present invention's dialysis solution"), or a composition for adding to peritoneal dialysis solution containing compound (I), etc. (hereinafter referred to as "the present invention's composition for addition").

[0096] Examples of the dialysis solution of the present invention include an aqueous solution containing compound (I) and the like in a composition comprising osmotic substances for correcting fluid excess, such as glucose, icodextrin, and amino acids, and electrolytes such as sodium ions, potassium ions, calcium ions, magnesium ions, chloride ions, lactate ions, and optionally bicarbonate ions, as well as a pH adjuster. The pH of the dialysis solution of the present invention is appropriately within the range of approximately 4.5 to 7.8, preferably within the range of 6.5 to 7.5, when administered to a subject, and the osmotic pressure ratio of the dialysis solution of the present invention is within the range of approximately 1.0 to 2.0, preferably within the range of 1.1 to 1.5.

[0097] Each of the above ions may be a compound that contains the ion as a component and can ionize and release the ion into the solution upon dissolution in a solvent. Examples of such compounds include, in the case of sodium ions, sodium hydroxide and sodium lactate; in the case of calcium ions, calcium chloride; in the case of magnesium ions, magnesium chloride; in the case of chloride ions, chloride and hydrochloric acid; in the case of lactate ions, lactic acid; and in the case of bicarbonate ions, sodium bicarbonate.

[0098] The osmotic substance containing glucose varies depending on its type, but in the dialysate of the present invention, it is usually contained in the range of approximately 0.8 to 4.0 w / v% to approximately 1.3 to 3.8 w / v%. The sodium ion is usually contained in the dialysate of the present invention in the range of approximately 131 to 135 mEq / L to approximately 132 to 133 mEq / L. The calcium ion is usually contained in the dialysate of the present invention in the range of approximately 1.2 to 4.0 mEq / L to approximately 2.5 to 3.5 mEq / L. The magnesium ion is usually contained in the dialysate of the present invention in the range of approximately 0.5 to 1.5 mEq / L. The chloride ion is usually contained in the dialysate of the present invention in the range of approximately 90 to 106 mEq / L to approximately 93 to 102 mEq / L. The lactate ions are typically present in the dialysate of the present invention in a range of approximately 10 to 45 mEq / L or approximately 15 to 40 mEq / L. The bicarbonate ions are typically present in the dialysate of the present invention in a range of 0 to approximately 30 mEq / L or approximately 25 mEq / L.

[0099] The dialysis solution of the present invention contains an appropriate amount of pH adjusting agent so that the pH is, for example, in the range of 4.5 to 7.8, preferably in the range of 6.5 to 7.5. The pH adjusting agent is not particularly limited as long as it is a pharmaceutically acceptable acid or base, and examples include acids such as hydrochloric acid, and bases such as sodium hydroxide and sodium bicarbonate. Furthermore, the dialysis solution of the present invention may contain an appropriate amount of a stabilizer such as histidine, as needed.

[0100] The content (concentration) of compound (I) etc. in the dialysate of the present invention is not particularly limited as long as the effects of the present invention are achieved, but for example, a range of 1 μg / L to 6 mg / L is appropriate. Preferably, it is in the range of 6 μg / L to 600 μg / L. More preferably, it is in the range of 12 μg / L to 60 μg / L. As for the dosage and administration of compound (I) etc. in the dialysate of the present invention, for example, 0.033 to 2000 μg / kg / day can be added to the dialysate and administered once a day. However, if necessary, it may be administered in divided doses of 2 to 4 times a day within the maximum volume range (2000 μg / kg / day).

[0101] The dialysis fluid of the present invention may be sealed in a single container, for example, an infusion container. However, to maintain the stability of osmotic substances such as glucose, the fluid containing glucose and other substances, and the fluid containing certain electrolytes, may be sealed in two separate containers (chambers). Specifically, the dialysis fluid of the present invention may contain a first solution with a low pH (e.g., pH 2.5 to 3.5) containing osmotic substances such as glucose, calcium ions, magnesium ions, and optionally a pH adjuster, and a second solution with a high pH (e.g., pH 7 to 8) containing lactate ions, sodium ions, and optionally a pH adjuster, sealed in two separate chambers. Compound (I), etc., can be sealed in one or both of the two chambers, but it is preferable to seal it in the first solution at the above concentration. Compound (I), etc., may also be sealed in a chamber other than the two chambers mentioned above.

[0102] The two or three chambers are opened at the time of use, and the first and second liquids, or compositions containing compound (I), etc., sealed in each chamber, are generally mixed together by physical mixing, and the mixture is administered to the subject. Alternatively, an additional empty chamber may be provided for mixing, in which the first and second liquids, etc., are mixed. The pH after mixing the first and second liquids, etc., is suitable, for example, within the range of 6.0 to 7.5.

[0103] The dialysis solution of the present invention can also be prepared by encapsulating or packaging compound (I) or the like in a commercially available peritoneal dialysis solution. Such commercially available peritoneal dialysis solutions or dialysis agents are not particularly limited, but examples include Dianil N (registered trademark, manufactured by Baxter), StaySafe Balance (registered trademark, manufactured by Fresenius Medical Care Japan), Midperic (registered trademark, manufactured by Terumo), Beriset (registered trademark, manufactured by JMS), Gambrosol Trio / Unica (registered trademark, manufactured by Gambro), Regunil (registered trademark, manufactured by Baxter), Physioneal (registered trademark, manufactured by Baxter), BicaVera (registered trademark, manufactured by Fresenius), Extranil (registered trademark, manufactured by Baxter), Kindaly (registered trademark, manufactured by Fuso Pharmaceutical Industries), Subrad (registered trademark, manufactured by Fuso Pharmaceutical Industries), D-Dry (registered trademark, manufactured by Nikkiso), Rinpack (registered trademark, manufactured by Nipro), Bifil (registered trademark, manufactured by AY Pharma), and Carbostar (registered trademark, manufactured by AY Pharma). The dialysis solution of the present invention described above can be produced, for example, by directly adding compound (I) to a commercially available peritoneal dialysis solution and dissolving compound (I) or the like. Alternatively, it can be produced by adding the lyophilized preparation according to the composition of the present invention described above to a commercially available peritoneal dialysis solution and dissolving it.

[0104] The additive composition of the present invention can be used by physically mixing it with commercially available peritoneal dialysis fluid in an appropriate manner when using the above-mentioned products.

[0105] The additive composition of the present invention may consist of compound (I) alone or in combination with one or more pharmaceutically acceptable components. When the additive composition of the present invention contains compound (I) and one or more pharmaceutically acceptable carriers, the additive composition may include, for example, one or more pharmaceutically acceptable media (e.g., a solvent such as sterile water or a solution such as physiological saline), excipients, binders, vehicles, solubilizers, preservatives, stabilizers, disintegrants, disintegration inhibitors, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (e.g., vegetable oils), suspending agents, buffers, analgesics, antioxidants, sweeteners, and flavoring agents. The additive composition of the present invention may, for example, be a freeze-dried formulation of the composition of the present invention described above.

[0106] Another example of the present invention is a peritoneal dialysis fluid preparation kit comprising an additive composition of the present invention and a diluent for dissolving it. In this embodiment of the invention, the additive composition of the present invention and the diluent can be provided as a set. The diluent is not particularly limited as long as it can be used for intravenous fluid administration, but examples include isotonic saline and physiological saline. [Examples]

[0107] The present invention will be specifically described below with reference to examples, but the present invention is not limited to the scope of the examples.

[0108] [Example 1] Effects of Adrenomedullin The effect of native human adrenomedullin:hAM(1-52) (SEQ ID NO: 8) on a rat severe peritonitis model induced by zymozan stimulation after methylglyoxal (MGO) pretreatment was investigated.

[0109] The experimental animals used were 7-week-old male Sprague-Dawley rats (approximately 250g, manufactured by Chubu Kagaku Shizai Co., Ltd.). Peritoneal dialysis solution used was Dianeel® PD-4 4.25% (manufactured by Baxter).

[0110] The administration interval followed the protocol shown in Figure 1 for a rat model of severe peritonitis. Rats were pretreated 24 hours prior to administration with 10 mL / kg of MGO (MP Biomedical Co., Ltd.) adjusted to 20 mmol / L with peritoneal dialysate. These rats were then intraperitoneally administered daily with peritoneal dialysate mixed with zymozan (Sigma-Aldrich Co., Ltd.) and hAM(1-52) (800 ng / kg / day ip) until day 4. On day 5, the rats were euthanized, and changes in the parietal and visceral peritoneum were evaluated macroscopically and pathologically. Comparisons between multiple groups were performed using ANOVA (with Dunnett's test). Analysis between two groups was performed using an unpaired t-test or Welch's test. A two-sided P<0.05 was considered statistical significance. The results are shown in Figures 2-6. In the figure, * indicates a statistically significant difference at P<0.05, ** at P<0.01, *** at P<0.005, and **** at P<0.001. ns. indicates no statistically significant difference. The same criteria apply to the significance analysis below. In the figure, "Parietal" refers to the parietal peritoneum, and "Visceral" refers to the visceral peritoneum.

[0111] From the photograph in Figure 2, it is clear that, in macroscopic evaluation, peritoneal inflammation was milder in the adremedullin-administered group compared to the vehicle group (non-adrenomedullin-administered group). In particular, the reduction in peritoneal adhesions was clearly visible to the naked eye. As shown in Figures 3 and 4, adremedullin suppressed peritoneal thickness in a dose-dependent manner. In this animal model of peritonitis, deposition of complement activators C3b and C5b-9 was observed in the peritoneum due to tissue damage associated with peritoneal inflammation (Reference: Iguchi D, et al. Am J Physiol Renal Physiol. 320:F1123-F1132, 2021), but as shown in Figure 5, adremedullin administration suppressed C3b and C5b-9 deposition in the peritoneum. Adrenomedullin also significantly suppressed tissue infiltration in CD68-stained panmacrophages and esterase-stained neutrophils. iNOS-positive M1 macrophages and CD168-positive M2 macrophages both showed a significant decrease or reduced tendency in tissue infiltration.

[0112] [Example 2] Effects of Adrenomedullin Analogues Instead of natural human adrenomedullin:hAM(1-52), the experiment was carried out in the same manner as in Example 1, using compound (I):[Ala-44]hAM(13-52), which is an adrenomedullin analog and relates to Sequence ID No. 9. The dose of [Ala-44]hAM(13-52) was 600 ng / kg / day, which is equimolar to 800 ng of natural human adrenomedullin:hAM(1-52).

[0113] The results are shown in Figure 7. As is clear from Figure 7, similar to adrenomedullin, it showed a significantly greater effect in suppressing peritoneal thickness compared to the vehicle group.

Claims

1. A pharmaceutical composition for use in peritoneal dialysis patients for peritoneal disorders accompanied by peritoneal inflammation or peritoneal fibrosis, comprising as an active ingredient a peptide compound represented by the following general formula (I) (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 In formula (I), [Mod] represents a modifying group selected from the group consisting of an organic group containing a C4-C30 alkyl group, a C4-C30 alkenyl group, or a polyethylene glycol group, the Fc region of immunoglobulin, and serum albumin; [Lin] represents a divalent binding group represented by the following general formula (a); and [Pep] represents a peptide chain having one amino acid residue or an amino acid sequence consisting of 2 to 15 amino acid residues. 【Chemistry 2】 In equation (a), q and u are the same or different integers from 0 to 6. In equation (a), r, s, and t are identical or distinct integers of 0 or 1. (However, this excludes the case where q, r, s, t, and u in equation (a) are all zero.) In equation (I), t and s both represent 1, and m represents either 0 or 1. In formula (I), Xa1 is Val (valine residue), Met (methionine residue), or Phe (phenylalanine residue); Xa2 is Gln (glutamine residue) or His (histidine residue); Xa3 is Phe (phenylalanine residue) or Leu (leucine residue); Xa4 is Gly (glycine residue) or Asn (asparagine residue); Xa5 is Val (valine residue), Ser (serine residue), or Met (methionine residue); Xa6 is Arg (arginine residue), D-Arg (D-arginine residue), Lys (lysine residue), or Ala (alanine residue); Xa7 is Ser (serine residue) or Asn (asparagine residue); Xa8 is Tyr (tyrosine residue), or Tyr-NH 2 (Tyrosine residue - NH ２ These represent ), or Tyr-Gly (tyrosine residue - glycine residue), respectively. In formula (I), Bq represents -SH HS- or -SS-.

2. The pharmaceutical composition according to claim 1, wherein the organic group containing the polyethylene glycol group is any of the following structural formulas (α), (β), and (γ). 【Transformation 3】

3. The pharmaceutical composition according to claim 1 or 2, wherein the peritoneal disorder accompanied by inflammation of the peritoneum is peritonitis, acute peritonitis, chronic peritonitis, fungal peritonitis, bacterial peritonitis, or sterile peritonitis.

4. A peritoneal dialysis solution comprising the pharmaceutical composition described in Claim 1.

5. The peritoneal dialysis solution according to claim 4, comprising a first solution containing compound (I) or a pharmaceutically acceptable salt thereof having a concentration in the range of 1 μg / L to 6 mg / L and a pH adjusting agent, and having a pH in the range of 2.5 to 3.5, and a second solution containing a compound capable of releasing sodium ions, wherein the pH after mixing the first and second solutions is in the range of 6.0 to 7.

5.

6. A composition for adding to peritoneal dialysis fluid, comprising the pharmaceutical composition described in Claim 1.

7. A kit for preparing peritoneal dialysis fluid, comprising the composition according to claim 6 and a diluent.

Images