Copolymers containing poly(ethylene glycol) and poly(L-amino acid derivatives), microparticles thereof and their use in pharmaceutical compositions

Abstract

[Problem] The present invention addresses the problem of providing an ornithine assembly that has low toxicity, is effective even when administered orally, and has high bioavailability. In addition, the present invention addresses the problem of providing an ornithine assembly that effectively prevents or treats hepatopathy. [Solution] Provided is a condensate in which an acyl group was introduced to an ornithine side chain amino group of a polyethylene glycol-b-polyornithine, and further provided is a novel assembly that is not based on a PIC.

Description

[Technical Field]

[0001] The present invention relates to copolymers comprising poly(ethylene glycol) and poly(L-amino acid derivative), in particular copolymers comprising a poly(ornithine) segment as the L-amino acid derivative, or a poly(aspartic acid ester), poly(acylated arginine), or poly(ornithine)-co-poly(aspartic acid) segment, and their use in microparticles and pharmaceutical compositions. [Background technology]

[0002] Patients with liver disorders such as cirrhosis may develop pathological conditions such as hyperammonemia due to abnormalities in the urea cycle. It has been reported that when L-ornithine is administered to such patients, it functions as a substrate for urea production, and furthermore, it activates enzymes in the urea cycle, including carbamyl phosphate synthase (CPS) and ornithine transcarbamylase (OTC), thereby improving the urea cycle and reducing ammonia levels (Non-Patent Document 1).

[0003] Thus, L-ornithine and a mixture of L-ornithine and L-aspartic acid (LOLA) have been reported to have beneficial effects in lowering ammonia levels.

[0004] On the other hand, Non-Patent Document 2 confirms in a double-blind, randomized, placebo-controlled study that injection of the amino acid mixture is extremely ineffective, which is thought to be because water-soluble, low-molecular-weight amino acids are only poorly absorbed into the body and are metabolized extremely quickly.

[0005] To solve these problems, the inventors have previously designed a copolymer (polycationic polymer) of poly(ethylene glycol) and poly(arginine) and proposed a polyion complex (PIC) by combining it with a polyanion such as chondroitin sulfate (Patent Document 1). Furthermore, they have proposed an organizing drug (Nano ORNThe blood retention and liver accumulation of the ORN When Nano was administered to mice with acute liver damage caused by acetaminophen (APAP), not only did it reduce the blood ammonia level, which had risen significantly due to APAP liver damage, to normal levels, but it also significantly reduced the liver function markers AST and ALT levels, demonstrating improved liver function (Non-Patent Document 3). ORN It was confirmed that this treatment has the effect of improving liver function.

[0006] By incorporating L-ornithine into a structured drug and administering it subcutaneously, the bioavailability of L-ornithine was improved, resulting in an improvement in liver function.

[0007] On the other hand, the Nano, which is driven by PIC, ORN is unstable to changes in ionic strength and pH, liberates polycations, and can cause toxicity, making it unsuitable for oral administration. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2016-167333 Brochure [Non-patent literature]

[0009] [Non-Patent Document 1] Nutr. Res. 28 (11) 738(2008) [Non-patent document 2] Gastroenterology 136 (7) 2159(2009) [Non-patent document 3] Poly(ornithine)-based self-assembling drug for recovery of hyperammonemia and damage in acute liver injury, Long B. Vong, Yota Ibayashi, Yaroslav Lee, Dai-Nghiep Ngo, Yuji Nishikawa, Yukio Nagasaki, Journal of Controlled Release, 310, 74-81(2019) Summary of the Invention [Problem to be solved by the invention]

[0010] To solve the above problems, an object of the present invention is to provide a textured ornithine that is low in toxicity, effective even when administered orally, and has high bioavailability, as well as to provide a textured ornithine that is effective in preventing or treating liver damage. [Means for solving the problem]

[0011] The inventors have discovered that by introducing an acyl group or the like into the ornithine side chain amino group of poly(ethylene glycol)-b-poly(ornithine), it is possible to provide a copolymer capable of forming a new organized body without the need for PIC formation. They have also discovered that by combining the copolymer thus provided with another copolymer containing a poly(ethylene glycol) segment and a poly(side chain-protected L-amino acid) segment, the properties, functions, or actions of the former copolymer can sometimes be enhanced.

[0012] Therefore, the present invention provides the following aspects. (1) A copolymer represented by formula (I). JPEG0007795788000001.jpg78170In formula, A is, (i) a hydrogen atom, unsubstituted or substituted C1-C 12 Alkyl groups, unsubstituted or substituted C1-C 12represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituents are C1-C4 alkyl groups, C1-C4 alkoxy groups, aryl groups, formyl groups, and groups of the formula R 1 R 2 CH-(where R 1 and R 2 are independently C1-C4 alkoxy or R 1 and R 2 together represent -OCH2CH2O-, -O(CH2)3O- or -O(CH2)4O-; (ii) Formula JPEG0007795788000002.jpg59170, where: L' independently represents a linking group. Y and Y' are independently a hydrogen atom, C 1-21 Alkylcarbonyl, substituted C 1-4 Alkylcarbonyl, unsubstituted or substituted C 3-7 represents cycloalkylcarbonyl, unsubstituted or substituted arylcarbonyl, or unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein substituted C 1-4 The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C 3-7 cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C 1-4 It can be alkylamino, R 10 and R 10 ' is a hydrogen atom or R 11 -(C=O)-, and R 11 are each independently substituted or unsubstituted C1-C 21 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C1-C 21Alkoxy, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 alkoxy, aryl, m and m' are independently an integer of 2 to 300; n is an integer from 2 to 1,000, m or m' R in the formula 10 and R 10 'More than 20% are R 11 -(C=O)-. (2) The copolymer according to aspect (1), wherein R 10 is R 11 -(C=O)-, and m R 10 100% of R 11 -(C=O)-. (3) The copolymer according to embodiment (1), wherein A is defined as in (i). (4) The copolymer according to aspect (1), wherein A is defined in (i) and R 10 is R 11 -(C=O)-, and m R 10 is 100% R 11 -(C=O)-. (5) The copolymer according to embodiment (1), wherein A is defined as (ii). (6) The copolymer of embodiment 1, wherein A is defined in (ii) and R 10 and R 10 ' is R 11 -(C=O)-, and m and m' R 10 and R 10 ' is 100% R 11 -(C=O)-. (7) Ornithine microparticles comprising the copolymer according to any one of aspects (1) to (6) and having an average particle size of 1 nanometer to 100 micrometers. (8) A pharmaceutical composition comprising the copolymer according to any one of the aspects (1) to (6) as an active ingredient and an additive. (9) The pharmaceutical composition according to embodiment (8), wherein the pharmaceutical composition is an orally administered agent. (10) A composition for preventing or treating liver dysfunction, comprising the copolymer of any one of aspects 1 to 6 or the ornithine microparticles of aspect (7) as an active ingredient. (11) A pharmaceutical composition comprising, as an active ingredient, the copolymer according to any one of aspects (1) to (6) or the ornithine microparticles according to aspect 7, and a copolymer represented by formula (IV). JPEG0007795788000003.jpg65170In formula, A ASP is a hydrogen atom, unsubstituted or substituted C1-C 12 Alkyl groups, unsubstituted or substituted C1-C 12 represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituents are C1-C4 alkyl groups, C1-C4 alkoxy groups, aryl groups, formyl groups, and groups of the formula R 1 R 2 CH-(where R 1 and R 2 are independently C1-C4 alkoxy or R 1 and R 2 together represent -OCH2CH2O-, -O(CH2)3O- or -O(CH2)4O-; L ASP represents a linking group R ASP is a hydrogen atom, substituted or unsubstituted C1-C 21 alkyl, substituted or unsubstituted aryl, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 alkoxy, aryl, Y ASP is a hydrogen atom, C 1-21 Alkylcarbonyl, substituted C 1-4 Alkylcarbonyl, unsubstituted or substituted C 3-7 represents cycloalkylcarbonyl, unsubstituted or substituted arylcarbonyl, or unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein substituted C 1-4 The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C 3-7cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C 1-4 It can be alkylamino, m A is an integer between 2 and 300, n A is an integer between 2 and 1,000. (12) A pharmaceutical composition comprising, as an active ingredient, a copolymer according to any one of aspects (1) to (6) or ornithine microparticles according to aspect 7, and a copolymer represented by formula (V). JPEG0007795788000004.jpg65170In formula, A CO is a hydrogen atom, unsubstituted or substituted C1-C 12 Alkyl groups, unsubstituted or substituted C1-C 12 represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituents are C1-C4 alkyl groups, C1-C4 alkoxy groups, aryl groups, formyl groups, and groups of the formula R 1 R 2 CH-(where R 1 and R 2 are independently C1-C4 alkoxy or R 1 and R 2 together represent -OCH2CH2O-, -O(CH2)3O- or -O(CH2)4O-; n CO is an integer between 2 and 1,000, L CO represents a linking group R ASP is a hydrogen atom, substituted or unsubstituted C1-C 21 alkyl, substituted or unsubstituted aryl, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4alkoxy, aryl, m A is an integer between 2 and 300, R ORN is a hydrogen atom or R 11 -(C=O)-, and R 11 are each independently substituted or unsubstituted C1-C 21 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C1-C 21 Alkoxy, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 alkoxy, aryl, m O is an integer between 2 and 300, Y CO is a hydrogen atom, C 1-21 Alkylcarbonyl, substituted C 1-4 Alkylcarbonyl, unsubstituted or substituted C 3-7 represents cycloalkylcarbonyl, unsubstituted or substituted arylcarbonyl, or unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein substituted C 1-4 The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C 3-7 cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C 1-4 It can be alkylamino, where m A repeating units and m O Each amino acid in the repeating unit occurs randomly to form another block. (13) A pharmaceutical composition comprising, as an active ingredient, the copolymer according to any one of aspects (1) to (6) or the ornithine microparticles according to aspect 7, and a copolymer represented by formula (VI). JPEG0007795788000005.jpg76170In formula, A ARG is a hydrogen atom, unsubstituted or substituted C1-C 12 Alkyl groups, unsubstituted or substituted C1-C 12 represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituents are C1-C4 alkyl groups, C1-C4 alkoxy groups, aryl groups, formyl groups, and groups of the formula R 1 R 2 CH-(where R 1 and R 2 are independently C1-C4 alkoxy or R 1 and R 2 together represent -OCH2CH2O-, -O(CH2)3O- or -O(CH2)4O-; n G is an integer between 2 and 1,000, L ARG represents a linking group R ARG and R ARG’ are independently a hydrogen atom or R 11 -(C=O)-, and R 11 are each independently substituted or unsubstituted C1-C 21 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C1-C 21 Alkoxy, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 alkoxy, aryl, m G is an integer between 2 and 300, Y ARG is a hydrogen atom, C 1-21 Alkylcarbonyl, substituted C 1-4 Alkylcarbonyl, unsubstituted or substituted C 3-7 represents cycloalkylcarbonyl, unsubstituted or substituted arylcarbonyl, or unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein substituted C 1-4 The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C 3-7cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C 1-4 It can be alkylamino. (14) A copolymer represented by formula (IV-a). JPEG0007795788000006.jpg60170A ASP is a hydrogen atom, unsubstituted or substituted C1-C 12 Alkyl groups, unsubstituted or substituted C1-C 12 represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituents are C1-C4 alkyl groups, C1-C4 alkoxy groups, aryl groups, formyl groups, and groups of the formula R 1 R 2 CH-(where R 1 and R 2 are independently C1-C4 alkoxy or R 1 and R 2 together represent -OCH2CH2O-, -O(CH2)3O- or -O(CH2)4O-; L ASP represents a linking group Y ASP is C 1-21 Alkylcarbonyl, substituted C 1-4 Alkylcarbonyl, unsubstituted or substituted C 3-7 represents cycloalkylcarbonyl, unsubstituted or substituted arylcarbonyl, or unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein substituted C 1-4 The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C 3-7cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C 1-4 It can be alkylamino, R ASP is a substituted or unsubstituted C1-C 21 alkyl, substituted or unsubstituted aryl, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 alkoxy, aryl, but other than benzyl; m A is an integer between 2 and 300, n A is an integer between 2 and 1,000. (15) A copolymer represented by formula (V). JPEG0007795788000007.jpg66170In formula, A CO is a hydrogen atom, unsubstituted or substituted C1-C 12 Alkyl groups, unsubstituted or substituted C1-C 12 represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituents are C1-C4 alkyl groups, C1-C4 alkoxy groups, aryl groups, formyl groups, and groups of the formula R 1 R 2 CH-(where R 1 and R 2 are independently C1-C4 alkoxy or R 1 and R 2 together represent -OCH2CH2O-, -O(CH2)3O- or -O(CH2)4O-; n CO is an integer between 2 and 1,000, L CO represents a linking group R ASPis a hydrogen atom, substituted or unsubstituted C1-C 21 alkyl, substituted or unsubstituted aryl, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 alkoxy, aryl, m A is an integer between 2 and 300, R ORN is a hydrogen atom or R 11 -(C=O)-, and R 11 are each independently substituted or unsubstituted C1-C 21 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C1-C 21 Alkoxy, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 alkoxy, aryl, m O is an integer between 2 and 300, Y CO is a hydrogen atom, C 1-21 Alkylcarbonyl, substituted C 1-4 Alkylcarbonyl, unsubstituted or substituted C 3-7 represents cycloalkylcarbonyl, unsubstituted or substituted arylcarbonyl, or unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein substituted C 1-4 The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C 3-7 cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C 1-4 It can be alkylamino, where m A repeating units and m OEach amino acid in the repeating unit occurs randomly to form another block. (16) A copolymer represented by formula (VI-a). JPEG0007795788000008.jpg71170In formula, A ARG is a hydrogen atom, unsubstituted or substituted C1-C 12 Alkyl groups, unsubstituted or substituted C1-C 12 represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituents are C1-C4 alkyl groups, C1-C4 alkoxy groups, aryl groups, formyl groups, and groups of the formula R 1 R 2 CH-(where R 1 and R 2 are independently C1-C4 alkoxy or R 1 and R 2 together represent -OCH2CH2O-, -O(CH2)3O- or -O(CH2)4O-; n G is an integer between 2 and 1,000, L ARG represents a linking group R ARG and R ARG’ are independently 11 -(C=O)-, and R 11 are each independently substituted or unsubstituted C1-C 21 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C1-C 21 Alkoxy, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 alkoxy, aryl, but other than benzyloxycarbonyl and tert-butyloxycarbonyl; m G is an integer between 2 and 300, Y ARG is a hydrogen atom, C 1-21 Alkylcarbonyl, substituted C 1-4 Alkylcarbonyl, unsubstituted or substituted C 3-7represents cycloalkylcarbonyl, unsubstituted or substituted arylcarbonyl, or unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein substituted C 1-4 The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C 3-7 cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C 1-4 It can be alkylamino. [Effects of the Invention]

[0013] The organizing drug containing the copolymer of the present invention as an active ingredient is orally administered and used as a new therapeutic agent for liver damage. In particular, when orally administered, it accumulates in the intestinal mucosa, where it is hydrolyzed by degradative enzymes, gradually releasing ornithine, resulting in high bioavailability of ornithine in the body and sustained efficacy. Furthermore, the organizing drug of the present invention has low toxicity. [Brief explanation of the drawings]

[0014] [Figure 1] 1H-NMR chart of the compound synthesized in Production Example 4 [Figure 2] 1H-NMR chart of the compound synthesized in Production Example 5 [Figure 3] 1H-NMR chart of the compound synthesized in Production Example 6 [Figure 4] 1H-NMR chart of the compound synthesized in Production Example 7 [Figure 5] Dynamic light scattering measurement results of NanoORN(iBu) [Figure 6]Dynamic light scattering measurements of particle size (left) and scattering intensity (right) of NanoORN(Z), NanoORN(Me), and NanoORN(iBu) as a function of pH. [Figure 7] Evaluation results of blood ammonia concentration (a), ALT (b), and AST of ornithine nanoassemblies in mice with acute liver injury caused by acetaminophen (APAP) [Figure 8] Hematoxylin and eosin (H&E) staining of liver tissue after administration of nano-organized ornithine to mice with acute APAP liver injury [Figure 9] Body weight changes after administration of nano-organized bodies to normal mice [Figure 10] Changes in white blood cell and platelet counts after administration of nanoassembly materials to normal mice [Figure 11] Survival rate graph after administration of nano-organized materials to mice with acute APAP liver damage [Figure 12] Kinetic analysis results of 125I-labeled nanoorganized body (NanoORN(iBu)) after oral administration [Figure 13] Cytotoxicity evaluation results of each polyornithine nanoorganized body (NanoORN) [Figure 14] 1H-NMR chart of the compound synthesized in Production Example 16 [Figure 15] 1H-NMR chart of the compound synthesized in Production Example 17 [Figure 16] Dynamic light scattering measurements of particle size and pH dependence for NanoASP(Bz), NanoASP(Me), and NanoASP / ORN [Figure 17] Evaluation results of blood ammonia concentration (a), ALT (b), and AST in NanoASP(Bz), NanoASP(Me), NanoASP / ORN, and other tissues in mice with acetaminophen (APAP)-induced acute liver injury [Figure 18] 1H-NMR chart of the compound synthesized in Production Example 21 [Figure 19] 1H-NMR chart of the compound synthesized in Production Example 22 [Figure 20]Dynamic light scattering measurement results of NanoARG(Ac) and NanoARG(iBu) [Figure 21] Effect of oral administration of acetylated arginine aggregate on APAP-induced acute liver injury in mice [Figure 22] Effect of acetylated arginine aggregates on nonalcoholic steatohepatitis (NASH) model mice DETAILED DESCRIPTION OF THE INVENTION

[0015] Unless otherwise defined, technical terms used in this specification are used to represent the meanings commonly used in the art.

[0016] <Copolymer> The copolymer of the present invention is as represented by formula (I) in embodiment (1).

[0017] A in formula (I) is (i) a hydrogen atom, unsubstituted or substituted C1-C 12 Alkyl groups, unsubstituted or substituted C1-C 12 represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituents are C1-C4 alkyl groups, C1-C4 alkoxy groups, aryl groups, formyl groups, and groups of the formula R 1 R 2 CH-(where R 1 and R 2 are independently C1-C4 alkoxy or R 1 and R 2 and together represent -OCH2CHO-, -O(CH2)3O-, or -O(CH2)4O-.) or a group represented by formula (ii). The C1-C4 alkyl group, C1-C4 alkoxy group, and aryl group mentioned as substituents may be further substituted with a C1-C4 alkyl group, C1-C4 alkoxy group, or aryl group. In addition, aryl groups include phenyl, biphenyl, and naphthyl.

[0018] In formula (I), the linking groups L and / or L' can be any organic divalent group as long as it does not adversely affect the formation of ornithine microparticles, but generally, -O-(CH) a -NH-, -O-(CH2) a -O-, -(CH2) a -NH- or -(CH2) a represents —O—, preferably —O—(CH2) a -NH-, -(CH2) a -NH- (where a is an integer of 1 to 6, preferably 1 to 3), and the directionality of the bond of these linking groups is in the same direction as each moiety in the structural formula of each formula for L. For example, -O-(CH2) a For example, in the case of -NH-, the bond on the -O-(CH2) moiety is covalently bonded to the methylene in formula (I), and the NH- moiety is covalently bonded to the carbonyl group. In contrast, the direction of L' is opposite to that of L.

[0019] In formula (I), Y and Y′ are each independently a hydrogen atom, an unsubstituted C 1-21 Alkylcarbonyl, substituted C 1-4 Alkylcarbonyl, unsubstituted or substituted C 3-7 It represents cycloalkylcarbonyl, unsubstituted or substituted arylcarbonyl, or unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl.

[0020] The alkyl groups or portions of the groups can be straight or branched chain and include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, nonyl, undecyl, tridecyl, heptadecyl, nonadecyl, and the like. Preferred are C 1-6 C is selected from alkyl. 3-7The cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. The aryl can be phenyl, biphenyl, or naphthyl. The 5- or 6-membered heteroaryl is an unsaturated heterocyclic group containing one or two identical or different heteroatoms selected from oxygen, nitrogen, and sulfur atoms, and can be thienyl, furyl, pyranyl, pyrrolyl, isoxazole, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, or pyrimidinyl. These heterocyclic rings can also be benzo-fused. Examples of such fused rings include isoindolyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, and phenanthridinyl.

[0021] substitution C 1-4 The substituents of alkylcarbonyl are halogen atoms (Cl, F, Br, I), hydroxyl, carboxyl, unsubstituted or substituted C 3-7 cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C 1-4 The final substituent can be a substituted C 3-7 It also applies to cycloalkylcarbonyl, substituted arylcarbonyl, or substituted 5- or 6-membered heteroarylcarbonyl.

[0022] In the above definition, the cholesterol residue can be a residue in which any H on the 22nd to 27th carbons in the cholesterol molecule has been removed, or a hydrocarbon chain including any of the 22nd to 27th carbons has been removed. Examples of alkylcarbonyl substituted with such a residue include cholic acid and chenodeoxycholic acid. Preferred examples of Y include C 1-6 It is an alkylcarbonyl.

[0023] R in formulas (I) and (ii) 10 and R 10 ' are independently a hydrogen atom or R 11 -(C=O). Without being bound by theory, R 10 and R 10 ' is R 11 When -(C=O) is contained, the amide bond formed by this with the δ-amino group of the polyornithine segment and the amide (or peptide) bond of the polyornithine main chain are each expected to be subject to enzymatic degradation, releasing free ornithine. For example, they are expected to be decomposed by digestive enzymes in the digestive tract, gradually releasing ornithine.

[0024] R 11 is a substituted or unsubstituted C1-C 21 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C1-C 21 Alkoxy, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 Alkoxy, aryl, more preferably R 11 can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, (optionally branched) pentyl, (optionally branched) hexyl, (optionally branched) heptyl, (optionally branched) octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, benzyloxy, or tert-butyloxy group. These groups are preferred from the viewpoint of the efficiency of organizing the copolymer and forming ornithine microparticles. On the other hand, from the viewpoint of ease of synthesis, R 11 is preferably a methyl, propyl, isopropyl, butyl, isobutyl, (optionally substituted) phenyl, or (optionally substituted) benzyl group.

[0025] For example, R 11When R is methyl, it can be obtained by using, for example, acetic anhydride as a carboxylic acid ester in the condensation reaction of formula (II), which will be explained later in the production of the copolymer. 11 When R is ethyl, for example, propionic anhydride is used as 11 When R is propyl, for example, butyric anhydride is 11 When isopropyl is used, for example, isobutyric anhydride is used, and R 11 When butyl is used, for example, pentanoic anhydride is used, 11 When isobutyl is used, for example, isopentanoic anhydride is used, 11 When R is phenyl, for example, benzoic anhydride is used. 11 For example, if you want to use a benzyl group, you can use bisphenylacetic anhydride. By changing the type of carboxylic acid, you can obtain the desired R 11 By using a carboxylic acid ester having a substituent or a derivative, R 11 may also have a substituent.

[0026] m and m' may independently be an integer of preferably 2 to 300, more preferably 15 to 150, and most preferably 15 to 100, from the viewpoint of the stability of particles formed by the copolymer.

[0027] Similarly, n may be an integer of preferably 2 to 1000, more preferably 10 to 500, and most preferably 30 to 400.

[0028] m and m' R in formula (I) 10 and R 10 ' can be independently generally 80%, preferably up to 60%, more preferably up to 30%, and most preferably up to 10% hydrogen atoms, and most preferably all (100%) of m and m' are -R 11 -(C=O).

[0029] <Production of copolymer> An example of a copolymer synthesis scheme is shown below, but it should be noted that the following is merely an example and the present invention is not limited to this example in any way.

[0030] The copolymer may contain the corresponding PEG segment and polyornithine segment produced by any method as long as it is in accordance with the objectives of the present invention. However, the copolymer is preferably a copolymer that has a narrow molecular weight distribution and can be self-assembled in an aqueous medium to form ornithine microparticles with an appropriate average diameter.

[0031] The copolymer can be provided by first preparing a copolymer represented by the following formula (II), and then adding a compound such as a carboxylic acid ester to the δ-amino group in the segment derived from L-ornithine in the formula to introduce an acyl group. JPEG0007795788000009.jpg61170[In the formula, A is, (i)' Hydrogen atom, unsubstituted or substituted C1-C 12 Alkyl groups, unsubstituted or substituted C1-C 12 represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituents are C1-C4 alkyl groups, C1-C4 alkoxy groups, aryl groups, formyl groups, and groups of the formula R 1 R 2 CH-(where R 1 and R 2 are independently C1-C4 alkoxy or R 1 and R 2 together represent -OCH2CH2O-, -O(CH2)3O- or -O(CH2)4O-; (ii)' expression JPEG0007795788000010.jpg44170, L and L' independently represent a linking group. Y and Y' are independently a hydrogen atom, C 1-21 Alkylcarbonyl, substituted C 1-4 Alkylcarbonyl, unsubstituted or substituted C 3-7represents cycloalkylcarbonyl, unsubstituted or substituted arylcarbonyl, or unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein substituted C 1-4 The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C 3-7 cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C 1-4 It can be alkylamino, m and m' are independently an integer of 2 to 300, and n is an integer of 2 to 1,000.

[0032] A typical example of such a production is a condensation reaction between a copolymer represented by formula (II) and a carboxylic acid ester, as shown in the following scheme. JPEG0007795788000011.jpg54170

[0033] Examples of carboxylic acid esters include carboxylic acid halides, carboxylic acid anhydrides, carboxylic acid azides, and activated esters. Specifically, acetic anhydride, propionic anhydride, isobutyric anhydride, butyric anhydride, oxalic anhydride, succinic anhydride, glutaric anhydride, adipic anhydride, maleic anhydride, phthalic anhydride, benzoic anhydride, and bisphenylacetic anhydride can be used.

[0034] Here, when A in formula (II) in the above reaction scheme corresponds to that defined in (ii)' above, the δ-amino group in the ornithine-derived segment corresponding to the repeating unit m' in the formula described therein undergoes a condensation reaction in the same manner as that of the repeating unit m.

[0035] Furthermore, in order to provide the copolymer of the present invention having a narrow molecular weight distribution, it is preferable to produce the precursor copolymer represented by formula (II) (for example, when A in formula (II) is represented by (i)') according to the following synthesis scheme. JPEG0007795788000012.jpg112170

[0036] Here, compound 1 is either commercially available or prepared by a method similar to that of the manufacturer and has as narrow a molecular weight distribution as possible. Compound 1 is subjected to living ring-opening polymerization of N-carboxylic anhydride of ornithine having a protected amino group at the δ position, and then compound 2 is produced by a method known per se, in which the reaction is terminated using a living terminal modifier such as acetic anhydride, and the amino-protecting group in the poly(L-ornithine) segment is then removed.

[0037] According to such a reaction treatment using Compound 1 as a raw material, poly(L-ornithine) segments can also be provided as precursor copolymers with extremely narrow molecular weight distribution.

[0038] Therefore, the finally obtained block copolymer represented by formula (I) according to the present invention can be provided with a molecular weight distribution of 1.01 to 1.20, preferably 1.01 to 1.06.

[0039] On the other hand, when A in formula (II) is defined as (ii)', the starting material compound 1 in the above reaction scheme is NH2CH2CH2-(OCH2CH2) n The A moiety of each of the following compounds 2 to 4 can be a repeating unit corresponding to m repeating units. The triblock copolymer thus obtained, in which A in formula (II) is defined as (ii)', can be represented by the following formula (III): JPEG0007795788000013.jpg53170In the formula, L, L', Y, Y', m, m', and n are as defined in formula (II) above. It is expressed as:

[0040] As another example, the copolymer can also be synthesized by starting from the above compound 1 using a synthesis method as shown in the following scheme. JPEG0007795788000014.jpg65170

[0041] <Ornithine microparticles> Ornithine microparticles can be produced by assembling the copolymer represented by formula (I) in water or an aqueous medium (which may contain a water-soluble organic solvent or a buffer). 10 and R 10 Because the polyornithine segments containing ' are hydrophobic, they are thought to aggregate and self-assemble to form ornithine microparticles with the polyornithine segments as the core and the PEG segments as the shell. For example, ornithine microparticles can be obtained by dissolving the copolymer represented by formula (I) in a polar organic solvent such as dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) and then dialyzing it against water, an aqueous solution, or a buffer solution.

[0042] Although there are no particular limitations on the ornithine microparticles (or organized bodies), from the viewpoint of ease of administration or manufacturing, it is preferable that the average particle diameter is 1 mm or less, preferably 1 nanometer to 1 mm, and more preferably 1 nanometer to 100 micrometers. Furthermore, it is further preferable that the average particle diameter is 10 nanometers to 200 nanometers, and most preferably 20 nanometers to 70 nanometers. The particle size can be measured by dynamic light scattering (DLS) in water or an aqueous medium.

[0043] For example, polyion complex particles (PICs) can be obtained by adding a solution of a polyanionic compound polymer such as chondroitin to Compound 3 or Formula (II) to form a complex. On the other hand, the ornithine microparticles of the present invention are obtained by the self-assembly of poly(ethylene glycol)-β-poly(ornithine) copolymer or its derivative alone in an aqueous medium, and are characterized by not being formed into a complex with other polyanionic compound polymers. Therefore, the ornithine microparticles of the present invention are distinguished from PICs.

[0044] Thus, preferably, the ornithine particles of the present invention are characterized by comprising poly(ethylene glycol)-β-poly(ornithine) polymer or its derivatives as the main component, and not containing polyanionic polymers, etc. Examples of polyanionic polymers include polyacrylic acid, polymethacrylic acid, polysulfonic acid, polyanionic polysaccharides, anionic proteins, etc. More specifically, chondroitin sulfate, carrageenan, heparin, carboxymethyl dextran, xanthan gum, hyaluronic acid, polyaspartic acid, polyglutamic acid, polyacrylic acid, polymethacrylic acid, polyvinyl sulfate, polystyrene sulfonic acid, etc. However, the ornithine microparticles of the present invention may contain aqueous media, solvents, etc., as long as they do not adversely affect the stability of the particles.

[0045] The obtained ornithine microparticles can be separated by separation means such as centrifugation, and can be stored as a dry composition by freeze-drying, and can be reconstituted in an aqueous medium as needed. Such a dry composition can be provided as an aqueous solution of ornithine microparticles containing a physiologically acceptable diluent or excipient as needed. Such diluents can be sterilized water, physiological saline, a solution containing a physiologically acceptable buffer, etc., and further additives can be, for example, sorbitol, dextrin, glucose, mannitol, amino acids (e.g., glycine, isoleucine, valine, methionine, glutamic acid, etc.), etc.

[0046] In other words, as described above, the present invention provides, as one embodiment, the following method for producing ornithine microparticles: That is, the present invention comprises reacting a copolymer represented by the above formula (II) with a carboxylic acid ester compound to convert R 10 (wherein R 10 is R 11 -(C=O)-, and R 11 is a substituted or unsubstituted C1-C 21 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C1-C 21 Alkoxy, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 and assembling the resulting copolymer in water. <Additional Copolymers (which may contain novel compounds) that can be used together with or independently of the additives described above or below as other additives> The copolymer represented by formula (I) or ornithine microparticles made from said copolymer may be provided as a pharmaceutical composition containing the following copolymer, together with or independently of the additives mentioned above, for example, a pharmaceutical composition for preventing or treating liver dysfunction: A copolymer represented by formula (IV): In the formula, A ASP and L ASP has the same definition as A(i) and L in formula (I), and specifically, the explanation for L in formula (I) is applicable. ASP has the same definition as Y in formula (I). ASP is a hydrogen atom, substituted or unsubstituted C1-C 21 alkyl, substituted or unsubstituted aryl, and when these substituents are substituted, the substituents are C 1-4 Alkyl, C 1-4 alkoxy, aryl, and the C1-C 21 For alkyl and aryl, R in formula (I) 11Furthermore, the explanation for L ASP Specific examples of the linking group are the same as those specifically explained for L. m A is an integer of 2 to 300, preferably 15 to 150, and more preferably 15 to 100, n A is an integer of 2 to 1,000, preferably 10 to 500, and more preferably 30 to 400. The copolymer represented by formula (IV) can be obtained by using, for example, an N-carboxylic acid anhydride of a benzyl or alkylated β-carboxyl of aspartic acid instead of an N-carboxylic acid anhydride of ornithine with a protected δ-amino group in the reaction scheme from compound 1 to compound 4, and subjecting the N-carboxylic acid anhydride to living ring-opening polymerization at the omega (ω)-terminal amino group of compound 1, thereby providing a compound in which the m protected ornithine units in compound 2 are replaced with protected aspartic acid units. If necessary, the compound thus provided can be obtained through known procedures such as elimination of protecting groups, esterification, and alkyl group exchange reaction. ASP When is a hydrogen atom or benzyl, the compounds represented by formula (IV-a) may include known compounds, but other compounds represented by formula (IV-a) are, to the best of the inventors' knowledge, copolymers not described in prior art literature. Such copolymers can also self-assemble in aqueous media to form microparticles with sizes similar to those of the copolymer represented by formula (I). Since low molecular weight L-aspartic acid also has the effect of excreting harmful ammonia from the body, similar to low molecular weight L-ornithine, the copolymer represented by formula (IV) can also enhance the action or effect of the copolymer of formula (I) or can increase the stability of a pharmaceutical composition containing the copolymer of formula (I) or microparticles (organized bodies) thereof. A copolymer represented by formula (V): In the formula, A CO , L CO , n CO , R ASP , m A are the A's defined for formula (IV) above. ASP , L ASP , nA , R ASP , m A It is synonymous with A ORN , R ORN , m O and Y CO are the same as A(i), R, m, n and Y defined in formula (I), respectively. ASP Each unit in m ORN Each unit in the set can occur randomly. The copolymer represented by formula (V) can be obtained by, in the reaction scheme from compound 1 to compound 4 described above, substituting the N-carboxylic anhydride of ornithine with a protected δ-amino group with, for example, a mixture of the N-carboxylic anhydride of the benzyl β-carboxyl of aspartic acid and the N-carboxylic anhydride of ornithine with a protected δ-amino group, and subjecting these N-carboxylic anhydrides to living ring-opening polymerization with the omega (ω)-terminal amino group of compound 1 and the newly generated amino group. This provides a polymer in which the m protected ornithine units in compound 2 are randomly replaced with protected aspartic acid units and protected ornithine units, and can be obtained through known methods such as elimination of protecting groups, esterification, and / or acylation. The copolymer thus provided can also be organized in the same manner as the copolymer of formula (I). The copolymer represented by formula (V) can also have the same functions and effects as the copolymer represented by formula (I) or (IV) and their compositions. A copolymer of formula (VI): In the formula, A ARG , L ARG , n G , m G , Y ARG are the A's defined for formula (IV) above. ASP , L ASP , n A , m A , Y ARG is synonymous with R ARG and R ARG’ are independently R as defined for formula (IV) above. ASPThe copolymer of formula (IV) is advantageously a copolymer of formula (IV) and formula (IV) described in WO 2016 / 167333 A1. ARG and R ARG’ are H and Y ARG is defined as Y in formula (IV) ASP R is a copolymer that can be synonymous with ARG and R ARG’ The copolymers can be prepared by reacting them with an acid anhydride or carboxylic acid capable of forming the formula (I). The copolymers prepared in this manner can be organized without using a polyanionic polymer. In addition to the effects (antitumor effects) described in WO 2016 / 167333 A1, these copolymers and their organized products have been confirmed to exhibit antitumor effects in lung cancer metastasis model mice and subcutaneously transplanted cancer model mice, significantly reducing the adhesion of melanoma cells to the lungs, when administered orally (data not published). However, they may have the same effects and properties as the copolymers of formula (I) and their organized products.

[0047] <Composition for preventing or treating liver dysfunction> The ornithine microparticles (or assemblies) formed from the copolymer of formula (I) of the present invention are used as compositions for preventing and treating liver damage. That is, in one embodiment, the present invention provides a pharmaceutical composition that uses the ornithine microparticles of the present invention as an active ingredient and is used to prevent or treat liver dysfunction.

[0048] Ornithine functions as a substrate for urea synthesis in the body and activates enzymes in the urea cycle, including carbamyl phosphate synthase (CPS) and ornithine transcarbamylase (OTC). Through these actions, ornithine is expected to be effective in preventing and treating liver damage.

[0049] When ornithine microparticles of the present invention are orally administered, they accumulate in the intestinal mucosa and are gradually enzymatically degraded, causing the amide bonds inside the polymer to be hydrolyzed and releasing ornithine. As a result, they act effectively in the body, have high bioavailability, and are very effectively used in the prevention or treatment of liver dysfunction, as shown in the model animal experiments in the examples.

[0050] Liver dysfunction includes viral liver disease, drug- and alcohol-related liver disease, immune-mediated liver disease, metabolic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver failure, fulminant hepatic failure, hepatocellular carcinoma, and complications of liver transplantation.

[0051] The pharmaceutical composition of the present invention, ornithine microparticles or its aqueous solution, can be orally administered to mammals, particularly humans, that require administration.The pharmaceutical composition of the present invention has low toxicity, and is easily accumulated in the liver after injection, etc., and has the property of being hydrolyzed there to release ornithine, so it can be directly administered to veins, arteries, subcutaneously, abdominal cavity, etc., but is more advantageously used as an oral administration agent, because it is more effective in the intestine.

[0052] Examples of dosage forms of pharmaceutical compositions include liquids (including oral solutions, suspensions, emulsions, and syrups), solids (including tablets, pills, sublingual tablets, capsules, drops, and lozenges), granules, powders, and other powders. Solids can also be coated as needed into dosage forms known in the art, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, and multi-layered tablets. The shape and size of each dosage form may be within the range of dosage forms known in the art, and additives such as solubilizers, pH adjusters, carriers, excipients, diluents, binders, disintegrants, lubricants, emulsifiers, bulking agents, colorants, flavorings, sweeteners, stabilizers, and preservatives may be added.

[0053] The dosage and frequency of administration are adjusted within an optimal concentration range depending on the patient's age, sex, condition, severity of disease, etc., but it is preferable that the ornithine equivalent amount administered per day is approximately 10 μmg to 1 g per kg of body weight, more preferably 0.1 mg to 100 mg, and this amount may be administered in 1 to 3 divided doses, but since this pharmaceutical composition has high availability, it can be expected to be effective even when administered once a day.

[0054] The optimal dosage, administration method, and number of administrations can be determined by a person skilled in the art through animal experiments or experimental administration to humans, with reference to various literature. [Example]

[0055] The present invention will be described in more detail below with reference to specific examples, but it is not intended that the present invention be limited to these examples.

[0056] Production Example 1: Synthesis of CH3O-(CH2CH2O)n-CH2CH2OSO2CH3 (N813) To commercially available CHO-(CHCHO)nH (MW=5,000, 60 g, 12 mmol), THF (200 mL) and butyllithium (14.4 mL, 23 mmol, 1.6 M hexane) were added, followed by methanesulfonyl chloride (CHSOCl) (1.5 mL, 2.3 g, 20 mmol), and the mixture was allowed to react at 40°C for one day. The product was precipitated in 2-propanol (IPA), then dissolved in methanol and precipitated again. This procedure was repeated twice, and the precipitate was dried under reduced pressure to obtain the desired product (yield: 60 g).

[0057] Production Example 2: Synthesis of CHO-(CHCHO)-CHCHNH (N819) 600 mL of 28% aqueous ammonia was added to 60 g of CHO-(CHCHO)-CHCHOSOCH obtained in Preparation Example 1, and the mixture was allowed to react at 50°C for one day. It was then extracted with 50 mL of chloroform, the chloroform phase was dehydrated with NaHSO, filtered, and precipitated in 2-propanol (IPA). The resulting precipitate was dissolved in methanol and precipitated again. This procedure was repeated twice, and the precipitate was dried under reduced pressure to obtain the desired product (yield: 54 g).

[0058] Production Example 3: Synthesis of L-ornithine(Z)-N-carboxylic anhydride (L-Orn(Z)-NCA) (N831) Boc-ornithine(Z)-OH (Boc-Orn(Z)-OH, 15 g) was dissolved in 100 mL of THF and cooled to 0°C. A solution of thionyl chloride (SOCl2, 10 mL, 16 g) in 50 mL of THF was added and the mixture was allowed to react at 0°C for 1 hour and at room temperature for 3 hours. The reaction solution was poured into 1 L of hexane, and the precipitate was filtered. The precipitate was dissolved in 100 mL of ethyl acetate, precipitated in 1 L of hexane, and filtered. This process was repeated twice, and the resulting precipitate was dried under reduced pressure to obtain the desired product (yield: 10 g).

[0059] Production Example 4: Synthesis of CHO-(CHCHO)-CHCHNH-(COCH(CHCHCHNH(Z))NH)H (N857) N819 (5 g) obtained in Production Example 2 was dissolved in 30 mL of DMF, and a DMF (20 mL) solution of N831 (5 g) obtained in Production Example 3 was added thereto, followed by stirring at room temperature for 2 days. This solution was added to hexane:2-propanol (8:2, 500 mL), and the polymer was obtained by centrifugation. The polymer was then dried under reduced pressure to obtain the target product (6.3 g). The NMR measurement results of the obtained N857 are shown in Figure 1.

[0060] Production Example 5: Synthesis of CHO-(CHCHO)-CHCHNH-(COCH(CHCHCHNH)NH)H (PEG-b-POrn); N967) N833 (4.3 g) obtained in Production Example 4 was dissolved in 45 mL of trifluoroacetic acid, and after ice-cooling to 0°C, 3% HBr (acetic acid solution, 15 mL) was added and reacted for 4 hours. This was poured into 800 mL of cooled 2-propanol to obtain a precipitate, which was then dried in vacuo to obtain the target product (yield 3.3 g). The NMR measurement results of the obtained N967 are shown in Figure 2.

[0061] Preparation Example 6: Synthesis of CHO-(CHCHO)-CHCHNH-(COCH(CHCHCHNHC(=O)CH)NH)C(=O)CH (PEG-b-POrn(COCH); N977) N967 (1 g) obtained in Production Example 5 was dissolved in 1 mL of DMF, and 5 mL of triethylamine and 10 mL of acetic anhydride were added and reacted at room temperature for 1 hour. This was then added to hexane:2-propanol (8:2, 500 mL), centrifuged to obtain a polymer, which was then dried under reduced pressure to obtain the target product (1.0 g). The NMR measurement results of the obtained N977 are shown in FIG.

[0062] Preparation Example 7: Synthesis of CHO-(CHCHO)-CHCHNH-(COCH(CHCHCHNHC(=O)CH(CH))NH)C(=O)CH(CH) (PEG-b-POrn(COCH(CH)); N841) The target polymer (1.4 g) was obtained in exactly the same manner as in Production Example 6, except that isobutyric anhydride was used instead of acetic anhydride. The NMR measurement results of the obtained N841 are shown in FIG.

[0063] Production Example 8: Polyion complex particles (Nano) of CHO-(CHCHO)-CHHNH-(COCH(CHCHCHNH)NH)H and chondroitin sulfate ORN ) PEG-b-POrn (N836, 1 g) prepared in the same manner as in Preparation Example 5 was dissolved in 20 mL of DMF, 20 mL of water was added, and the solution was placed in a dialysis membrane (molecular weight cutoff (MWCO) = 3.5 kDa) and dialyzed against 0.01 M HCl (2 L) for 24 hours. This was then dialyzed against 2 L of distilled and ion-exchanged water (DI water) for 48 hours (the dialysis water was changed every 12 hours) to obtain an aqueous solution (85 mL). The total cation charge in this aqueous solution was calculated, and chondroitin sulfate solution (2.7 mg / mL, 115 mL) was added so that the ratio of the total anion charge to the total cation charge was 1:1. The resulting mixture was stirred for 30 minutes to form polyion complex (PIC) particles (Nano ORN ) was obtained.

[0064] Production example 9: PEG-b-POrn(Z) structured body (Nano ORN(Z) Preparation of N833 (1 g) synthesized in Production Example 4 was dissolved in 20 mL of DMF, and 20 mL of DI water was added. The solution was placed in a dialysis membrane (molecular weight cutoff (MWCO) = 12 KDa-14 KDa) and dialyzed against 2 L of DI water for 72 hours (the dialysis water was changed every 12 hours) to obtain an aqueous solution.

[0065] Production example 10: PEG-b-POrn(COCH3) structured body (Nano ORN(Me) Preparation of It was prepared in exactly the same manner as in Production Example 9, except that N977 (1 g) synthesized in Production Example 6 was used.

[0066] Production example 11: PEG-b-POrn(COCH(CH3)2) structured body (Nano ORN(iBu) Preparation of (N978) The assembly was prepared in the same manner as in Production Example 9, except that N841 (1 g) synthesized in Production Example 7 was used. ORN(iBu) The results of dynamic light scattering measurements of the 2000-kJ / kg sample are shown in Figure 5.

[0067] Test Example 1: Stability of nanostructured bodies The change in size of the nano-organized particles prepared in Production Examples 9 to 11 as a function of pH is shown in Figure 6. All particles are stable with no change in size or scattering intensity up to a pH of about 12. In Figures 6, 7, and other descriptions, the Nano XX The XX part may be written as NanoXX without being a superscript, but this is equivalent to a superscript.

[0068] Test Example 2: Effect of oral administration of organized ornithine on acetaminophen (APAP)-induced acute liver damage in mice Six C57BL / 6N male mice per group were given free access to the following samples (ornithine content was adjusted to approximately 200 mg / kg for groups 3 to 7) in water. Three days after the start of administration, APAP aqueous solutions (15 mg / mL, 0.5 mL, 300 mg / kg-BW) were intraperitoneally administered. 24 hours later, blood and liver samples were collected. Whole blood was used to measure blood ammonia levels, and plasma was used to measure liver damage markers AST and ALT. Livers were stained with hematoxylin and eosin for histological diagnosis.

[0069] Group 1: Healthy group Group 2: APAP administration group Group 3: APAP administration group / 2 mg / mL L-ornithine orally and free access to water Group 4: APAP administration group / 5mg / mL Nano ORN Oral free water intake Group 5: APAP administration group / 5 mg / mL PEG-b-POrn(Z) composite (Nano ORN(Z) ) Oral free Water intake Group 6: APAP administration group / 5 mg / mL PEG-b-POrn(COCH3) composite (Nano ORN(Me) ) Oral Ad libitum water intake Group 7: APAP administration group / 5 mg / mL PEG-b-POrn(COCH(CH3)2) composite (Nano ORN(iBU) ) Oral free water intake

[0070] As shown in Figure 7a), the blood ammonia concentration in the APAP-administered group was significantly higher than that in the healthy group, and low-molecular-weight ornithine was unable to lower it. ORN Although PEG-b-POrn(COCH(CH3)2) assembly (Nano ORN(iBu) ) Nano ORN It was confirmed that it significantly reduces the

[0071] Figure 7b) and c) show the blood aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Both values ​​increased significantly with APAP administration, indicating liver damage. Both AST and ALT levels were significantly elevated in the Nano ORN (PIC: ion complex), PEG-b-POrn(COCH3) assembly (Nano ORN(Me) ) and PEG-b-POrn(COCH(CH3)2) assemblies (Nano ORN(iBu) ) was decreased by APAP administration.

[0072] Figure 8 shows hematoxylin and eosin (H&E) stained liver tissue sections from these tests. Necrosis of the liver tissue was observed in the APAP-administered group. ORN , Nano ORN(Z) Although the same trend is observed in Nano ORN(Me) and Nano ORN(iBu) The necrosis is significantly suppressed.

[0073] Test Example 3: Effect of oral administration of ornithine tissue to healthy C57 / BL mice (toxicity evaluation) Six C57BL / 6N male mice per group were orally administered 0.5 mL of the following sample (adjusted to an ornithine content of approximately 200 mg / kg for groups 2 to 7) using a gavage syringe. Body weight was measured daily, and after four days of administration, whole blood was used to measure blood counts, and plasma was used to measure liver damage markers AST and ALT.

[0074] n=6 Group 1: Healthy group Group 2: 10 mg / mL L-ornithine oral gavage (probe) Group 3: 20 mg / mL PEG-b-Orn oral gavage (sonde) Group 4: 20 mg / mL Nano ORN Oral gavage (probe) Group 5: 20 mg / mL PEG-b-POrn(Z) assembly (Nano ORN(Z) ) Oral gavage (probe) Group 6: 20 mg / mL PEG-b-POrn(COCH3) assembler (Nano ORN(Me) ) Oral gavage (probe) Group 7: 20 mg / mL PEG-b-POrn(COCH(CH3)2) assembler (Nano ORN(iBu) ) Oral gavage (probe)

[0075] Figure 9 shows the changes in mouse body weight. A significant weight loss was observed after oral gavage of PEG-b-POrn, confirming toxicity. As shown in Figure 10, the changes in body weight were observed after oral gavage of PEG-b-POrn and Nano ORN In the group administered with Nano, an increase in the number of white blood cells and a decrease in the number of red blood cells were observed. ORN(iBu) There is almost no change and no toxicity is observed.

[0076] Test Example 4: Effect of oral administration of ornithine complex on acetaminophen (APAP)-induced acute liver damage in mice (2) Six C57BL / 6N male mice per group were orally administered 0.5 mL of the following sample (adjusted to an ornithine content of approximately 200 mg / kg for groups 3 to 5) using a gavage syringe. Three days after the start of administration, APAP aqueous solutions (15 mg / mL, 0.5 mL, 300 mg / kg-BW) were intraperitoneally administered. The survival of the mice was then monitored for up to 14 days.

[0077] Group 1: Healthy group Group 2: APAP administration group Group 3: APAP group / 10 mg / mL L-ornithine + 10 mg / mL L-aspartic acid oral gavage (sonde) Group 4: APAP administration group / 20mg / mL Nano ORN Oral gavage (probe) Group 5: APAP administration group / 20 mg / mL PEG-b-POrn(COCH(CH3)2) composite (Nano ORN(iBu) ) Oral gavage (probe)

[0078] As shown in Figure 11, the survival rate after 14 days in the APAP-administered group was 33%, while that in the Nano ORN In the group administered Nano, 50% ORN(iBu) The group receiving the drug had an extremely high survival rate of 83%, demonstrating its high effectiveness.

[0079] Reference Production Example 1: Synthesis of CHO-CH-CHO-(CHCHO)-CHCHOSOCH (N953(2)) In a 100 mL flask, 50 mL of ultra-dehydrated THF was added to commercially available CHOCHCHOH (1 mmol), potassium naphthalene (1 mmol), and ethylene oxide (115 mmol). The mixture was allowed to react under water cooling for 1 day, after which methanesulfonyl chloride (5 mmol) was added. After 20 minutes, the mixture was poured into 500 mL of 2-propanol to precipitate, and then dissolved in methanol and precipitated again. This procedure was repeated twice, and the precipitate was dried under reduced pressure to obtain the target product.

[0080] Reference Manufacturing Example 2: Synthesis of CHO-CH-CHO-(CHCHO)-CHCHNH (N956) 600 mL of 28% aqueous ammonia was added to the CHO-C6H5-CHO-(CH2CHO)n-CH2CH2OSO2CH3 obtained in Experimental Example 1, and the mixture was allowed to react at 50°C for one day. The mixture was then extracted with 50 mL of chloroform. The chloroform phase was dehydrated with NaHSO4, filtered, and precipitated in 2-propanol (IPA). The resulting precipitate was dissolved in methanol and precipitated again. This procedure was repeated twice, and the precipitate was dried under reduced pressure to obtain the target product.

[0081] Reference Production Example 3: Synthesis of CH3O-C6H5-CH2O-(CH2CH2O)n-CH2CH2NH-(CO(CH2CH2CH2NH(Z))NH)m- H (N962) N956 obtained in Reference Production Example 2 was dissolved in DMF, and a DMF solution of commercially available N-benzyl-aspartic acid (NCA) was added and stirred at room temperature for 2 days. This solution was added to hexane:2-propanol (8:2, 500 mL), centrifuged to obtain a polymer, which was then dried under reduced pressure to obtain the target product.

[0082] Reference Production Example 4: Synthesis of CHO-C6H5-CH2O-(CH2CH2O)n-CH2CH2NH-(CO(CH2CH2CH2NH2)NH)mH (PEG-b-POrn); N973) N962 obtained in Reference Production Example 3 was dissolved in trifluoroacetic acid, ice-cooled to 0°C, and then 3% HBr (acetic acid solution) was added and reacted for 4 hours. This was added to 800 mL of cooled 2-propanol to obtain a precipitate, which was then dried in vacuo to obtain the target product.

[0083] Production Example 12: Synthesis of CHO-C6H5-CHO-(CHCHO)-CHCHNH-(CO(CHCHCHNHC(=O)CH(CH))NH)H (PEG-b-POrn(COCH(CH)); N978) The target polymer (1.4 g) was obtained in exactly the same manner as in Production Example 7, except that N973 synthesized in Reference Production Example 4 was used instead of N841.

[0084] Test Example 5: 125 Kinetic analysis using I-labeled PEG-b-POrn(COCH(CH3)2) N978 synthesized in Production Example 125 was dissolved in DMSO and dialyzed against 2 L of DI water for 72 hours (the dialysis water was changed every 12 hours) to obtain an aqueous solution of the organized body. 125 By mixing I, the phenyl group introduced at the end of the PEG chain is 125 Labeled with I.

[0085] To investigate pharmacokinetics, 15 ICR mice were prepared, three for each endpoint: 0.5 h, 1 h, 2 h, 4 h, and 24 h. After oral administration of the labeled tissues by gavage, the mice were sacrificed at each endpoint. The heart, lungs, digestive tract, liver, spleen, kidneys, and blood were extracted, and the radioactivity of each organ was measured using a gamma counter. As shown in Figure 12, 125 I-labeled Nano ORN(iBu) was localized in the gastrointestinal tract and was hardly detected in the blood or organs.

[0086] Preparation Example 13: Synthesis of PEG-b-Orn(iBu)-TAMRA or PEG-b-Orn(iBu)-Cy5 The former target compound was synthesized in exactly the same manner as in Production Example 7, except that 1 mg of commercially available TAMRA-N=C=S was added before the addition of isobutyric anhydride and the reaction was carried out for 10 minutes.

[0087] The latter target compound was synthesized in exactly the same manner as in Production Example 7, except that 1 mg of commercially available Cy5-NHS was added before the addition of isobutyric anhydride and the reaction was carried out for 10 minutes.

[0088] Test Example 6: Nano Porn In vitro toxicity evaluation of Prepare 5-10 × 10 BAEC (bovine aortic endothelial cells), L-929 (mouse fibroblasts), and RAW264.7 (mouse macrophages) cells. 3 The cells were seeded in a 96-well plate. ORN(Z) , Nano ORN(Me) , Nano ORN(iBu) , and Nano ORN was added to each well. After culturing for 24 or 48 hours, MTT reagent was added. After another 4 hours, DMSO was added to solubilize the formazan crystals. Absorbance was measured at a wavelength of 575 nm.

[0089] The results are shown in Figure 13. ORN(Z) , Nano ORN(Me) For L-929 cells, Nano ORNshowed relatively high toxicity to RAW264.7 macrophage cells, whereas Nano ORN(iBu) It was shown that it showed almost no cytotoxicity and was extremely safe. Production Example 14: Synthesis of CH3O-(CH2CH2O)n-CH2H2NH-(COCH(CH2COOCH2Ph)NH)mH (N865)(PEG-b-PBLA) JPEG0007795788000015.jpg27170 N819 (10 g), synthesized according to Preparation Example 2, was dissolved in 60 mL of DMF. 10 g of commercially available L-aspartic acid (CH2Ph)-N-carboxylic anhydride (L-ASP(Z)-NCA) was dissolved in 40 mL of DMF. The two were mixed and reacted at room temperature for two days. The resulting polymer was precipitated in 2-propanol (IPA), dissolved in acetone, and precipitated in hexane. This procedure was repeated twice, and the precipitate was dried under reduced pressure to obtain the target product. (Yield: 16 g; n=114; m=15.5) Production Example 15: Synthesis of L-aspartic acid (Me)-N-carboxylic anhydride (L-ASP(Me)-NCA) (N871) Commercially available L-aspartic acid 4-methyl ester hydrochloride (15 g; 81.6 mmol) was dissolved in 90 mL of THF, and α-pinene (33 g; 252 mmol) and triphosgene (12.2 g; 40.8 mmol) were added. The mixture was allowed to react at 50°C for 2 hours. The reaction solution was poured into 1 L of hexane, and the precipitate was filtered. The solution was then dissolved in 100 mL of 2-propanol, precipitated in 1 L of hexane, and filtered. This process was repeated twice, and the resulting precipitate was dried under reduced pressure to obtain the desired product (yield: 10.2 g). Production Example 16: Synthesis of CHO-(CHCHO)-CHHNH-(COCH(CHCOOCH)NH)H (N869) (PEG-b-PASP(Me)) JPEG0007795788000016.jpg24170 5 g of N819 synthesized according to Preparation Example 2 was dissolved in 30 mL of DMF. 5 g of L-aspartic acid (CH3)-N-carboxylic anhydride (L-ASP(Me)-NCA) synthesized in Preparation Example 15 was dissolved in 20 mL of DMF. The two were mixed and reacted at room temperature for 2 days. The resulting polymer was precipitated in 2-propanol (IPA), dissolved in methanol, and precipitated in ether. This procedure was repeated twice, and the precipitate was dried under reduced pressure to obtain the target product. (Yield: 6.4 g; n=114; m=10) Production Example 17: Synthesis of PEG-bP(Orn(Z)-co-Asp(CHPh)) (N877) JPEG0007795788000017.jpg35170PEG-NH2(N866) (5 g; 1 mmol) synthesized according to Preparation Example 2 was dissolved in 30 mL of DMF. L-Orn(Z)-NCA (N854) (6 g; 20 mmol) synthesized according to the manufacturing example and commercially available L-aspartic acid (CHPh)-N-carboxylic anhydride (L-ASP(Z)-NCA) (2.5 g; 10 mmol) were dissolved in 20 mL of DMF. The two were mixed and reacted at room temperature for 2 days. The resulting polymer was precipitated in 2-propanol (IPA) / hexane (1:9 v / v), then dissolved in acetone and precipitated in hexane. This procedure was repeated twice, and the precipitate was dried under reduced pressure to obtain the desired product. (Yield: 8.8 g; n=114; number of asparagine units: 15; number of ornithine units: 20) Production example 18: PEG-b-PBLA structured body (Nano ASP(Bz) Preparation of N865 (1 g) synthesized according to Preparation Example 14 was dissolved in 20 mL of DMF, and 20 mL of DI water was added. The solution was placed in a dialysis membrane (molecular weight cutoff (MWCO) = 12 kDa-14 kDa) and dialyzed against 2 L of DI water for 72 hours (the dialysis water was changed every 12 hours) to obtain an aqueous solution containing the desired organized body. Production example 19: PEG-b-PASP(Me) structured body (Nano ASP(Me) Preparation of The same procedure as in Preparation Example 18 was repeated except that N869 (1 g) synthesized according to Preparation Example 16 was used, to obtain an aqueous solution containing the desired assembled bodies. Production example 20: PEG-bP(Orn(Z)-co-Asp(CH2Ph)) tissue (Nano ASP / ORN Preparation of (N978) The same procedure as in Preparation Example 18 was repeated except that N877 (1 g) synthesized according to Preparation Example 17 was used, to obtain an aqueous solution containing the desired assembled bodies. Test Example 7: Nano ASP(Bz) , Nano ASP(Me) , Nano ASP / ORN Stability evaluation of The particle size of each of the particles produced in Production Examples 16 to 18 was measured by dynamic light scattering. Nano ASP(Bz) formed stable nanoparticles of approximately 120-140 nm up to pH 12 over 24 hours. Nano ASP(Me) At all pH values ​​measured, aggregates of approximately 10 nm were formed within 6 hours. After 24 hours, aggregates of approximately 100 nm were observed at pH 1 and 5. Nano ASP / ORN At all pH values ​​measured, the cellulose formed aggregates of approximately 100 nm for up to 24 hours. Also Nano ASP(Bz) , Nano ASP(Me) , Nano ASP / ORN According to the results of the weight change of mice with acute liver damage orally administered (by gavage), PEG-b-POrn(Z) assembled body (Nano ORN(Z) ) and PEG-b-POrn(Me) assemblies (Nano ORN(Me) ) showed no substantial toxicity to mice. Test Example 7: Effect of oral administration of the following samples on acetaminophen (APAP)-induced acute liver damage in mice The samples used were those shown in the following groups, and the method of Test Example 2 was repeated. Group 1: Healthy group Group 2: APAP administration group Group 3: APAP administration group / 200 mg / kg L-aspartic acid oral administration (sonde) Group 4: APAP administration group / 200 mg / kg PEG-b-POrn(Z) aggregate (Nano ORN(Z) ) Oral administration (sonde) Group 5: APAP administration group / 200 mg / kg PEG-b-POrn(Me) composite (Nano ORN(Me) ) Oral administration (sonde) Group 6: APAP administration group / 200 mg / kg PEG-b-PBLA composite (Nano ASP(Me) ) Oral administration (sonde) Group 7: APAP administration group / 200 mg / kg PEG-b-PAsp(Me) assembler (Nano ORN(Bz) ) Oral administration (sonde) Group 8: APAP administration group / 200 mg / kg PEG-b-PAsp(Me) assembler (Nano ASP / ORN ) Oral administration (sonde) As a result of the above test, these organized bodies showed weight changes equivalent to those of the healthy group, showed little toxicity, and also showed blood ammonia levels, AST and ALT levels in mice with acute liver damage, as shown in Figure 17. Preparation Example 21: Synthesis of PEG-b-PArg(Ac)2 (N1047) PEG-b-PArg (N1046; 2.4 g), synthesized in the same manner as in Example 5 of PCT / JP2016 / 62062 A1, was dissolved in 50 mL of DMF. 30 mL of acetic anhydride was added, and the mixture was reacted at 50°C for 5 hours and then at room temperature for 1 day. The resulting polymer was precipitated in t-butyl methyl ether and washed with hexane. This procedure was repeated twice, and the precipitate was dried under reduced pressure to obtain the target product. (Yield: 2.4 g; n=114; m=28) 1 The H-NMR chart is shown in Figure 18. Preparation Example 22: Synthesis of PEG-b-PArg(iBu)2 (N1063) The target product was obtained in exactly the same manner as in Production Example 21, except that acetic anhydride was replaced with isobutyric anhydride (yield: 2.4 g; n=114; m=28). 1 The H-NMR chart is shown in Figure 19. Preparation Example 23: PEG-b-PArg(Ac)2 Assembly (Nano Arg(Ac) Preparation of N1047 (1 g) synthesized according to Production Example 21 was dissolved in 20 mL of DMF, and 20 mL of DI water was added. The mixture was placed in a dialysis membrane (molecular weight cutoff (MWCO) = 12 KDa-14 KDa) and dialyzed against 2 L of DI water for 72 hours (dialysis water was changed every 12 hours). Arg(Ac) An aqueous solution containing the compound was obtained (average particle size 132 nm, zeta potential +4.9 mV). Preparation Example 24: PEG-b-PARG(iBu)2 Assembly (Nano Arg(iBu) Preparation of An assembled body was prepared in exactly the same manner as in Preparation Example 23, except that N1063 (1 g) synthesized in Preparation Example 22 was used. Average particle size: 44 nm, ζ potential: -2.2 mV Nano Arg(Ac) and Nano Arg(iBu) The results of measuring the light scattering particle size in the aqueous solution are shown in FIG. Test Example 8: Effects of oral and intravenous administration of acetylated arginine complex on acetaminophen (APAP)-induced acute liver damage in mice The method of Test Example 2 was repeated, except that acetylated arginine was used instead of the ornithine-organized compound. The results are shown in Figure 21. As shown in Figure 21, the acetylated polyarginine particles (Nano Arg(Ac) ) was ineffective when administered orally, but significantly reduced blood ammonia levels when administered intravenously. Test Example 9: Effect of oral administration of acetylated arginine constructs on non-alcoholic steatohepatitis (NASH) model mice Six C57BL / 6J male mice were placed in each group and injected with acetylated polyarginine particles (Nano Arg(Ac) ) aqueous solution ([Nano Arg(Ac)] = 5 mg / mL) was orally administered via free access to water (days 0-8). One day after the start of oral administration, mice were fed a choline-deficient, methionine-reduced, high-fat diet (CADHFD) (days 1-8). Blood and liver samples were collected on day 8 after the start of CADHFD feeding. Plasma was used to measure triglycerides (TG). GP1 Health Group GP2 CADHFD-fed group GP3 CADHFD feeding group / 5 mg / mL acetylated polyarginine particles (Nano Arg(Ac) ) aqueous solution was orally administered (free drinking water) GP4 CADHFD feeding group / 1.5 mg / mL L-arginine solution was orally administered (free drinking water) The results are shown in Figure 22. From the figure, it can be seen that oral administration significantly reduced triglycerides. [Industrial Applicability]

[0090] The copolymer and ornithine microparticles of the present invention can be used, but are not limited to, as a drug for preventing and treating liver dysfunction, and can be utilized at least in the pharmaceutical industry.

Claims

1. A copolymer represented by formula (I): 【Chemistry 1】 During the ceremony, A is, (i) a hydrogen atom, unsubstituted or substituted C １ -C １２ alkyl group, unsubstituted or substituted C 1 -C 12 represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituent is C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, aryl group, formyl group, formula R １ R ２ CH- (where R １ and R ２ is independent, C １ -C ４ Alkoxy or R １ and R ２ Let's get together -OCH ２ CH ２ O-, -O(CH ２ ) ３ O- or -O(CH ２ ) ４ O—) or (ii) Formula 【Chemistry 2】 represents L and L' independently represent a linking group. Y and Y′ are independently a hydrogen atom, C １－２１ Alkylcarbonyl, substituted C １－４ Alkylcarbonyl, unsubstituted or substituted C ３－７ represents a cycloalkylcarbonyl, an unsubstituted or substituted arylcarbonyl, or an unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein １－４ The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C ３－７ cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C １－４ It can be alkylamino, R １０ is R １１ -(C=O)-, and R １０ ' is hydrogen or R １１ -(C=O)-, and R １１ are each independently substituted or unsubstituted C １ -C ２１ Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C １ -C ２１ is an alkoxy, １ -C ２１ When the alkyl and the aryl are substituted, the substituents are C １－４ Alkyl, C １－４ alkoxy, aryl, １ -C ２１ When the alkoxy is substituted, the substituent is C １－４ Alkyl, C １－４ is an alkoxy; m and m' are independently integers from 2 to 300; n is an integer from 2 to 1,000.

2. 2. The copolymer of claim 1, wherein A is defined as (i).

3. 2. The copolymer of claim 1, wherein A is defined as (ii).

4. Formula (I): 【Transformation 3】 During the ceremony, A is, (i) a hydrogen atom, unsubstituted or substituted C １ -C １２ alkyl group, unsubstituted or substituted C 1 -C 12 represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituent is C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, aryl group, formyl group, formula R １ R ２ CH- (where R １ and R ２ is independent, C １ -C ４ Alkoxy or R １ and R ２ Let's get together -OCH ２ CH ２ O-, -O(CH ２ ) ３ O- or -O(CH ２ ) ４ O—) or (ii) Formula 【Chemistry 4】 represents Y and Y′ are independently a hydrogen atom, C １－２１ Alkylcarbonyl, substituted C １－４ Alkylcarbonyl, unsubstituted or substituted C ３－７ represents a cycloalkylcarbonyl, an unsubstituted or substituted arylcarbonyl, or an unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein １－４ The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C ３－７ cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C １－４ It can be alkylamino, R １０ and R １０ ' is a hydrogen atom or R １１ -(C=O)-, and R １１ are each independently substituted or unsubstituted C １ -C ２１ Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C １ -C ２１ and alkoxy, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ alkoxy, aryl, m and m' are independently integers from 2 to 300; n is an integer from 2 to 1,000, m or m' R in the formula １０ and R １０ 'More than 20% are R １１ -(C=O)-. The copolymer is represented by the formula: The copolymer is prepared by introducing an acyl group into the ornithine side chain amino group of poly(ethylene glycol)-b-poly(ornithine), Ornithine microparticles having an average particle size of 1 nanometer to 100 micrometers.

5. A pharmaceutical composition comprising the copolymer according to any one of claims 1 to 3 as an active ingredient and an additive.

6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is an oral administration agent.

7. A composition for preventing or treating liver dysfunction, comprising as an active ingredient the copolymer described in any one of claims 1 to 3 or the ornithine microparticles described in claim 4.

8. A pharmaceutical composition comprising as an active ingredient a copolymer according to any one of claims 1 to 3 or ornithine microparticles according to claim 4 and a copolymer represented by formula (IV). 【Transformation 5】 During the ceremony, A ＡＳＰ is a hydrogen atom, unsubstituted or substituted C １ -C １２ alkyl group, unsubstituted or substituted C 1 -C 12 represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituent is C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, aryl group, formyl group, formula R １ R ２ CH- (where R １ and R ２ is independent, C １ -C ４ Alkoxy or R １ and R ２ Let's get together -OCH ２ CH ２ O-, -O(CH ２ ) ３ O- or -O(CH ２ ) ４ represents a group of the formula: L ＡＳＰ represents a linking group R ＡＳＰ represents a hydrogen atom, a substituted or unsubstituted C １ -C ２１ alkyl, substituted or unsubstituted aryl, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ alkoxy, aryl, Y ＡＳＰ is a hydrogen atom, C １－２１ Alkylcarbonyl, substituted C １－４ Alkylcarbonyl, unsubstituted or substituted C ３－７ represents a cycloalkylcarbonyl, an unsubstituted or substituted arylcarbonyl, or an unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein １－４ The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C ３－７ cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C １－４ It can be alkylamino, m Ａ is an integer from 2 to 300, n Ａ is an integer from 2 to 1,000.

9. A pharmaceutical composition comprising as an active ingredient a copolymer according to any one of claims 1 to 3 or ornithine microparticles according to claim 4 and a copolymer represented by formula (V). 【Transformation 6】 During the ceremony, A ＣＯ is a hydrogen atom, unsubstituted or substituted C １ -C １２ alkyl group, unsubstituted or substituted C 1 -C 12 represents an alkoxy group, an unsubstituted or substituted aryl group, and when substituted, the substituent is C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, aryl group, formyl group, formula R １ R ２ CH- (where R １ and R ２ is independent, C １ -C ４ Alkoxy or R １ and R ２ Let's get together -OCH ２ CH ２ O-, -O(CH ２ ) ３ O- or -O(CH ２ ) ４ represents a group of the formula: n ＣＯ is an integer from 2 to 1,000, L ＣＯ represents a linking group R ＡＳＰ represents a hydrogen atom, a substituted or unsubstituted C １ -C ２１ alkyl, substituted or unsubstituted aryl, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ alkoxy, aryl, m Ａ is an integer from 2 to 300, R ＯＲＮ is a hydrogen atom or R １１ -(C=O)-, and R １１ are each independently substituted or unsubstituted C １ -C ２１ Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C １ -C ２１ and alkoxy, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ alkoxy, aryl, m Ｏ is an integer from 2 to 300, Y ＣＯ is a hydrogen atom, C １－２１ Alkylcarbonyl, substituted C １－４ Alkylcarbonyl, unsubstituted or substituted C ３－７ represents a cycloalkylcarbonyl, an unsubstituted or substituted arylcarbonyl, or an unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein １－４ The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C ３－７ cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C １－４ It can be alkylamino, Here, m Ａ repeating units and m Ｏ Each amino acid in the repeating unit occurs randomly to form another block.

10. A pharmaceutical composition comprising as an active ingredient a copolymer according to any one of claims 1 to 3 or ornithine microparticles according to claim 4 and a copolymer represented by formula (VI). 【Transformation 7】 During the ceremony, A ＡＲＧ is a hydrogen atom, unsubstituted or substituted C １ -C １２ represents an alkyl group, an unsubstituted or substituted aryl group, and when these substituents are substituted, the substituents are C １－４ Alkyl base, C １－４ Alkoxy group, aryl group, formyl group, formula R １ R ２ CH- (where R １ and R ２ is independent, C １－４ Alkoxy or R １ and R ２ Let's get together -OCH ２ CH ２ O-, -(CH ２ ) ３ O- or -(CH ２ ) ４ represents a group of the formula: n Ｇ is an integer from 2 to 1,000, L ＡＲＧ represents a linking group R ＡＲＧ and R ＡＲＧ’ are independently a hydrogen atom or R １１ -(C=O)-, and R １１ are each independently substituted or unsubstituted C １ -C ２１ Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C １ -C ２１ and alkoxy, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ alkoxy, aryl, m Ｇ is an integer from 2 to 300, Y ＡＲＧ is a hydrogen atom, C １－２１ Alkylcarbonyl, substituted C １－４ Alkylcarbonyl, unsubstituted or substituted C ３－７ represents a cycloalkylcarbonyl, an unsubstituted or substituted arylcarbonyl, or an unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein １－４ The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C ３－７ cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C １－４ It can be alkylamino.

11. A copolymer represented by formula (V): 【Transformation 8】 During the ceremony, A ＣＯ is a hydrogen atom, unsubstituted or substituted C １ -C １２ represents an alkyl group, an unsubstituted or substituted aryl group, and when substituted, the substituent is C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, aryl group, formyl group, formula R １ R ２ CH- (where R １ and R ２ is independent, C １ -C ４ Alkoxy or R １ and R ２ Let's get together -OCH ２ CH ２ O-, -O(CH ２ ) ３ O- or -O(CH ２ ) ４ represents a group of the formula: n ＣＯ is an integer from 2 to 1,000, L ＣＯ represents a linking group R ＡＳＰ represents a hydrogen atom, a substituted or unsubstituted C １ -C ２１ alkyl, substituted or unsubstituted aryl, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ alkoxy, aryl, m Ａ is an integer from 2 to 300, R ＯＲＮ is a hydrogen atom or R １１ -(C=O)-, and R １１ are each independently substituted or unsubstituted C １ -C ２１ Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C １ -C ２１ and alkoxy, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ alkoxy, aryl, m Ｏ is an integer from 2 to 300, Y ＣＯ is a hydrogen atom, C １－２１ Alkylcarbonyl, substituted C １－４ Alkylcarbonyl, unsubstituted or substituted C ３－７ represents a cycloalkylcarbonyl, an unsubstituted or substituted arylcarbonyl, or an unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein １－４ The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C ３－７ cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C １－４ It can be alkylamino, Here, m Ａ repeating units and m Ｏ Each amino acid in the repeating unit occurs randomly to form another block.

12. A copolymer represented by formula (VI-a): 【Chemistry 9】 During the ceremony, A ＡＲＧ is a hydrogen atom, unsubstituted or substituted C １ -C １２ represents an alkyl group, an unsubstituted or substituted aryl group, and when these substituents are substituted, the substituents are C １－４ Alkyl base, C １－４ Alkoxy group, aryl group, formyl group, formula R １ R ２ CH- (where R １ and R ２ is independent, C １－４ Alkoxy or R １ and R ２ Let's get together -OCH ２ CH ２ O-, -(CH ２ ) ３ O- or -(CH ２ ) ４ represents a group of the formula: n Ｇ is an integer from 2 to 1,000, L ＡＲＧ represents a linking group R ＡＲＧ and R ＡＲＧ’ are independently R １１ -(C=O)-, and R １１ are each independently substituted or unsubstituted C １ -C ２１ alkyl, substituted or unsubstituted aryl, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ alkoxy, aryl, m Ｇ is an integer from 2 to 300, Y ＡＲＧ is a hydrogen atom, C １－２１ Alkylcarbonyl, substituted C １－４ Alkylcarbonyl, unsubstituted or substituted C ３－７ represents a cycloalkylcarbonyl, an unsubstituted or substituted arylcarbonyl, or an unsubstituted or substituted 5- or 6-membered heteroarylcarbonyl, wherein １－４ The substituents of the alkylcarbonyl are halogen atoms, hydroxyl, carboxyl, unsubstituted or substituted C ３－７ cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted adamantyl, unsubstituted or substituted cholesterol residues, and when these substituents are substituted, the substituents are C １－４ Alkyl, C １－４ Alkyloxy, hydroxyl, carboxyl, cyano, nitro, halogen atoms, or mono- or di-C １－４ It can be alkylamino.

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