WO2023153507A1 - 腹膜障害用の医薬組成物 - Google Patents

腹膜障害用の医薬組成物 Download PDF

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WO2023153507A1
WO2023153507A1 PCT/JP2023/004731 JP2023004731W WO2023153507A1 WO 2023153507 A1 WO2023153507 A1 WO 2023153507A1 JP 2023004731 W JP2023004731 W JP 2023004731W WO 2023153507 A1 WO2023153507 A1 WO 2023153507A1
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residue
peritoneal
compound
group
peritonitis
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French (fr)
Japanese (ja)
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和雄 北村
正司 水野
恒秀 金
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国立大学法人宮崎大学
国立大学法人東海国立大学機構
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof

Definitions

  • the present invention belongs to the technical field of pharmaceutical compositions containing peptide derivatives.
  • the present invention relates, in the technical field, to adrenomedullin (hereinafter also referred to as "AM") or derivatives or analogues thereof.
  • AM adrenomedullin
  • the present invention relates to a pharmaceutical composition for peritoneal disorders or peritoneal fibrosis containing adrenomedullin or the like as an active ingredient.
  • Adrenomedullin is a bioactive peptide isolated and identified from human pheochromocytoma in 1993 (Non-Patent Document 1). At the time of its discovery, adrenomedullin was found to exert a strong vasodilatory antihypertensive action, but subsequent research has revealed that it has various actions such as cardiovascular protective action, anti-inflammatory action, angiogenesis action, and tissue repair promotion action. demonstrated to perform. In particular, it is expected to be useful as a therapeutic agent for inflammatory bowel disease, peripheral vascular disease, acute myocardial infarction, and novel coronavirus pneumonia. ing.
  • Patent Documents 1 and 2 A therapeutic agent for inflammatory bowel disease containing an adrenomedullin analogue as an active ingredient is disclosed in Patent Documents 1 and 2, for example.
  • Patent Document 1 discloses that adrenomedullin analogues are useful as prophylactic or therapeutic agents for non-bacterial inflammatory diseases.
  • Patent Document 2 discloses that adrenomedullin analogues are useful as prophylactic or therapeutic agents for steroid-resistant or steroid-dependent intractable inflammatory bowel disease.
  • Artificial dialysis includes hemodialysis (HD) and peritoneal dialysis (PD).
  • Hemodialysis is a method of extracting a large amount of blood from the body and passing it through a device equipped with a special filter to remove waste products and unnecessary water from the blood. He goes to the hospital about three times a week and undergoes intensive dialysis treatment for about four to five hours each time. Due to such intensive dialysis treatment, physiological changes occur rapidly and the burden on the circulatory system is great.
  • peritoneal dialysis is a dialysis method that uses the patient's own peritoneum, which is a biological membrane, as a dialysis membrane. Old dialysate containing waste products in the blood is drained out of the body through a catheter inserted into the peritoneum during surgery, and new dialysate is injected into the peritoneum to replace the waste products in the blood and unnecessary substances. It is a method of removing moisture.
  • CCD continuous ambulatory peritoneal dialysis
  • APD automatic peritoneal dialysis
  • peritoneal dialysis is also superior in terms of quality of life (QOL).
  • Adrenomedullin a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun, April 30, 1993, Vol. 192(2) , pp. 553-560
  • Peritoneal dialysis is an excellent renal replacement therapy that can be treated at home with less impact on hemodynamics and less time constraints than hemodialysis (HD).
  • peritoneal dialysis causes deterioration of the peritoneum used as a dialysis membrane, and peritonitis may develop, forcing the patient to abandon the continuation of peritoneal dialysis.
  • fungal peritonitis is intractable, has a high mortality rate, and has a poor prognosis. It has also been suggested to be associated with encapsulating peritoneal sclerosis (EPS), a fatal complication of peritoneal dialysis.
  • EPS encapsulating peritoneal sclerosis
  • An object of the present invention is to provide a new pharmaceutical composition and a new peritoneal dialysate mainly for peritoneal disorders or peritoneal fibrosis accompanied by peritoneal inflammation, including peritonitis.
  • adrenomedullin or its analogues to model animals of peritonitis and peritoneal fibrosis, which are complications of peritoneal dialysis, can induce peritonitis, peritoneal fibrosis, and adhesion.
  • the inventors have found that it can be suppressed remarkably, and have completed the present invention.
  • [Mod] represents a modifying group
  • [Lin] represents a binding group
  • [Pep] represents a peptide chain having an amino acid sequence consisting of one amino acid residue or 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 Gly (glycine residue) or Asn (asparagine residue)
  • Xa5 Val valine residue
  • Ser seerine residue
  • Xa7 is Ser
  • the modifying group [Mod] in the compound (I) is a C 4 -C 30 alkyl group, a C 4 -C 30 alkenyl group, or an organic group containing a polyethylene glycol group, the Fc region of an immunoglobulin, and serum albumin.
  • the pharmaceutical composition according to [1] above which is selected from the group consisting of: [3] 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 bonding group [Lin] in the compound (I) is the following
  • a peritoneal dialysate preparation kit comprising the composition according to [9] above and a diluent solution.
  • t is 0, s is 0, m is 1, and
  • [Pep] is a peptide chain or amino acid residue having an amino acid sequence represented by the following formula (II):
  • Xb1 is Met (methionine residue) or Leu (leucine residue)
  • Xb2 is Leu (leucine residue)
  • Pro proline residue
  • Ser serine residue
  • Xb3 is Phe (phenylalanine residue). residue) or Asn (asparagine residue), respectively.
  • Any one of m1 to m15 is 1, and those other than 1 are 0.
  • peritoneal disorders associated with peritoneal inflammation such as peritonitis can be prevented or ameliorated, and fibrosis and adhesion of the peritoneum can be suppressed.
  • a dosing scheme is shown. Numbers represent days.
  • the "MGO” arrow indicates the day of methylglyoxal administration
  • the "PD fluid with Zymosan” arrow indicates the day of peritoneal dialysis
  • the "Adrenomedullin or vehicle” arrow indicates the day of adrenomedullin or vehicle administration. , respectively.
  • Figure 3 shows the histological evaluation results of peritoneal thickness.
  • the left graph shows the results for the side wall and the right graph shows the results for the visceral wall.
  • the left side shows the administration results of the adrenomedullin group
  • the right side shows the administration results of the non-adrenomedullin administration group.
  • the vertical axis indicates thickness ( ⁇ m).
  • Figure 3 shows the histological evaluation results of peritoneal thickness.
  • the left graph shows the results for the lateral wall
  • the right graph shows the results for the visceral wall.
  • the left side shows the results of the non-adrenomedullin administration group
  • the middle shows the results of the adrenomedullin administration group
  • the right side shows the non-adrenomedullin administration group ( 800ng/kg/day) are shown respectively.
  • the vertical axis indicates thickness ( ⁇ m). Results for C3 staining (left) and C5b9 staining (right) are shown. In each result, the bottom two figures are staining photographs.
  • the left graph shows the results for the side wall
  • the right graph shows the results for the visceral wall, respectively. show.
  • the vertical axis of each graph indicates the expression level (unit, score).
  • amino acids are sometimes referred to by the one-letter or three-letter code conforming to the nomenclature for amino acids given in the IUPAC-IUB guidelines.
  • the amino acid sequences described herein are always N-terminal on the left and C-terminal on the right.
  • amino acid residue means each amino acid (-NH-C(R)(H)-CO-) contained in a peptide chain, unless otherwise specified, and the N-terminal amino acid and C A term that includes the terminal amino acid.
  • amino acid residue is an L-type amino acid residue, but may be a D-type amino acid residue as long as the effects of the present invention are not impaired.
  • composition of the present invention has the following general formula (I ) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • [Mod], [Lin], [Pep], t, s, m, Xa1 to Xa8, and Bq are as defined above.
  • [Pep] is a peptide chain having an amino acid sequence represented by the following formula (II).
  • Xb1 to Xb3 and m1 to m15 are the same as defined above.
  • m1 to m15 are each independently one of which is 1 and the other is 0, and such "1" indicates that one amino acid residue is present. and such "0” means that the amino acid residue is absent, respectively.
  • Compound (I) includes adrenomedullin (AM) and derivatives or analogues thereof.
  • AM adrenomedullin
  • compound (I) is a peptide compound having the amino acid sequence of bovine adrenomedullin (sequence number 5).
  • adrenomedullin 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".
  • Natural adrenomedullin which is purified from human pheochromocytoma and binds to a specific receptor on the platelet membrane to lead to an increase in intercellular cAMP, has one intramolecular disulfide bond and the C-terminal Tyr is an amide has been made
  • Natural human adrenomedullin has a structure represented by Chemical Formula 7 below.
  • native human adrenomedullin is also referred to as "hAM(1-52)" (SEQ ID NO: 8).
  • AM or AM analogues can be extracted and purified from cell tissues by a known and commonly used method, or can be produced using a commonly used peptide synthesizer.
  • 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). Moreover, it can also be produced according to the descriptions of each international publication etc. described later.
  • AM analogues are more stable in serum than AM, and have high bioavailability when subcutaneously administered, while maintaining the same level of bioactivity as AM.
  • An AM derivative in which a modifying group is bound to the N-terminal ⁇ -amino group of AM or an AM analog with or without a linking group exhibits a physiological activity strength equivalent to that of AM or an AM analog, and It has a longer plasma half-life compared to AM analogues.
  • the modifying group Mod is an organic group comprising a C 4 -C 30 alkyl group, a C 4 -C 30 alkenyl group, a C 4 -C 30 alkanoyl group or a polyethylene glycol (PEG) group, the Fc of immunoglobulin region, and a modifying group selected from the group consisting of serum albumin.
  • sugar groups such as monovalent groups (e.g., glycosyl groups) derived from monosaccharides, disaccharides, oligosaccharides or polysaccharides; groups (eg, N-terminal amino groups, C-terminal carboxyl groups, or monovalent groups that form bonds through side groups); peptide groups;
  • the C 4 -C 30 alkyl group is a linear or branched alkyl group having 4 to 30 carbon atoms.
  • a linear or branched alkyl group having 14 to 22 carbon atoms (C 14 -C 22 ) is preferred.
  • alkyl groups include butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, myristyl, pentadecyl, palmityl, stearyl, isostearyl, Mention may be made of eicosil.
  • the C 4 -C 30 alkenyl group is a straight or branched chain alkenyl group having 4 to 30 carbon atoms.
  • a linear or branched alkenyl group having 14 to 22 carbon atoms (C 14 -C 22 ) is preferred.
  • Specific examples of such alkenyl groups include butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, palmitoleyl, elaidyl, oleyl, linoleyl and erucyl.
  • the organic groups may also be organic groups including C4 - C30 alkanoyl groups such as butanoyl, palmitoyl, stearoyl, myristoyl, oleoyl groups.
  • the linking group Lin can be a divalent linking group represented by the following general formula (a).
  • the organic group containing a polyethylene glycol (PEG) group contains one or more PEG groups.
  • the embodiment containing one or more PEG groups is not particularly limited.
  • one or more PEG groups may be placed at the end of the organic group containing the PEG group or placed internally within the organic group containing the PEG group.
  • Organic groups comprising PEG groups typically have a weight average molecular weight in the range of 1-2000 kDa, such as 1-1000 kDa, preferably in the range of 1-100 kDa, preferably in the range of 5-80 kDa. more preferably have a weight average molecular weight of , more preferably in the range of 10 to 80 kDa, particularly preferably in the range of 20 to 80 kDa, or 30 to 60 kDa.
  • the organic group containing a PEG group has a structure represented by any of the following formulas ( ⁇ ) to ( ⁇ ).
  • the organic group containing a PEG group may be various groups known in the art as linear or branched groups containing a PEG group.
  • Known groups that can be used as an organic group containing a PEG group include, but are not limited to, Publication No. 2005/079838, WO 2002/060978, WO 2001/048052, WO 1998/055500, WO 1996/021469, WO 2003/040211, and JP-A-H9 Groups disclosed in 04-108827 and the like can be mentioned.
  • u can be an integer 0 in general formula (a).
  • a combination of q to t in this case may be where q is an integer from 0 to 6, s and r are integers 0 or 1, t is an integer 0, and u is an integer 0.
  • q can be an integer from 1 to 6, r, t and u can be the integer 0 and s can be the integer 1.
  • Specific examples of compound (I) in which an organic group containing a polyethylene glycol group is bonded via such a linking group include amide-linked long-acting compounds disclosed in the specification of WO 2015/141819. It is an adrenomedullin derivative.
  • u may be an integer of 1-6 in general formula (a).
  • q and u may be the same or different integers from 1 to 6, and r, s, and t may be the same or different integers of 0 or 1.
  • a combination of q to u can be where q is an integer of 0, u is an integer of 1 to 6, and r, s, and t are an integer of 1.
  • a specific example of the compound (I) in which an organic group containing a polyethylene glycol group is bonded via such a linking group is an alkylamine-linked long-acting compound disclosed in the specification of WO 2017/047788. is a type adrenomedullin derivative.
  • q may be an integer from 0 to 6
  • r and s may be integers 1
  • t and u may be integers 0.
  • a specific example of the 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 compound disclosed in the specification of International Publication No. 2017/047788. It is an adrenomedullin derivative.
  • the linking group Lin can be a linking group consisting of a peptide having any amino acid sequence.
  • the modification group Mod is preferably the Fc region of immunoglobulin G1 (IgG1) or the Fc region of immunoglobulin G4 (IgG4).
  • the mammal from which the Fc region of the immunoglobulin used as the modifying group Mod is derived can be appropriately selected based on the subject to which the pharmaceutical or the like of this embodiment is applied, which will be described below.
  • Modification groups Mod are immunoglobulins derived from human or non-human mammals (e.g.
  • warm-blooded animals such as pigs, dogs, cows, rats, mice, guinea pigs, rabbits, chickens, sheep, cats, monkeys, baboons or chimpanzees.
  • Fc region more preferably an immunoglobulin Fc region derived from the same human or non-human mammal as the subject to which the pharmaceutical or the like of this embodiment is applied.
  • a linking group Lin consisting of a peptide having an arbitrary amino acid sequence is, for example, (GGGS)n (SEQ ID NO: 17) (n is an integer in the range of 2 to 10, preferably in the range of 4 to 6, where n is the number of repetitions). integer.), (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 1 to 9 an integer in the range, preferably an integer in the range 2-6.), or (GGGGS)n+GGGGK (SEQ ID NOS: 18 and 20), where n is an integer in the range 1-6, preferably an integer in the range 2-5. ) is a linking group having an amino acid sequence of In one embodiment, the peptide linking group Lin is:
  • GGGGSGGGGSGGGGGS SEQ ID NO: 21
  • GGGGSGGGGSGGGGK SEQ ID NO: 22
  • a linking group consisting of a peptide having an amino acid sequence of Compound (I) of this embodiment has a protein or polypeptide structure as a whole.
  • a specific example of a compound in which the modifying group is an Fc region and the linking group is a peptide linking group is the immunoglobulin Fc region-linked long-acting type disclosed in the specification of International Publication No. 2018/181638. It is an adrenomedullin derivative.
  • Specific examples of the compound (I) in which the modifying group Mod is serum albumin include the serum albumin-linked long-acting adrenomedullin derivatives disclosed in the specification of PCT/JP2021/29112 before the publication of the application. can.
  • Compound (I) may be a salt with a pharmaceutically acceptable counterion.
  • Such counterions are not particularly limited as long as they are pharmaceutically acceptable ions. Examples include cations such as sodium ion, potassium ion, calcium ion, magnesium ion, or substituted or unsubstituted ammonium ion, and chloride.
  • Compound (I) and its pharmaceutically acceptable salts may be in the form of solvates.
  • Solvents in such solvates are not particularly limited as long as they are pharmaceutically acceptable. Examples include water, methanol, ethanol, 2-propanol (isopropyl alcohol), dimethylsulfoxide (DMSO), acetic acid, ethanolamine. , acetonitrile or ethyl acetate.
  • Compound (I), its pharmaceutically acceptable salts and solvates are hereinafter collectively referred to as "compound (I) etc.”.
  • Compound (I) and the like may also have a protecting group introduced to one or more of its functional groups (for example, the side chain amino group of a lysine residue).
  • a protecting group is a group introduced into a specific functional group in order to prevent the progress of an undesired reaction, quantitatively removed under specific reaction conditions, and under other reaction conditions It means a group which is substantially stable, ie reaction inert.
  • the protecting group is not particularly limited as long as it can fulfill its role.
  • 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);
  • Protecting groups include benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzhydryloxycarbonyl, 2-(p-biphenyl)isopropyl oxycarbonyl, 2-(3,5-dimethoxyphenyl)isopropyloxycarbonyl,
  • Compound (I) and the like also include individual enantiomers and diastereomers of the compound, as well as mixtures of stereoisomers of the compound, such as racemates.
  • the term "for peritoneal disorders” refers to use for treatment or prevention of peritoneal disorders.
  • "For peritoneal fibrosis” means use for treatment or prevention of peritoneal fibrosis.
  • the composition of the present invention is useful for treating or preventing peritoneal disorders or peritoneal fibrosis accompanied by inflammation of the peritoneum. Therefore, the composition of the present invention can be used for the prophylaxis or treatment of subjects exhibiting or likely to exhibit peritoneal inflammation or peritoneal fibrosis.
  • Such subjects can include humans or non-human mammals (eg, warm-blooded animals such as pigs, dogs, cows, rats, mice, guinea pigs, rabbits, chickens, sheep, cats, monkeys, baboons or chimpanzees).
  • the subject is a human patient.
  • "accompanied by inflammation of the peritoneum” refers to the onset or concomitant inflammation of the peritoneum as a pathological condition.
  • the inflammation includes both acute inflammation and chronic inflammation.
  • 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.
  • peritoneal disorders that can manifest the pathology of peritoneal inflammation include, for example, peritonitis (bacterial peritonitis, fungal peritonitis, carcinomatous peritonitis, etc.) described later, ileus (adhesive ileus, etc.), gastrointestinal ulcer, Appendicitis, female genital diseases. These diseases can be multiple concurrent or secondary.
  • the peritoneum is a membrane that covers the outside and inside walls of abdominal organs such as the liver, stomach, small intestine, and large intestine, the diaphragm, and the pelvic floor.
  • the peritoneum is usually sterile, but a disease caused by inflammation for some reason is called peritonitis.
  • the causes include, for example, irritation due to gastrointestinal perforation, bacterial or fungal infection, and viral infection.
  • Bacterial peritonitis is caused by bacterial infection, fungal peritonitis by fungal infection, and aseptic peritonitis by viral infection.
  • peritoneal disorders such as loss of mesothelial cells, fibrosis and sclerosis of the submesothelial stroma, and increased blood vessels are exhibited.
  • Peritonitis includes acute peritonitis, chronic peritonitis, and carcinomatous peritonitis.
  • peritonitis includes idiopathic and secondary, such as idiopathic bacterial peritonitis. Most secondary peritonitis presents as acute peritonitis with bacterial infection.
  • CAPD continuous ambulatory peritoneal dialysis
  • composition of the present invention can be used for prevention or treatment of peritoneal disorders caused by any peritonitis.
  • peritoneal disorders caused by peritonitis caused by peritoneal dialysis (PD) such as continuous ambulatory peritoneal dialysis (CAPD).
  • PD peritoneal dialysis
  • CAPD continuous ambulatory peritoneal dialysis
  • Peritoneal fibrosis is a phenomenon of abnormal proliferation of connective tissue in peritoneal tissue, and is a condition caused by excessive deposition of extracellular matrix such as collagen produced by fibroblasts in peritoneal tissue. Such peritoneal fibrosis can also occur as a complication of peritoneal dialysis. Fibrosis of the peritoneum eventually causes the peritoneum to malfunction.
  • composition of the present invention can be used to suppress peritoneal fibrosis. It can be used to inhibit peritoneal fibrosis from peritoneal dialysis (PD), such as continuous ambulatory peritoneal dialysis (CAPD).
  • PD peritoneal dialysis
  • CAPD continuous ambulatory peritoneal dialysis
  • prevention means to substantially prevent the occurrence (onset or manifestation) of the symptom, disease or disorder.
  • treatment means suppressing (for example, suppressing progression), alleviating, repairing, or curing the symptom, disease, or disorder that has occurred (onset or manifested).
  • composition 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 composition of the present invention can also be provided in a form containing compound (I) etc. and one or more pharmaceutically acceptable carriers.
  • composition of the present invention may contain one or more pharmaceutically acceptable media (e.g., solvents such as sterile water or solutions such as saline), excipients, binders, vehicles, Solubilizers, preservatives, stabilizers, disintegrants, disintegration inhibitors, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (e.g. vegetable oils), suspending agents, buffers, soothing agents, antioxidants Additives such as agents, sweeteners and flavoring agents may also be included.
  • solvents such as sterile water or solutions such as saline
  • excipients e.g., sterile water or solutions such as saline
  • binders such as sterile water or solutions such as saline
  • vehicles such as sterile water or solutions such as saline
  • Solubilizers e.g., sterile water or solutions such as saline
  • preservatives e.g., sterile water or solutions
  • the dosage form of the composition of the present invention is not particularly limited, and may be a formulation for parenteral administration, transmucosal (e.g., nasal, sublingual or oral mucosa), intravenous, It may be a formulation for use in skin, anal (enema) or vaginal administration, or may be a formulation for oral administration.
  • the dosage form of the composition of the present invention may be a unit dosage form preparation or a multiple dosage form preparation.
  • Formulations for parenteral administration include, for example, injections such as sterile solutions or suspensions with water or other pharmaceutically acceptable liquids.
  • Additives that can be incorporated into injections include, but are not limited to, isotonicity, including physiological saline, glucose or other adjuvants (eg, D-sorbitol, D-mannitol, or sodium chloride).
  • Vehicles such as liquids, alcohols (e.g. ethanol or benzyl alcohol), esters (e.g. benzyl benzoate), solubilizers such as polyalcohols (e.g. propylene glycol or polyethylene glycol), polysorbate 80 or polyoxyethylene hydrogenated castor.
  • Non-ionic surfactants such as oils, oily liquids such as sesame oil or soybean oil, buffers such as phosphate buffers or sodium acetate buffers, soothing agents such as benzalkonium chloride or procaine hydrochloride. , stabilizers such as human serum albumin or polyethylene glycol, preservatives, and antioxidants.
  • a prepared injection is usually filled into a suitable container (eg, vial or ampoule) and stored under an appropriate environment until use.
  • Additives included in formulations for use in transmucosal administration include, for example, vehicles, emulsifying agents, suspending agents, antibacterial agents (e.g., chlorobutanol), isotonic agents (e.g., sodium chloride), pH adjusting agents and Penetrants may be mentioned.
  • Additives contained in formulations for use in transdermal administration include, for example, vehicles, antipruritic agents, antifoaming agents, emollients, surfactants, emulsifiers, thickening agents, suspending agents, buffers, viscosity Elevating agents, humectants, antioxidants, chemical stabilizers, colorants and bleaching agents may be mentioned.
  • Additives included in formulations for use in rectal administration can include, for example, vehicles, emulsifiers and solid fatty bases.
  • Additives included in formulations for use in vaginal administration include, for example, vehicles, buffers, oily solutions, suspending agents, wetting agents, surfactants, antioxidants, antibacterial agents and isotonic agents. be able to.
  • composition of the present invention may be, for example, in the form of a freeze-dried preparation as described in JP-A-2017-178866. Such freeze-dried preparations are usually used after being reconstituted by adding water for injection or the like.
  • a peptide solution containing compound (I) and the like is prepared prior to freeze-drying.
  • the peptide solution is prepared using an aqueous solution substantially free of buffer components such as acid salts.
  • D-mannitol which is a tonicity agent, is added to the aqueous solution for dissolving the compound (I) and the like, and the pH adjustment performed as necessary is not particularly limited, but sodium hydroxide or hydrochloric acid It is preferable to use
  • the amount of D-mannitol to be added is within the range of 1 mg to 2500 mg of D-mannitol, preferably within the range of 50 to 200 mg of D-mannitol, more preferably 100 mg of D-mannitol per 1 mg of compound (I) and the like.
  • the pH of the peptide solution is preferably within the range of 3.0 to 9.0, more preferably within the range of 4.0 to 7.0.
  • an appropriate amount of pharmaceutically acceptable additives can be added to the peptide solution as necessary.
  • Such additives include suspending agents (benzalkonium chloride, sodium lauryl sulfate, laurylaminopropionic acid, glyceryl monostearate, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, etc.), dispersing agents.
  • the resulting peptide solution is generally sterile filtered using a sterile filter.
  • a sterilizing filter a sterile filter with a pore size of 0.22 ⁇ m or less or a filter with at least an equivalent ability to collect microorganisms is used.
  • the peptide solution is then poured into vials or ampoules and transferred to the next freeze-drying step.
  • freeze-drying includes a freezing process that cools and freezes under normal pressure, a primary drying (sublimation) process that sublimes and dries free water that is not bound by the solute under reduced pressure, and a second process that removes the adsorbed water and water of crystallization specific to the solute. It is carried out through three processes of subsequent drying (dehumidification).
  • Temperatures suitable for each process are ⁇ 60° C. to ⁇ 40° C. for freezing, ⁇ 50° C. to 0° C. for primary drying, and 4° C. to 40° C. for secondary drying.
  • the temperature of the freezing process may be a cryogenic temperature below -60°C, such as -85°C or -80°C.
  • the vacuum pressure in the primary drying process is preferably controlled at 0.1-50 Pa, preferably 1-20 Pa.
  • the vacuum pressure in the secondary drying process is preferably controlled at a higher vacuum. As an example, it is preferable to carry out in a high vacuum state of 0.01 to 10 Pa.
  • the pressure inside the drying chamber is restored.
  • aseptic air or inert gas for example, aseptic nitrogen gas, aseptic helium gas, etc.
  • a method of restoring pressure is preferred. It is preferable to cap the vial after the primary pressure recovery.
  • a freeze-dried preparation of the composition of the present invention can be produced.
  • composition of the present invention can also be formulated as a depot preparation.
  • the compositions of the invention in depot form can be implanted, for example, subcutaneously or intramuscularly, or administered by intramuscular injection.
  • the composition of the present invention can be sustained over a long period of time.
  • composition of the present invention is preferably formulated as a single-dose formulation, more preferably as a single-dose subcutaneous formulation.
  • Compound (I) etc. can also be used in combination with one or more other drugs.
  • it may be provided as a single composition of the present invention containing compound (I) etc. and one or more other drugs, and compound (I) etc. and one or more other drugs may be provided separately.
  • It may also be provided in the form of a pharmaceutical combination or kit containing multiple formulated formulations. When in the form of a pharmaceutical combination or kit, each formulation can be administered simultaneously or separately (eg, sequentially).
  • compositions of the present invention When administering the compositions of the present invention to a subject, particularly a human, the precise dosage and administration will depend on the subject's age, sex, the condition to be prevented or treated, the precise state (e.g., severity) of the disease and/or disorder. , and route of administration, the therapeutically effective dosage regimen should ultimately be determined by the attending physician. Therefore, in the composition of the present invention, the active ingredients such as compound (I) are administered to the subject in therapeutically effective dosage and administration (eg, dosage, administration frequency and administration route).
  • therapeutically effective dosage and administration eg, dosage, administration frequency and administration route
  • the dose of compound (I) or the like used as an active ingredient is usually within the range of 0.005 to 1000 ⁇ g/kg body weight/day, preferably , within the range of 0.01-250 ⁇ g/kg body weight/day, more preferably within the range of 0.05-100 ⁇ g/kg body weight/day.
  • composition of the present invention can be administered at any number of doses and by any route of administration.
  • the compositions of the invention are administered in a single dose.
  • the compositions of the present invention are preferably administered by parenteral routes such as intravenous, enema, subcutaneous, intramuscular or intraperitoneal administration.
  • Peritoneal dialysate composition for adding peritoneal dialysate, etc.
  • the compound (I) and the like according to the present invention can be administered (combinedly) in combination with a so-called peritoneal dialysate. This makes it possible to prevent or treat peritoneal disorders and peritoneal fibrosis accompanied by inflammation of the peritoneum while performing peritoneal dialysis.
  • a method of combining compound (I) and the like with peritoneal dialysate for example, a method of preliminarily containing compound (I) and the like in peritoneal dialysate, and a method of applying peritoneal dialysate to a patient, using peritoneal dialysate.
  • a method of containing the compound (I) and the like in a separate composition to be added to for example, a method of preliminarily containing compound (I) and the like in peritoneal dialysate, and a method of applying peritoneal dialysate to a patient, using peritoneal dialysate.
  • the dialysate of the present invention a peritoneal dialysate containing compound (I) or the like
  • additive a peritoneal dialysate additive composition containing compound (I) or the like
  • the dialysate of the present invention includes, for example, glucose, icodextrin, osmotic substances for correcting excess body fluid such as amino acids, sodium ions, potassium ions, calcium ions, magnesium ions, chloride ions, lactate ions, and optionally Compositions containing an electrolyte such as bicarbonate ion and a pH adjuster may include aqueous solutions containing compound (I) and the like.
  • the pH of the dialysate of the present invention is suitably in the range of about 4.5 to 7.8, preferably in the range of 6.5 to 7.5, as the pH at the time of administration to the subject.
  • the osmotic pressure ratio of the dialysate of the invention is approximately in the range of 1.0 to 2.0, preferably in the range of 1.1 to 1.5.
  • Each of the above ions can be a compound that contains the ion as a composition and can be ionized when dissolved in a solvent to release the ion into the solution.
  • examples of such compounds include sodium hydroxide and sodium lactate in the case of sodium ions.
  • calcium ions for example, calcium chloride can be mentioned.
  • Magnesium ions include, for example, magnesium chloride.
  • chloride ions include chloride and hydrochloric acid. Lactate ions include, for example, lactic acid.
  • hydrogencarbonate ions for example, sodium hydrogencarbonate can be mentioned.
  • the osmotic substance containing the glucose varies depending on its type, it is usually in the range of about 0.8 to 4.0 w/v% to about 1.3 to 3.8 w/v% in the dialysate of the present invention.
  • included in The sodium ions are generally contained within the range of about 131-135 mEq/L to about 132-133 mEq/L in the dialysate of the present invention.
  • the calcium ions are generally contained within the range of about 1.2-4.0 mEq/L to about 2.5-3.5 mEq/L in the dialysate of the present invention.
  • the magnesium ion content in the dialysate of the present invention is generally within the range of about 0.5-1.5 mEq/L.
  • the chloride ions are generally contained within the range of about 90-106 mEq/L to about 93-102 mEq/L in the dialysate of the present invention.
  • the lactate ion is generally contained in the dialysate of the present invention within the range of about 10-45 mEq/L to about 15-40 mEq/L.
  • Such bicarbonate ions are generally contained in the dialysate of the present invention within the range of 0 to about 30 mEq/L to within the range of 0 to about 25 mEq/L.
  • the dialysate of the present invention contains an appropriate amount of pH adjuster 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 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 hydrogen carbonate.
  • the dialysate of the present invention can contain an appropriate amount of a stabilizer such as histidine, if necessary.
  • the content (concentration) of compound (I) or the like in the dialysate of the present invention is not particularly limited as long as the effects of the present invention can be exhibited, but is suitably within the range of 1 ⁇ g/L to 6 mg/L, for example. . It is preferably within the range of 6 ⁇ g/L to 600 ⁇ g/L. More preferably, it is in the range of 12 ⁇ g/L to 60 ⁇ g/L.
  • a dosage and administration of compound (I) etc. in the dialysate of the present invention for example, 0.033 to 2000 ⁇ g/kg/day can be added to the dialysate and administered once a day. However, if necessary, the dosage may be divided into 2 to 4 times a day within the range of the maximum dose (2000 ⁇ g/kg/day).
  • the dialysate of the present invention may be enclosed in a single container, for example, an infusion container. may be divided into two containers (chambers) and sealed.
  • the dialysate of the present invention contains an osmotic agent such as glucose, calcium ions, magnesium ions, and, if necessary, a pH adjuster, etc., at a low pH (for example, pH 2.5 to 3.5).
  • a first liquid and a high pH (for example, pH 7 to 8) second liquid containing lactate ions, sodium ions, and optionally a pH adjuster, etc. are enclosed in two chambers. good too.
  • Compound (I) and the like can be enclosed in one or both of the two chambers, but are preferably enclosed in the first liquid at the above concentrations.
  • compound (I) and the like may be sealed in a chamber other than the two chambers.
  • the two or three chambers are opened at the time of use, and the first liquid and the second liquid enclosed in each chamber, or the composition containing the compound (I) and the like, are generally mixed by physical mixing. They are mixed together and the mixture is administered to the subject. It should be noted that another empty chamber may be provided for the mixing, in which the first liquid, the second liquid, etc. may be mixed.
  • the pH after mixing the first liquid and the second liquid is preferably in the range of 6.0 to 7.5.
  • the dialysate of the present invention can also be prepared by encapsulating or wrapping compound (I) in a commercially available peritoneal dialysate.
  • peritoneal dialysate or dialysis agent is not particularly limited, but for example, Dianyl N (registered trademark, manufactured by Baxter), Staysafe (registered trademark) Balance (manufactured by Fresenius Medical Care Japan), Midperic (registered trademark) , Terumo), Verisate (registered trademark, manufactured by JMS), Gambrosol Trio/Unica (registered trademark, manufactured by Gambro), Regunir (registered trademark, manufactured by Baxter), Physioneal (registered trademark, manufactured by Baxter), BicaVera (registered trademark, manufactured by Fresenius), Extraneal (registered trademark, manufactured by Baxter), Kindery (registered trademark, manufactured by Fuso Pharmaceutical Co., Ltd.), Sablad (registered trademark, manufactured by Fuso Pharmaceutical Co.
  • the dialysate of the present invention can be produced, for example, by adding the compound (I) or the like directly to a commercially available peritoneal dialysate and dissolving the compound (I) or the like. It can also be produced by adding the freeze-dried preparation of the composition of the present invention to a commercially available peritoneal dialysate and dissolving it.
  • the additive composition of the present invention can be used by physically mixing it with the peritoneal dialysate by a suitable method.
  • the additive composition of the present invention may consist of compound (I) or the like alone or in combination with one or more pharmaceutically acceptable ingredients.
  • the additive composition of the present invention may contain, for example, one or more pharmaceutically acceptable Vehicles (e.g., solvents such as sterile water or solutions such as saline), excipients, binders, vehicles, solubilizers, preservatives, stabilizers, disintegrants, disintegration inhibitors, swelling agents, lubricants additives such as agents, surfactants, emulsifiers, oily liquids (eg, vegetable oils), suspending agents, buffers, soothing agents, antioxidants, sweeteners and flavoring agents.
  • the composition of the present invention for addition may be, for example, a freeze-dried preparation of the composition of the present invention described above.
  • the present invention also includes a peritoneal dialysate preparation kit containing the additive composition of the present invention and a diluent solution for dissolving it.
  • the inventive composition for addition and the solution for dilution can be provided as a set.
  • the diluent solution is not particularly limited as long as it can be used for infusion, and examples thereof include isotonic saline and physiological saline.
  • Example 1 Effect of adrenomedullin Native human adrenomedullin against rat severe peritonitis model (MGO / Zymosan induced peritonitis model) induced by zymosan stimulation after methylglyoxal (MGO) pretreatment: hAM(1-52) (SEQ ID NO: The effect of 8) was examined.
  • the experimental animals used were 7-week-old male Sprague-Dawley rats (approximately 250 g, manufactured by Chubu Kagaku Shizai Co., Ltd.).
  • Dianyl (registered trademark) PD-4 4.25% (manufactured by Baxter) was used as the peritoneal dialysate.
  • hAM(1-52) 800 ng/kg/day i.p was intraperitoneally administered every day until 4 days later. After 5 days, the rats were euthanized and changes in the parietal peritoneum and visceral peritoneum were evaluated macroscopically and pathologically.
  • adrenomedullin administration suppressed peritoneal C3b and C5b-9 deposition.
  • Adrenomedullin also significantly suppressed tissue infiltration for CD68-staining-positive pan-macrophages and esterase-staining-positive neutrophils.
  • Both iNOS staining-positive M1 and CD168 staining-positive M2 macrophages show a tendency to significantly decrease or less tissue infiltration.
  • Example 2 Effect of adrenomedullin analogue Natural human adrenomedullin: Instead of hAM(1-52), compound (I) according to SEQ ID NO: 9, which is one of adrenomedullin analogues: [Ala-44]hAM( 13-52), the experiment was conducted in the same manner as in Example 1.
  • the dose of [Ala-44]hAM(13-52) was 600 ng/kg/day, which is equimolar to 800 ng of native human adrenomedullin: hAM(1-52).

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Citations (4)

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JP2000038348A (ja) * 1998-05-21 2000-02-08 Nissho Corp アルブミン含有腹膜透析液
WO2018181638A1 (ja) * 2017-03-29 2018-10-04 国立大学法人宮崎大学 長時間作用型アドレノメデュリン誘導体
WO2021201271A1 (ja) * 2020-04-02 2021-10-07 国立大学法人宮崎大学 新規アドレノメデュリン類縁体、その製造方法及びその医薬用途
WO2022030580A1 (ja) * 2020-08-06 2022-02-10 国立大学法人宮崎大学 長時間作用型新規アドレノメデュリン誘導体、その製造方法及びその医薬用途

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JP2000038348A (ja) * 1998-05-21 2000-02-08 Nissho Corp アルブミン含有腹膜透析液
WO2018181638A1 (ja) * 2017-03-29 2018-10-04 国立大学法人宮崎大学 長時間作用型アドレノメデュリン誘導体
WO2021201271A1 (ja) * 2020-04-02 2021-10-07 国立大学法人宮崎大学 新規アドレノメデュリン類縁体、その製造方法及びその医薬用途
WO2022030580A1 (ja) * 2020-08-06 2022-02-10 国立大学法人宮崎大学 長時間作用型新規アドレノメデュリン誘導体、その製造方法及びその医薬用途

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KUROISHI NOBUKO, NAGATA SAYAKA, AKASHI EMIKO, ASHIZUKA SHINYA, KATO JOHJI, YAMASAKI MOTOO, KITAMURA KAZUO: "Development of a novel human adrenomedullin derivative: human serum albumin-conjugated adrenomedullin", JOURNAL OF BIOCHEMISTRY, OXFORD UNIVERSITY PRESS, GB, vol. 170, no. 4, 4 December 2021 (2021-12-04), GB , pages 445 - 451, XP055895503, ISSN: 0021-924X, DOI: 10.1093/jb/mvab057 *

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