CNP conjugate dry pharmaceutical formulation

Abstract

To provide suitable formulations of CNP conjugates comprising CNP covalently linked via a reversible linker to a polymeric moiety, where the peptide will exhibit an acceptable impurity profile and limited premature CNP release even after extended storage.SOLUTION: A dry pharmaceutical formulation is provided. The pharmaceutical formulation comprises a CNP conjugate, a buffering agent, and a bulking agent. The CNP conjugate comprises a CNP moiety that is covalently and reversibly conjugated to a polymeric moiety.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a dry pharmaceutical formulation comprising a CNP conjugate, a buffer, and a volume extender. [Background technology]

[0002] Achondroplasia (ACH) is a genetic disorder caused by autosomal dominant mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, leading to abnormalities in cartilage formation and resulting in dwarfism. C-type natriuretic peptide (CNP) is a hormone that binds to and activates peptide receptor B (NPR-B), thereby inhibiting FGFR3 downstream signaling. This then induces cartilage growth and skeletal hypergrowth, as observed in both mice and humans overexpressing CNP. Overproduction of CNP in cartilage or continuous delivery of CNP via intravenous (iv) injection normalizes dwarfism in achondroplasic mice, suggesting that administration of CNP at hyperphysiological levels is a strategy for treating ACH.

[0003] Human prepro CNP, containing 126 amino acids, is further cleaved by furin to produce CNP-53. While CNP-53 is physiologically active, it is typically processed by an unknown mechanism to become the physiologically active 22-amino acid form, CNP-22, in circulation. The physiological activity of CNP is strictly regulated, and its clearance from plasma is very rapid. Therefore, considering CNP's short in vivo half-life (2 minutes after intravenous injection), its use as a therapeutic agent is difficult in pediatric populations, as it would require continuous infusion.

[0004] Various methods have been studied to lengthen the in vivo half-life of CNP. For example, Lorget et al. (Am. J. Hum. Genet. 91, 1108-1114, 2012) disclosed recombinant CNP-39 (also known as BMN111), which has pharmacological activity similar to human CNP, consisting of the 37 C-terminal amino acid of human CNP-53 plus glycine and proline added to the N-terminus of its peptide. BMN111 is more resistant to NEP cleavage, but this is associated with a short exposure to effective drug levels when administered once daily, due to its half-life of only 20 minutes. [Overview of the project] [Problems that the invention aims to solve]

[0005] The expansion of the in vivo half-life extension range of CNPs based on conjugation to water-soluble carrier moieties such as PEG via a reversible prodrug linker has been investigated in WO2016 / 110577A1, WO2017 / 118693A1, WO2017 / 118698A1, WO2017 / 118700A1, WO2017 / 118703A1, WO2017 / 118704A1 and WO2017 / 118707A1. However, no information is provided regarding formulations that enable the stable storage of these reversible conjugates.

[0006] Pharmaceutical formulations of CNP conjugates, in which a polymer is bound to CNPs via a reversible linkage, must provide sufficient CNP conjugate stability to avoid premature CNP release during storage. If the reversible linkage between the polymer and CNP deteriorates during storage, the concentration of the drug capable of exerting its therapeutic effect may increase, thereby creating a risk of overdose during administration, which could lead to hypotension.

[0007] Furthermore, any drugs released during storage undergo rapid renal clearance upon administration to the patient, resulting in a shorter time for long-acting compositions to deliver a therapeutically appropriate dose. This creates a risk that medical needs may not be met.

[0008] Furthermore, it is known that CNP or its variants, conjugates, or derivatives may undergo degradation reactions during storage, which can lead to the following impurities / peptide damage in the corresponding formulation. • Decomposition products resulting from the oxidation of methionine (Met / M) residues to methionine sulfoxide and methionine sulfone; For example, degradation products resulting from the isomerization of aspartic acid or aspartate residues (Asp / D) to isoaspartic acid or isoaspartate via succinimide intermediates; For example, degradation products resulting from the deamidation of asparagine residues (Asn / N) to aspartic acid or aspartate, and / or isoaspartic acid or isoaspartate, via succinimide intermediates; For example, degradation products resulting from the deamidation of glutamine residues (Gln / Q) to glutamic acid or isoglutamic acid via glutarimide intermediates; • Degradation products resulting from the isomerization of glutamic acid or glutamate residues (Glu / E) to isoglutamic acid or isoglutamate via a glutarimide intermediate; and • Aggregates resulting from the aggregation of peptides.

[0009] Since the degradation products or oligomers that may be generated during storage can impair the physiological activity of the CNP portion, it is desirable to reduce their generation. Furthermore, the reversible linkage between the CNP portion and the polymer portion makes it difficult to store pharmaceutical formulations containing CNP conjugates.

[0010] Therefore, it is important to identify a suitable formulation of a CNP conjugate containing CNPs covalently linked to the polymer portion via a reversible linker, which exhibits an acceptable impurity profile and limited early CNP release even after long-term storage of the peptide.

[0011] Therefore, the object of the present invention is to overcome at least partially the above-mentioned drawbacks. [Means for solving the problem]

[0012] This objective is achieved by a dry pharmaceutical formulation comprising a CNP conjugate, a buffer, and a volume extender, wherein the CNP conjugate comprises a CNP portion covalently and reversibly bonded to a polymer portion. [Effects of the Invention]

[0013] Surprisingly, the dried pharmaceutical formulation of the present invention has been found to enable stable long-term storage. [Modes for carrying out the invention]

[0014] Within the scope of the meaning of this invention, the terms are used as follows:

[0015] In this specification, the term “about” as used in combination with a number is used to indicate not only the number itself, but also a range of plus / minus 10% or less of the number, in a particular embodiment, 8% or less of the number, in a particular embodiment, 5% or less of the number, and in a particular embodiment, 2% or less of the number. For example, the phrase “about 200” is used to mean a range of 200+ / -10%, i.e., the range of 180 to 220; in a particular embodiment, a range of 200+ / -8%, i.e., the range of 184 to 216; in a particular embodiment, a range of 200+ / -5%, i.e., the range of 190 to 210; and in a particular embodiment, a range of 200+ / -2%, i.e., the range of 196 to 204. A percentage indicated as “about 20%” is understood not to mean “20%+ / -10%”, i.e., a range of 10 to 30%, but rather to mean a range of 18 to 22%, i.e., plus / minus 10% of the number 20.

[0016] As used herein, the term “antimicrobial agent” refers to chemical substances such as chemicals that kill or inhibit the growth of microorganisms such as bacteria, fungi, yeasts, protozoa, molds, and / or destroy viruses.

[0017] As used herein, the term “adsorption inhibitor” primarily refers to ionic or nonionic surfactants, proteins, or soluble polymers used to coat or competitively adsorb to the inner surface of a container holding a formulation. The selected concentration and type of excipient are determined by the effects to be avoided, but typically a single layer of surfactant is formed at the interface slightly above the critical micelle concentration (CMC).

[0018] As used herein, the term “bulking agent” refers to a compound that provides structure to a dried or lyophilized formulation. A bulking agent is added to a formulation to increase its total mass. In addition to providing a pharmaceutically acceptable formulation, bulking agents can also alter lyophilization process conditions by changing their decay temperature, thereby further enhancing peptide stability over long-term storage. Therefore, during the drying of a mixture containing a bulking agent, the bulking agent may act as a solubility protectant. During the regeneration of a dried pharmaceutical formulation into a regenerated pharmaceutical formulation, the bulking agent may act as an isotonic modifier.

[0019] As used herein, the terms “buffer” or “buffering agent” refer to compounds that maintain pH within a desired range. Physiologically tolerable buffers include, for example, sodium phosphate, succinates, histidine, bicarbonates, citrates, acetates, sulfates, nitrates, chlorides, and pyruvates. Antacids such as Mg(OH)2 or ZnCO3 may also be used.

[0020] As used herein, the term “CNP” means, in certain embodiments, all CNP polypeptides derived from mammalian species, e.g., humans and mammalian species, particularly humans and murid species, as well as their variants, analogs, orthologues, homologs and derivatives, and fragments thereof, which are characterized by their control of chondrocyte growth, proliferation and differentiation. The term “CNP” also includes all CNP variants, analogs, orthologues, homologs, derivatives and fragments thereof. CNP variants, analogs, orthologues, homologs, derivatives and fragments thereof disclosed in WO2009 / 067639A2 and WO2010 / 135541A2 are incorporated herein by reference.

[0021] As used herein, the term “CNP polypeptide variant” refers to a polypeptide derived from the same species but distinct from the reference CNP polypeptide. Generally, the differences are limited, so the amino acid sequences of the reference and the variant are very similar as a whole and identical in many regions. In certain embodiments, a CNP polypeptide variant is at least 70%, 80%, 90%, or 95% identical to the reference CNP polypeptide. A polypeptide having an amino acid sequence that is, for example, at least 95% “identical” to a query amino acid sequence means that the amino acid sequence of the target polypeptide is identical to the query sequence, except that it may contain no more than 5 amino acid changes per 100 amino acids of the query amino acid sequence. Such changes in the reference sequence may occur at the amino-terminus (N-terminus) or carboxy-terminus (C-terminus) of the reference amino acid sequence, or anywhere between those terminal positions, individually scattered among residues in the reference sequence, or scattered as one or more adjacent groups within the reference sequence. The query sequence may be the complete amino acid sequence of the reference sequence or any designated fragment described herein. Such CNP polypeptide variants may be isoforms encoded by a natural variant, such as a natural allele variant encoded by one of several alternative forms of CNP occupying a specific locus of a chromosome or organism, or a natural splice variant derived from a single primary transcript. Alternatively, a CNP polypeptide variant may be a variant not known to be natural and that can be produced by mutagenesis techniques known in the art. It is known in the art that one or more amino acids may be deleted from the N-terminus or C-terminus of a bioactive peptide or protein with little loss of physiological function. Such N-terminal and / or C-terminal deletions are also encompassed by the term CNP polypeptide variant.

[0022] It is also recognized by those skilled in the art that the amino acid sequence of a portion of a CNP polypeptide can be altered without significantly affecting the structure or function of the peptide. Such variants include deletions, insertions, inversions, repeats, and substitutions selected according to principles known in the art so as to have little effect on activity. For example, guidance on methods for making phenotypic silent amino acid substitutions is given in Bowie et al. (1990), Science 247:1306-1310, which is incorporated herein by reference in its entirety, in which the authors show that there are two main approaches to considering the tolerance of changes in the amino acid sequence.

[0023] As used herein, the term "CNP analog" refers to a CNP from a different, unrelated organism that performs the same function in each organism but does not originate from an ancestral structure common to the ancestors of those organisms. Instead, the analog CNPs arose separately and subsequently evolved to perform the same or similar functions. In other words, an analog CNP polypeptide is a polypeptide with a considerably different amino acid sequence that achieves the same biological activity, namely, the regulation of chondrocyte growth, proliferation, and differentiation in the chondrocytes of the chondrocyte growth plate.

[0024] As used herein, the term "CNP ortholog" refers to a CNP present in two different species whose sequences are related to each other through common homologous CNPs in the ancestral species, but have evolved to be distinct.

[0025] As used herein, the term "CNP homolog" refers to a CNP from a different organism that performs the same function in that organism and originates from an ancestral structure common to the ancestors of those organisms. In other words, a homologous CNP polypeptide is a polypeptide having a very similar amino acid sequence that achieves the same biological activity, namely, the control of the growth, proliferation, and differentiation of chondrocytes in the chondrocyte growth plate. In certain embodiments, a CNP polypeptide homolog can be defined as a polypeptide that exhibits at least 40%, 50%, 60%, 70%, 80%, 90%, or 95% identity with respect to a reference CNP polypeptide.

[0026] Therefore, the CNP polypeptide can be, for example, (i) a CNP polypeptide in which at least one of the amino acid residues is substituted in a particular embodiment with a conserved amino acid residue, and such substituted amino acid residue may or may not be encoded by the gene code; and / or (ii) a CNP polypeptide in which at least one of the amino acid residues contains a substituent; and / or (iii) a CNP polypeptide fused with another compound, the compound being, for example, a compound that prolongs the half-life of the polypeptide (e.g., polyethylene glycol); and / or (iv) a CNP polypeptide in which an additional amino acid is fused to the CNP polypeptide, the amino acid being, for example, an IgG Fc fusion region peptide, or a leader sequence, or a secretion sequence, or a sequence used for the purification of the polypeptide in the above form, or a preprotein sequence.

[0027] As used herein, the term "CNP polypeptide fragment" refers to any peptide containing a continuous range of a portion of the amino acid sequence of a CNP polypeptide.

[0028] More specifically, a CNP polypeptide fragment contains at least six consecutive amino acids of a CNP polypeptide, for example, at least eight, at least ten, or at least seventeen consecutive amino acids. A CNP polypeptide fragment can further be described as a subgenus of a CNP polypeptide containing at least six amino acids, where "at least six" is defined as any integer between six and the integer representing the C-terminal amino acid of the CNP polypeptide. Furthermore, the term "CNP polypeptide fragment" includes all CNP polypeptide fragments of at least six amino acid length as described above, which are further specified in terms of their N-terminal and C-terminal positions. In other words, any combination of N-terminal and C-terminal positions that a fragment of at least six consecutive amino acid residues can occupy on any given amino acid sequence of a CNP polypeptide.

[0029] The term CNP includes the variants, analogs, orthologues, homologs, derivatives, and fragments of CNP; therefore, any reference to a specific location within the reference sequence also includes the equivalent location in the variants, analogs, orthologues, homologs, derivatives, and fragments of the CNP portion, even if not explicitly mentioned.

[0030] Natural CNP-22 (SEQ ID NO: 1) has the following sequence. GLSKGCFGLKLDRIGSMSGLGC In the formula, the cysteine ​​at positions 6 and 22 are linked via disulfide bridges.

[0031] In certain embodiments, "CNP" refers to the following peptide sequence: Sequence ID 2 (CNP-53): DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 3 (G-CNP-53): GDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 4 (M-CNP-53): MDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 5 (P-CNP-53): PDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 6 (CNP-53 M48N): DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; Sequence ID 7 (CNP-53 Δ15-31): DLRVDTKSRAAWARGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 8 (CNP-52): LRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 9 (CNP-51): RVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 10 (CNP-50): VDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 11 (CNP-49): DTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 12 (CNP-48): TKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 13 (CNP-47): KSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 14 (CNP-46): SRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 15 (CNP-45): RAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 16 (CNP-44): AAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 17 (CNP-44 Δ14-22): AAWARLLQEHPNAGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 18 (CNP-44 Δ15-22): AAWARLLQEHPNARGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 19 (CNP-43): AWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 20 (CNP-42): WARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 21 (CNP-41): ARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 22 (CNP-40): RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 23 (CNP-39): LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 24 (CNP-38): LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, Here, the cysteine ​​molecules at positions 22 and 38 are linked by a disulfide bridge; Sequence ID 25 (CNP-37): QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 26 (CNP-37 Q1pQ, where pQ = pyroglutamic acid): pQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 27 (G-CNP-37): GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 28 (P-CNP-37): PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 29 (M-CNP-37): MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 30 (PG-CNP-37): PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 31 (MG-CNP-37): MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 32 (CNP-37 M32N): QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; Sequence ID 33 (G-CNP-37 M32N): GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; Sequence ID 34 (G-CNP-37 K14Q): GQEHPNARKYKGANQKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 35 (G-CNP-37 K14P): GQEHPNARKYKGANPKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 36 (G-CNP-37 K14Q, Δ15): GQEHPNARKYKGANQGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 37 (G-CNP-37 K14Q, K15Q): GQEHPNARKYKGANQQGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 38 (CNP-36): EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 39 (CNP-35): HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 40 (CNP-34): PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 41 (CNP-33): NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 42 (CNP-32): ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 43 (CNP-31): RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 44 (CNP-30): KYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 45 (CNP-29): YKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 46 (CNP-28): KGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 47 (GHKSEVAHRF-CNP-28): GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 48 (CNP-27): GANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 49 (CNP-27 K4Q, K5Q): GANQQGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 50 (CNP-27 K4R, K5R): GANRRGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 51 (CNP-27 K4P, K5R): GANPRGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 52 (CNP-27 K4S, K5S): GANSSGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 53 (CNP-27 K4P, K5R): GANGANPRGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 54 (CNP-27 K4R, K5R, K9R): GANRRGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 55 (CNP-27 K4R, K5R, K9R, M22N): GANRRGLSRGCFGLKLDRIGSNSGLGC; Sequence ID 56 (P-CNP-27 K4R, K5R, K9R): PGANRRGLSRGCFGLKLDRIGSMSGLGC; Sequence ID: 57 (M-CNP-27 K4R, K5R, K9R): MGANRRGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 58 (HSA fragment-CNP-27): GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLG; Sequence ID 59 (HSA fragment-CNP-27 M22N): GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSNSGLGC; Sequence ID 60 (M-HSA fragment-CNP-27): MGHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 61 (P-HSA fragment-CNP-27): PGHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 62 (CNP-26): ANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 63 (CNP-25): NKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 64 (CNP-24): KKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 65 (CNP-23): KGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 66 (R-CNP-22): RGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 67 (ER-CNP-22): ERGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 68 (R-CNP-22 K4R): RGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 69 (ER-CNP-22 4KR): ERGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 70 (RR-CNP-22): RRGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 71 (HRGP fragment-CNP-22): GHHSHEQHPHGANQQGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 72 (HRGP fragment-CNP-22): GAHHPHEHDTHGANQQGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 73 (HRGP fragment-CNP-22): GHHSHEQHPHGANPRGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 74 (IgG1(F c ) fragment-CNP-22): GQPREPQVYTLPSGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 75 (HSA fragment-CNP-22): GQHKDDNPNLPRGANPRGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 76 (HSA fragment-CNP-22): GERAFKAWAVARLSQGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 77 (Osteoclinic NPR C inhibitor fragment-CNP22): FGIPMDRIGRNPRGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 78 (FGF2 heparin-binding region fragment - CNP22): GKRTGQYKLGSKTGPGPKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 79 (IgG1(F c ) Fragment-CNP-22 K4R): GQPREPQVYTGANQQGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 80 (HSA fragment-CNP-22 K4R): GVPQVSTSTGANQQGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 81 (Fibronectin fragment-CNP-22 K4R): GQPSSSSQSTGANQQGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 82 (Fibronectin fragment-CNP-22 K4R): GQTHSSGTQSGANQQGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 83 (Fibronectin fragment-CNP-22 K4R): GSTGQWHSESGANQQGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 84 (Zinc finger fragment-CNP-22 K4R): GSSSSSSSSSGANQQGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 85 (CNP-21): LSKGCFGLKLDRIGSMSGLGC; Sequence ID 86 (CNP-20): SKGCFGLKLDRIGSMSGLGC; Sequence ID 87 (CNP-19): KGCFGLKLDRIGSMSGLGC; Sequence ID 88 (CNP-18): GCFGLKLDRIGSMSGLGC; Sequence ID 89 (CNP-17): CFGLKLDRIGSMSGLGC; Sequence ID 90 (BNP fragment-CNP-17-BNP fragment): SPKMVQGSGCFGLKLDRIGSMSGLGCKVLRRH; Sequence ID 91 (CNP-38 L1G): GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 92 (Ac-CNP-37; where Ac = acetyl): Ac-QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 93: QEHPNARX1YX2GANX3X4GLSX5GCFGLX6LDRIGSMSGLGC, Here, X1, X2, X3, X4, X5, and X6 are independently selected from the group consisting of K, R, P, S, and Q, provided that at least one of X1, X2, X3, X4, X5, and X6 is selected from the group consisting of R, P, S, and Q; in a particular embodiment, X1, X2, X3, X4, X5, and X6 are selected from the group consisting of K and R, provided that at least one of X1, X2, X3, X4, X5, and X6 is R; Sequence ID 94: QEHPNARKYKGANX1X2GLSX3GCFGLX4LDRIGSMSGLGC, Here, X1, X2, X3, and X4 are independently selected from the group consisting of K, R, P, S, and Q, provided that at least one of X1, X2, X3, and X4 is selected from the group consisting of R, P, S, and Q; in a particular embodiment, X1, X2, X3, and X4 are selected from K and R, provided that at least one of X1, X2, X3, and X4 is R; Sequence ID 95: QEHPNARKYKGANX1X2GLSKGCFGLKLDRIGSMSGLGC, Here, X1X2 is selected from the group consisting of KR, RK, KP, PK, SS, RS, SR, QK, QR, KQ, RQ, RR, and QQ.

[0032] In sequence numbers 2 through 95, it is understood that the cysteine ​​molecules corresponding to positions 22 and 38 in sequence number 24 are linked by disulfide bridges.

[0033] The term "CNP" also includes poly(amino acid) conjugates, such as depsipeptides, which have the sequence described above but have a backbone containing both amide and non-amide bonds, such as ester bonds. A depsipeptide is a chain of amino acid residues whose backbone contains both amide (peptide) and ester bonds. Therefore, as used herein, the term "side chain" refers to the portion attached to the α-carbon of the amino acid moiety when the amino acid moiety is linked by an amine bond, as in a polypeptide, or to any carbon-carbon-containing portion attached to the backbone of a poly(amino acid) conjugate, as in the case of a depsipeptide. In certain embodiments, the term "CNP" refers to a polypeptide having a backbone formed by amide (peptide) bonds.

[0034] As used herein, the term “ring portion” refers to a sequence of consecutive amino acid residues located between two cysteine ​​residues that form an intramolecular disulfide crosslink, or between homologous amino acid residues linked via a chemical crosslinking agent. Preferably, the ring portion is located between two cysteine ​​residues that form an intramolecular disulfide crosslink. These two cysteines correspond to the cysteines at positions 22 and 38 in the sequence of CNP-38 (SEQ ID NO: 24). Therefore, when the CNP drug or CNP portion has the sequence of CNP-38, amino acids 23 to 37 are located in the aforementioned ring portion.

[0035] Regardless of the length of the CNP portion, the sequence of the ring portion of the wild-type CNP is FGLKLDRIGSMSGLG (sequence number 96).

[0036] Since the term CNP includes the variants, analogs, orthologues, homologs, derivatives, and fragments of CNP mentioned above, the term “ring portion” also includes the corresponding variants, analogs, orthologues, homologs, derivatives, and fragments of sequence SEQ ID NO: 96. Therefore, any reference to a specific position within the reference sequence, even if not explicitly mentioned, also includes the equivalent position in the variants, analogs, orthologues, homologs, derivatives, and fragments of the CNP portion.

[0037] As used herein, the term "cryoprotectant" refers to a compound added to a formulation to protect a drug or drug conjugate during the freezing process.

[0038] The term "C" as used herein, either alone or in combination with other terms. 1-4 "Alkyl" refers to a linear or branched alkyl group having 1 to 4 carbon atoms. When present at the end of a molecule, it can be linear or branched. 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Two parts of the molecule are C 1-4When it is bonded by an alkyl, such a C 1-4 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. C 1-4 Each hydrogen of the alkyl carbon may optionally be replaced by a substituent as defined above. Optionally, C 1-4 One or more moieties as defined below may be inserted into the alkyl.

[0039] The term "C 1-6 alkyl" used herein alone or in combination means a straight-chain or branched alkyl moiety having 1 to 6 carbon atoms. When present at the end of a molecule, straight-chain and branched C 1-6 Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. When two moieties of a molecule are bonded by a C 1-6 alkyl group, such a C 1-6 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. C 1-6 Each hydrogen atom of the carbon may optionally be replaced by a substituent as defined above. Optionally, C 1-6 One or more moieties as defined below may be inserted into the alkyl.

[0040] Thus, "C 1-10 alkyl", "C 1-20 alkyl", or "C 1-50 alkyl" each means an alkyl chain having 1 to 10, 1 to 20, or 1 to 50 carbon atoms, respectively, and C 1-10 , C 1-20 or C 1-50Each hydrogen atom of carbon may be replaced by a substituent as defined above. 1-10 or C 1-50 The alkyl group may have one or more subgroups as defined below.

[0041] The term "C" as used herein, either alone or in combination with other terms. 2-6 An "alkenyl" refers to a straight-chain or branched hydrocarbon segment containing 2 to 6 carbon atoms and at least one carbon-carbon double bond. When present at the end of a molecule, examples include -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3, and -CH=CH-CH=CH2. Two parts of a molecule are C 2-6 When bonded by an alkenyl, such C 2-6 An example of an alkenil is -CH=CH-. 2-6 Each hydrogen atom in the alkenyl moiety may be replaced by a substituent as defined above. 2-6 An alkenil may have one or more parts, as defined below, inserted into it.

[0042] Therefore, the term "C" can be used alone or in combination with other terms. 2-10 Alkenil, "C 2-20 "Alkenil" or "C 2-50 "Alkenyl" refers to a straight-chain or branched hydrocarbon portion containing at least one carbon-carbon double bond, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms. 2-10 Alkenil, C 2-20 Alkenyl or C 2-50 Each hydrogen atom of the alkenyl group may be optionally replaced by a substituent as defined above. In some cases, C 2-10 Alkenil, C 2-20 Alkenyl or C 2-50 An alkenil may have one or more parts, as defined below, inserted into it.

[0043] The term "C" as used herein, either alone or in combination with other terms. 2-6"Alkynyl" refers to a straight-chain or branched hydrocarbon moiety containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond. When present at the end of a molecule, examples include -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, and CH2-C≡C-CH3. When two parts of a molecule are linked by an alkynyl group, an example is -C≡C-. 2-6 Each hydrogen atom of the alkynyl group may optionally be replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-6 Alkinyl may have one or more parts, as defined below, inserted into it.

[0044] Therefore, the term "C" used herein, either alone or in combination, is used herein. 2-10 Alkinyl, C 2-20 "Alkinyl" or "C 2-50 "Alkynyl" refers to a linear or branched hydrocarbon moiety containing at least one carbon-carbon triple bond, each having 2-10, 2-20, or 2-50 carbon atoms, respectively. 2-10 Alkinyl, C 2-20 Alkinyl or C 2-50 Each hydrogen atom of the alkynyl group may optionally be replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-10 Alkinyl, C 2-20 Alkinyl or C 2-50 Alkinyl may have one or more parts, as defined below, inserted into it.

[0045] As mentioned above, C 1-4 Alkyl, C 1-6 Alkyl, C 1-10 Alkyl, C 1-20 Alkyl, C 1-50 Alkyl, C 2-6 Alkenil, C 2-10 Alkenil, C 2-20 Alkenil, C 2-50 Alkenil, C 2-6 Alkinyl, C 2-10 Alkinyl, C2-20 Alkenyl or C 2-50 The alkynyl may have one or more parts interspersed within it, and in a particular embodiment, [ka] (In the formula, The dashed line indicates binding to the aforementioned portion or the remainder of the reagent. -R and -R a (These are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.) It is selected from the group consisting of the following.

[0046] The term "C" as used herein 3-10 "Cycloalkyl" means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. 3-10 Each hydrogen atom of a cycloalkyl carbon may be replaced by a substituent as defined above. 3-10 "Cycloalkyl" also includes cross-linked birings such as norbornane or norbornene.

[0047] The term "8-30 membered carbopolycyclyl" or "8-30 membered carbon polycyclic" means a cyclic moiety of two or more rings having 8 to 30 ring atoms, where two adjacent rings share at least one ring atom, and which may contain up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings). Preferably, an 8-30 membered carbopolycyclyl means a cyclic moiety of 2, 3, 4, or 5 rings, more preferably 2, 3, or 4 rings.

[0048] As used herein, the terms “3- to 10-membered heterocyclyl” or “3- to 10-membered heterocycle” mean a ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, wherein at least one ring atom and up to four ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and which may contain up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), and the remainder of the molecule is bonded by carbon or nitrogen atoms. Examples of 3- to 10-membered heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azirine, oxilen, thiirane, azetidine, oxetane, thietan, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazoline, isothiazoline, thiadiazole, thiadiazole, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazoline, isothiazoline, thiadiazole, thiadiazole, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazoline, sulforane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyridine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidin, diazepane, azepine, and homopiperazine. Each hydrogen atom of a 3- to 10-membered heterocyclyl or 3- to 10-membered heterocyclic group may optionally be replaced by a substituent as defined below.

[0049] As used herein, the terms “8-11 membered heterobicyryl” or “8-11 membered heterobicyclic” mean a bicyclic heterocyclic portion having 8 to 11 ring atoms and potentially containing up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated aromatic or non-aromatic rings), wherein at least one ring atom is shared by both rings, and at least one ring atom, up to a maximum of six ring atoms, are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is bonded to the remainder of the molecule by carbon or nitrogen atoms. Examples of 8- to 11-membered heterobicyclic rings include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzimidazole, benzimidazolin, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, and pteridine. The term 8- to 11-membered heterobicyclic ring also includes bicyclic spiro structures such as 1,4-dioxa-8-azaspiro[4.5]decane, or bridging heterocyclic rings such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom of an 8- to 11-membered heterobicyclyl or 8- to 11-membered heterobicyclic carbon may optionally be replaced by substituents as defined below.

[0050] Similarly, the terms “8-30 membered heterocyclic” or “8-30 membered heterocyclic” mean a heterocyclic moiety having 8 to 30 ring atoms and potentially containing up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), comprising two or more rings, in particular embodiments three, four, or five rings, wherein two adjacent rings share at least one ring atom, and at least one ring atom, up to a maximum of ten ring atoms, is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is bonded to the remainder of the molecule by carbon or nitrogen atoms.

[0051] Structure below: [ka] Regarding the part, "Pair R x / R y Together with the atoms to which they are bonded, C 3-10 The phrase "forms a cycloalkyl or 3-10 membered heterocycline" is R x and R y However, it is understood that this means forming the following structure. [ka] In the formula, R is C 3-10 They are cycloalkyl or 3-10 membered heterocyclines.

[0052] Structure below: [ka] Regarding the part, "Pair R x / R y The phrase "they, together with the atoms to which they are bonded, form ring A" is R x and R y However, it is also understood that this means forming the following structure. [ka]

[0053] As used herein, the term “dried pharmaceutical formulation” means that the pharmaceutical formulation is provided in a dried form. Suitable drying methods are spray drying and freeze-drying. Such dried pharmaceutical formulations containing CNP conjugate have a residual moisture content of up to 10%, less than 5% in certain embodiments, and less than 2% in certain embodiments, as measured by the Karl Fischer method. In certain embodiments, the dried pharmaceutical formulation of the present invention is dried by freeze-drying.

[0054] As used herein, the term “drug” refers to a substance used to treat, cure, prevent or diagnose a disease, or to otherwise promote physical or mental well-being. When a drug, such as CNP, is bound to another part, the resulting product derived from that drug is referred to as the “drug moiety.”

[0055] As used herein, the term “excipient” refers to a compound administered together with a pharmaceutical or pharmaceutical conjugate, such as a buffer, isotonic modifier, preservative, stabilizer, adsorption inhibitor, antioxidant, or other adjuvant. However, in some cases, a single excipient may have a dual or triple function. The term “excipient” may also refer to a diluent, adjuvant, or carrier used together with a pharmaceutical or pharmaceutical conjugate for administration. Such pharmaceutical excipients may be sterile solutions, such as water and oil, where oil may be of petroleum, animal, plant, or synthetic origin, including, but not limited to, peanut oil, soybean oil, mineral oil, and sesame oil. When a pharmaceutical preparation is administered orally, water is a preferred excipient. When a pharmaceutical preparation is administered intravenously or subcutaneously, physiological saline and glucose aqueous solutions are preferred excipients. In certain embodiments, physiological saline, glucose aqueous solutions, and glycerol solutions are used as liquid excipients for injection solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, and ethanol. Pharmaceutical preparations may also contain small amounts of humectants or emulsifiers, pH buffers such as acetates, succinates, Tris (tris(hydroxymethyl)aminomethane), carbonates, phosphates, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), surfactants such as Tween®, poloxamer, poloxamine, CHAPS, Igepal®, or amino acids such as glycine, lysine, or histidine. These pharmaceutical formulations can take the form of liquids, suspensions, emulsions, tablets, pills, capsules, powders, and sustained-release formulations. Pharmaceutical formulations can also be prepared as suppositories using conventional binders and excipients, such as triglycerides.Oral formulations may contain standard excipients, such as pharmaceutical mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. Such formulations will contain a therapeutically effective amount of the drug or pharmaceutical portion, along with an appropriate amount of excipients to provide a form suitable for appropriate administration to the patient. The formulation should be appropriate for the method of administration.

[0056] As used herein, the terms “formulation” or “drug formulation” refer to a formulation comprising one or more CNP conjugates and one or more excipients, and a product resulting directly or indirectly from a combination, complexation or aggregation of two or more components of the composition, or from one or more dissociations of those components, or from one or more other types of reactions or interactions of those components. Accordingly, the drug formulations of the present invention include formulations or compositions made by mixing one or more CNP conjugates with pharmaceutically acceptable excipients, such as buffers and fillers.

[0057] As used herein, the term “free form” of a pharmaceutical product refers to the pharmaceutical product in its unmodified, fully pharmacologically active form, for example, after it has been released from a conjugate.

[0058] As used herein, the term “functional group” means a group of atoms that can react with other groups of atoms. Functional groups include, but are not limited to, the following: carboxylic acids (-(C=O)OH), primary or secondary amines (-NH2, -NH-), maleimides, thiols (-SH), sulfonic acids (-(O=S=O)OH), carbonates, carbamates (-O(C=O)N<), hydroxyls (-OH), aldehydes (-(C=O)H), ketones (-(C=O)-), hydrazines (>NN<), isocyanates, isothiocyanates, phosphoric acids (-O(P=O)OHOH), phosphonic acids (-O(P=O)OHH), haloacetyls, alkyl halides, acryloyls, aryl fluorides, hydroxylamines, disulfides, sulfonamides, sulfonic acids, vinyl sulfones, vinyl ketones, diazoalkanes, oxiranes, and aziridines.

[0059] As used herein, the term "halogen" means fluoro, chloro, bromo, or iodine. The halogen is generally preferred to be fluoro or chloro.

[0060] As used herein, the term “interrupted” means that a portion is inserted between two carbon atoms, or, if the insertion is at one end of the portion, between a carbon or heteroatom and a hydrogen atom, or in certain embodiments, between a carbon and a hydrogen atom.

[0061] As used herein, the term "isotonic modifier" refers to a compound that reduces pain, irritation, and tissue damage that may result from cellular damage caused by osmotic pressure differences between an injected solution and plasma.

[0062] As used herein, the term “lyophilized formulation” means a formulation containing CNP conjugate that has been first frozen and then dehydrated by reduced pressure. This term does not exclude any additional drying steps performed in the manufacturing process before the formulation is filled into final containers.

[0063] As used herein, the terms “lyophilization” or “freeze-drying” are used interchangeably and refer to a dehydration process characterized by freezing the formulation, then reducing the ambient pressure, and optionally adding heat, thereby directly sublimating the frozen water in the formulation from a solid phase to a gas. Typically, the replaced water is recovered by sublimation.

[0064] As used herein, the term "lyoprotectant" refers to a molecule that, when combined with the active ingredient in question, significantly prevents or reduces the chemical and / or physical instability of the active ingredient during drying in general, and especially during freeze-drying and subsequent storage. Exemplary lyoprotectants include sugars, e.g., sucrose or trehalose; amino acids, e.g., sodium glutamate, histidine, or arginine; methylamines, e.g., betaine; lyotropic salts, e.g., magnesium sulfate; polyhydric alcohols, e.g., trihydric or higher sugar alcohols, e.g., glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol; ethylene glycol; propylene glycol; polyethylene glycol; Pluronics; hydroxyalkyl starches, e.g., hydroxyethyl starch (HES), and combinations thereof. Lyoprotectants can also act as volume extenders in dry pharmaceutical formulations and as isotonic modifiers in regenerative pharmaceutical formulations.

[0065] As used herein, the term “part” means a portion of a molecule that lacks one or more atoms compared to the corresponding drug. For example, when a reagent of the formula “HXH” reacts with another reagent and becomes part of a reaction product, the corresponding part of the reaction product has the structure “HX-” or “-X-”, where each “-” indicates a bond to another part. Thus, a pharmaceutical part, such as a CNP part, is released from the conjugate as a pharmaceutical such as CNP.

[0066] When an arrangement or chemical structure of an atomic group is provided in which an atomic group is bonded to two parts or interposed to one part, it is understood that, unless otherwise explicitly stated, the arrangement or chemical structure may be bonded to the two parts in either orientation. For example, part "-C(O)N(R 1 )-" is "-C(O)N(R 1 )-" or "-N(R 1 As ")C(O)-", it can be bonded to two parts, or it can be inserted into one part. Similarly, part: [ka] teeth, [ka] as, or [ka] It can be either joined to two parts, or it can be inserted into one part.

[0067] If the CNP moiety contains one or more acidic or basic groups, the pharmaceutical preparation also includes corresponding pharmaceutically or toxicologically acceptable salts thereof, in particular pharmaceutically usable salts thereof. Thus, CNP moieties containing one or more acidic groups can exist and can be used, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More detailed examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine, etc.) or amino acids, as well as other salts or amines known to those skilled in the art. CNP moieties containing one or more basic groups, i.e., protonable groups, can also exist and can be used in the form of addition salts thereof with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. Further methods of converting basic groups to cations, such as alkylation of amine groups to provide suitable counterions for positively charged ammonium groups and their salts, are known to those skilled in the art. When the CNP moiety contains both acidic and basic groups, the pharmaceutical formulations according to the present invention also include intramolecular salts or betaines (amphoteric ions) in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, such as by contacting these conjugates with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts. The formulations according to the present invention also include all salts of CNP conjugates, which, due to their low physiological compatibility, are not directly suitable for use in pharmaceuticals, but can be used, for example, as intermediates in chemical reactions or in the preparation of pharmaceutically acceptable salts.

[0068] As used herein, the terms “antioxidant” or “oxidative protective agent” refer to compounds that inhibit the oxidation of other compounds, such as peptides.

[0069] As used herein, the term "pH adjuster" refers to a compound used to adjust the pH of a formulation solution before filling and freeze-drying.

[0070] As used herein, the term “pharmaceutically acceptable” means a substance that does not cause harm when administered to a patient and is preferably approved for use in animals, preferably for use in humans, by a regulatory authority, e.g., the EMA (Europe) and / or the FDA (United States) and / or any other national regulatory authority.

[0071] As used herein, the term "physiological conditions" refers to aqueous buffer conditions with a pH of 7.4 and a temperature of 37°C.

[0072] As used herein, the term "polypeptide" refers to a chain of 2 to 50 amino acid monomer portions linked by peptide (amide) linkages. Only in the case of CNP pharmaceuticals and CNP portions, sequences having more than 50 amino acids are also briefly referred to as "polypeptides."

[0073] As used herein, the term “preservative” refers to a chemical substance that has antimicrobial properties and prevents chemical degradation.

[0074] As used herein, the term "protein" refers to a chain of more than 50 amino acid monomer moieties linked by peptide linkages, preferably comprising 12,000 or fewer amino acid monomers linked by peptide linkages, such as 10,000 or fewer amino acid monomer moieties, 8,000 or fewer amino acid monomer moieties, 5,000 or fewer amino acid monomer moieties, or 2,000 or fewer amino acid monomer moieties.

[0075] As used herein, the term “polymer” means a molecule comprising repeating structural units, i.e., monomers, linked by chemical bonds in a linear, cyclic, branched, crosslinked, or dendrimer manner, or in a combination thereof, which may be of synthetic origin, bio-origin, or a combination of both. It is understood that polymers may also include one or more other chemical groups and / or parts, such as one or more functional groups. In certain embodiments, a soluble polymer has a molecular weight of at least 0.5 kDa, e.g., at least 1 kDa, at least 2 kDa, at least 3 kDa, or at least 5 kDa. If the polymer is soluble, in certain embodiments it may have a molecular weight of up to 1000 kDa, e.g., up to 750 kDa, e.g., up to 500 kDa, e.g., up to 300 kDa, e.g., up to 200 kDa, e.g., up to 100 kDa.

[0076] It is understood that proteins or polypeptides are polymers in which amino acids are repeating structural units, even though the side chains of each amino acid may differ.

[0077] As used herein, the terms “polymeric” or “polymeric part” mean a reagent or part comprising one or more polymers or polymeric parts. A polymeric agent or part may optionally also comprise one or more other parts, which in particular embodiments are selected from the group consisting of: ·C 1-50 Alkyl, C 2-50 Alkenil, C 2-50 Alkinyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and • The following are examples of connections selected from the following groups: [ka] During the ceremony, The dashed line indicates binding to the aforementioned portion or the remainder of the reagent. -R and -Ra These are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0078] Those skilled in the art will understand that polymerization products obtained from polymerization reactions do not necessarily all have the same molecular weight, but rather exhibit a molecular weight distribution. Consequently, the molecular weight range, molecular weight, monomer number range in the polymer, and monomer number in the polymer used herein refer to the number-average molecular weight and monomer number average, that is, the arithmetic mean of the molecular weight of the polymer or polymer portion, and the arithmetic mean of the monomer number of the polymer or polymer portion.

[0079] Therefore, for a polymer portion containing "x" monomer units, any integer substituted for "x" corresponds to the arithmetic mean of the monomers. Any range of integers substituted for "x" provides an integer range in which the arithmetic mean of the monomers resides. An integer "x" expressed as "approximately x" means that the arithmetic mean of the monomers lies in the integer range of x+ / -10%, in a particular embodiment, in the integer range of x+ / -8%, in a particular embodiment, in the integer range of x+ / -5%, and in a particular embodiment, in the integer range of x+ / -2%.

[0080] As used herein, the term “PEG-based” with respect to a portion or reagent means that the portion or reagent contains PEG. In certain embodiments, a PEG-based portion or reagent contains at least 10% by weight of PEG, e.g., at least 20% by weight of PEG, e.g., at least 30% by weight of PEG, e.g., at least 40% by weight of PEG, e.g., at least 50% by weight, e.g., at least 60% by weight of PEG, e.g., at least 70% by weight of PEG, e.g., at least 80% by weight of PEG, e.g., at least 90% by weight, e.g., at least 95% by weight of PEG. The remaining weight percentage of the PEG-based portion or reagent is other portions selected from the following portions and combinations. ·C 1-50 Alkyl, C 2-50 Alkenil, C2-50 Alkynyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indanyl, and tetralinyl, and · A linkage selected from the group consisting of:

Chemical formula

[0081] As used herein, the term "PEG-based containing at least X% PEG" with respect to a moiety or reagent means that the said moiety or reagent contains at least X weight % ethylene glycol units (-CH2CH2O-), and the ethylene glycol units can be arranged in an alternating block pattern or can be randomly distributed within the said moiety or reagent. In certain embodiments, all of the ethylene glycol units of the said moiety or reagent are present within one block, and the remaining weight percentage of the PEG-based moiety or reagent is, in certain embodiments, another moiety selected from the following moieties and linkages. · C 1-50 Alkyl, C 2-50 Alkenyl, C 2-50 Alkynyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indanyl, and tetralinyl, and · A linkage selected from the group consisting of:

Chemical formula

[0082] As used herein, the term "hyaluronic acid-based system containing at least X% hyaluronic acid" is used as appropriate.

[0083] Those skilled in the art will also recognize that the conjugate of the present invention is a prodrug. As used herein, the term “prodrug” refers to a pharmaceutical moiety, such as a CNP moiety, reversibly and covalently bonded to a polymer moiety, such as -Z, via a reversible linker moiety. A prodrug releases the reversibly and covalently bonded pharmaceutical moiety in the form of its corresponding pharmaceutical. That is, a prodrug is a conjugate comprising a pharmaceutical moiety, such as a CNP moiety, covalently and reversibly bonded to a polymer moiety via a reversible linker moiety, where the covalent and reversible bond of the polymer moiety to the reversible linker moiety is either direct or via a spacer. Such a prodrug or conjugate releases the previously bonded pharmaceutical moiety in the form of a free pharmaceutical.

[0084] As used herein, the term “random coil” refers to a peptide or protein that, in certain embodiments, adopts / has / forms a three-dimensional structure substantially lacking distinct secondary and tertiary structures, as identified by circular dichroism spectroscopy performed in aqueous buffer at pH 7.4 at room temperature. In certain embodiments, room temperature (ambient temperature) is approximately 20°C, i.e., 18°C ​​to 22°C, while in other embodiments, the ambient temperature is 20°C.

[0085] As used herein, the term "reversible linkage" refers to a linkage that can be cleaved in the absence of enzymes under physiological conditions (pH 7.4 aqueous buffer, 37°C) and has a half-life ranging from 1 hour to 6 months, e.g., 1 hour to 4 months, e.g., 1 hour to 3 months, 1 hour to 2 months, or 1 hour to 1 month.

[0086] As used herein, the term "reagent" means a compound that contains at least one functional group for reaction with a functional group of another compound or pharmaceutical. It is understood that a pharmaceutical containing a functional group (e.g., a primary or secondary amine or a hydroxy functional group) is also a reagent.

[0087] As used herein, the term "reversible linker moiety" is a moiety that is covalently bound to a pharmaceutical moiety such as a CNP moiety by reversible linkage and is also covalently bound to a polymer moiety such as -Z, where the covalent bond to the polymer moiety is either direct or via a spacer moiety such as -L 2 -. In certain embodiments, the linkage between -Z and -L 2 - is a stable linkage.

[0088] As used herein, the term "reconstitution" means adding a liquid to a dry pharmaceutical formulation to return it to its original form, such as a solution formulation.

[0089] As used herein, the term "reconstituted formulation" refers to a formulation obtained by reconstitution of a dry pharmaceutical formulation by adding a reconstitution solution.

[0090] <0003l00>As used herein, the term "reconstitution solution" refers to a liquid used to reconstitute a dry pharmaceutical formulation prior to administration to a patient as needed.

[0091] As used herein, the term "spacer" or "spacer moiety" refers to a moiety suitable for connecting two moieties. Suitable spacers can be selected from the group consisting of C 1-50 alkyl, C 2-50 alkenyl or C 2-50 [[ID=so]]alkynyl, and C 1-50 alkyl, C 2-50 alkenyl or C 2-50 alkynyl may be -NH-, -N(C 1-4 alkyl)-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)N(C 1-4It may be interposed by one or more groups selected from alkyl)-, -OC(O)-, -S(O)-, -S(O)2-, 4- to 7-membered heterocyclyl, phenyl, and naphthyl.

[0092] As used herein, the term “substituted” means that one or more -H atoms in a molecule or part are replaced by different atoms or groups of atoms referred to as “substituents.”

[0093] In certain embodiments, one or more such substituents are, independently of each other, halogen, -CN, -COOR x1 , -OR x1 , -C(O)R x1 ,-C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 ,-S(O)R x1 , -N(R x1 )S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O)2R x1a , -N(R x1 )S(O)R x1a , -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; -T 0 , C 1-50 Alkyl, C2-50 Alkenyl and C 2-50 Alkinyl has one or more identical or different -R x2 It is also acceptable if it is replaced with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 It may also be interrupted by one or more elements selected from the group consisting of )-;

[0094] -R x1 ,-R x1a ,-R x1b -H, -T are independent of each other. 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl has one or more identical or different -R x2 It is also acceptable if it is replaced with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 )-;-S(O)2-,-S(O)-,-N(R x3 )S(O)2N(R x3a)-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 It may also be interrupted by one or more elements selected from the group consisting of )-;

[0095] Each T 0 These are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl; each T 0 These are independently one or more identical or different -R x2 It is also acceptable if it is replaced with;

[0096] Each-R x2 These are independently halogen, -CN, oxo (=O), and -COOR. x4 , -OR x4 , -C(O)R x4 ,-C(O)N(R x4 R x4a ), -S(O)2N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O)2R x4 ,-S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b), -OC(O)N(R x4 R x4a ), and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 Alkyl may be substituted with one or more halogens, either identical or different;

[0097] Each-R x3 ,-R x3a ,-R x4 ,-R x4a ,-R x4b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 The alkyl group may be substituted with one or more halogens, which may be the same or different.

[0098] In certain embodiments, the one or more substituents are, independently of each other, halogen, -CN, and -COOR x1 , -OR x1 , -C(O)R x1 ,-C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 ,-S(O)R x1 , -N(R x1 )S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O)2R x1a , -N(R x1 )S(O)R x1a , -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T0 , C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyls; -T 0 , C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl has one or more identical or different -R x2 It is also acceptable if it is replaced with C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl is -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 It may also be interrupted by one or more elements selected from the group consisting of )-;

[0099] Each-R x1 ,-R x1a ,-R x1b ,-R x3 ,-R x3a These are independently -H, halogen, and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls;

[0100] Each T 0 These are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl; each T 0 These are independently one or more identical or different -R x2It is also acceptable if it is replaced with;

[0101] Each-R x2 These are independently halogen, -CN, oxo (=O), and -COOR. x4 , -OR x4 , -C(O)R x4 ,-C(O)N(R x4 R x4a ), -S(O)2N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O)2R x4 ,-S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ), and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 Alkyl may be substituted with one or more halogens, either identical or different;

[0102] Each-R x4 ,-R x4a ,-R x4b These are independently -H, halogen, and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls.

[0103] In certain embodiments, the one or more substituents are, independently of each other, halogen, -CN, and -COOR x1 , -OR x1 , -C(O)R x1 ,-C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 ,-S(O)R x1 , -N(R x1 )S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O)2R x1a , -N(R x1 )S(O)R x1a , -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls; -T 0 , C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl has one or more identical or different -R x2 It is also acceptable if it is replaced with C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl is -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3)-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 It may also be interrupted by one or more elements selected from the group consisting of )-;

[0104] Each-R x1 ,-R x1a ,-R x1b ,-R x2 ,-R x3 ,-R x3a These are independently -H, halogen, and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls;

[0105] Each T 0 These are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl; each T 0 These are independently one or more identical or different -R x2 It's also acceptable if it's replaced with [another term].

[0106] In certain embodiments, up to six hydrogen atoms in a molecule that may be substituted are independently replaced by substituents, for example, five hydrogen atoms are independently replaced by substituents, four hydrogen atoms are independently replaced by substituents, three hydrogen atoms are independently replaced by substituents, two hydrogen atoms are independently replaced by substituents, or one hydrogen atom is independently replaced by a substituent.

[0107] As used herein, the terms “stable” and “stable” in relation to pharmaceutical formulations mean that, after a period of storage, for example after 1 month, 2 months, 4 months, 6 months, 8 months, 12 months, 18 months, 24 months, 36 months, 48 ​​months, 60 months, and especially after a specified storage period, the pharmaceutical formulation contains less than 5% of the pharmaceutical in free form and less than 20%, for example less than 10%, or less than 5% of impurities, for example aspartic acid or isomerization of aspartic acid, oxidation of methionine, and aggregation of peptides. Impurities can be quantified by RP-HPLC or SEC based on the individual peak area relative to the total peak area of ​​all CNP conjugate-related peaks in the chromatogram, and impurities in the CNP portion of the CNP conjugate can be determined by proteolytic digestion and quantified based on the individual peak area relative to the peak area of ​​the corresponding unmodified proteolytic peptide.

[0108] As used herein, the term “stabilizer” refers to a compound used to stabilize a pharmaceutical conjugate. Stabilization can be achieved by enhancing the peptide stabilizing power or by the direct binding of an excipient to the pharmaceutical conjugate.

[0109] As used herein, the term “surfactant” refers to a wetting agent that reduces the surface tension of a liquid.

[0110] As used herein, the term “seal a container” means to seal a container so that it is airtight, preventing any gas exchange between the outside and inside, and keeping the contents sterile.

[0111] As used herein, the term “therapeutic dose” means an amount sufficient to cure, alleviate, or partially prevent the clinical symptoms of a given disease and its complications. The effective dose for each purpose depends not only on the severity of the disease or injury, but also on the subject’s weight and overall condition. As is understood, determining an appropriate dose can be done using routine experiments by constructing a numerical matrix and testing various points within that matrix, all of which are within the normal range of skill of a skilled physician. Within the scope of this invention, a therapeutic dose relates to a dose aimed at achieving a therapeutic effect over a long period, such as at least one day, for example two days, for example three days, for example four days, for example five days, for example six days, for example one week, or for example two weeks.

[0112] As used herein, the term “trace-free linker” means a reversible linker that releases the drug in its free form upon cleavage.

[0113] As used herein, the term "unit dose" means the amount of medicine administered to a patient in a single dose.

[0114] As used herein, the term “water-soluble” in relation to a polymer portion means that, when such a polymer portion is part of a CNP conjugate, at least 1 g of a CNP conjugate containing such a water-soluble polymer portion can be dissolved in 1 liter of water at 20°C to form a homogeneous solution.

[0115] Generally, the terms "comprise" or "comprising" also encompass "consist of" or "consisting of."

[0116] In a particular embodiment, the CNP portion of the CNP conjugate has the sequence of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 30. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 20, 21, 22, 23, 24, or 25. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 20. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 21. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 21. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 22. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 23. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 24. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 25.

[0117] In certain embodiments, the polymer portion is defined as a variable element-Z, which is described in more detail elsewhere in this specification.

[0118] The dry pharmaceutical formulation according to the present invention includes a buffering agent. Examples of buffering agents can be selected from the group consisting of succinic acid, citric acid, lactic acid, acetic acid, glutamic acid, fumaric acid, aspartic acid, glutaric acid, phosphoric acid, histidine, gluconic acid, tartaric acid, malic acid, and mixtures thereof. It will be apparent to those skilled in the art that the buffering agent may also include corresponding conjugate bases or salts, such as succinate, citrate, lactate, acetate, glutamate, fumarate, aspartate, glutarate, phosphate, gluconate, tartrate, malate, and mixtures thereof.

[0119] In certain embodiments, the buffer is succinic acid. In certain embodiments, the buffer is citric acid. In certain embodiments, the buffer is lactic acid. In certain embodiments, the buffer is acetic acid. In certain embodiments, the buffer is glutamic acid. In certain embodiments, the buffer is fumaric acid. In certain embodiments, the buffer is aspartic acid. In certain embodiments, the buffer is glutaric acid. In certain embodiments, the buffer is phosphoric acid. In certain embodiments, the buffer is histidine. In certain embodiments, the buffer is gluconic acid. In certain embodiments, the buffer is tartaric acid. In certain embodiments, the buffer is malic acid.

[0120] In certain embodiments, the buffer has a concentration of about 0.2% to about 3.2% by weight. In certain embodiments, the buffer has a concentration of about 0.6% to about 1.6% by weight. In certain embodiments, the buffer has a concentration of about 0.9% to about 1.0% by weight. In certain embodiments, the buffer has a concentration of about 1.0% by weight.

[0121] The dried pharmaceutical formulation according to the present invention includes a volume extender.

[0122] The bulking agent can be selected from the group consisting of trehalose, mannitol, sucrose, raffinose, gelatin, lactose, dipotassium hydrogen phosphate, sorbitol, xylitol, glycine, histidine, hydroxyethyl starch, dextrose, dextran, Ficoll®, propylene glycol, and mixtures thereof.

[0123] In certain embodiments, the bulking agent can be selected from the group consisting of trehalose, mannitol, sucrose, raffinose, gelatin, lactose, dipotassium hydrogen phosphate, sorbitol, xylitol, glycine, histidine, hydroxyethyl starch, dextrose, dextran, propylene glycol, and mixtures thereof.

[0124] In certain embodiments, the bulking agent is selected from the group consisting of trehalose, sucrose, and glycine.

[0125] In certain embodiments, the bulking agent is a non-reducing sugar such as trehalose or sucrose.

[0126] In certain embodiments, the bulking agent is trehalose. In certain embodiments, the bulking agent is mannitol. In certain embodiments, the bulking agent is sucrose. In certain embodiments, the bulking agent is raffinose. In certain embodiments, the bulking agent is gelatin. In certain embodiments, the bulking agent is lactose. In certain embodiments, the bulking agent is dipotassium hydrogen phosphate. In certain embodiments, the bulking agent is sorbitol. In certain embodiments, the bulking agent is xylitol. In certain embodiments, the bulking agent is glycine. In certain embodiments, the bulking agent is histidine. In certain embodiments, the bulking agent is hydroxyethyl starch. In certain embodiments, the bulking agent is dextrose. In certain embodiments, the bulking agent is dextran. In certain embodiments, the bulking agent is Ficoll®. In certain embodiments, the bulking agent is propylene glycol.

[0127] Where defined herein, the term “trehalose” is intended to encompass all salts and hydrated states of trehalose, such as trehalose anhydrous or trehalose dihydrate. In certain embodiments, the term “trehalose” refers to trehalose anhydrous. In certain embodiments, the term “trehalose” refers to trehalose dihydrate.

[0128] In certain embodiments, the formulation may include a plurality of volume extenders.

[0129] In certain embodiments, reducing sugars should be avoided because they can react with the CNP moiety. Therefore, in certain embodiments, the pharmaceutical formulation does not contain reducing sugars.

[0130] In certain embodiments, the bulking agent has a concentration in the range of about 52.6% to about 98.4% by weight. In certain embodiments, the bulking agent has a concentration in the range of about 62.4% to about 70.4% by weight. In certain embodiments, the bulking agent has a concentration in the range of about 85.7% to about 91.6% by weight. In certain embodiments, the bulking agent has a concentration in the range of about 65.2% by weight.

[0131] The dried pharmaceutical formulation according to the present invention contains a pH adjuster. In certain embodiments, the pH adjuster is an acid or an acidic salt thereof. The acid can be selected from the group consisting of hydrochloric acid, phosphoric acid, carbonic acid, nitric acid, and mixtures thereof.

[0132] In certain embodiments, the pH adjuster is hydrochloric acid. In certain embodiments, the pH adjuster is phosphoric acid. In certain embodiments, the pH adjuster is carbonic acid. In certain embodiments, the pH adjuster is nitric acid.

[0133] In certain embodiments, the pH adjuster is a base or a basic salt thereof. The base can be selected from the group consisting of Tris (tris(hydroxymethyl)aminomethane), sodium hydroxide, potassium hydroxide, lysine, and mixtures thereof.

[0134] In certain embodiments, the pH adjuster is Tris. In certain embodiments, the pH adjuster is sodium hydroxide. In certain embodiments, the pH adjuster is potassium hydroxide. In certain embodiments, the pH adjuster is lysine.

[0135] In certain embodiments, the dry pharmaceutical formulation according to the present invention comprises a mixture of one or more acid and base pH adjusters.

[0136] In certain embodiments, the pH adjuster or mixture of pH adjusters has a concentration of about 0.1% to about 5.6% by weight. In certain embodiments, the pH adjuster or mixture of pH adjusters has a concentration of about 0.2% to about 2.8% by weight. In certain embodiments, the pH adjuster or mixture of pH adjusters has a concentration of about 0.5% to about 1.4% by weight. In certain embodiments, the pH adjuster or mixture of pH adjusters has a concentration of about 1.2% by weight. It is understood that, in the case of a mixture of pH adjusters, the concentration provided refers to the total concentration of all pH adjusters.

[0137] The dried pharmaceutical formulation of the present invention contains a CNP conjugate.

[0138] In certain embodiments, the CNP conjugate has a concentration of about 23.8% to about 38.7% by weight. In certain embodiments, the CNP conjugate has a concentration of about 5.8% to about 12.4% by weight. In certain embodiments, the CNP conjugate has a concentration of about 1.4% to about 3.7% by weight.

[0139] In certain embodiments, the CNP conjugate is of the following formula (Ia) or (Ib). [ka] During the ceremony, -D is the CNP part; -L 1 - is the reversible linker part; -L 2 - represents a single chemical bond or spacer portion; -Z is the polymer part; x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16; y is an integer selected from the group consisting of 1, 2, 3, 4, and 5.

[0140] -D in equation (Ia) or (Ib) is -L 1 - is covalently and reversibly bonded to it.

[0141] In a particular embodiment, x in formula (Ia) is an integer selected from the group consisting of 1, 2, 3, 4, 6, and 8. In a particular embodiment, x in formula (Ia) is an integer selected from the group consisting of 1, 2, 4, and 6. In a particular embodiment, x in formula (Ia) is an integer selected from the group consisting of 1, 4, and 6, and in a particular embodiment, x in formula (Ia) is 1.

[0142] In a particular embodiment, y in formula (Ib) is an integer selected from the group consisting of 2, 3, 4, and 5. In a particular embodiment, y in formula (Ib) is an integer selected from the group consisting of 2, 3, and 4. In a particular embodiment, y in formula (Ib) is an integer selected from the group consisting of 2 and 3. In a particular embodiment, y in formula (Ib) is an integer selected from the group consisting of 1, 2, and 3. In a particular embodiment, y in formula (Ib) is 1. In a particular embodiment, y in formula (Ib) is 2.

[0143] In a particular embodiment, the CNP conjugate is of equation (Ia) where x=1.

[0144] In certain embodiments, -D in formula (Ia) or (Ib) has a sequence of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 30. In certain embodiments, -D in formula (Ia) or (Ib) has a sequence of SEQ ID NOs: 20, 21, 22, 23, 24, or 25.

[0145] In certain embodiments, -D of formula (Ia) or (Ib) has the sequence of sequence number 20. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence of sequence number 21. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence of sequence number 22. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence of sequence number 23. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence of sequence number 24. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence of sequence number 25.

[0146] Part of equation (Ia) or (Ib) - L 1 - is bonded to a functional group on the side chain of an amino acid residue of -D, or to the N-terminal amine functional group or C-terminal carboxyl functional group of -D, or to a nitrogen atom in the backbone polypeptide chain of -D. Bonding to either the N-terminus or C-terminus can be direct via the corresponding amine or carboxyl functional group, respectively, or the spacer portion is first bonded to the spacer portion -L 1 - can be indirectly bonded to an amine or carboxyl functional group to which it is attached.

[0147] Part of equation (Ia) or (Ib) - L 1 - is a drug, namely DH, which is a reversible prodrug linker released in its free form, i.e., -L 1 - is a linker that leaves no trace. Suitable reversible linkers, such as the reversible linker portions disclosed in WO 2005 / 099768 A2, WO 2006 / 136586 A2, WO 2011 / 089216 A1 and WO 2013 / 024053 A1, which are incorporated herein by reference, are known in the art.

[0148] In certain embodiments, -L 1- is a reversible linker as described in WO 2011 / 012722 A1, WO 2011 / 089214 A1, WO 2011 / 089215 A1, WO 2013 / 024052 A1 and WO 2013 / 160340 A1, which are incorporated herein by reference.

[0149] Part-L 1 - can be connected to -D via any kind of coupling, however it is reversible. In certain embodiments, -L 1 - is linked to -D via a linkage selected from the group consisting of amides, esters, carbamates, acetals, aminals, imines, oximes, hydrazones, disulfides, and acylguanidines. In certain embodiments, -L 1 - is linked to -D via a linkage selected from the group consisting of amides, esters, carbamates, and acylguanidines. These linkages do not have to be reversible themselves, and -L 1 It is understood that the adjacent groups included in the - may also be those that make the linkage reversible.

[0150] In certain embodiments, part-L 1 - is connected to -D via an amide connector.

[0151] Part-L 1 - is disclosed in WO 2009 / 095479 A2. Therefore, in certain embodiments, part -L 1 - is equation (II):

[0152] [ka] (In the formula, The dashed line indicates the bonding of the CNP moiety, -D, to nitrogen by forming an amide bond, and -X- is -C(R 4 R 4a )-,-N(R 4 )-, -O-, -C(R 4 R 4a )-C(R5 R 5a )-,-C(R 5 R 5a )-C(R 4 R 4a )-,-C(R 4 R 4a )-N(R 6 )-,-N(R 6 )-C(R 4 R 4a )-,-C(R 4 R 4a )-O-, -OC(R 4 R 4a )-, or -C(R 7 R 7a )- and, X 1 is C, or S(O), -X 2 - is -C(R 8 R 8a )-, or -C(R 8 R 8a )-C(R 9 R 9a )- and, =X 3 is =O, =S, or =N-CN, -R 1 ,-R 1a ,-R 2 ,-R 2a ,-R 4 ,-R 4a ,-R 5 ,-R 5a ,-R 6 ,-R 8 ,-R 8a ,-R 9 ,-R 9a These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, -R 3 ,-R 3a These are independently -H and C 1-6 Selected from the group consisting of alkyl, except -R 3 ,-R 3a If one or both of them are not -H, then they are SP to the N to which they are bonded. 3 Linked by hybrid carbon atoms, -R7 is -N(R 10 R 10a ), or -NR 10 -(C=O)-R 11 And, -R 7a ,-R 10 ,-R 10a ,-R 11 These are, independently of each other, -H or C 1-6 It is alkyl, Depending on the circumstances, Pair-R 1a / -R 4a ,-R 1a / -R 5a ,-R 1a / -R 7a ,-R 4a / -R 5a ,-R 8a / -R 9a One or more of them form a chemical bond, Depending on the circumstances, Pair-R 1 / -R 1a ,-R 2 / -R 2a ,-R 4 / -R 4a ,-R 5 / -R 5a ,-R 8 / -R 8a ,-R 9 / -R 9a One or more of them, together with the atom they are bonded to, C 3-10 Forming cycloalkyl or 3-10 membered heterocyclines, Depending on the circumstances, Pair-R 1 / -R 4 ,-R 1 / -R 5 ,-R 1 / -R 6 ,-R 1 / -R 7a ,-R 4 / -R 5 ,-R 4 / -R 6 ,-R 8 / -R 9 ,-R 2 / -R 3 One or more of these, together with the atoms to which they are bonded, form ring A. Depending on the case, R 3 / R 3a These, together with the nitrogen atoms to which they are bonded, form a 3- to 10-membered heterocycle. A is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 (Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl), -L 1 - is -L 2 -Z is substituted, and in some cases, -L 1 - is further substituted, except that the hydrogen with an asterisk in equation (II) is -L 2 -Z or substituents are not replaced, -L 2 - is a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0153] In a particular embodiment, -L of formula (II) 1 - is one part -L 2 It is replaced with -Z.

[0154] In a particular embodiment, -L of formula (II) 1 - has not been further replaced.

[0155] -R in equation (II) 3 / -R 3a However, when they combine with the nitrogen atom to which they are bonded to form a 3- to 10-membered heterocycle, the atom directly bonded to the nitrogen is SP 3 It is understood that only such 3- to 10-membered heterocycles, which are hybrid carbon atoms, can be formed. In other words, -R 3 / -R 3a Such 3- to 10-membered heterocycles, formed by these atoms and the nitrogen atoms to which they are bonded, have the following structure: [ka] (In the formula, The dashed line is -L 1- indicates the connection to the remainder, The ring contains 3 to 10 atoms, including at least one nitrogen atom, and R # and R ## is, sp 3 (Represents a hybrid carbon atom.)

[0156] It is also understood that 3- to 10-membered complex rings may be further substituted.

[0157] -R in equation (II) 3 / -R 3a A suitable exemplary embodiment of a 3- to 10-membered heterocycle formed by these atoms and the nitrogen atoms to which they are bonded is as follows: [ka] (In the formula, The dashed line indicates the bond to the rest of the molecule. -R is -H and C 1-6 (Selected from the group consisting of alkyl groups).

[0158] Depending on the case, -L in equation (II) 1 - may be further substituted. In general, any substituent may be used as long as it does not affect the principle of cleavage, that is, the hydrogen with the asterisk in formula (II) is not substituted, and part of formula (II) [ka] The nitrogen remains as part of the primary, secondary, or tertiary amine, i.e., -R 3 and -R 3a These are either -H independently of each other, or SP 3 It is linked to -N< by hybridized carbon atoms.

[0159] In certain embodiments, -R of formula (II) 1 or -R 1a is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 2 or -R 2ais, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 3 or -R 3a is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 4 is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 5 or -R 5a is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 6 is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 7 or -R 7a is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 8 or -R 8a is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 9 or -R 9a is, -L 2 It is replaced with -Z.

[0160] In certain embodiments, -R of formula (II) 4 is, -L 2 It is replaced with -Z.

[0161] In a particular embodiment, -X- in formula (II) is -C(R 4 R 4a )- or -N(R 4 )-is.

[0162] In a particular embodiment, -X- in formula (II) is -C(R 4 R 4a )-is.

[0163] In a particular embodiment, X of formula (II) 1 It is C.

[0164] In a particular embodiment, equation (II) = X3 The answer is = O.

[0165] In a particular embodiment, -X of formula (II) 2 - is -C(R 8 R 8a )-is.

[0166] In certain embodiments, -R of formula (II) 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (II) 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (II) 8 and -R 8a Both are -H.

[0167] In certain embodiments, -R of formula (II) 1 and -R 1a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (II) 1 and -R 1a At least one of them is -H. In certain embodiments, -R of formula (II) 1 and -R 1a Both are -H.

[0168] In certain embodiments, -R of formula (II) 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (II) 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (II) 2 and -R 2a Both are H.

[0169] In certain embodiments, -R of formula (II) 3 and -R 3aThe is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (II) 3 and -R 3a At least one of them is methyl. In certain embodiments, -R of formula (II) 3 and -R 3a Both are -H. In certain embodiments, -R of formula (II) 3 and -R 3a Both are methyl. In certain embodiments, the -R of formula (II) 3 is -H, and -R in equation (II) 3a It is methyl.

[0170] In certain embodiments, -R of formula (II) 4 and -R 4a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (II) 4 and -R 4a At least one of them is -H. In certain embodiments, -R of formula (II) 4 and -R 4a Both are -H.

[0171] In certain embodiments, part-L 1 - is equation (IIa): [ka] (In the formula, The dashed line indicates the bonding of the CNP moiety, -D, to nitrogen by forming an amide bond, and -R 1 ,-R 1a ,-R 2 ,-R 2a ,-R 3 ,-R 3a ,-R 4 ,-R 4a and -X 2 - is used as defined for equation (II). It has, Said-L 1 - is -L 2-Z is substituted, and in some cases, the aforementioned -L 1 - is further substituted, except that the hydrogen with an asterisk in equation (IIa) is -L 2 -Z cannot be replaced by a substituent.

[0172] In a particular embodiment, -L of formula (IIa) 1 - is one part -L 2 It is replaced with -Z.

[0173] In a particular embodiment, part L of formula (IIa) 1 - has not been further replaced.

[0174] In certain embodiments, -R of formula (IIa) 1 and -R 1a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa) 1 and -R 1a At least one of them is -H. In certain embodiments, -R of formula (IIa) 1 and -R 1a Both are -H.

[0175] In certain embodiments, -R of formula (IIa) 4 and -R 4a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa) 4 and -R 4a At least one of them is -H. In certain embodiments, -R of formula (IIa) 4 and -R 4a Both are -H.

[0176] In a particular embodiment, -X of formula (IIa) 2 - is -C(R 8 R 8a )-is.

[0177] In certain embodiments, -R of formula (IIa) 8 and -R8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa) is used. 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (IIa) 8 and -R 8a Both are -H.

[0178] In certain embodiments, -R of formula (IIa) 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa) 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (IIa) 2 and -R 2a Both are H.

[0179] In certain embodiments, -R of formula (IIa) 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (IIa) 3 and -R 3a At least one of them is methyl. In certain embodiments, -R of formula (IIa) 3 and -R 3a Both are -H. In certain embodiments, -R of formula (IIa) 3 and -R 3a Both are methyl. In certain embodiments, the -R of formula (IIa) 3 is -H, and -R in equation (IIa) 3a It is methyl.

[0180] In certain embodiments, part-L 1 - is equation (IIb): [ka] (In the formula, The dashed line indicates the bonding of the CNP moiety, -D, to nitrogen by forming an amide bond, and -R 2 ,-R 2a ,-R 3 ,-R 3a and -X 2 - is used as defined for equation (II). It has, Said-L 1 - is -L 2 -Z is substituted, and in some cases, the aforementioned -L 1 - is further substituted, except that the hydrogen with the asterisk in equation (IIb) is -L 2 -Z cannot be replaced by a substituent.

[0181] In certain embodiments, -L of formula (IIb) 1 - is one part -L 2 It is replaced with -Z.

[0182] In a particular embodiment, part L of formula (IIb) 1 - has not been further replaced.

[0183] In a particular embodiment, -X of formula (IIb) 2 - is -C(R 8 R 8a )-is.

[0184] In certain embodiments, -R of formula (IIb) 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb) 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (IIb) 8 and -R 8a Both are -H.

[0185] In certain embodiments, -R of formula (IIb) 2 and -R 2aThe is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb) 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (IIb) 2 and -R 2a Both are H.

[0186] In certain embodiments, -R of formula (IIb) 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (IIb) 3 and -R 3a At least one of them is methyl. In certain embodiments, -R of formula (IIb) 3 and -R 3a Both are -H. In certain embodiments, -R of formula (IIb) 3 and -R 3a Both are methyl. In certain embodiments, the -R of formula (IIb) 3 is -H, and -R in equation (IIb) 3a It is methyl.

[0187] In certain embodiments, part-L 1 - is equation (IIb'): [ka] (In the formula, The dashed line indicates the bonding of the CNP portion, D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates -L 2 - indicates binding to -R 2 ,-R 2a ,-R 3 ,-R 3a , and -X 2 - is used as defined for equation (II). It has, Depending on the circumstances, the above-L 1- is further substituted, except that the hydrogen atom with the asterisk in formula (IIb') is not replaced by a substituent.

[0188] In a particular embodiment, part L of formula (IIb') 1 - has not been further replaced.

[0189] In a particular embodiment, -X in formula (IIb') 2 - is -C(R 8 R 8a )-is.

[0190] In certain embodiments, the -R of formula (IIb') 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb') 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (IIb') 8 and -R 8a Both are -H.

[0191] In certain embodiments, the -R of formula (IIb') 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb') is used. 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (IIb') 2 and -R 2a Both are H.

[0192] In certain embodiments, the -R of formula (IIb') 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (IIb') 3 and -R 3a At least one of them is methyl. In certain embodiments, -R of formula (IIb') 3 and -R3a Both are -H. In certain embodiments, -R of formula (IIb') 3 and -R 3a Both are methyl. In certain embodiments, the -R of formula (IIb') 3 is -H, and -R in equation (IIb') 3a It is methyl.

[0193] In certain embodiments, part-L 1 - is equation (IIc): [ka] (In the formula, the dashed line indicates the bonding of the CNP portion, -D, to nitrogen by forming an amide bond.) It has, Said-L 1 - is -L 2 -Z has been replaced, Said-L 1 - is sometimes further substituted, except that the hydrogen with an asterisk in formula (IIc) is -L 2 -Z cannot be replaced by a substituent.

[0194] In certain embodiments, the -L of formula (IIc) 1 - is one part -L 2 It is replaced with -Z.

[0195] In a particular embodiment, part L of formula (IIc) 1 - has not been further replaced.

[0196] In certain embodiments, part-L 1 - is equation (IIc-a): [ka] (In the formula, the dashed line indicates the bonding of the CNP portion, -D, to nitrogen by forming an amide bond.) It has, Said-L 1 - is -L 2-Z has been replaced, Said-L 1 - is sometimes further substituted, except that the hydrogen with an asterisk in formula (IIc-a) is -L 2 -Z cannot be replaced by a substituent.

[0197] In a particular embodiment, -L of formula (IIc-a) 1 - is one part -L 2 It is replaced with -Z.

[0198] In a particular embodiment, part L of formula (IIc-a) 1 - has not been further replaced.

[0199] In certain embodiments, part-L 1 - is equation (IIc-b): [ka] (In the formula, the dashed line indicates the bonding of the CNP portion, -D, to nitrogen by forming an amide bond.) It has, Said-L 1 - is -L 2 -Z has been replaced, Depending on the circumstances, the above-L 1 - is further substituted, except that the hydrogen with an asterisk in formula (IIc-b) is -L 2 -Z cannot be replaced by a substituent.

[0200] In certain embodiments, the -L of formula (IIc-b) 1 - is one part -L 2 It is replaced with -Z.

[0201] In a particular embodiment, part L of formula (IIc-b) 1 - has not been further replaced.

[0202] In certain embodiments, part-L 1- is in equations (IIc-i), (IIc-ii), (IIc-iii), (IIc-iv), and (IIc-v): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates -L 2 (Indicates bonding to -Z) Selected from the group consisting of, Said-L 1 - is further substituted in some cases, except that the asterisked hydrogen in formulas (IIc-i), (IIc-ii), (IIc-iii), (IIc-iv) and (IIc-v) is not replaced by a substituent.

[0203] In a particular embodiment, part L of formulas (IIc-i), (IIc-ii), (IIc-iii), (IIc-iv) and (IIc-v) 1 - has not been further replaced.

[0204] In certain embodiments, part-L 1 - is equation (IIc-ii): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates -L 2 (Indicates bonding to -Z) That is the case.

[0205] In a particular embodiment, the -L of formula (IIc-ii) 1 - is one part -L 2 It is replaced with -Z.

[0206] In certain embodiments, part-L 1- represents equations (IIc-i'), (IIc-ii'), (IIc-iii'), (IIc-iv'), and (IIc-v'): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates -L 2 (Indicates bonding to -Z) Selected from the group consisting of, Depending on the circumstances, the above-L 1 - is further substituted, however, the asterisked hydrogens in formulas (IIc-i'), (IIc-ii'), (IIc-iii'), (IIc-iv') and (IIc-v') are not replaced by substituents.

[0207] In a particular embodiment, part L of formulas (IIc-i'), (IIc-ii'), (IIc-iii'), (IIc-iv') and (IIc-v') 1 - has not been further replaced.

[0208] In certain embodiments, part-L 1 - is equation (IIc-ii'): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates -L 2 (Indicates bonding to -Z) That is the case.

[0209] In a particular embodiment, -L of formula (IIc-ii') 1 - is one part -L 2 It is replaced with -Z.

[0210] In certain embodiments, part-L 1- is the expression (IIc-i''), (IIc-ii''), (IIc-iii''), and (IIc-iv''): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates -L 2 (Indicates bonding to -Z) Selected from the group consisting of, Depending on the circumstances, the above-L 1 - is further substituted, however, the asterisked hydrogens in formulas (IIc-i''), (IIc-ii''), (IIc-iii'') and (IIc-iv'') are not replaced by substituents.

[0211] In a particular embodiment, part L of formulas (IIc-i''), (IIc-ii''), (IIc-iii'') and (IIc-iv'') 1 - has not been further replaced.

[0212] In certain embodiments, part-L 1 - is equation (IIc-ii''): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates -L 2 (Indicates bonding to -Z) That is the case.

[0213] In a particular embodiment, the -L of formula (IIc-ii'') 1 - is one part -L 2 It is replaced with -Z.

[0214] Formula (II), (IIa), (IIb), (IIb'), (IIc), (IIc-a), (IIc-b), (IIc-i), (IIc-ii), (IIc-iii), (IIc-iv), (IIc-v), (I -L of Ic-i'), (IIc-ii'), (IIc-iii'), (IIc-iv'), (IIc-v'), (IIc-i''), (IIc-ii''), (IIc-iii'') and (IIc-iv'') 1 Further optional substituents of - are, in certain embodiments, as described above.

[0215] Another part - L 1 - is disclosed in International Publication No. 2016 / 020373, Brochure A1. Therefore, in certain embodiments, part -L 1 - is equation (III): [ka] (In the formula, The dashed lines indicate bonding by forming amide or ester bonds to the primary or secondary amine or hydroxyl group of the CNP portion -D, respectively. -R 1 ,-R 1a ,-R 2 ,-R 2a ,-R 3 and -R 3a These are -H, -C(R 8 R 8a R 8b ), -C(=O)R 8 -C≡N, -C(=NR) 8 )R 8a ,-CR 8 (=CR 8a R 8b ), -C≡CR 8 Selected from the group consisting of and -T, -R 4 ,-R 5 and -R 5a These are -H, -C(R 9 R 9a R 9b Selected from the group consisting of ) and -T, a1 and a2 are independently 0 or 1. Each-R 6 ,-R 6a ,-R 7 ,-R 7a ,-R 8 ,-R 8a ,-R 8b ,-R 9 ,-R 9a ,-R 9b These are -H, halogen, -CN, and -COOR, which are independent of each other. 10 , -OR 10 , -C(O)R 10 ,-C(O)N(R 10 R 10a ), -S(O)2N(R 10 R 10a ), -S(O)N(R 10 R 10a ), -S(O)2R 10 ,-S(O)R 10 , -N(R 10 )S(O)2N(R 10a R 10b ), -SR 10 , -N(R 10 R 10a ), -NO2, -OC(O)R 10 , -N(R 10 )C(O)R 10a , -N(R 10 )S(O)2R 10a , -N(R 10 )S(O)R 10a , -N(R 10 )C(O)OR 10a , -N(R 10 )C(O)N(R 10a R 10b ), -OC(O)N(R 10 R 10a ), -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Selected from the group consisting of alkynyl, where -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is the same or different -R of one or more R's. 11 In some cases, it is replaced by C 1-20Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl may optionally be interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 12 ), -S(O)2N(R 12 ), -S(O)N(R 12 ), -S(O)2-, -S(O)-, -N(R 12 )S(O)2N(R 12a ), -S-, -N(R 12 ), -OC(OR 12 )(R 12a ), -N(R 12 )C(O)N(R 12a ), and -OC(O)N(R 12 ), and each -R , -R 10 , -R 10a , -R 10b is independently selected from the group consisting of -H, -T, C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl, and the -T, C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl may optionally be substituted with one or more of the same or different -R 11 , and the C 1-20 alkyl, C 2-20 alkenyl and C 2-20 [[ID=5!]]alkynyl may optionally be interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 12 ), -S(O)2N(R 12 ), -S(O)N(R 12 ), -S(O)2-, -S(O)-, -N(R 12 )S(O)2N(R 12a ), -S-, -N(R 12 ), -OC(OR 12 )(R 12a ), -N(R​​​​​​ Each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, and each T is independently optionally substituted with one or more of the same or different -R 11 as the case may be, each -R 11 is independently selected from the group consisting of halogen, -CN, oxo (=O), -COOR 13 , -OR 13 , -C(O)R 13 , -C(O)N(R 13 R 13a ), -S(O)2N(R 13 R​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​selected from the group consisting of alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more of the same or different halogen atoms, optionally, a pair -R 1 / -R 1a 、-R 2 / -R 2a 、-R 3 / -R 3a 、-R 6 / -R 6a 、-R 7 / -R 7a one or more of which, together with the atoms to which they are attached, form a C 3-10 cycloalkyl or a 3- to 10-member heterocyclyl, optionally, a pair -R 1 / -R 2 、-R 1 / -R 3 、-R 1 / -R 4 、-R 1 / -R 5 、-R 1 / -R 6 ...、-R 6 / -R​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​7 One or more of these, together with the atoms to which they are bonded, form ring A. A is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 (Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl) It has, Said-L 1 - is -L 2 -Z is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, -L 2 - is a single chemical bond or spacer, -Z represents the water-soluble polymer portion.

[0216] -L in equation (III) 1 Further optional substituents of - are, in certain embodiments, as described above.

[0217] In certain embodiments, -L of formula (III) 1 - is one part -L 2 It is replaced with -Z.

[0218] In certain embodiments, -L of formula (III) 1 - has not been further replaced.

[0219] -L 1 Further embodiments of - are disclosed in European Patent No. 1536334B1, WO2009 / 009712A1, WO2008 / 034122A1, WO2009 / 143412A2, WO2011 / 082368A2, and U.S. Patent No. 8,618,124B2, which are incorporated herein by reference in their entirety.

[0220] -L 1 Further embodiments of - are disclosed in U.S. Patent No. 8,946,405B2 and U.S. Patent No. 8,754,190B2, which are incorporated herein by reference in their entirety. Therefore, part -L1 - is equation (IV): [ka] (In the formula, The dashed line indicates a bond to the CNP portion, -D, and this bond is due to a functional group of -D selected from the group consisting of -OH, -SH, and -NH2. m is either 0 or 1. -R 1 and -R 2 At least one or both of these are, independently of each other, -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -C(O)R 3 ,-S(O)R 3 -S(O)2R 3 , and -SR 4 Selected from the group consisting of, -R 1 and -R 2 One or only one of these is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl. -R 3 -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 9 and -N(R 9 Selected from the group consisting of )2, -R 4 This is selected from the group consisting of optionally substituted alkyls, optionally substituted aryls, optionally substituted arylalkyls, optionally substituted heteroaryls, and optionally substituted heteroarylalkyls. Each-R 5These are independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. -R 9 This is selected from the group consisting of -H and optionally substituted alkyl groups, -Y- does not exist, and -X- is either -O- or -S-, or -Y- is -N(Q)CH2-, and -X- is -O-, Q is selected from the group consisting of optionally substituted alkyls, optionally substituted aryls, optionally substituted arylalkyls, optionally substituted heteroaryls, and optionally substituted heteroarylalkyls. Depending on the case, -R 1 and -R 2 They may also come together to form a 3-8 membered ring, and Depending on the case, both -R 9 (These atoms, together with the nitrogen atoms they are bonded to, form a heterocyclic ring.) It has, Said-L 1 - is -L 2 -Z is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, -L 2 - is a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0221] -L in equation (IV) 1 Further optional substituents of - are, in certain embodiments, as described above.

[0222] In certain embodiments, -L of formula (IV) 1 - is one part -L 2 It is replaced with -Z.

[0223] In certain embodiments, -L of formula (IV) 1 - has not been further replaced.

[0224] The term used exclusively in relation to formula (IV) has the following meanings:

[0225] The term "alkyl" as used herein includes linear, branched, or cyclic saturated hydrocarbon groups comprising 1 to 8 carbon atoms, or in some embodiments, 1 to 6 or 1 to 4 carbon atoms.

[0226] The term "alkoxy" includes alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and similar groups.

[0227] The term "alkenyl" includes non-aromatic unsaturated hydrocarbons that have a carbon-carbon double bond.

[0228] The term "alkynyl" includes non-aromatic unsaturated hydrocarbons that have a carbon-carbon triple bond.

[0229] The term "aryl" includes aromatic hydrocarbon groups with 6 to 18 carbon atoms, and in certain embodiments, 6 to 10 carbon atoms, including groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" includes aromatic rings with 3 to 15 carbon atoms, and at least one N, O, or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and similar groups, and in certain embodiments, 3 to 7 carbon atoms, and at least one N, O, or S atom.

[0230] In certain embodiments, the alkenyl, alkynyl, aryl, or heteroaryl moiety may be coupled to the remainder of the molecule by an alkylene bond. The substituents under these circumstances are referred to as alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that the alkylene moiety lies between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is coupled.

[0231] The term "halogen" includes bromo, fluoro, chloro, and iodine.

[0232] The term "heterocyclic ring" refers to a 4-8 member aromatic or aromatic ring containing 3-7 carbon atoms and at least one N, O, or S atom. Examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the good example groups provided above for the term "heteroaryl."

[0233] When the ring system is optionally substituted, suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or further rings, each of which may be further substituted. Optional substituents for any of the above groups include halo, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SO2R, -SONR2, and -SO2NR2, where each R is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or two R groups together with the atom to which they are bonded form a ring.

[0234] -L 1 Further embodiments of - are disclosed in WO2013 / 036857A1, which is incorporated herein by reference in its entirety. Thus, in certain embodiments, part -L 1 - is equation (V): [ka] (In the formula, The dashed line indicates the bond to the CNP portion, -D, and this bond is due to the amine functional group of -D. -R 1 These include optionally substituted C1-C6 linear, branched, or cyclic alkyl groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, alkoxy groups, and -NR groups. 5 Selected from a group consisting of 2, -R 2 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. -R 3 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. -R 4 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. Each-R 5 These are independently selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, or together, two -R 5 (This can be a cycloalkyl or cycloheteroalkyl group.) It has, Said-L 1 - is -L 2 -Z is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, -L 2 - is a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0235] -L in equation (V) 1 Further optional substituents of - are, in certain embodiments, as described above.

[0236] In certain embodiments, -L of formula (V) 1 - is one part -L 2 It is replaced with -Z.

[0237] In certain embodiments, -L of formula (V) 1 - has not been further replaced.

[0238] The term used exclusively in relation to the expression (V) has the following meanings:

[0239] "Alkyl," "alkenyl," and "alkynyl" refer to linear, branched, or cyclic hydrocarbon groups comprising 1 to 8, 1 to 6, or 1 to 4 carbon atoms, wherein alkyl is a saturated hydrocarbon, alkenyl contains one or more carbon-carbon double bonds, and alkynyl contains one or more carbon-carbon triple bonds. Unless otherwise specified, these contain 1 to 6 carbon atoms.

[0240] "Aryl" includes aromatic hydrocarbon groups with 6 to 18 carbon atoms, and in certain embodiments, 6 to 10 carbon atoms, including groups such as phenyl, naphthyl, and anthracene. "Heteroaryl" includes aromatic rings with 3 to 15 carbon atoms, and at least one N, O, or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and similar groups, and in certain embodiments, 3 to 7 carbon atoms, and at least one N, O, or S atom.

[0241] The term "substituted" refers to an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group that contains one or more substituents in place of one or more hydrogen atoms. Substituents generally include halogens (including F, Cl, Br, and I), lower alkyls (including linear, branched, and cyclic), lower haloalkyls (including fluoroalkyls, chloroalkyls, bromoalkyls, and iodoalkyls), OH, lower alkoxys (including linear, branched, and cyclic), SH, lower alkylthios (including linear, branched, and cyclic), aminos, alkylaminos, dialkylaminos, silyls (including alkylsilyls, alkoxysilyls, and arylsilyls), nitros, cyanos, carbonyls, carboxylic acids, carboxylic acid esters, carboxylic acid amides, aminocarbonyls, aminoacyls, carbamates, ureas, and thios. The following may be selected: carbamates, thioureas, ketones, sulfones, sulfonamides, aryls (including phenyl, naphthyl, and anthracenyl), and heteroaryls (including five-membered heteroaryls such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole, and tetrazole; six-membered heteroaryls such as pyridine, pyrimidine, and pyrazine; and fusion heteroaryls such as benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzoisoxazole, and benzoisothiazole).

[0242] -L 1 Further embodiments of - are disclosed in U.S. Patent No. 7,585,837 B2, which is incorporated herein by reference in its entirety. Thus, in certain embodiments, part -L 1 - is equation (VI): [ka] (In the formula, The dashed line indicates the bond to the CNP portion, -D, and this bond is due to the amine functional group of -D. R1 and R 2 These are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkalyl, aralkyl, halogen, nitro, -SO3H, -SO2HH 5 Selected from the group consisting of amino, ammonium, carboxyl, PO3H2 and OPO3H2, R 3 , R 4 and R 5 It independently has (selected from the group consisting of hydrogen, alkyl and aryl), Said-L 1 - is -L 2 -Z is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, -L 2 - is a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0243] Suitable substituents for formula (VI) are alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g., C 2-6 Alkenyl), Alkinyl (for example, C 2-6 The moiety is an alkynyl, aryl (e.g., phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (e.g., an aromatic 4-7 membered heterocycle), or halogen moiety.

[0244] In certain embodiments, -L of formula (VI) 1 - is one part -L 2 It is replaced with -Z.

[0245] -L of equation (VI) 1 Further optional substituents of - are, in certain embodiments, as described above.

[0246] In certain embodiments, -L of formula (VI) 1 - has not been further replaced.

[0247] The term used exclusively in relation to formula (VI) has the following meanings:

[0248] The terms "alkyl," "alkoxy," "alkoxyalkyl," "aryl," "alkalil," and "aralkyl" refer to alkyl radicals with 1 to 8 carbon atoms, and in certain embodiments, 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and butyl, and aryl radicals with 6 to 10 carbon atoms, such as phenyl and naphthyl. The term "halogen" includes bromo, fluoro, chloro, and iodine.

[0249] -L 1 Further embodiments of - are disclosed in WO2002 / 089789A1, which is incorporated herein by reference in its entirety. Thus, part -L 1 - is equation (VII): [ka] (In the formula, The dashed line indicates the bond to the CNP portion, -D, and this bond is due to the amine functional group of -D. L1 is a bifunctional bonding group, Y1 and Y2 are independently O, S, or NR 7 And, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C 1-6 Alkyl, C 3-12 Branched alkyl, C 3-8 Cycloalkyl, C 1-6 Substituting alkyl, C 3-8 Substituted cycloalkyl, aryl, substituted aryl, aralkyl, C 1-6 Heteroalkyl, substituted C 1-6 Heteroalkyl, C 1-6 Alkoxy, phenoxy and C 1-6 Selected from the group consisting of heteroalkoxys, When Ar is included in formula (VII), it is the part that forms a polysubstituted aromatic hydrocarbon or a polysubstituted heterocyclic group. X is a chemical bond, or a portion that is actively transported to the target cell, a hydrophobic portion, or a combination thereof. (y is either 0 or 1) It has, Said-L 1 - is -L 2 -Z is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, -L 2 - is a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0250] In certain embodiments, -L of formula (VII) 1 - is one part -L 2 It is replaced with -Z.

[0251] -L in equation (VII) 1 Further optional substituents of - are, in certain embodiments, as described above.

[0252] In certain embodiments, -L of formula (VII) 1 - has not been further replaced.

[0253] The term used exclusively in relation to formula (VII) has the following meanings:

[0254] The term "alkyl" is used, for example, in alkoxy, C 3-8 Linear, branched, and substituted carbon atoms, including cycloalkyl or substituted cycloalkyl groups. 1-12 It is understood that it contains alkyl groups.

[0255] The term "substituted" shall be understood to include the addition of one or more atoms contained in a functional group or compound, and the replacement of one or more different atoms.

[0256] Substituted alkyls include carboxyalkyls, aminoalkyls, dialkylaminos, hydroxyalkyls, and mercaptoalkyls; substituted cycloalkyls include parts such as 4-chlorocyclohexyl; aryls include parts such as naphthyl; substituted aryls include parts such as 3-bromophenyl; aralkyls include parts such as toluyl; heteroalkyls include parts such as ethylthiophene; substituted heteroalkyls include parts such as 3-methoxythiophene; alkoxys include parts such as methoxy; and phenoxys include parts such as 3-nitrophenoxy. Halos are understood to include fluoro, chloro, iodine, and bromo.

[0257] In certain embodiments, -L 1 - is a substructure of equation (VIII) [ka] (In the formula, The dashed line with an asterisk indicates the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. Dashed lines without a mark are -L 1 (Indicates connection to the remainder) Includes, Said-L 1 - is -L 2 -Z is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, and here, -L 2 - is a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0258] In certain embodiments, the -L of formula (VIII) 1 - is one part -L 2 It is replaced with -Z.

[0259] -L in equation (VIII) 1 Further optional substituents are as described above.

[0260] In certain embodiments, the -L of formula (VIII) 1 - has not been further replaced.

[0261] In certain embodiments, -L 1 - is a substructure of equation (IX) [ka] (In the formula, The dashed lines with asterisks indicate bonding through the formation of a carbamate bond to the nitrogen of the CNP portion -D. Dashed lines without a mark are -L 1 (Indicates connection to the remainder) Includes, Said-L 1 - is -L 2 -Z is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, -L 2 - is a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0262] -L in equation (IX) 1 Further optional substituents are as described above.

[0263] In certain embodiments, -L of formula (IX) 1 - is one part -L 2 It is replaced with -Z.

[0264] In certain embodiments, -L of formula (IX) 1 - has not been further replaced.

[0265] Part -D is -L via any functional group of DH 1 -Can be linked to -L via the amine functional group of DH. 1 - is linked. This may be an amine functional group provided by an N-terminal amine functional group or a lysine side chain, i.e., if the CNP has the sequence of SEQ ID NO: 24, by the lysine at positions 9, 11, 15, 16, 20 and 26.

[0266] -L to the ring of the CNP portion 1 The binding of the hyphen significantly reduces the affinity of the CNP conjugate for NPR-B compared to binding to the N-terminus or acyclic portion of the CNP. This reduced affinity for NPR-B, in turn, reduces the risk of cardiovascular side effects such as hypotension.

[0267] Therefore, -L 1 - is, in certain embodiments, bonded to the side chain of an amino acid residue of the ring portion of -D or to the backbone of the ring portion of -D. In certain embodiments, -L 1 - is covalently and reversibly bound to the side chain of the amino acid residue of the ring portion of -D. If -D is the CNP portion having the sequence of SEQ ID NO: 24, then -L 1 - is bonded in certain embodiments to the amine functional group provided by lysine at the 26th position of the corresponding drug DH.

[0268] Part-L 2 - represents a chemical bond or spacer portion.

[0269] In certain embodiments, -L 2 - represents a chemical bond.

[0270] In certain embodiments, -L 2 - indicates the spacer portion.

[0271] Part-L 2 - replaces any existing -H with -L unless explicitly excluded. 1 -It can be connected to something else.

[0272] -L 2 -If it is not a monochemical bond, -L 2 - stands for -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-,-S(O)2N(R y1 )-,-S(O)N(R y1)-, -S(O)2-, -S(O)-, -N(R y1 )S(O)2N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from alkinyl; -T-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R y2 It is also acceptable if it is replaced with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y3 )-,-S(O)2N(R y3 )-,-S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-,-N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- may optionally include one or more groups selected from the group consisting of;

[0273] -R y1 and -R y1a -H, -T, C are independent of each other. 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; -T, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R y2It is also acceptable if it is replaced with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y4 )-,-S(O)2N(R y4 )-,-S(O)N(R y4 )-, -S(O)2-, -S(O)-, -N(R y4 )S(O)2N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-,-N(R y4 )C(O)N(R y4a )-, and -OC(O)N(R y4 )- may optionally include one or more groups selected from the group consisting of;

[0274] Each T independently consists of phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C. 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered polycyclic carbon, and 8-30 membered heteropolycyclic; each T independently has one or more identical or different -R y2 It is also acceptable if it is replaced with;

[0275] Each-R y2 These are independently halogen, -CN, oxo (=O), and -COOR. y5 , -OR y5 , -C(O)R y5 ,-C(O)N(R y5 R y5a ), -S(O)2N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O)2R y5 ,-S(O)R y5 , -N(R y5 )S(O)2N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a), -NO2, -OC(O)R y5 , -N(R y5 )C(O)R y5a , -N(R y5 )S(O)2R y5a , -N(R y5 )S(O)R y5a , -N(R y5 )C(O)OR y5a , -N(R y5 )C(O)N(R y5a R y5b ), -OC(O)N(R y5 R y5a ), and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 The alkyl group may be substituted with one or more identical or different halogens; each -R y3 ,-R y3a ,-R y4 ,-R y4a ,-R y5 ,-R y5a and -R y5b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 The alkyl group may be substituted with one or more identical or different halogens.

[0276] -L 2 -If it is not a monochemical bond, -L 2 - stands for -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-,-S(O)2N(R y1 )-,-S(O)N(R y1 )-, -S(O)2-, -S(O)-, -N(R y1 )S(O)2N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20Selected from the group consisting of alkynnyls; -T-, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is one or more identical or different -R y2 It is also acceptable if it is replaced with C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y3 )-,-S(O)2N(R y3 )-,-S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-,-N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- may optionally include one or more groups selected from the group consisting of;

[0277] -R y1 and -R y1a -H, -T, C are independent of each other. 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyls; -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl is one or more identical or different -R y2 It is also acceptable if it is replaced with C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y4 )-,-S(O)2N(R y4 )-,-S(O)N(R y4 )-, -S(O)2-, -S(O)-, -N(R y4 )S(O)2N(R y4a )-, -S-, -N(Ry4 )-, -OC(OR y4 )(R y4a )-,-N(R y4 )C(O)N(R y4a )-, and -OC(O)N(R y4 )- may optionally include one or more groups selected from the group consisting of;

[0278] Each T independently consists of phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C. 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered polycyclic carbon, and 8-30 membered heteropolycyclic; each T independently has one or more identical or different -R y2 It is also acceptable if it is replaced with;

[0279] -R y2 These are halogen, -CN, oxo (=O), and -COOR. y5 , -OR y5 , -C(O)R y5 ,-C(O)N(R y5 R y5a ), -S(O)2N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O)2R y5 ,-S(O)R y5 , -N(R y5 )S(O)2N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO2, -OC(O)R y5 , -N(R y5 )C(O)R y5a , -N(R y5 )S(O)2R y5a , -N(R y5 )S(O)R y5a , -N(R y5 )C(O)OR y5a , -N(R y5 )C(O)N(R y5a R y5b ), -OC(O)N(R y5R y5a ), and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 Alkyl can be substituted with one or more identical or different halogens;

[0280] Each-R y3 ,-R y3a ,-R y4 ,-R y4a ,-R y5 ,-R y5a and -R y5b -H and C are independent of each other. 1-6 Selected from the group consisting of alkyl groups; C 1-6 The alkyl group may be substituted with one or more identical or different halogens.

[0281] -L 2 -If it is not a monochemical bond, -L 2 - stands for -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-,-S(O)2N(R y1 )-,-S(O)N(R y1 )-, -S(O)2-, -S(O)-, -N(R y1 )S(O)2N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; -T-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R y2 It is also acceptable if it is replaced with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y3)-,-S(O)2N(R y3 )-,-S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-,-N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- may optionally include one or more groups selected from the group consisting of;

[0282] -R y1 and -R y1a These are independently -H, -T, and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkinyls;

[0283] Each T independently consists of phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C. 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered polycyclic carbon, and 8-30 membered heteropolycyclic carbon;

[0284] Each-R y2 is halogen and C 1-6 Selected from the group consisting of alkyl groups;

[0285] Each-R y3 ,-R y3a ,-R y4 ,-R y4a ,-R y5 ,-R y5a and -R y5b -H and C are independent of each other. 1-6 Selected from the group consisting of alkyl groups; C 1-6 The alkyl group may be substituted with one or more identical or different halogens.

[0286] In certain embodiments, -L 2 - is C1-20 It is an alkyl chain, which independently consists of -O-, -T- and -C(O)N(R) y1 )- may optionally include one or more elements selected from; C 1-20 The alkyl chains are independently -OH, -T, and -C(O)N(R) y6 R y6a ) may be replaced by one or more elements selected from ;-R y1 ,-R y6 ,-R y6a H and C are independent of each other. 1-4 Selected from the group consisting of alkyl groups, T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 The group is selected from cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered polycyclic carbon, and 8-30 membered heteropolycyclic carbon.

[0287] In certain embodiments, -L 2 - has a molecular weight in the range of 14 g / mol to 750 g / mol (including both ends).

[0288] In certain embodiments, -L 2 - has a chain length of 1 to 20 atoms.

[0289] When used herein, part-L 2 The term "chain length" in relation to -L 1 -L exists in the shortest connection between - and -Z 2 - Refers to the number of atoms.

[0290] In certain embodiments, -L 2 - is the same as in equation (i) below. [ka] During the ceremony, The dashed line marked with an asterisk is -L 1 - refers to a connection to; Unmarked dashed lines indicate connections to -Z; -R 1 is -H, C 1-6Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls; n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18; The part of equation (i) may be further substituted.

[0291] In certain embodiments, -R of formula (i) 1 The is selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (i) 1 is selected from the group consisting of -H, methyl, ethyl, and propyl. In certain embodiments, -R of formula (i) 1 is selected from the group consisting of -H and methyl. In certain embodiments, -R of formula (i) 1 It is methyl.

[0292] In a particular embodiment, n in formula (i) is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In a particular embodiment, n in formula (i) is selected from the group consisting of 0, 1, 2, 3, 4, and 5. In a particular embodiment, n in formula (i) is selected from the group consisting of 0, 1, 2, and 3. In a particular embodiment, n in formula (i) is selected from the group consisting of 0 and 1. In a particular embodiment, n in formula (i) is 0.

[0293] In certain embodiments, -L 2 -teeth, [ka] It is a part selected from the group consisting of; During the ceremony, The dashed line marked with an asterisk is -L 1 - indicates a connection to; Unmarked dashed lines indicate joining to -Z; Parts (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), and (xvii) may be further optionally substituted.

[0294] In certain embodiments, -L 2 -teeth, [ka] Selected from the group consisting of; The dashed line marked with an asterisk is -L 1 - indicates a connection to; Unmarked dashed lines indicate joining to -Z.

[0295] In certain embodiments, -L 2 -teeth, [ka] Selected from the group consisting of, The dashed line marked with an asterisk is -L 1 - indicates a connection to; Unmarked dashed lines indicate joining to -Z.

[0296] In certain embodiments, -L 2 - is from the following equation (xvi). [ka] During the ceremony, The dashed line marked with an asterisk is -L 1 - indicates a connection to; Unmarked dashed lines indicate joining to -Z.

[0297] In certain embodiments, part-L 1 -L 2 -teeth, [ka] Selected from the group consisting of; During the ceremony, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; The dashed lines marked with asterisks indicate connections to -Z.

[0298] In certain embodiments, part-L 1 -L 2 - is the same as in the following equation (IId-ii). [ka] During the ceremony, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; The dashed lines marked with asterisks indicate connections to -Z.

[0299] In certain embodiments, part-L 1 -L 2 - is the same as in the following equation (IId-ii'). [ka] During the ceremony, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; The dashed lines marked with asterisks indicate connections to -Z.

[0300] In certain embodiments, part-L 1 -L 2 -teeth, [ka] Selected from the group consisting of, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; The dashed lines marked with asterisks indicate connections to -Z.

[0301] In certain embodiments, part-L 1-L 2 - is the same as in the following equation (IId-iia). [ka] During the ceremony, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; The dashed lines marked with asterisks indicate connections to -Z.

[0302] In certain embodiments, part-L 1 -L 2 - is the same as in the following equation (IId-iia′). [ka] During the ceremony, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; The dashed lines marked with asterisks indicate connections to -Z.

[0303] In certain embodiments, part-L 1 -L 2 -teeth, [ka] Selected from the group consisting of; During the ceremony, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; The dashed lines marked with asterisks indicate connections to -Z.

[0304] In certain embodiments, part-L 1 -L 2 - is the same as in the following equation (IId-iib). [ka] During the ceremony, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; The dashed lines marked with asterisks indicate connections to -Z.

[0305] In certain embodiments, part-L 1 -L 2 - is the same as in the following equation (IId-iib′). [ka] During the ceremony, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; The dashed lines marked with asterisks indicate connections to -Z.

[0306] In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight in the range of 5 to 200 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight in the range of 8 to 100 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight in the range of 10 to 80 kDa. In certain embodiments, -Z of (Ia) or (Ib) has a molecular weight in the range of 12 to 60 kDa. In certain embodiments, -Z of (Ia) or (Ib) has a molecular weight in the range of 15 to 40 kDa. In certain embodiments, -Z of (Ia) or (Ib) has a molecular weight of about 20 kDa. In certain embodiments, -Z of (Ia) or (Ib) has a molecular weight of about 40 kDa.

[0307] The polymer portion -Z of formula (Ia) or (Ib) comprises a polymer. In certain embodiments, -Z of formula (Ia) or (Ib) is 2-methacryloyloxyethyl phosphorylcholine derivatives, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy)polymers, poly(amides), poly(amideamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(shea Poly(acrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyl oxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl oxazolines), poly(hydroxymethacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), Poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic acid-coglycolates), poly(methacrylamides), poly(methacrylates), poly(methyl oxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinyl methyl ethers), poly(vinyl The polymers include polymers selected from the group consisting of nylpyrrolidones, silicones, celluloses, carbomethylcelluloses, hydroxypropylmethylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and their derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon polymers, xylans, and copolymers thereof.

[0308] In certain embodiments, -Z in formula (Ia) or (Ib) comprises a protein. Preferred proteins are selected from the group consisting of carboxyl-terminal peptides of chorionic gonadotropins as described in US2012 / 0035101A1 (incorporated herein by reference); albumin; XTEN sequences as described in WO2011123813A2 (incorporated herein by reference); proline / alanine random coil sequences as described in WO2011 / 144756A1 (incorporated herein by reference); proline / alanine / serine random coil sequences as described in WO2008 / 155134A1 and WO2013 / 024049A1 (incorporated herein by reference); and Fc fusion proteins.

[0309] In certain embodiments, -Z in formula (Ia) or (Ib) is polysarcosine. In certain embodiments, -Z in formula (Ia) or (Ib) contains poly(N-methylglycine). In certain embodiments, -Z in formula (Ia) or (Ib) contains a random coil protein moiety. In certain embodiments, -Z in formula (Ia) or (Ib) contains one random coil protein moiety. In certain embodiments, -Z in formula (Ia) or (Ib) contains two random coil protein moieties. In certain embodiments, -Z in formula (Ia) or (Ib) contains three random coil protein moieties. In certain embodiments, -Z in formula (Ia) or (Ib) contains four random coil protein moieties. In certain embodiments, -Z in formula (Ia) or (Ib) contains five random coil protein moieties. In certain embodiments, -Z in formula (Ia) or (Ib) contains six random coil protein moieties. In certain embodiments, -Z in formula (Ia) or (Ib) comprises seven random coil protein moieties. In certain embodiments, -Z in formula (Ia) or (Ib) comprises eight random coil protein moieties.

[0310] In certain embodiments, such a random coil protein moiety contains at least 25 amino acid residues and at most 2000 amino acids. In certain embodiments, such a random coil protein moiety contains at least 30 amino acid residues and at most 1500 amino acid residues. In certain embodiments, such a random coil protein moiety contains at least 50 amino acid residues and at most 500 amino acid residues.

[0311] In certain embodiments, -Z in formula (Ia) or (Ib) comprises a random coil protein moiety in which at least 80%, in certain embodiments at least 85%, in certain embodiments at least 90%, in certain embodiments at least 95%, in certain embodiments at least 98%, and in certain embodiments at least 99% of the total number of amino acids forming the random coil protein moiety are selected from alanine and proline. In certain embodiments, at least 10% but less than 75%, and in certain embodiments less than 65%, of the total number of amino acid residues in such a random coil protein moiety are proline residues. In certain embodiments, such a random coil protein moiety is one described in WO2011 / 144756A1 (the entire contents of which are incorporated herein by reference). In certain embodiments, -Z includes at least one portion selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 51, and 61, as disclosed in WO2011 / 144756 (incorporated herein by reference). Such a portion containing alanine and proline, comprising a random coil protein, is referred to as "PA" or "PA portion".

[0312] Therefore, -Z in equation (Ia) or (Ib) includes the PA portion.

[0313] In certain embodiments, -Z in formula (Ia) or (Ib) comprises a random coil protein moiety in which at least 80%, in certain embodiments at least 85%, in certain embodiments at least 90%, in certain embodiments at least 95%, in certain embodiments at least 98%, and in certain embodiments at least 99% of the total number of amino acids forming the random coil protein moiety are selected from alanine, serine, and proline. In certain embodiments, at least 4% but less than 40% of the total number of amino acid residues in such a random coil protein moiety are proline residues. In certain embodiments, such a random coil protein moiety is one described in WO2008 / 155134A1 (which is incorporated herein in its entirety by reference). In certain embodiments, -Z in formula (Ia) or (Ib) comprises at least one portion selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 42, 44, 46, 50, 52, 54, and 56, as disclosed in WO2008 / 155134A1 (incorporated herein by reference). The portion comprising such a random coil protein portion containing alanine, serine, and proline is referred to as "PAS" or "PAS portion".

[0314] Therefore, -Z in equation (Ia) or (Ib) includes the PAS part.

[0315] In certain embodiments, -Z in formula (Ia) or (Ib) comprises a random coil protein moiety in which at least 80%, in certain embodiments at least 85%, in certain embodiments at least 90%, in certain embodiments at least 95%, in certain embodiments at least 98%, and in certain embodiments at least 99% of the total number of amino acids forming the random coil protein moiety are selected from alanine, glycine, and proline. The moiety comprising such a random coil protein moiety containing alanine, glycine, and proline is referred to as "PAG" or "PAG moiety".

[0316] Therefore, -Z in equation (Ia) or (Ib) includes the PAG portion.

[0317] In certain embodiments, -Z in formula (Ia) or (Ib) comprises a random coil protein moiety in which at least 80%, in certain embodiments at least 85%, in certain embodiments at least 90%, in certain embodiments at least 95%, in certain embodiments at least 98%, and in certain embodiments at least 99% of the total number of amino acids forming the random coil protein moiety are selected from proline and glycine. Such a random coil protein moiety comprising proline and glycine is referred to as "PG" or "PG moiety".

[0318] In a particular embodiment, such a PG portion includes the portion of the following formula (a-0). [(Gly) p -Pro-(Gly) q ] r (a-0); During the ceremony, p is selected from the group consisting of 0, 1, 2, 3, 4, and 5; q is selected from the group consisting of 0, 1, 2, 3, 4, and 5; r is an integer in the range of 10 to 1000 (including both ends); However, at least one of p and q is at least 1.

[0319] In a particular embodiment, p in formula (a-0) is selected from the group consisting of 1, 2, and 3.

[0320] In a particular embodiment, q in formula (a-0) is selected from 0, 1, and 2.

[0321] In a particular embodiment, the PG portion includes the sequence sequence 97:GGPGGPGPGGPGGPGPGGPG.

[0322] In a particular embodiment, the PG portion includes the sequence of the following formula (a-0-a). (GGPGGPGPGGPGGPGPGGPG) v (a-0-a) [In the formula, v is an integer in the range of 1 to 50 (including both ends)].

[0323] The array (a-0-a) is understood to contain v iterations of the array with sequence number 97.

[0324] Therefore, -Z in equation (Ia) or (Ib) includes the PG portion.

[0325] In certain embodiments, -Z in formula (Ia) or (Ib) comprises a random coil protein moiety in which at least 80%, in certain embodiments at least 85%, in certain embodiments at least 90%, in certain embodiments at least 95%, in certain embodiments at least 98%, and in certain embodiments at least 99% of the total number of amino acids forming the random coil protein moiety are selected from alanine, glycine, serine, threonine, glutamic acid, and proline. In certain embodiments, such a random coil protein moiety is one described in WO2010 / 091122A1 (incorporated herein by reference). In certain embodiments, -Z in formula (Ia) or (Ib) is the sequence numbers 182, 183, 184; 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213 disclosed in WO2010 / 091122A1 (incorporated herein by reference). , comprising at least one part selected from the group consisting of SEQ ID NOs: 214, 215, 216, 217, 218, 219, 220, 221, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 1715, 1716, 1718, 1719, 1720, 1721, and 1722.Such random coil protein moieties containing alanine, glycine, serine, threonine, glutamic acid, and proline are referred to as "XTEN" or "XTEN moiety," consistent with the designation in WO2010 / 091122A1.

[0326] Therefore, -Z in equation (Ia) or (Ib) includes the XTEN part.

[0327] In certain embodiments, -Z in formula (Ia) or (Ib) is a hyaluronic acid-based polymer.

[0328] In certain embodiments, -Z in formula (Ia) or (Ib) is a polymer portion disclosed in WO2013 / 024047A1 (incorporated herein by reference).

[0329] In certain embodiments, -Z in formula (Ia) or (Ib) is a polymer portion disclosed in WO2013 / 024048A1 (incorporated herein by reference).

[0330] In certain embodiments, -Z in formula (Ia) or (Ib) is a PEG-based polymer. In certain embodiments, -Z is a branched or highly branched PEG-based polymer.

[0331] In certain embodiments, -Z in formula (Ia) or (Ib) is a branched polymer. In certain embodiments, -Z in formula (Ia) or (Ib) is a branched polymer having 1, 2, 3, 4, 5, or 6 branch points. In certain embodiments, -Z in formula (Ia) or (Ib) is a branched polymer having 1, 2, or 3 branch points. In certain embodiments, -Z in formula (Ia) or (Ib) is a branched polymer having 1 branch point. In certain embodiments, -Z in formula (Ia) or (Ib) is a branched polymer having 2 branch points. In certain embodiments, -Z in formula (Ia) or (Ib) is a branched polymer having 3 branch points.

[0332] In certain embodiments, the branch point is selected from the group consisting of -N<, -CH<, and >C<.

[0333] In certain embodiments, such branch portion-Z of formula (Ia) or (Ib) is a PEG system.

[0334] In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight in the range of 5 kDa to 500 kDa (including both ends). In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight in the range of 10 kDa to 250 kDa (including both ends). In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight in the range of 10 kDa to 150 kDa (including both ends). In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight in the range of 12 kDa to 100 kDa (including both ends). In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight in the range of 15 kDa to 80 kDa (including both ends). In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight in the range of 10 kDa to 80 kDa (including both ends). In certain embodiments, the molecular weight is about 10 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 20 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 30 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 40 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 50 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 60 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 70 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 80 kDa. In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight of about 40 kDa.

[0335] In a particular embodiment, -Z includes the following portion: [ka]

[0336] In certain embodiments, -Z includes an amide bond.

[0337] In certain embodiments, -Z in formula (Ia) or (Ib) includes the portion of formula (a) below. [ka] During the ceremony, The dashed line is -L 2 - or - indicates a bond to the remainder (remaining part) of Z; BP a is a branch point selected from the group consisting of -N<, -CR<, and >C<; -R is -H and C 1-6 Selected from the group consisting of alkyl groups; a is BP a If -N< or -CR<, then it is 0, and a is BP a If >C< then it is 1; -S a -, -S a′ -, -S a″ -and-S a″′ - are they chemically bonded to each other independently, or C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R 1 It is also acceptable if it is replaced with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 2 )-,-S(O)2N(R 2)-,-S(O)N(R 2 )-, -S(O)2-, -S(O)-, -N(R 2 )S(O)2N(R 2a )-, -S-, -N(R 2 )-, -OC(OR 2 )(R 2a )-,-N(R 2 )C(O)N(R 2a )-, and -OC(O)N(R 2 )- may optionally include one or more groups selected from the group consisting of; Each -T- is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered polycyclic carbon, and 8-30 membered heterocyclic carbon; each -T- independently has one or more identical or different -R 1 It is also acceptable if it is replaced with; Each-R 1 These are independently halogen, -CN, oxo (=O), and -COOR. 3 , -OR 3 , -C(O)R 3 ,-C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3 ,-S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R3a R 3b ), -OC(O)N(R 3 R 3a ) and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 Alkyl can be substituted with one or more identical or different halogens; Each-R 2 ,-R 2a ,-R 3 ,-R 3a and -R 3b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, C 1-6 Alkyl can be substituted with one or more identical or different halogens; -P a′ , -P a″ and -P a″′ These are independently polymer parts.

[0338] In some cases, the part of formula (a) is substituted with one or more substituents.

[0339] In a particular embodiment, the BP of formula (a) a The value is -N<.

[0340] In a particular embodiment, the BP of formula (a) a is -CR<. In certain embodiments, -R is -H.

[0341] Therefore, in a particular embodiment, a in equation (a) is 0.

[0342] In a particular embodiment, the BP of formula (a) a is >C<.

[0343] In certain embodiments, the -S of formula (a) a - represents a chemical bond.

[0344] In a particular embodiment, -S of formula (a) a - is C 1-10 Alkyl, C 2-10 Alkenyl and C2-10 Selected from the group consisting of alkynnyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynnyl is -C(O)O-, -O-, -C(O)-, -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4 )-, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-,-N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4 )- may optionally include one or more chemical groups selected from the group consisting of -R 4 and -R 4a -H, methyl, ethyl, propyl, and butyl are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -S of formula (a) a - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and they are -O-, -C(O)- and -C(O)N(R 4 )- may optionally include one or more chemical groups selected from the group consisting of )-.

[0345] In certain embodiments, -S of formula (a) a′ It is a chemical bond.

[0346] In a particular embodiment, -S of formula (a) a′ - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl is -C(O)O-, -O-, -C(O)-, -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4)-, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-,-N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4 )- may optionally include one or more chemical groups selected from the group consisting of -R 4 and -R 4a -H, methyl, ethyl, propyl, and butyl are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -S of formula (a) a′ - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and they are -O-, -C(O)- and -C(O)N(R 4 )- may optionally include one or more chemical groups selected from the group consisting of )-.

[0347] In a particular embodiment, -S of formula (a) a″ - represents a chemical bond.

[0348] In a particular embodiment, -S of formula (a) a″ - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynnyl is -C(O)O-, -O-, -C(O)-, -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4 )-,-S(O)2-,-S(O)-,-N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-,-N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4)- may optionally include one or more chemical groups selected from the group consisting of -R 4 and -R 4a -H, methyl, ethyl, propyl, and butyl are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -S of formula (a) a″ - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and they are -O-, -C(O)- and -C(O)N(R 4 )- may optionally include one or more chemical groups selected from the group consisting of )-.

[0349] In a particular embodiment, -S of formula (a) a″′ - represents a chemical bond.

[0350] In a particular embodiment, -S of formula (a) a″′ - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynnyl is -C(O)O-, -O-, -C(O)-, -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4 )-,-S(O)2-,-S(O)-,-N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-,-N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4 )- may optionally include one or more chemical groups selected from the group consisting of -R 4 and -R 4a -H, methyl, ethyl, propyl, and butyl are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -S of formula (a) a″′- is selected from the group consisting of methyl, ethyl, propyl, and butyl, and they are -O-, -C(O)- and -C(O)N(R 4 )- may optionally include one or more chemical groups selected from the group consisting of )-.

[0351] In a particular embodiment, -P of formula (a) a′ , -P a″ and -P a″′These are independently 2-methacryloyloxyethyl phosphorylcholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy)polymers, poly(amides), poly(amideamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), and poly(dimethyl) polymers. Acrylamides, poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyl oxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl oxazolines), poly(hydroxymethacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl o Xazolines, poly(iminocarbonates), poly(lactic acids), poly(lactic acid-coglycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinyl methyl ethers), poly(vinylpyrrolidones) The polymers include polymers selected from the group consisting of (similar to), silicones, celluloses, carbomethylcelluloses, hydroxypropylmethylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and their derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon polymers, xylans, and copolymers thereof.

[0352] In a particular embodiment, -P of formula (a) a′ , -P a″ and -P a″′Independently, each has a molecular weight in the range of 5 kDa to 50 kDa (including both ends), and in certain embodiments, it has a molecular weight in the range of 5 kDa to 40 kDa (including both ends), in certain embodiments, it has a molecular weight in the range of 7.5 kDa to 35 kDa (including both ends), in certain embodiments, it has a molecular weight in the range of 7.5 to 30 kDa (including both ends), and in certain embodiments, it has a molecular weight in the range of 10 to 30 kDa (including both ends).

[0353] In a particular embodiment, -P of formula (a) a′ , -P a″ and -P a″′ It has a molecular weight of approximately 5 kDa. In certain embodiments, -P of formula (a) a′ , -P a″ and -P a″′ It has a molecular weight of approximately 7.5 kDa. In certain embodiments, -P of formula (a) a′ , -P a″ and -P a″′ It has a molecular weight of approximately 10 kDa. In certain embodiments, -P of formula (a) a′ , -P a″ and -P a″′ It has a molecular weight of approximately 12.5 kDa. In certain embodiments, -P of formula (a) a′ , -P a″ and -P a″′ It has a molecular weight of approximately 15 kDa. In certain embodiments, -P of formula (a) a′ , -P a″ and -P a″′ It has a molecular weight of approximately 20 kDa.

[0354] In a particular embodiment, -P of formula (a) a′ , -P a″ and -P a″′ It independently includes a PEG-based portion. In certain embodiments, -P of formula (a) a′ , -P a″ and -P a″′The PEG-based portion independently includes at least 20% PEG, at least 30% in a particular embodiment, at least 40% in a particular embodiment, at least 50% PEG in a particular embodiment, at least 60% PEG in a particular embodiment, at least 70% PEG in a particular embodiment, at least 80% PEG in a particular embodiment, and at least 90% PEG in a particular embodiment.

[0355] In a particular embodiment, -P of formula (a) a′ , -P a″ and -P a″′ Each independently comprises a protein moiety, in a particular embodiment, a random coil protein moiety, and in a particular embodiment, a random coil protein moiety selected from the group consisting of PA, PAS, PAG, PG, and XTEN moieties.

[0356] In a particular embodiment, -P of formula (a) a′ , -P a″ and -P a″′ This is the PA portion. In certain embodiments, -P of formula (a) a′ , -P a″ and -P a″′ This is the PAS portion. In certain embodiments, -P of formula (a) a′ , -P a″ and -P a″′ This is the PAG portion. In certain embodiments, -P of formula (a) a′ , -P a″ and -P a″′ This is the PG portion. In certain embodiments, -P of formula (a) a′ , -P a″ and -P a″′ This is the XTEN part.

[0357] In a particular embodiment, -Z includes one part of formula(a). In a particular embodiment, -Z includes two parts of formula(a). In another embodiment, -Z includes three parts of formula(a). In a particular embodiment, -Z includes four parts of formula(a). In a particular embodiment, -Z includes five parts of formula(a). In a particular embodiment, -Z includes six parts of formula(a).

[0358] In certain embodiments, -Z includes the portion of formula (b) below. [ka] During the ceremony, The dashed line is -L 2 - Indicates a bond to the remainder of -Z; b1 is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; b2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; b3 is an integer in the range of 150 to 1000 (inclusive); in a particular embodiment, in the range of 150 to 500 (inclusive); in a particular embodiment, in the range of 200 to 460 (inclusive); b4 is an integer in the range of 150 to 1000 (inclusive); in a particular embodiment, in the range of 150 to 500 (inclusive); and in a particular embodiment, in the range of 200 to 460 (inclusive).

[0359] In some cases, the part of formula (b) is substituted with one or more substituents.

[0360] In certain embodiments, b3 and b4 in equation (b) are the same integer.

[0361] In certain embodiments, both b3 and b4 in formula (b) are integers in the range of 200 to 250, and in certain embodiments, b3 and b4 in formula (b) are approximately 225. In certain embodiments, both b3 and b4 in formula (b) are integers in the range of 400 to 500, and in certain embodiments, b3 and b4 in formula (b) are approximately 450.

[0362] In a particular embodiment, b1 in formula (b) is selected from the group consisting of 0, 1, 2, 3, and 4. In a particular embodiment, b1 in formula (b) is selected from the group consisting of 1, 2, and 3. In a particular embodiment, b1 in formula (b) is 2.

[0363] In a particular embodiment, b2 in formula (b) is selected from the group consisting of 1, 2, 3, 4, and 5. In a particular embodiment, b2 in formula (b) is selected from the group consisting of 2, 3, and 4. In a particular embodiment, b2 in formula (b) is 3.

[0364] In a particular embodiment, b1 in formula (b) is 2, b2 in formula (b) is 3, and both b3 and b4 are approximately 450. In a particular embodiment, b1 in formula (b) is 2, b2 in formula (b) is 3, and both b3 and b4 are approximately 225.

[0365] In a particular embodiment, -Z includes one part of formula(b). In a particular embodiment, -Z includes two parts of formula(b). In a particular embodiment, -Z includes three parts of formula(b). In a particular embodiment, -Z includes four parts of formula(b). In a particular embodiment, -Z includes five parts of formula(b). In a particular embodiment, -Z includes six parts of formula(b).

[0366] In certain embodiments, -Z includes the part of formula (c). [ka] During the ceremony, The dashed line is -L 2 - Indicates a bond to the remainder of -Z; c1 and c2 are independent integers in the range of 150 to 500 (inclusive); in a particular embodiment, they are integers in the range of 200 to 460 (inclusive).

[0367] In some cases, the part of formula (c) is substituted with one or more substituents.

[0368] In a particular embodiment, both c1 and c2 in equation (c) are the same integer.

[0369] In certain embodiments, c1 and c2 of formula (c) are in the range of 200 to 250 (inclusive), and in certain embodiments, they are about 225. In certain embodiments, c1 and c2 of formula (c) are in the range of 400 to 500 (inclusive), and in certain embodiments, c1 and c2 of formula (c) are about 450.

[0370] In formula (c), c1 and c2, part -Z, are branched PEG polymers containing at least 10% PEG, having one branch point and two PEG polymer arms, and having a molecular weight of approximately 40 kDa. Thus, each of the two PEG polymer arms has a molecular weight of approximately 20 kDa. In formula (c), the branch point of c1 and c2 is -CH<.

[0371] In a particular embodiment, -Z includes one part of formula(c). In a particular embodiment, -Z includes two parts of formula(c). In a particular embodiment, -Z includes three parts of formula(c). In a particular embodiment, -Z includes four parts of formula(c). In a particular embodiment, -Z includes five parts of formula(c). In a particular embodiment, -Z includes six parts of formula(c).

[0372] In a particular embodiment, part-Z is given by formula (d) below. [ka] During the ceremony, The dashed line is -L 2 - indicates a connection to; -Z b - is C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; C 1-50Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R 1 It is also acceptable if it is replaced with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 2 )-,-S(O)2N(R 2 )-,-S(O)N(R 2 )-, -S(O)2-, -S(O)-, -N(R 2 )S(O)2N(R 2a )-, -S-, -N(R 2 )-, -OC(OR 2 )(R 2a )-,-N(R 2 )C(O)N(R 2a )-, and -OC(O)N(R 2 )- may optionally include one or more groups selected from the group consisting of; Each -T- is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered polycyclic carbon, and 8-30 membered heterocyclic carbon; each -T- independently has one or more identical or different -R 1 It is also acceptable if it is replaced with; Each-R 1 These are independently halogen, -CN, oxo (=O), and -COOR. 3 , -OR 3 , -C(O)R 3 ,-C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3 ,-S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ) and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 Alkyl can be substituted with one or more identical or different halogens; Each-R 2 ,-R 2a ,-R 3 ,-R 3a and -R 3b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, C 1-6 Alkyl can be substituted with one or more identical or different halogens; -Z a The following are: [ka] and; During the ceremony, BP a , -S a -, -S a′ -, -S a″ -, -S a″′ -, -P a′ , -P a″ , -P a″′ And a are used in equation (a) as in the definition.

[0373] In some cases, the part of formula (d) is substituted with one or more substituents.

[0374] In a particular embodiment, the BP of formula (d) a , -S a-, -S a′ -, -S a″ -, -S a″′ -, -P a′ , -P a″ , -P a″′ The definition of equation (a) is as defined above.

[0375] In a particular embodiment, -Z of equation (d) a This is the formula (b). In a particular embodiment, b1, b2, b3, and b4 are as described for formula (b).

[0376] In certain embodiments, the part-Z of formula (Ia) or (Ib) is that of formula (e) below. [ka] During the ceremony, The dashed line is -L 2 - indicates a connection to; e is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15; -Z a The following are: [ka] And, b1, b2, b3, and b4 are used with respect to equation (b) as defined.

[0377] In some cases, the part of formula (e) is substituted with one or more substituents.

[0378] In a particular embodiment, b1, b2, b3, and b4 of formula (e) are as defined above for formula (b).

[0379] In a particular embodiment, e in formula (e) is 1. In a particular embodiment, e in formula (e) is 2. In a particular embodiment, e in formula (e) is 3. In a particular embodiment, e in formula (e) is 4. In a particular embodiment, e in formula (e) is 5. In a particular embodiment, e in formula (e) is 6. In a particular embodiment, e in formula (e) is 7. In a particular embodiment, e in formula (e) is 8. In a particular embodiment, e in formula (e) is 9. In a particular embodiment, e in formula (e) is 10. In a particular embodiment, e in formula (e) is 11. In a particular embodiment, e in formula (e) is 12. In a particular embodiment, e in formula (e) is 13. In a particular embodiment, e in formula (e) is 14. In a particular embodiment, e in formula (e) is 15.

[0380] In a particular embodiment, e in formula (e) is selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, and 9. In a particular embodiment, e in formula (e) is selected from 3, 4, 5, and 6. In a particular embodiment, e in formula (e) is 5.

[0381] In a particular embodiment, e in formula (e) is 5, b1 in formula (e) is 2, b2 in formula (e) is 3, and both b3 and b4 in formula (e) are approximately 450.

[0382] In certain embodiments, part-Z of formula (Ia) or (Ib) is of the following formula (ei) or (ei'). [ka] During the ceremony, The dashed line is -L 2 - indicates binding to e is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15; -Z a The following are: [ka] And, b1, b2, b3, and b4 are used with respect to equation (b) as defined.

[0383] In certain embodiments, b1, b2, b3, and b4 of formulas (ei) and (ei') are defined above for formula (b).

[0384] In certain embodiments, e in formulas (ei) and (ei') is as described for formula (e).

[0385] In certain embodiments, b1 in formulas (ei) and (ei') is 2, b2 in formulas (ei) and (ei') is 3, and b3 and b4 in formulas (ei) and (ei') are both approximately 450.

[0386] In certain embodiments, -Z in formula (Ia) or (Ib) is the same as that in formula (ei).

[0387] In a particular embodiment, part -Z is a branched PEG-based polymer containing at least 10% PEG, having three branching points and four PEG-based polymer arms, and having a molecular weight of about 40 kDa. Thus, each of the four PEG-based polymer arms has a molecular weight of about 10 kDa. In a particular embodiment, each of the three branching points is -CH<.

[0388] In a particular embodiment, part-Z is given by the following formula (f). [ka] During the ceremony, The dashed line is -L 2 - indicates a connection to; BP f is a branch point selected from the group consisting of -N<, -CR<, and >C<; -R is -H and C 1-6 Selected from the group consisting of alkyl groups; f is BP f If -N< or -CR<, then it is 0, and f is BPf If >C< then it is 1; -S f -, -S f′ -, -S f″ -and-S f″′ - is independently a chemical bond, or independently C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R 1 It is also acceptable if it is replaced with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 2 )-,-S(O)2N(R 2 )-,-S(O)N(R 2 )-, -S(O)2-, -S(O)-, -N(R 2 )S(O)2N(R 2a )-, -S-, -N(R 2 )-, -OC(OR 2 )(R 2a )-,-N(R 2 )C(O)N(R 2a )-, and -OC(O)N(R 2 )- may optionally include one or more groups selected from the group consisting of; Each -T- is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered polycyclic carbon, and 8-30 membered heterocyclic carbon; each -T- independently has one or more identical or different -R 1 It is also acceptable if it is replaced with; Each R 1 These are independently halogen, -CN, oxo (=O), and -COOR. 3 , -OR 3 , -C(O)R 3 ,-C(O)N(R 3 R3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3 ,-S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ), and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 Alkyl can be substituted with one or more identical or different halogens; Each-R 2 ,-R 2a ,-R 3 ,-R 3a and -R 3b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, C 1-6 Alkyl can be substituted with one or more identical or different halogens; -Z a′ , -Z a″ and -Z a″′ Independently, [ka] And, During the ceremony, BP a , -S a -, -S a′ -, -S a″-, -S a″′ -, -P a′ , -P a″ , -P a″′ And a are used in equation (a) as in the definition.

[0389] In some cases, the part of formula (f) is substituted with one or more substituents.

[0390] In a particular embodiment, the BP of formula (f) a , -S a -, -S a′ -, -S a″ -, -S a″′ -, -P a′ , -P a″ and -P a″′ The definition of equation (a) is as defined above.

[0391] In a particular embodiment, the BP of formula (f) f is -CR < and r is 0. In certain embodiments, -R is -H.

[0392] In certain embodiments, the -S of formula (f) f - represents a chemical bond.

[0393] In a particular embodiment, -Z of formula (f) a′ , -Z a″ and -Z a″′ They have the same structure. In a particular embodiment, -Z of formula (f) a′ , -Z a″ and -Z a″′ This is the one in equation (b).

[0394] In a particular embodiment, b1, b2, b3, and b4 are as described for formula (b).

[0395] In certain embodiments, the -S of formula (f) f - represents a chemical bond, and is the BP of formula (f). a -CR< and -R is -H. In certain embodiments, -S of formula (f) f- represents a chemical bond, and is the BP of formula (f). a -CR<, -R is -H, and -Z in equation (f) a′ , -Z a″ and -Z a″′ This is the one in equation (b).

[0396] In certain embodiments, -Z is given by the following formula (g). [ka] During the ceremony, The dashed line is -L 2 - indicates a connection to; -S g -, -S g′ -and-S g″ - is independent, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R 1 It is also acceptable if it is replaced with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 2 )-,-S(O)2N(R 2 )-,-S(O)N(R 2 )-, -S(O)2-, -S(O)-, -N(R 2 )S(O)2N(R 2a )-, -S-, -N(R 2 )-, -OC(OR 2 )(R 2a )-,-N(R 2 )C(O)N(R 2a )-, and -OC(O)N(R 2 )- may optionally include one or more groups selected from the group consisting of; Each -T- is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered polycyclic carbon, and 8-30 membered heterocyclic carbon; each -T- independently has one or more identical or different -R 1 It is also acceptable if it is replaced with; Each R 1 These are independently halogen, -CN, oxo (=O), and -COOR. 3 , -OR 3 , -C(O)R 3 ,-C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3 ,-S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ) and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 Alkyl can be substituted with one or more identical or different halogens; Each-R 2 ,-R 2a ,-R 3 ,-R 3a and -R 3b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, C 1-6Alkyl can be substituted with one or more identical or different halogens; -Z a and -Z a′ Independently, [ka] And, During the ceremony, BP a , -S a -, -S a′ -, -S a″ -, -S a″′ -, -P a′ , -P a″ , -P a″′ And a are used in equation (a) as in the definition.

[0397] In some cases, the (g) portion of formula is substituted with one or more substituents.

[0398] In a particular embodiment, the BP of formula (g) a , -S a -, -S a′ -, -S a″ -, -S a″′ -, -P a′ , -P a″ and -P a″′ The definition of equation (a) is as defined above.

[0399] In certain embodiments, the -S of formula (g) g - is C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from a group consisting of alkynnyls, these are one or more identical or distinct -R 1 It is also acceptable if it is replaced with -R 1 These are halogens, oxo (=O), and -COOR 3 , -OR 3 , -C(O)R 3 ,-C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R3 R 3a ), -S(O)2R 3 ,-S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ), and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 Alkyl can be substituted with one or more identical or different halogens; -R 3 ,-R 3a and -R 3b The element is independently selected from -H, methyl, ethyl, propyl, and butyl.

[0400] In certain embodiments, the -S of formula (g) g - is C 1-6 Selected from alkyl groups.

[0401] In certain embodiments, the -S of formula (g) g′ - is C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls, these are one or more identical or distinct -R 1 It is also acceptable if it is replaced with -R 1 These are halogens, oxo (=O), and -COOR 3 , -OR 3 , -C(O)R3 ,-C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3 ,-S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ), and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 Alkyl can be substituted with one or more identical or different halogens; -R 3 ,-R 3a and -R 3b The element is independently selected from -H, methyl, ethyl, propyl, and butyl.

[0402] In certain embodiments, the -S of formula (g) g′ - is C 1-6 Selected from alkyl groups.

[0403] In certain embodiments, the -S of formula (g) g″ - is C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynyls, one or more identical or distinct -R 1It is also acceptable if it is replaced with -R 1 These are halogens, oxo (=O), and -COOR 3 , -OR 3 , -C(O)R 3 ,-C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3 ,-S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ), and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 Alkyl can be substituted with one or more identical or different halogens; -R 3 ,-R 3a and -R 3b The element is independently selected from -H, methyl, ethyl, propyl, and butyl.

[0404] In certain embodiments, the -S of formula (g) g″ - is C 1-6 Selected from alkyl groups.

[0405] In a particular embodiment, -Z of formula (g) a and -Z a′They have the same structure. In a particular embodiment, -Z of formula (g) a and -Z a′ This is the one in equation (b).

[0406] In certain embodiments, -Z in formula (Ia) or (Ib) is the same as that in formula (gi) below. [ka] During the ceremony, The dashed line is -L 2 - indicates a connection to; -S g -, -S g′ -and-S g″ - is independent, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R 1 It is also acceptable if it is replaced with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 2 )-,-S(O)2N(R 2 )-,-S(O)N(R 2 )-, -S(O)2-, -S(O)-, -N(R 2 )S(O)2N(R 2a )-, -S-, -N(R 2 )-, -OC(OR 2 )(R 2a )-,-N(R 2 )C(O)N(R 2a )-, and -OC(O)N(R 2 )- may optionally include one or more groups selected from the group consisting of; Each -T- is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered polycyclic carbon, and 8-30 membered heterocyclic carbon; each -T- independently has one or more identical or different -R 1 It is also acceptable if it is replaced with; Each R 1 These are independently halogen, -CN, oxo (=O), and -COOR. 3 , -OR 3 , -C(O)R 3 ,-C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3 ,-S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ), and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 Alkyl can be substituted with one or more identical or different halogens; Each-R 2 ,-R 2a ,-R 3 ,-R 3a and -R 3b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, C 1-6Alkyl can be substituted with one or more identical or different halogens; -Y a1 - and -Y a1′ -teeth, [ka] and; -Z a and -Z a′ Independently, [ka] And, During the ceremony, BP a , -S a -, -S a′ -, -S a″ -, -S a″′ -, -P a′ , -P a″ , -P a″′ And a are used in relation to equation (a) as in the definition.

[0407] In some cases, the (gi) part of the formula is substituted with one or more substituents.

[0408] In a particular embodiment, the -Y of formula (gi) a1 - and -Y a1′ - Both are, [ka] And, During the ceremony, The dashed lines marked with an asterisk represent -Z. a or -Z a′ It is connected.

[0409] In a particular embodiment, the BP of formula (gi) a , -S a -, -S a′ -, -S a″ -, -S a″′ -, -P a′ , -P a″ and -P a″′The definition of equation (a) is as defined above.

[0410] In certain embodiments, the -S of formula (gi) g -, -S g′ -and-S g″ - is defined as in equation (g). In certain embodiments, -Z in equation (gi) a and -Z a′ They have the same structure. In a particular embodiment, the -Z of formula (gi) a and -Z a′ This is the formula (b). In a particular embodiment, b1, b2, b3, and b4 are as described for formula (b).

[0411] In certain embodiments, -Z is the value of formula (h) below. [ka] During the ceremony, The dashed line is -L 2 - indicates a connection to; Each-Z c The following section: [ka] And, During the ceremony, Each c1 is an independent integer in the range of 200 to 250.

[0412] In some cases, the (h) part of formula is substituted with one or more substituents.

[0413] In certain embodiments, both c1 in formula (h) are identical. In certain embodiments, both c1 in formula (h) are approximately 225.

[0414] In certain embodiments, -Z in formula (Ia) or (Ib) is the following formula (ha): [ka] It is, During the ceremony, The dashed line is -L 2 - indicates a connection to; Each k is independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; -Y a1 - and -Y a1′ -teeth, [ka] and; Each-Z c The following section: [ka] And, During the ceremony, Each c1 is an independent integer in the range of 200 to 250.

[0415] In some cases, the (ha) part of the formula is substituted with one or more substituents.

[0416] In certain embodiments, each k in formula (ha) is independently selected from the group consisting of 2, 3, 4, 5, 6, and 7. In certain embodiments, both k in formula (ha) are identical.

[0417] In certain embodiments, both c1 in formula (ha) are identical.

[0418] In certain embodiments, both c1 in formula (ha) are approximately 225.

[0419] In certain embodiments, the -Y of formula (ha) a1 - and -Y a1′ - Both are, [ka] And, During the ceremony, The dashed line marked with an asterisk is -Z c It is connected.

[0420] In a particular embodiment, part -Z is given by the following formula (hi). [ka] During the ceremony, The dashed line is -L 2 - indicates a connection to; Each-Z c The following section: [ka] And, Each c1 is an independent integer in the range of 200 to 250.

[0421] In some cases, the (hi) part of formula is substituted with one or more substituents.

[0422] In certain embodiments, both c1 in formula (hi) are the same. In certain embodiments, both c1 in formula (hi) are approximately 225.

[0423] In certain embodiments, the part -Z of formula (Ia) or (Ib) is the part of formula (h-ia) shown below. [ka] During the ceremony, The dashed line is -L 2 - indicates a connection to; Each k is independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; -Y a1 - and -Y a1′ -teeth, [ka] and; Each-Z c The following section: [ka] And, Each c1 is an independent integer in the range of 200 to 250.

[0424] In certain embodiments, each k in formula (h-ia) is independently selected from the group consisting of 2, 3, 4, 5, 6, and 7. In certain embodiments, both k in formula (h-ia) are identical.

[0425] In certain embodiments, both c1 in formula (h-ia) are identical. In certain embodiments, both c1 in formula (h-ia) are approximately 225.

[0426] In certain embodiments, -Y of formula (h-ia) a1 - and -Y a1′ - Both are, [ka] And, The dashed line marked with an asterisk is -Z c It is connected.

[0427] In certain embodiments, -Z in formula (Ia) or (Ib) includes a portion selected from the group consisting of the following: [ka] TIFF0007864798000081.tif239151TIFF0007864798000082.tif146159In the formula, The dashed line is -L 2 - indicates a connection to; s1, s2, s3, s4, s5, s6, s7, s8, s9, s10, s11, s12, s13, s14 and s15 are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; -X d1 -X d2 -X d3 and -X d4 These are -OH, -SH, and -NR, which are independent of each other. g1 R g2 Selected from the group consisting of; preferably -OH; -X e1 -X e2-X e3 and -X e4 -H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls; -R g1 and -R g2 -H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls; -X f1 -X f2 -X f3 -X f4 -X f5 -X f6 -X f7 -X f8 -X f9 -X f10 -X f11 -X f12 -X f13 and -X f14 -H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls; preferably -H; -Y d1 -, -Y d2 -, -Y d3 - and -Y d4 - are independent of each other, [ka] Selected from the group consisting of; -Z d1 , -Z d2 , -Z d3 and -Z d4 These are proteins, in a particular embodiment, random coil proteins, and in a particular embodiment, random coil proteins selected from the group consisting of PA, PAS, PAG, PG, and XTEN.

[0428] In certain embodiments, -Y in formulas (j-iv), (jv), and (j-vi)d1 - and -Y d2 -and the expression (j-vii) -Y d1 -, -Y d2 -, -Y d3 - and -Y d4 -teeth, [ka] That is the case.

[0429] In certain embodiments, -Y in formulas (j-iv), (jv), and (j-vi) d1 - and -Y d2 -and the expression (j-vii) -Y d1 -, -Y d2 -, -Y d3 - and -Y d4 -teeth, [ka] and; During the ceremony, The dashed lines marked with an asterisk represent -Z. d1 , -Z d2 , -Z d3 and -Z d4 The dashed lines that are not marked are -L 2 It is heading in that direction.

[0430] In a particular embodiment, the -X of formula (ji) f1 -X f2 -X f3 -X f4 -X f5 -X f6 -X f7 and -X f8 is -H; -X of equation (ji) d1 and -X d2 is -OH; -X of formula (ji) e1 and -X e2 is selected from the group consisting of -H and methyl; s1, s2, s3 and s4 of formula (ji) are selected from the group consisting of 2, 3, 4, 5 and 6.

[0431] In a particular embodiment, the -X of formula (ji) f1 -X f2 -X f3 -X f4 -X f5 -X f6 -X f7 and -X f8 is -H; -X of equation (ji) d1 and -X d2 is -OH; -X of formula (ji) e1 and -X e2 is -H; s1, s2, s3 and s4 in equation (ji) are 4.

[0432] In certain embodiments, -Xf1, -Xf2, -Xf3, and -Xf4 in formula (j-ii) are -H; -Xd1, -Xd2, -Xd3, and -Xd2 in formula (j-ii) are -OH; -Xe1, -Xe2, -Xe3, and -Xe4 in formula (j-ii) are selected from the group consisting of -H and methyl; and s1, s2, s3, s4, and s5 in formula (j-ii) are selected from the group consisting of 1, 2, 3, 4, 5, and 6. In a particular embodiment, -Xf1, -Xf2, -Xf3, and -Xf4 in formula (j-ii) are -H; -Xd1, -Xd2, -Xd3, and -Xd2 in formula (j-ii) are -OH; -Xe1, -Xe2, -Xe3, and -Xe4 in formula (j-ii) are -H; s1 is 4 in formula (j-ii), and s2, s3, s4, and s5 in formula (j-ii) are 1.

[0433] In a particular embodiment, -X of formula (j-iii) f1 -X f2 -X f3 -X f4 -X f5 -X f6 -X f7 -X f8 -X f9 and -X f10 is -H; -X of equation (j-iii) d1 -X d2 -X d3 and -X d4 is -OH; -X in equation (j-iii) e1 -X e2-X e3 and -X e4 -H and methyl are selected from the group consisting of s1, s2 and s3 of formula (j-iii) are selected from the group consisting of 2, 3, 4, 5 and 6. In certain embodiments, -X of formula (j-iii) f1 -X f2 -X f3 -X f4 -X f5 -X f6 -X f7 -X f8 -X f9 and -X f10 is -H; -X of equation (j-iii) d1 -X d2 -X d3 and -X d4 is -OH; -X in equation (j-iii) e1 -X e2 -X e3 and -X e4 is -H; s1, s2 and s3 in equation (j-iii) are 4.

[0434] In a particular embodiment, -X of formula (j-iv) f1 -X f2 -X f3 -X f4 -X f5 and -X f6 is -H; s1, s2, s3, s4, s5, s6 and s7 in equation (j-iv) are selected from the group consisting of 1, 2, 3, 4, 5, 6 and 7; -Y d1 - and -Y d2 -teeth, [ka] It is selected from the group consisting of the following.

[0435] In a particular embodiment, -X of formula (j-iv) f1 -X f2 -X f3 -X f4 -X f5 and -X f6is -H; s1 of equation (j-iv) is 3, s2 of equation (j-iv) is 5, s3 of equation (j-iv) is 2, s4 of equation (j-iv) is 4, s5 of equation (j-iv) is 5, s6 of equation (j-iv) is 2, s7 of equation (j-iv) is 4; -Y of equation (j-iv) d1 - and -Y d2 -teeth, [ka] That is the case.

[0436] In a particular embodiment, -X of formula (j-iv) f1 -X f2 -X f3 -X f4 -X f5 and -X f6 is -H; s1 of equation (j-iv) is 3, s2 of equation (j-iv) is 5, s3 of equation (j-iv) is 2, s4 of equation (j-iv) is 4, s5 of equation (j-iv) is 5, s6 of equation (j-iv) is 2, s7 of equation (j-iv) is 4; -Y of equation (j-iv) d1 - and -Y d2 -teeth, [ka] and; In the formula, the dashed lines marked with an asterisk represent -Z. d1 , -Z d2 , -Z d3 and -Z d4 It is pointing in that direction, and the unmarked dashed line is -L 2 It is heading in that direction.

[0437] In a particular embodiment, -X of formula (jv) f1 -X f2 -X f3 and -X f4 is -H; s1, s2, s3, s4 and s5 of equation (jv) are selected from the group consisting of 1, 2, 3, 4, 5, 6 and 7; and -Y of equation (jv) d1 - and -Y d2 -teeth, [ka] It is selected from the group consisting of the following.

[0438] In a particular embodiment, -X of formula (jv) f1 -X f2 -X f3 and -X f4 is -H; s1 of equation (jv) is 3, s2 of equation (jv) is 2, s3 of equation (jv) is 1, s4 of equation (jv) is 2, s5 of equation (jv) is 1; -Y of equation (jv) d1 - and -Y d2 -teeth, [ka] That is the case.

[0439] In a particular embodiment, -X of formula (jv) f1 -X f2 -X f3 and -X f4 is -H; s1 of equation (jv) is 3, s2 of equation (jv) is 2, s3 of equation (jv) is 1, s4 of equation (jv) is 2, s5 of equation (jv) is 1; -Y of equation (jv) d1 - and -Y d2 -teeth, [ka] and; In the formula, the dashed lines marked with an asterisk represent -Z. d1 , -Z d2 , -Z d3 and -Z d4 It is oriented in that direction, and the unmarked dashed line is -L 2 It is facing in that direction.

[0440] In a particular embodiment, -X of formula (j-vi) f1 -X f2 -X f3 -X f4 -X f5-X f6 -X f7 -X f8 -X f9 and -X f10 is -H; s1, s2, s3, s4, s5, s6, s7, s8 and s9 in equation (j-vi) are selected from the group consisting of 1, 2, 3, 4, 5, 6 and 7; and -Y in equation (j-vi) d1 - and -Y d2 -teeth, [ka] It is selected from the group consisting of the following.

[0441] In a particular embodiment, -X of formula (j-vi) f1 -X f2 -X f3 -X f4 -X f5 -X f6 -X f7 -X f8 -X f9 and -X f10 is -H; s1 of equation (j-vi) is 4, s2 of equation (j-vi) is 5, s3 of equation (j-vi) is 2, s4 of equation (j-vi) is 4, s5 of equation (j-vi) is 4, s6 of equation (j-vi) is 5, s7 of equation (j-vi) is 2, s8 of equation (j-vi) is 4, s9 of equation (j-vi) is 4; -Y of equation (jv) d1 - and -Y d2 -teeth, [ka] That is the case.

[0442] In a particular embodiment, -X of formula (j-vi) f1 -X f2 -X f3 -X f4 -X f5 -X f6 -X f7 -X f8 -X f9 and -X f10is -H; s1 of equation (j-vi) is 4, s2 of equation (j-vi) is 5, s3 of equation (j-vi) is 2, s4 of equation (j-vi) is 4, s5 of equation (j-vi) is 4, s6 of equation (j-vi) is 5, s7 of equation (j-vi) is 2, s8 of equation (j-vi) is 4, s9 of equation (j-vi) is 4; -Y of equation (jv) d1 - and -Y d2 -teeth, [ka] and; In the formula, the dashed lines marked with an asterisk represent -Z. d1 , -Z d2 , -Z d3 and -Z d4 It is oriented in that direction, and the unmarked dashed line is -L 2 It is facing in that direction.

[0443] In a particular embodiment, -X in formula (j-vii) f1 -X f2 -X f3 -X f4 -X f5 -X f6 -X f7 -X f8 -X f9 -X f10 -X f11 -X f12 -X f13 and -X f14 is -H; s1, s2, s3, s4, s5, s6, s7, s8, s9, s10, s11, s12, s13, s14 and s15 of equation (j-vii) are selected from the group consisting of 1, 2, 3, 4, 5, 6 and 7; -Y of equation (j-vii) d1 -, -Y d2 -, -Y d3 - and -Y d4 -teeth, [ka] It is selected from the group consisting of the following.

[0444] In a particular embodiment, -X in formula (j-vii) f1 -X f2 -X f3 -X f4 -X f5 -X f6 -X f7 -X f8 -X f9 -X f10 -X f11 -X f12 -X f13 and -X f14 is -H; -H; s1 of equation (j-vii) is 4, s2 of equation (j-vii) is 4, s3 of equation (j-vii) is 5, s4 of equation (j-vii) is 2, s5 of equation (j-vii) is 4, s6 of equation (j-vii) is 5, s7 of equation (j-vii) is 2, s8 of equation (j-vii) is 4, s9 of equation (j-vii) is 4, s10 of equation (j-vii) is 5, s11 of equation (j-vii) is 2, s12 of equation (j-vii) is 4, s13 of equation (j-vii) is 5, s14 of equation (j-vii) is 2, s15 of equation (j-vii) is 4; -Y of equation (j-vii) d1 -, -Y d2 -, -Y d3 - and -Y d4 -teeth, [ka] That is the case.

[0445] In a particular embodiment, -X in formula (j-vii) f1 -X f2 -X f3 -X f4 -X f5 -X f6 -X f7 -X f8 -X f9 -X f10 -X f11 -X f12 -X f13 and -X f14is -H; -H; s1 of equation (j-vii) is 4, s2 of equation (j-vii) is 4, s3 of equation (j-vii) is 5, s4 of equation (j-vii) is 2, s5 of equation (j-vii) is 4, s6 of equation (j-vii) is 5, s7 of equation (j-vii) is 2, s8 of equation (j-vii) is 4, s9 of equation (j-vii) is 4, s10 of equation (j-vii) is 5, s11 of equation (j-vii) is 2, s12 of equation (j-vii) is 4, s13 of equation (j-vii) is 5, s14 of equation (j-vii) is 2, s15 of equation (j-vii) is 4; -Y of equation (j-vii) d1 -, -Y d2 -, -Y d3 - and -Y d4 -teeth, [ka] and; The dashed lines marked with an asterisk represent -Z. d1 , -Z d2 , -Z d3 and -Z d4 It is oriented in that direction, and the unmarked dashed line is -L 2 It is facing in that direction.

[0446] In certain embodiments, the -Z of formulas (ji), (j-ii), (j-iii), (j-iv), (jv), (j-vi), and (j-vii) d1 , -Z d2 , -Z d3 and -Z d4 They have the same structure. In certain embodiments, the -Z of formulas (ji), (j-ii), (j-iii), (j-iv), (jv), (j-vi), and (j-vii) d1 , -Z d2 , -Z d3 and -Z d4 This is the PA portion. In certain embodiments, -Z of formulas (ji), (j-ii), (j-iii), (j-iv), (jv), (j-vi), and (j-vii) d1 , -Z d2 , -Z d3 and -Zd4 This is the PAS portion. In certain embodiments, -Z of formulas (ji), (j-ii), (j-iii), (j-iv), (jv), (j-vi), and (j-vii) d1 , -Z d2 , -Z d3 and -Z d4 This is the PAG portion. In certain embodiments, -Z of formulas (ji), (j-ii), (j-iii), (j-iv), (jv), (j-vi), and (j-vii) d1 , -Z d2 , -Z d3 and -Z d4 This is the PG portion. In certain embodiments, -Z of formulas (ji), (j-ii), (j-iii), (j-iv), (jv), (j-vi), and (j-vii) d1 , -Z d2 , -Z d3 and -Z d4 This is the XTEN part.

[0447] In a particular embodiment, the CNP conjugate has the formula (IIf): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates structure: [ka] This shows a bond to -Z having, in the formula, Each-Z a teeth, [ka] (where each c1 in the formula is an independent integer in the range of 200 to 250).

[0448] In certain embodiments, each c1 in formula (IIf) is approximately 225.

[0449] In a particular embodiment, the CNP conjugate has the formula (IIf-i): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates structure: [ka] This shows a bond to -Z having, in the formula, Each-Z a teeth, [ka] (And in this formula, each c1 is an independent integer in the range of 200 to 250).

[0450] In certain embodiments, each c1 in formula (IIf-i) is approximately 225.

[0451] In a particular embodiment, the CNP conjugate has the formula (IIf-ii): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates structure: [ka] This shows a bond to -Z having, in the formula, Each-Z a teeth, [ka] (And in this formula, each c1 is an independent integer in the range of 200 to 250).

[0452] In certain embodiments, each c1 in formula (IIf-ii) is approximately 225.

[0453] In certain embodiments, the -D in formulas (IIf), (IIf-i), and (IIf-ii) is a CNP portion, i.e., the conjugates of formulas (IIf), (IIf-i), and (IIf-ii) are CNP conjugates. In certain embodiments, the -D in formulas (IIf), (IIf-i), and (IIf-ii) is a CNP portion having an array of sequence number 24, sequence number 25, or sequence number 30. In certain embodiments, the -D in formulas (IIf), (IIf-i), and (IIf-ii) is a CNP portion having an array of sequence number 24. In certain embodiments, the -D portion in formulas (IIf), (IIf-i), and (IIf-ii) is a CNP portion having an array of sequence number 20. In certain embodiments, the -D portion in formulas (IIf), (IIf-i), and (IIf-ii) is a CNP portion having an array of sequence number 21. In certain embodiments, the -D portion of formulas (IIf), (IIf-i), and (IIf-ii) is a CNP portion having the sequence of sequence number 22. In certain embodiments, the -D portion of formulas (IIf), (IIf-i), and (IIf-ii) is a CNP portion having the sequence of sequence number 23. In certain embodiments, the -D portion of formulas (IIf), (IIf-i), and (IIf-ii) is a CNP portion having the sequence of sequence number 30.

[0454] In certain embodiments, -D in formulas (IIf), (IIf-i), and (IIf-ii) is -L via the nitrogen of the N-terminal amine functional group of the CNP. 1 This is the CNP portion that is bonded to the -.

[0455] In certain embodiments, -D in formulas (IIf), (IIf-i), and (IIf-ii) is -L via nitrogen provided by the amine functional group of the lysine side chain of the CNP moiety. 1 This is the CNP portion that is bonded to the -.

[0456] In certain embodiments, when the CNP portion is that of SEQ ID NO: 24, the lysine side chain is not part of a ring formed by a disulfide bridge between the cysteine ​​residues at positions 22 and 38.

[0457] Therefore, in a particular embodiment, if the CNP has the sequence of SEQ ID NO: 24, the CNP portion is the -L in the CNP conjugates of formulas (IIf), (IIf-i), and (IIf-ii) via the amine functional group provided by the lysine side chain at position 9. 1 - is linked to

[0458] In a particular embodiment, if the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is the -L in the CNP conjugates of formulas (IIf), (IIf-i), and (IIf-ii) via the amine functional group provided by the lysine side chain at position 11. 1 - is linked to

[0459] In a particular embodiment, if the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is in the CNP conjugates of formulas (IIf), (IIf-i), and (IIf-ii) via the amine functional group provided by the lysine side chain at position 15. 1 - is linked to

[0460] In a particular embodiment, if the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is the -L in the CNP conjugates of formulas (IIf), (IIf-i), and (IIf-ii) via the amine functional group provided by the lysine side chain at position 16. 1 - is linked to

[0461] In a particular embodiment, if the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is the -L in the CNP conjugates of formulas (IIf), (IIf-i), and (IIf-ii) via the amine functional group provided by the lysine side chain at position 20. 1 - is linked to

[0462] In a particular embodiment, if the CNP portion is that of SEQ ID NO: 24, the lysine side chain is part of a ring formed by a disulfide bridge between cysteine ​​residues at positions 22 and 38.

[0463] Therefore, in a particular embodiment, if the CNP has the sequence of SEQ ID NO: 24, the CNP portion is the -L in the CNP conjugate of formulas (IIf), (IIf-i), and (IIf-ii) via the amine functional group provided by the lysine side chain at position 26. 1 - is linked to

[0464] In certain embodiments, the CNP conjugate has the formula (IIf-i), where c1 is approximately 225, and the CNP portion has the sequence of SEQ ID NO: 24, via an amine functional group provided by the lysine side chain at position 26 -L 1 - is connected to

[0465] In certain embodiments, the CNP conjugate has the formula (IIf), where c1 is approximately 225, -D is a CNP moiety having the sequence of SEQ ID NO: 20, and -L is provided by the amine functional group via the lysine side chain at position 30. 1 - is connected to

[0466] In certain embodiments, the CNP conjugate has the formula (IIf-i), where c1 is approximately 225, and the CNP portion has the sequence of SEQ ID NO: 20, via an amine functional group provided by the lysine side chain at position 30 -L 1 - is connected to

[0467] In certain embodiments, the CNP conjugate has the formula (IIf-ii), where c1 is approximately 225, and the CNP portion has the sequence of SEQ ID NO: 20, via an amine functional group provided by the lysine side chain at position 30 -L 1 - is connected to

[0468] In certain embodiments, the CNP conjugate has the formula (IIf), where c1 is approximately 225, -D is a CNP moiety having the sequence of SEQ ID NO: 21, and -L via an amine functional group provided by the lysine side chain at position 29. 1 - is connected to

[0469] In certain embodiments, the CNP conjugate has the formula (IIf-i), where c1 is approximately 225, and the CNP portion has the sequence of SEQ ID NO: 21, via an amine functional group provided by the lysine side chain at position 29 -L 1 - is connected to

[0470] In certain embodiments, the CNP conjugate has the formula (IIf-ii), where c1 is approximately 225, and the CNP portion has the sequence of SEQ ID NO: 21, via an amine functional group provided by the lysine side chain at position 29 -L 1 - is connected to

[0471] In certain embodiments, the CNP conjugate has the formula (IIf), where c1 is approximately 225, -D is a CNP moiety having the sequence of SEQ ID NO: 22, and -L is provided by the amine functional group via the lysine side chain at position 28. 1 - is connected to

[0472] In certain embodiments, the CNP conjugate has the formula (IIf-i), where c1 is approximately 225, and the CNP portion has the sequence of SEQ ID NO: 22, via an amine functional group provided by the lysine side chain at position 28 -L 1 - is connected to

[0473] In certain embodiments, the CNP conjugate has the formula (IIf-ii), where c1 is approximately 225, and the CNP portion has the sequence of SEQ ID NO: 22, via an amine functional group provided by the lysine side chain at position 28 -L 1 - is connected to

[0474] In certain embodiments, the CNP conjugate has the formula (IIf), where c1 is approximately 225, -D is a CNP moiety having the sequence of SEQ ID NO: 23, and -L via an amine functional group provided by the lysine side chain at position 27. 1 - is connected to

[0475] In certain embodiments, the CNP conjugate has the formula (IIf-i), where c1 is approximately 225, and the CNP portion has the sequence of SEQ ID NO: 23, via an amine functional group provided by the lysine side chain at position 27 -L 1 - is connected to

[0476] In certain embodiments, the CNP conjugate has the formula (IIf-ii), where c1 is approximately 225, and the CNP portion has the sequence of SEQ ID NO: 23, via an amine functional group provided by the lysine side chain at position 27 -L 1 - is connected to

[0477] In certain embodiments, the CNP conjugate has the formula (IIf), where c1 is approximately 225, -D is a CNP moiety having the sequence of SEQ ID NO: 30, and -L is provided by the amine functional group via the lysine side chain at position 27. 1 - is connected to

[0478] In certain embodiments, the CNP conjugate has the formula (IIf-i), where c1 is approximately 225, and the CNP portion has the sequence of SEQ ID NO: 30, via an amine functional group provided by the lysine side chain at position 27 -L 1 - is connected to

[0479] In certain embodiments, the CNP conjugate has the formula (IIf-ii), where c1 is approximately 225, and the CNP portion has the sequence of SEQ ID NO: 30, via an amine functional group provided by the lysine side chain at position 27 -L 1 - is connected to

[0480] In certain embodiments, the CNP conjugate has the formula (IIf-ii), where c1 is approximately 225, and the CNP portion has the sequence of SEQ ID NO: 24, via an amine functional group provided by the lysine side chain at position 26 -L 1 - is connected to

[0481] The positions of cysteine ​​and lysine described above vary depending on the length of the CNP moiety, and it is understood that a person skilled in the art will not have difficulty identifying the corresponding cysteine ​​and lysine in longer or shorter versions of the CNP moiety, and that, for example, some lysine may not be present in shorter CNP moieties. It is further understood that, for example, as a result of site-directed mutagenesis, more lysine residues may be present in the acyclic and / or cyclic portions of the CNP moiety.

[0482] In certain embodiments, the CNP conjugate has the formula (IIf), where c1 is approximately 225, -D is a CNP moiety having the sequence of SEQ ID NO: 24, and -L via an amine functional group provided by the lysine side chain at position 26. 1 - is connected to

[0483] In a particular embodiment, the CNP conjugate of the present invention has formula (IIf'): [ka] (In the formula, The unmarked dashed lines indicate the bond to nitrogen provided by the lysine side chain at position 26 of the CNP moiety of Sequence ID No. 24, by forming an amide bond. The dashed line with an asterisk indicates structure: [ka] This shows a bond to -Z having, in the formula, each Z a teeth, [ka] (where each c1 in the formula is an independent integer in the range of 200 to 250).

[0484] In certain embodiments, each c1 in formula (IIf') is approximately 225.

[0485] In a particular embodiment, the CNP conjugate has the formula (IIf-i'): [ka] (In the formula, The unmarked dashed lines indicate the bond to nitrogen provided by the lysine side chain at position 26 of the CNP moiety of Sequence ID No. 24, by forming an amide bond. The dashed line with an asterisk indicates structure: [ka] This shows a bond to -Z having, in the formula, each Z a teeth, [ka] (And in this formula, each c1 is an independent integer in the range of 200 to 250).

[0486] In certain embodiments, each c1 in formula (IIf-i') is approximately 225.

[0487] In a particular embodiment, the CNP conjugate has the formula (IIf-ii'): [ka] (In the formula, The unmarked dashed lines indicate the bond to nitrogen provided by the lysine side chain at position 26 of the CNP moiety of Sequence ID No. 24, by forming an amide bond. The dashed line with an asterisk indicates structure: [ka] This shows a bond to -Z having, in the formula, each Z a teeth, [ka] (And in this formula, each c1 is an independent integer in the range of 200 to 250).

[0488] In certain embodiments, each c1 in formula (IIf-ii') is approximately 225.

[0489] In a particular embodiment, the CNP conjugate is of the following formula (IIfa). [ka] During the ceremony, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; The dashed lines marked with asterisks have the following structure: [ka] It shows a bond to -Z that has, k is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; Each-Z a teeth, [ka] And, Each c1 is an independent integer in the range of 200 to 250.

[0490] In a particular embodiment, k in formula (IIfa) is selected from the group consisting of 2, 3, 4, 5, 6, and 7.

[0491] In a particular embodiment, each c1 in formula (IIfa) is approximately 225.

[0492] In a particular embodiment, the CNP conjugate is of the following formula (IIfa-i). [ka] During the ceremony, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; The dashed lines marked with asterisks have the following structure: [ka] It shows a bond to -Z that has, k is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; Each-Z a teeth, [ka] And, Each c1 is an independent integer in the range of 200 to 250.

[0493] In a particular embodiment, k in formula (IIfa-i) is selected from the group consisting of 2, 3, 4, 5, 6, and 7.

[0494] In a particular embodiment, each c1 in formula (IIfa-i) is approximately 225.

[0495] In a particular embodiment, the CNP conjugate is of the following formula (IIfa-ii). [ka] During the ceremony, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; The dashed lines marked with asterisks have the following structure: [ka] It shows a bond to -Z that has, k is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; Each-Z a teeth, [ka] And, Each c1 is an independent integer in the range of 200 to 250.

[0496] In a particular embodiment, each c1 in formula (IIfa-ii) is approximately 225.

[0497] In a particular embodiment, the CNP portion of the CNP conjugates of formulas (IIfa), (IIfa-i), and (IIfa-ii) has the sequence of sequence number 25.

[0498] In a particular embodiment, the CNP portion of the CNP conjugates of formulas (IIfa), (IIfa-i), and (IIfa-ii) has the sequence of sequence number 20.

[0499] In a particular embodiment, the CNP portion of the CNP conjugates of formulas (IIfa), (IIfa-i), and (IIfa-ii) has the sequence of sequence number 21.

[0500] In a particular embodiment, the CNP portion of the CNP conjugates of formulas (IIfa), (IIfa-i), and (IIfa-ii) has the sequence of sequence number 22.

[0501] In a particular embodiment, the CNP portion of the CNP conjugates of formulas (IIfa), (IIfa-i), and (IIfa-ii) has the sequence of sequence number 23.

[0502] In a particular embodiment, the CNP portion of the CNP conjugates of formulas (IIfa), (IIfa-i), and (IIfa-ii) has the sequence of sequence number 30.

[0503] In a particular embodiment, the CNP portion of the CNP conjugates of formulas (IIfa), (IIfa-i), and (IIfa-ii) has the sequence of sequence number 24.

[0504] In one embodiment, the CNP portion is connected to the -L in the CNP conjugates of formulas (IIfa), (IIfa-i), and (IIfa-ii) via the nitrogen of the N-terminal amine functional group of the CNP. 1 It is connected to -.

[0505] In a particular embodiment, the CNP conjugate is of the following formula (IIfa'). [ka] During the ceremony, The unmarked dashed lines indicate the bond to nitrogen provided by the lysine side chain at position 26 of the CNP moiety in Sequence ID No. 24 by forming an amide bond; The dashed lines marked with asterisks have the following structure: [ka] It shows a bond to -Z that has, k is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; each Z a teeth, [ka] And, Each c1 is an independent integer in the range of 200 to 250.

[0506] In a particular embodiment, k in formula (IIfa') is selected from the group consisting of 2, 3, 4, 5, 6, and 7.

[0507] In a particular embodiment, each c1 in formula (IIfa') is approximately 225.

[0508] In a particular embodiment, the CNP conjugate is of the following formula (IIfa-i′). [ka] During the ceremony, The unmarked dashed lines indicate the bond to nitrogen provided by the lysine side chain at position 26 of the CNP moiety in Sequence ID No. 24 by forming an amide bond; The dashed lines marked with asterisks have the following structure: [ka] It shows a bond to -Z that has, k is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; each Z a teeth, [ka] And, Each c1 is an independent integer in the range of 200 to 250.

[0509] In a particular embodiment, k in formula (IIfa-i′) is selected from the group consisting of 2, 3, 4, 5, 6, and 7.

[0510] In a particular embodiment, each c1 in formula (IIfa-i′) is approximately 225.

[0511] In a particular embodiment, the CNP conjugate is of the following formula (IIfa-ii'). [ka] During the ceremony, The unmarked dashed lines indicate the bond to nitrogen provided by the lysine side chain at position 26 of the CNP moiety in Sequence ID No. 24 by forming an amide bond; The dashed lines marked with asterisks have the following structure: [ka] It shows a bond to -Z that has, k is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; each Z a teeth, [ka] And, Each c1 is an independent integer in the range of 200 to 250.

[0512] In a particular embodiment, k in formula (IIfa-ii') is selected from the group consisting of 2, 3, 4, 5, 6, and 7.

[0513] In a particular embodiment, each c1 in formula (IIfa-ii') is approximately 225.

[0514] In certain embodiments, the dried formulation of the present invention may contain one or more excipients, such as preservatives, stabilizers, adsorption inhibitors, cryoprotectants, antioxidants, and other auxiliary agents. It is understood that one excipient may have multiple functions, such as dual or triple functions.

[0515] In certain embodiments, the dried pharmaceutical formulation of the present invention may contain preservatives selected from the group consisting of benzoic acid, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, potassium sorbate, chlorobutanol, benzyl alcohol, phenylmercury nitrate thimerosal, sorbic acid, potassium sorbate, chlorocresol, benzalkonium chloride, 2-ethoxyethanol, chlorhexidine, chlorobutanol, phenylethyl alcohol, phenylmercury acetate, m-cresol, and mixtures thereof.

[0516] In certain embodiments, the dried formulation of the present invention may contain stabilizers selected from the group consisting of alanine; arginine; aspartic acid; glycine; histidine; lysine; proline; sugars such as glucose, sucrose, and trehalose; polyols such as glycerol, mannitol, and sorbitol; salts such as potassium phosphate and sodium sulfate; chelating agents such as EDTA and hexaphosphate; ligands such as divalent metal ions; organic molecules such as other salts or phenol derivatives; and stabilizers selected from the group consisting of cyclodextrin, dextran, dendrimers, PEG, PVP, protamine, and HSA.

[0517] In certain embodiments, the dry pharmaceutical formulation of the present invention may contain an adsorption inhibitor, such as an ionic or nonionic surfactant or an adsorption inhibitor selected from the group consisting of other proteins or soluble polymers, used to competitively coat or adsorb onto the inner surface of the formulation or the container of the formulation, such as poloxamer (Pluronic F-68), PEG dodecyl ether (Brij 35), dextran, polyethylene glycol, PEG-polyhistidine, BSA, HSA, gelatin, etc. The type and concentration of the excipient are selected according to the effects to be avoided, but usually a monolayer of the surfactant is formed at the interface at a higher concentration than that of the CMC.

[0518] In certain embodiments, the dried pharmaceutical formulations of the present invention may include cryoprotectants selected from the group consisting of sugars, polyhydric alcohols, surfactants, amino acids, non-aqueous solvents, and peptides. During freeze-drying or spray-drying, the cryoprotectant can counteract the destabilizing effects caused by hydrogen bond breakdown and water removal. Trehalose is particularly efficient in reducing water-induced aggregation and also improves the thermal stability that may be caused by the exposure of the compound's hydrophobic groups to water. Mannitol and sucrose can also be used as individual lioprotectants / cryoprotectants or in combination with each other, in which case it is known that a higher mannitol:sucrose ratio increases the physical stability of the compound in the dried pharmaceutical formulation. Mannitol can also be combined with trehalose. Trehalose can also be combined with sorbitol, or sorbitol can be used as a single inhibitor. Starch or starch derivatives can also be used.

[0519] In certain embodiments, the dry pharmaceutical formulation of the present invention may contain antioxidants selected from the group consisting of, for example, methionine, butylhydroxytoluene, butylhydroxyanisole, tocopherol, propyl gallate, ascorbic acid, sodium bisulfite, ethylenediaminetetraacetic acid (EDTA), cysteine, glutathione, monothioglycerol, poly(ethyleneimine), vitamin E, ectoin, morin, and mixtures thereof.

[0520] In certain embodiments, the dry pharmaceutical formulation of the present invention may include further excipients selected from the group consisting of wetting agents, viscosity modifiers, and antibiotics.

[0521] In certain embodiments, the dried pharmaceutical formulation of the present invention comprises CNP conjugate, succinic acid, trehalose, and Tris.

[0522] In a particular embodiment, the dry pharmaceutical formulation according to the present invention is based on the total weight of the dry pharmaceutical formulation. CNP Conjugate: 1.3-45.4% by weight Succinic acid: 0.2-3.2% by weight Trehalose dihydrate: 52.6-98.4% by weight Tris: 0.1~5.6% by weight Includes.

[0523] In a particular embodiment, the dry pharmaceutical formulation according to the present invention is based on the total weight of the dry pharmaceutical formulation. CNP Conjugate: 1.3-38.7% by weight Succinic acid: 0.2-3.2% by weight Trehalose dihydrate: 52.6-98.4% by weight Tris: 0.1~5.6% by weight Includes.

[0524] Because of the large difference in patient weight ranges, for example, between 3 and 60 kg, in certain embodiments it is advantageous to have dry pharmaceutical formulations having different intensities, i.e., different concentrations, for example, high, medium, and low intensities, of the CNP conjugate. Accordingly, in one embodiment, the dry pharmaceutical formulation is provided in multiple concentrations, for example, two different concentrations, for example, three different concentrations, for example, four different concentrations, for example, five different concentrations, for example, six different concentrations, for example, seven different concentrations, for example, eight different concentrations, for example, nine different concentrations, for example, ten different concentrations, for example, eleven different concentrations, for example, twelve different concentrations.

[0525] In a particular embodiment, the dry pharmaceutical formulation is determined based on the total weight of the dry pharmaceutical formulation. CNP Conjugate: 23.8-38.7% by weight Succinic acid: 0.2-3.1% by weight Trehalose dihydrate: 52.6-75.9% by weight Tris: 0.1~5.6% by weight Includes.

[0526] In a particular embodiment, the dry pharmaceutical formulation is determined based on the total weight of the dry pharmaceutical formulation. CNP Conjugate: 5.8-12.4% by weight Succinic acid: 0.3-3.2% by weight Trehalose dihydrate: 78.8-93.8% by weight Tris: 0.1~5.6% by weight Includes.

[0527] In a particular embodiment, the dry pharmaceutical formulation is determined based on the total weight of the dry pharmaceutical formulation. CNP Conjugate: 1.4-3.7% by weight Succinic acid: 0.3-3.2% by weight Trehalose dihydrate: 87.5-98.2% by weight Tris: 0.1~5.6% by weight Includes.

[0528] In a particular embodiment, the dry pharmaceutical formulation is determined based on the total weight of the dry pharmaceutical formulation. CNP Conjugate: 28.8-33.2% by weight Succinic acid: 0.6-1.6% by weight Trehalose dihydrate: 62.4-70.4% by weight Tris: 0.2~2.8% by weight Includes.

[0529] In a particular embodiment, the dry pharmaceutical formulation is determined based on the total weight of the dry pharmaceutical formulation. CNP Conjugate: 7.4-8.8% by weight Succinic acid: 0.8-2.0% by weight Trehalose dihydrate: 85.7-91.6% by weight Tris: 0.2~3.5% by weight Includes.

[0530] In a particular embodiment, the dry pharmaceutical formulation is determined based on the total weight of the dry pharmaceutical formulation. CNP Conjugate: 2.0-2.5% by weight Succinic acid: 0.8-2.1% by weight Trehalose dihydrate: 91.7-97.0% by weight Tris: 0.2~3.8% by weight Includes.

[0531] In a particular embodiment, the dry pharmaceutical formulation is determined based on the total weight of the dry pharmaceutical formulation. CNP Conjugate: 32.2-34.0% by weight Succinic acid: 0.9-1.0% by weight Trehalose dihydrate: 64.5-65.5% by weight Tris: 0.5~1.4% by weight Includes.

[0532] In a particular embodiment, the dry pharmaceutical formulation is determined based on the total weight of the dry pharmaceutical formulation. CNP Conjugate: 8.3-8.9% by weight Succinic acid: 1.2-1.3% by weight Trehalose dihydrate: 88.6-89.1% by weight Tris: 0.7~1.8% by weight Includes.

[0533] In a particular embodiment, the dry pharmaceutical formulation is determined based on the total weight of the dry pharmaceutical formulation. CNP conjugate: 2.3-2.4% by weight Succinic acid: 1.3-1.4% by weight Trehalose dihydrate: 94.4-95.6% by weight Tris: 0.7~1.9% by weight Includes.

[0534] In certain embodiments, the dry pharmaceutical formulation comprises, based on the total weight of the dry pharmaceutical formulation, about 45.4% by weight of CNP conjugate, about 0.9% by weight of succinic acid, about 52.6% by weight of trehalose dihydrate, and about 1.1% by weight of Tris.

[0535] In certain embodiments, the dry pharmaceutical formulation comprises, based on the total weight of the dry pharmaceutical formulation, 45.4% by weight CNP conjugate, 0.9% by weight succinic acid, 52.6% by weight trehalose dihydrate, and 1.1% by weight Tris.

[0536] In certain embodiments, the dry pharmaceutical formulation comprises, based on the total weight of the dry pharmaceutical formulation, about 32.6% by weight of CNP conjugate, about 1.0% by weight of succinic acid, about 65.2% by weight of trehalose dihydrate, and about 1.2% by weight of Tris.

[0537] In certain embodiments, the dry pharmaceutical formulation comprises, based on the total weight of the dry pharmaceutical formulation, 33 wt% CNP conjugate, 1 wt% succinic acid, 65 wt% trehalose dihydrate, and 1 wt% Tris.

[0538] In certain embodiments, the dry pharmaceutical formulation comprises, based on the total weight of the dry pharmaceutical formulation, 32.6% by weight CNP conjugate, 1.0% by weight succinic acid, 65.2% by weight trehalose dihydrate, and 1.2% by weight Tris.

[0539] In certain embodiments, the dry pharmaceutical formulation comprises, based on the total weight of the dry pharmaceutical formulation, about 8.2% by weight of CNP conjugate, about 1.2% by weight of succinic acid, about 89.1% by weight of trehalose dihydrate, and about 1.5% by weight of Tris.

[0540] In certain embodiments, the dry pharmaceutical formulation comprises, based on the total weight of the dry pharmaceutical formulation, 8 wt% CNP conjugate, 1 wt% succinic acid, 89 wt% trehalose dihydrate, and 2 wt% Tris.

[0541] In certain embodiments, the dry pharmaceutical formulation comprises, based on the total weight of the dry pharmaceutical formulation, 8.2% by weight of CNP conjugate, 1.2% by weight of succinic acid, 89.1% by weight of trehalose dihydrate, and 1.5% by weight of Tris.

[0542] In certain embodiments, the dry pharmaceutical formulation comprises, based on the total weight of the dry pharmaceutical formulation, about 2.3 wt% CNP conjugate, about 1.3 wt% succinic acid, about 94.9 wt% trehalose dihydrate, and about 1.6 wt% Tris.

[0543] In certain embodiments, the dry pharmaceutical formulation comprises, based on the total weight of the dry pharmaceutical formulation, 2 wt% CNP conjugate, 1 wt% succinic acid, 95 wt% trehalose dihydrate, and 2 wt% Tris.

[0544] In certain embodiments, the dry pharmaceutical formulation comprises, based on the total weight of the dry pharmaceutical formulation, 2.3 wt% CNP conjugate, 1.3 wt% succinic acid, 94.9 wt% trehalose dihydrate, and 1.6 wt% Tris.

[0545] The dried pharmaceutical formulation of the present invention is a dried pharmaceutical formulation that is stable for at least 6 months, for example, at least 7 months, for example, at least 8 months, for example, at least 9 months, for example, at least 10 months, for example, at least 11 months, for example, at least 12 months. In a particular embodiment, the dried pharmaceutical formulation is stable for at least 14 months, for example, at least 16 months, for example, at least 18 months, for example, at least 20 months, for example, at least 22 months, for example, at least 24 months, for example, at least 40 months, for example, at least 60 months.

[0546] In certain embodiments, the dried pharmaceutical formulation of the present invention is stored at a temperature in the range of -80°C to 25°C, for example -20°C to 25°C, for example -15°C to 25°C, for example -10°C to 25°C, for example -5°C to 5°C, -5°C to 25°C, for example 0°C to 5°C, for example 0°C to 25°C, for example 2°C to 10°C, or for example 4°C to 8°C. In certain embodiments, the dried pharmaceutical formulation is stored at 2°C. In certain embodiments, the dried pharmaceutical formulation is stored at 5°C. In certain embodiments, the dried pharmaceutical formulation is stored at 6°C. In certain embodiments, the dried pharmaceutical formulation is stored at 8°C. In certain embodiments, the dried pharmaceutical formulation is stored at 10°C. In certain embodiments, the dried pharmaceutical formulation is stored at 16°C. In certain embodiments, the dried pharmaceutical formulation is stored at 20°C. In certain embodiments, the dried pharmaceutical formulation is stored at 25°C. In certain embodiments, the dried pharmaceutical formulation is stored at 30°C. In certain embodiments, the dried pharmaceutical formulation is stored at 40°C.

[0547] In certain embodiments, the dried pharmaceutical formulation is stable for at least 12 months when stored at 0-10°C. In certain embodiments, the dried pharmaceutical formulation is stable for at least 12 months when stored at 2-10°C. In certain embodiments, the dried pharmaceutical formulation is stable for at least 12 months when stored at 4-8°C. In certain embodiments, the dried pharmaceutical formulation is stable for at least 12 months when stored at 5°C.

[0548] In certain embodiments, the dried pharmaceutical formulation is stable for at least 24 months when stored at 5°C. In certain embodiments, the dried pharmaceutical formulation is stable for at least 36 months when stored at 5°C. In certain embodiments, the dried pharmaceutical formulation is stable for at least 48 months when stored at 5°C. In certain embodiments, the dried pharmaceutical formulation is stable for at least 60 months when stored at 5°C.

[0549] In certain embodiments, the dried pharmaceutical formulation is stable for 6 months when stored at 25°C. In certain embodiments, the dried pharmaceutical formulation is stable for at least 6 months when stored at 25°C. In certain embodiments, the dried pharmaceutical formulation is stable for at least 12 months when stored at 25°C.

[0550] In certain embodiments, the dried pharmaceutical formulation is stable for 6 months when stored at 30°C. In certain embodiments, the dried pharmaceutical formulation is stable for at least 6 months when stored at 30°C. In certain embodiments, the dried pharmaceutical formulation is stable for at least 12 months when stored at 30°C.

[0551] In certain embodiments, the dried pharmaceutical formulation is stable for 6 months when stored at 40°C. In certain embodiments, the dried pharmaceutical formulation is stable for at least 6 months when stored at 40°C. In certain embodiments, the dried pharmaceutical formulation is stable for at least 12 months when stored at 40°C.

[0552] In certain embodiments, the dry pharmaceutical formulation of the present invention is provided as a single dose, i.e., a solution containing the dry pharmaceutical formulation of CNP conjugate comprises one therapeutic dose.

[0553] The preferred drying method is freeze-drying; that is, the pharmaceutical preparation is a freeze-dried pharmaceutical preparation.

[0554] Another aspect of the present invention is a method for producing a dried pharmaceutical preparation according to the present invention, (i) A step of mixing the CNP conjugate with at least a buffer and a bulking agent; (ii) A step of adjusting the pH of the mixture from step (i); (iii) Optionally, a step of filtering the mixture from step (ii); (iv) A step of transferring an amount of the mixture from step (ii) or (iii) to a container that corresponds to the desired number of doses; (v) A step of drying the mixture; (vi) The process of sealing the container. Includes; This method is acceptable even if the order of steps (ii) and (iii) is reversed.

[0555] It is understood that during the drying step (v) of the mixture, the bulking agent may become a lioproctant.

[0556] In certain embodiments, steps (ii) and (iii) are not reversed.

[0557] In certain embodiments, the CNP conjugate in step (i) is mixed with a buffer and an extender.

[0558] The number of doses transferred into the container in step (iv) may be at least 1, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30, or may be greater than 30.

[0559] In a particular embodiment, the method for producing a dried pharmaceutical preparation according to the present invention is (i) Mix the CNP conjugate with at least succinic acid and trehalose dihydrate, CNP conjugate: 0.9-82.1 mg / mL Succinic acid: 1.3-57.6 mM Trehalose dihydrate: 67-111.6 mg / mL A process to obtain a formulation containing; (ii) A step of adjusting the pH of the mixture from step (i) to a pH in the range of pH 4.0 to pH 6.0; (iii) Optionally, a step of filtering the mixture from step (ii); (iv) A step of transferring an amount of the mixture from step (ii) or (iii) into a container that corresponds to the desired number of doses; (v) A step of drying the mixture; (vi) The process of sealing the container. Includes; The order of steps (ii) and (iii) may be reversed.

[0560] In certain embodiments, steps (ii) and (iii) are not reversed.

[0561] In a particular embodiment, in step (ii), the pH of the mixture from step (i) is adjusted by Tris.

[0562] In a particular embodiment, the CNP conjugate in step (i) is mixed with succinic acid and trehalose dihydrate, CNP conjugate: 0.9-82.1 mg / mL Succinic acid: 1.3~57.6 mM Trehalose dihydrate: 67-111.6 mg / mL Obtain a formulation containing the above.

[0563] In a particular embodiment, the formulation in step (i) is CNP conjugate: 19.8-73.6 mg / mL Succinic acid: 1.7~50 mM Trehalose dihydrate: 63-100 mg / mL Includes, In step (ii), the pH is adjusted to a pH within the range of pH 4.0 to pH 6.0.

[0564] In a particular embodiment, the formulation in step (i) is CNP conjugate: 19.8-73.6 mg / mL Succinic acid: 1.7~50 mM Trehalose dihydrate: 56-100 mg / mL Includes, In step (ii), the pH is adjusted to a pH within the range of pH 4.0 to pH 6.0.

[0565] In a particular embodiment, the formulation in step (i) is CNP conjugate: 4.2-16.5 mg / mL Succinic acid: 1.7~36.4 mM Trehalose dihydrate: 67-105 mg / mL Includes, In step (ii), the pH is adjusted to a pH within the range of pH 4.0 to pH 6.0.

[0566] In a particular embodiment, the formulation in step (i) is CNP conjugate: 1.0-4.4 mg / mL Succinic acid: 1.7-33 mM Trehalose dihydrate: 67-105 mg / mL Includes, In step (ii), the pH is adjusted to a pH within the range of pH 4.0 to pH 6.0.

[0567] In a particular embodiment, the formulation in step (i) is CNP conjugate: 27.5-50.5 mg / mL Succinic acid: 5.1~20.3 mM Trehalose dihydrate: 67-95 mg / mL Includes, In step (ii), the pH is adjusted to a pH within the range of pH 4.0 to pH 6.0.

[0568] In a particular embodiment, the formulation in step (i) is CNP conjugate: 5.8-10.8 mg / mL Succinic acid: 5.1~20.3 mM Trehalose dihydrate: 72-105 mg / mL Includes, In step (ii), the pH is adjusted to a pH within the range of pH 4.0 to pH 6.0.

[0569] In a particular embodiment, the formulation in step (i) is CNP conjugate: 1.5-2.9 mg / mL Succinic acid: 5.1~20.3 mM Trehalose dihydrate: 73-105 mg / mL Includes, In step (ii), the pH is adjusted to a pH within the range of pH 4.0 to pH 6.0.

[0570] In a particular embodiment, the formulation in step (i) is CNP conjugate: 37.4-42.9 mg / mL Succinic acid: 9.3~10.2 mM Trehalose dihydrate: 71-87 mg / mL Includes, In step (ii), the pH is adjusted to a pH in the range of pH 4.5 to pH 5.5.

[0571] In a particular embodiment, the formulation in step (i) is CNP conjugate: 7.5-9.1 mg / mL Succinic acid: 9.3-11 mM Trehalose dihydrate: 75-97 mg / mL Includes, In step (ii), the pH is adjusted to a pH in the range of pH 4.5 to pH 5.5.

[0572] In a particular embodiment, the formulation in step (i) is CNP conjugate: 1.9-2.4 mg / mL Succinic acid: 9.3-11 mM Trehalose dihydrate: 77-97 mg / mL Includes, In step (ii), the pH is adjusted to a pH in the range of pH 4.5 to pH 5.5.

[0573] In a particular embodiment, the formulation in step (i) comprises about 60.4 mg / mL CNP conjugate, about 10 mM succinic acid, and about 70 mg / mL trehalose dihydrate, and in step (ii), the pH is adjusted to pH 5.

[0574] In a particular embodiment, the formulation in step (i) comprises 60.4 mg / mL CNP conjugate, 10 mM succinic acid, and 70 mg / mL trehalose dihydrate, and in step (ii), the pH is adjusted to pH 5.

[0575] In a particular embodiment, the formulation in step (i) comprises approximately 39.6 mg / mL CNP conjugate, approximately 10 mM succinic acid, and approximately 79.0 mg / mL trehalose dihydrate, and in step (ii), the pH is adjusted to pH 5.

[0576] In a particular embodiment, the formulation in step (i) comprises 40 mg / mL CNP conjugate, 10 mM succinic acid, and 79 mg / mL trehalose dihydrate, and in step (ii), the pH is adjusted to pH 5.

[0577] In a particular embodiment, the formulation in step (i) comprises 39.6 mg / mL CNP conjugate, 10 mM succinic acid, and 79.0 mg / mL trehalose dihydrate, and in step (ii), the pH is adjusted to pH 5.

[0578] In a particular embodiment, the formulation in step (i) comprises about 8.2 mg / mL CNP conjugate, about 10 mM succinic acid, and about 89.0 mg / mL trehalose dihydrate, and in step (ii), the pH is adjusted to pH 5.

[0579] In a particular embodiment, the formulation in step (i) comprises 8 mg / mL CNP conjugate, 10 mM succinic acid, and 89 mg / mL trehalose dihydrate, and in step (ii), the pH is adjusted to pH 5.

[0580] In a particular embodiment, the formulation in step (i) comprises 8.2 mg / mL CNP conjugate, 10 mM succinic acid, and 89.0 mg / mL trehalose dihydrate, and in step (ii), the pH is adjusted to pH 5.

[0581] In a particular embodiment, the formulation in step (i) comprises about 2.2 mg / mL CNP conjugate, about 10 mM succinic acid, and about 89.5 mg / mL trehalose dihydrate, and in step (ii), the pH is adjusted to pH 5.

[0582] In a particular embodiment, the formulation in step (i) comprises 2 mg / mL CNP conjugate, 10 mM succinic acid, and 90 mg / mL trehalose dihydrate, and in step (ii), the pH is adjusted to pH 5.

[0583] In a particular embodiment, the formulation in step (i) comprises 2.2 mg / mL CNP conjugate, 10 mM succinic acid, and 89.5 mg / mL trehalose dihydrate, and in step (ii), the pH is adjusted to pH 5.

[0584] Before administering the dried pharmaceutical formulation of the present invention to a patient requiring administration, the dried pharmaceutical formulation is regenerated (reconstituted). Regeneration of the dried pharmaceutical formulation into a reconstituted formulation is performed by adding a predetermined amount of regeneration solution to the dried pharmaceutical formulation. Therefore, a further aspect of the present invention is a method for regenerating the dried pharmaceutical formulation of the present invention, (a) A method comprising the step of contacting the dried pharmaceutical formulation of the present invention with a regeneration solution.

[0585] Another aspect of the present invention is a regenerated pharmaceutical formulation that can be obtained from the method for regenerating a dried pharmaceutical formulation of the present invention.

[0586] It should be understood that the volume-increasing agent for the dry pharmaceutical formulation of the present invention performs its volume-increasing function only in the dry pharmaceutical formulation; that is, it does not exhibit this function in the regenerated pharmaceutical formulation, and when the dry pharmaceutical formulation is regenerated, the volume-increasing agent functions as an isotonic agent.

[0587] Regeneration can be carried out in a container in which the dry pharmaceutical formulation containing CNP conjugate is provided, such as a vial; a syringe, such as a two-chamber syringe; an ampoule; a cartridge, such as a two-chamber cartridge; or the dry pharmaceutical formulation can be transferred to a different container and then regenerated.

[0588] In certain embodiments, the container used for regenerating the dried pharmaceutical preparation is a vial.

[0589] In certain embodiments, the container for regenerating the dried pharmaceutical preparation is a syringe. In certain embodiments, the container for regenerating the dried pharmaceutical preparation is a two-chamber syringe. In certain embodiments, the container for regenerating the dried pharmaceutical preparation is a cartridge. In certain embodiments, the container for regenerating the dried pharmaceutical preparation is a two-chamber cartridge.

[0590] In certain embodiments, the dried pharmaceutical formulation according to the present invention is supplied in the first chamber of a two-chamber syringe, and the regenerated solution is supplied in the second chamber of the two-chamber syringe.

[0591] In certain embodiments, the dried pharmaceutical formulation according to the present invention is provided in a first chamber of a two-chamber cartridge, and the regenerated solution is provided in a second chamber of the two-chamber cartridge.

[0592] Another aspect of the present invention refers to a container containing the dried pharmaceutical formulation or regenerated formulation of the present invention.

[0593] The regeneration time of the dry pharmaceutical formulation was found to be suitable for the treatment setting. In certain embodiments, the regeneration time of the dry pharmaceutical formulation is extended by adding a surfactant, such as polysorbate 20 or polysorbate 80, to the formulation containing CNP conjugate. Therefore, in certain embodiments, the dry pharmaceutical formulation according to the present invention does not contain a surfactant, such as polysorbate 20 or polysorbate 80.

[0594] The regeneration solution is a sterile liquid, such as water or a buffer solution, and may contain further additives, such as preservatives and / or antimicrobial agents.

[0595] In certain embodiments, the regeneration solution comprises one or more preservatives and / or antimicrobial agents and / or antioxidants.

[0596] In certain embodiments, the regeneration solution contains one or more preservatives.

[0597] The preservative can be selected from the group consisting of m-cresol, benzoic acid, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, potassium sorbate, chlorobutanol, benzyl alcohol, phenylmercury nitrate, thimerosal, sorbic acid, potassium sorbate, chlorocresol, benzalkonium chloride, 2-ethoxyethanol, chlorhexidine, chlorobutanol, phenylethyl alcohol, phenylmercury acetate, and mixtures thereof.

[0598] In certain embodiments, the preservative is m-cresol. In certain embodiments, the preservative is benzyl alcohol. In certain embodiments, the preservative is benzoic acid. In certain embodiments, the preservative is phenol. In certain embodiments, the preservative is methylparaben. In certain embodiments, the preservative is ethylparaben. In certain embodiments, the preservative is propylparaben. In certain embodiments, the preservative is butylparaben. In certain embodiments, the preservative is potassium sorbate. In certain embodiments, the preservative is benzyl alcohol. In certain embodiments, the preservative is phenylmercury nitrate. In certain embodiments, the preservative is thimerosal. In certain embodiments, the preservative is sorbic acid. In certain embodiments, the preservative is potassium sorbate. In certain embodiments, the preservative is chlorocresol. In certain embodiments, the preservative is benzalkonium chloride. In certain embodiments, the preservative is 2-ethoxyethanol. In certain embodiments, the preservative is chlorhexidine. In certain embodiments, the preservative is chlorobutanol. In certain embodiments, the preservative is phenylethyl alcohol. In certain embodiments, the preservative is phenylmercury acetate.

[0599] In certain embodiments, the preservative has a concentration in the range of 1 to 10 mg / mL. In certain embodiments, the preservative has a concentration in the range of 1.5 to 3.5 mg / mL. In certain embodiments, the preservative has a concentration in the range of 2 to 3 mg / mL.

[0600] The antioxidant can be selected from the group consisting of methionine, butylhydroxytoluene, butylhydroxyanisole, tocopherol, propyl gallate, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), poly(ethyleneimine), vitamin E, and mixtures thereof.

[0601] In certain embodiments, the preservative is methionine. In certain embodiments, the preservative is butylhydroxytoluene. In certain embodiments, the preservative is butylhydroxyanisole. In certain embodiments, the preservative is tocopherol. In certain embodiments, the preservative is propyl gallate. In certain embodiments, the preservative is ethylenediaminetetraacetic acid. In certain embodiments, the preservative is poly(ethyleneimine). In certain embodiments, the preservative is vitamin E.

[0602] As defined herein, the term "methionine" encompasses both D-methionine and L-methionine, as well as mixtures thereof. In certain embodiments, the term "methionine" refers to L-methionine. In certain embodiments, the term "methionine" refers to D-methionine. In certain embodiments, the term "methionine" refers to a mixture of D-methionine or L-methionine. In certain embodiments, the term "methionine" refers to L-methionine hydrochloride.

[0603] Where defined herein, the term "EDTA" encompasses all types of EDTA known in the art, such as EDTA salts, metal salts, disodium EDTA, potassium EDTA, calcium EDTA, magnesium EDTA, or mixtures thereof. In certain embodiments, EDTA refers to disodium EDTA. In certain embodiments, the term "EDTA" refers to calcium EDTA. In certain embodiments, the term "EDTA" refers to anhydrous EDTA.

[0604] In certain embodiments, the molar ratio of the antioxidant to the CNP portion is approximately 0.1:1 to approximately 100:1. In certain embodiments, the molar ratio of the antioxidant to the CNP portion is approximately 0.1:1 to approximately 70:1. In certain embodiments, the molar ratio of the antioxidant to the CNP portion is approximately 0.1:1 to approximately 15:1. In certain embodiments, the molar ratio of the antioxidant to the CNP portion is approximately 1:1 to approximately 10:1. In certain embodiments, the molar ratio of the antioxidant to the CNP portion is approximately 3:1 to approximately 7:1.

[0605] In certain embodiments, the regeneration solution does not contain an antibacterial agent.

[0606] In certain embodiments, the regeneration solution contains an antimicrobial agent.

[0607] In certain embodiments, the regeneration solution comprises one or more excipients.

[0608] In certain embodiments, the regeneration solution is sterile water.

[0609] In certain embodiments, the regeneration solution is sterile water containing 0.7-1.1% benzyl alcohol.

[0610] In certain embodiments, the regeneration solution is sterile water containing 0.9% benzyl alcohol.

[0611] In certain embodiments, the regeneration solution includes a pH adjuster.

[0612] As used herein, the term "pH adjuster" refers to a compound used to adjust the pH of a regeneration solution.

[0613] In certain embodiments, the pH adjuster may be an acid or an acidic salt thereof. The acid may be selected from the group consisting of acetic acid, citric acid, succinic acid, hydrochloric acid, phosphoric acid, carbonic acid, nitric acid, and mixtures thereof.

[0614] In certain embodiments, the pH adjuster may be a base or a basic salt thereof. The base may be selected from the group consisting of Tris (tris(hydroxymethyl)aminomethane), sodium hydroxide, potassium hydroxide, lysine, and mixtures thereof.

[0615] After regeneration, the single-dose formulation containing the CNP conjugate has a volume of 4 mL or less, for example, about 0.03 to about 1.1 mL. In certain embodiments, the volume is about 0.03 mL. In certain embodiments, the volume is about 0.05 mL. In certain embodiments, the volume is about 0.1 mL. In certain embodiments, the volume is about 0.3 mL. In certain embodiments, the volume is about 0.8 mL. In certain embodiments, the volume is about 1 mL. In certain embodiments, the volume is about 2 mL. In certain embodiments, the volume is about 3 mL. In certain embodiments, the volume is about 4 mL.

[0616] In certain embodiments, the CNP conjugate is administered in the formulation in an amount sufficient to provide a therapeutically effective amount of CNP over a period of at least 3 days, e.g., at least 4 days, e.g., at least 5 days, e.g., at least 6 days, in a single dose.

[0617] In certain embodiments, the CNP conjugate is administered in the formulation in an amount sufficient to provide a therapeutically effective amount of CNP over a week.

[0618] The buffer maintains the pH of the regenerated formulation within a desired range. In certain embodiments, the pH of the regenerated formulation is 6 or less because reversible linkage within the CNP conjugate may not be stable under basic conditions.

[0619] In certain embodiments, the pH of the regenerated formulation is approximately pH 4 to approximately pH 6. In certain embodiments, the pH of the regenerated formulation is approximately pH 4.5 to approximately pH 5.5. In certain embodiments, the pH of the regenerated formulation is approximately 5. In certain embodiments, the pH of the regenerated formulation is 5.

[0620] In certain embodiments, the buffer has a concentration in the regenerated formulation ranging from 1.3 to 57.6 mM. In certain embodiments, the buffer has a concentration in the regenerated formulation ranging from 1.7 to 33 mM. In certain embodiments, the buffer has a concentration in the regenerated formulation ranging from 5.1 to 20.3 mM. In certain embodiments, the buffer has a concentration of approximately 10 mM in the regenerated formulation.

[0621] In certain embodiments, the regenerated formulation is CNP conjugate: 0.9-82.1 mg / mL Succinic acid: 1.3-57.6 mM Trehalose dihydrate: 67-111.6 mg / mL Includes, It has a pH in the range of pH 4.0 to pH 6.0.

[0622] The regenerated formulation is also available in different intensities, i.e., different concentrations, such as high, medium, and low intensities, of the CNP conjugate. Accordingly, another aspect of the present invention is that the regenerated formulation of the present invention is provided in different concentrations of the CNP conjugate, for example, 2 different concentrations, 3 different concentrations, 4 different concentrations, 5 different concentrations, 6 different concentrations, 7 different concentrations, 8 different concentrations, 9 different concentrations, 10 different concentrations, 11 different concentrations, and 12 different concentrations.

[0623] Those skilled in the art will recognize that there may be rounding errors in the concentrations of elements contained in the regenerated formulation of the present invention; that is, when starting from a particular dried formulation, the composition of the corresponding regenerated formulation may vary to some extent for the necessary rounding.

[0624] In certain embodiments, the regenerated formulation is CNP conjugate: 19.8-73.6 mg / mL Succinic acid: 1.7~50 mM Trehalose dihydrate: 63-100 mg / mL It contains [specific ingredient] and has a pH in the range of pH 4.0 to pH 6.0.

[0625] In certain embodiments, the regenerated formulation is CNP conjugate: 4.2-16.5 mg / mL Succinic acid: 1.7~36.4 mM Trehalose dihydrate: 67-105 mg / mL It contains [specific ingredient] and has a pH in the range of pH 4.0 to pH 6.0.

[0626] In certain embodiments, the regenerated formulation is CNP conjugate: 1.0-4.4 mg / mL Succinic acid: 1.7~33 mM Trehalose dihydrate: 67-105 mg / mL It contains [specific ingredient] and has a pH in the range of pH 4.0 to pH 6.0.

[0627] In certain embodiments, the regenerated formulation is CNP conjugate: 27.5-50.5 mg / mL Succinic acid: 5.1~20.3 mM Trehalose dihydrate: 67-95 mg / mL It contains [specific ingredient] and has a pH in the range of pH 4.0 to pH 6.0.

[0628] In certain embodiments, the regenerated formulation is CNP conjugate: 5.8-10.8 mg / mL Succinic acid: 5.1~20.3 mM Trehalose dihydrate: 72-105 mg / mL It contains [specific ingredient] and has a pH in the range of pH 4.0 to pH 6.0.

[0629] In certain embodiments, the regenerated formulation is CNP conjugate: 1.5-2.9 mg / mL Succinic acid: 5.1~20.3 mM Trehalose dihydrate: 73-105 mg / mL It contains [specific ingredient] and has a pH in the range of pH 4.0 to pH 6.0.

[0630] In certain embodiments, the regenerated formulation is CNP conjugate: 37.4-42.9 mg / mL Succinic acid: 9.3~10.2 mM Trehalose dihydrate: 71-87 mg / mL It contains [specific ingredients] and has a pH in the range of pH 4.5 to pH 5.5.

[0631] In certain embodiments, the regenerated formulation is CNP conjugate: 7.5-9.1 mg / mL Succinic acid: 9.3-11 mM Trehalose dihydrate: 75-97 mg / mL It contains [specific ingredients] and has a pH in the range of pH 4.5 to pH 5.5.

[0632] In certain embodiments, the regenerated formulation is CNP conjugate: 1.9-2.4 mg / mL Succinic acid: 9.3-11 mM Trehalose dihydrate: 77-97 mg / mL It contains [specific ingredients] and has a pH in the range of pH 4.5 to pH 5.5.

[0633] In certain embodiments, the regenerated formulation contains approximately 60.4 mg / mL CNP conjugate, approximately 10 mM succinic acid, and approximately 70 mg / mL trehalose dihydrate, and has a pH of 5.

[0634] In a particular embodiment, the regenerated formulation contains 60.4 mg / mL CNP conjugate, 10 mM succinic acid, and 70 mg / mL trehalose dihydrate, and has a pH of 5.

[0635] In certain embodiments, the regenerated formulation contains approximately 60.4 mg / mL CNP conjugate, approximately 10 mM succinic acid, and approximately 56 mg / mL trehalose dihydrate, and has a pH of 5.

[0636] In a particular embodiment, the regenerated formulation contains 60.4 mg / mL CNP conjugate, 10 mM succinic acid, and 56 mg / mL trehalose dihydrate, and has a pH of 5.

[0637] In certain embodiments, the regenerated formulation contains approximately 39.6 mg / mL CNP conjugate, approximately 10 mM succinic acid, and approximately 79.0 mg / mL trehalose dihydrate, and has a pH of 5.

[0638] In certain embodiments, the regenerated formulation contains 40 mg / mL CNP conjugate, 10 mM succinic acid, and 79 mg / mL trehalose dihydrate, and has a pH of 5.

[0639] In a particular embodiment, the regenerated formulation contains 39.6 mg / mL CNP conjugate, 10 mM succinic acid, and 79.0 mg / mL trehalose dihydrate, and has a pH of 5.

[0640] In certain embodiments, the regenerated formulation contains approximately 8.2 mg / mL CNP conjugate, approximately 10 mM succinic acid, and approximately 89.0 mg / mL trehalose dihydrate, and has a pH of 5.

[0641] In certain embodiments, the regenerated formulation contains 8 mg / mL CNP conjugate, about 10 mM succinic acid, and 89 mg / mL trehalose dihydrate, and has a pH of 5.

[0642] In a particular embodiment, the regenerated formulation contains 8.2 mg / mL CNP conjugate, 10 mM succinic acid, and 89.0 mg / mL trehalose dihydrate, and has a pH of 5.

[0643] In certain embodiments, the regenerated formulation contains approximately 2.2 mg / mL CNP conjugate, approximately 10 mM succinic acid, and approximately 89.5 mg / mL trehalose dihydrate, and has a pH of 5.

[0644] In a particular embodiment, the regenerated formulation contains 2 mg / mL CNP conjugate, 10 mM succinic acid, and 90 mg / mL trehalose dihydrate, and has a pH of 5.

[0645] In a particular embodiment, the regenerated formulation contains 2.2 mg / mL CNP conjugate, 10 mM succinic acid, and 89.5 mg / mL trehalose dihydrate, and has a pH of 5.

[0646] The regenerative formulation can be administered by injection, infusion, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, and intraperitoneal.

[0647] In certain embodiments, the regenerative formulation containing the CNP conjugate is administered by subcutaneous injection.

[0648] In certain embodiments, the regenerated formulation containing the CNP conjugate is administered by subcutaneous injection using a syringe, needle, pen injector, or autoinjector.

[0649] In certain embodiments, the regenerated formulation containing the CNP conjugate is administered by subcutaneous injection using a syringe.

[0650] In certain embodiments, the regenerated formulation containing CNP conjugate is administered by subcutaneous injection using a pen syringe.

[0651] In certain embodiments, the regenerated formulation containing the CNP conjugate is administered by subcutaneous injection using an auto-injector.

[0652] Another aspect of the present invention is a dried or regenerated pharmaceutical preparation of the present invention, used as a pharmaceutical.

[0653] In another embodiment, the present invention relates to a dried or regenerative pharmaceutical formulation used for the treatment, treatment, treatment, treatment or prevention of one or more diseases treatable, treatment, treatment, treatment or prevention by CNP.

[0654] In certain embodiments, the present invention relates to a dried or regenerative pharmaceutical preparation used for the treatment of one or more diseases treatable by CNP.

[0655] A further aspect of the present invention is a method for treating, suppressing, delaying or preventing one or more diseases treatable by CNP in a patient, comprising administering to the patient a therapeutically effective amount of the regenerative medicine formulation of the present invention.

[0656] In certain embodiments, the patient is an adult. In certain embodiments, the patient is a pediatric patient.

[0657] In a particular embodiment, the one or more diseases that can be treated, suppressed, delayed, or prevented by CNP are selected from the group consisting of bone-related disorders, such as skeletal malformations; cancer; autoimmune diseases; fibrosis; inflammatory diseases; central nervous system diseases, such as neurodegenerative diseases; infectious diseases; lung diseases; cardiovascular diseases; metabolic diseases; and eye diseases.

[0658] In certain embodiments, the one or more diseases that can be treated, suppressed, delayed, or prevented by CNP include chondrodysplasia, hypochondrodysplasia, short stature, dwarfism, osteochondrodysplasia, fatal osteodysplasia, osteogenesis imperfecta, chondrodysplasia punctata, homozygous chondrodysplasia, flexor limb dysplasia, congenital fatal hypophosphatasia, perinatal fatal osteogenesis imperfecta, short-rib polydactyly syndrome, rhomboid chondrodysplasia punctata, Janssen type metaphyseal dysplasia, congenital spondyloepophysitis, osteogenesis imperfecta, torsional osteogenesis imperfecta, congenital femoral shortening, Langer type intermediate limb dysplasia, Nibelgeld type intermediate limb dysplasia, Robinow syndrome, Reinhardt syndrome, acroosteogenesis imperfecta, peripheral osteogenesis imperfecta Insufficiency, Kneist's dysplasia, fibrous chondrodysplasia, Roberts syndrome, distal intermediate limb dysplasia, microlimia, Morquio syndrome, Kneist syndrome, degenerative dysplasia, vertebral epiphyseal metaphysical dysplasia, neurofibromatosis, Regius syndrome, Leopard syndrome, Noonan syndrome, hereditary gingival fibromatosis, neurofibromatosis type 1, Regius syndrome, cardiac-facial-cutaneous syndrome, Costello syndrome, SHOX deficiency, idiopathic short stature, growth hormone deficiency, osteoarthritis, cleidocranial dysplasia, craniosynostosis (e.g., Muenke syndrome, Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome, or Crouzon dermoskeletal syndrome) Syndrome)), dactyly, brachydactyly, polydactyly, syndactyly, dysphagia, enchondromatosis, fibrous dysplasia, hereditary multiple exostosis, hypophosphatemic rickets, Jaffe-Lichtenstein syndrome, Marfan syndrome, McCune-Albright syndrome, osteopetrosis, osteomatosis, hemorrhagic shock, hypertension, restenosis, arteriosclerosis, acute decompensated heart failure, congestive heart failure, cardiac edema, renal edema, hepatic edema, acute renal failure, chronic renal failure, glaucoma, ocular hypertension, multiple myeloma, myeloproliferative syndrome, leukemia, plasma cell leukemia, lymphoma, gliablastoma, prostate cancer, bladder cancer, breast cancer, growth retardation, cranial deformity, orthodontic defects The following conditions are selected from the group consisting of defects, cervical spinal cord compression, spinal cord stenosis, hydrocephalus, hearing loss due to chronic otitis, cardiovascular disease, neurological disease, and obesity.

[0659] In certain embodiments, the one or more diseases that can be treated, suppressed, delayed, or prevented by CNP are chondrodysplasia, e.g., homozygous chondrodysplasia, hypochondrodysplasia, short stature, dwarfism, osteochondrodysplasia, fatal osteodysplasia, osteogenesis imperfecta, chondrodysplasia punctata, flexor limb dysplasia, congenital fatal hypophosphatasia, perinatal fatal osteodysplasia, short-rib polydactyly, rhomboid chondrodysplasia punctata (proximal limb shortening chondrodysplasia punctata), Janssen metaphyseal dysplasia, congenital spondyloepophysitis, osteodysplasia, torsional dysplasia, congenital femoral shortening, Langer intermediate limb dysplasia, Nibelgeld intermediate limb dysplasia, Robinow syndrome, Reinhardt syndrome, and apicophyte Dysplasia, peripheral osteogenesis imperfecta, Kneist's dysplasia, fibrous chondrodysplasia, Roberts syndrome, distal intermediate limb dysplasia, microlimia, Morquio syndrome, Kneist's syndrome, degenerative dysplasia, vertebral epiphyseal metaphysical dysplasia, neurofibromatosis, Regius syndrome, Leopard syndrome, Noonan syndrome, hereditary gingival fibromatosis, neurofibromatosis type 1, Regius syndrome, cardiac-facial-cutaneous syndrome, Costello syndrome, SHOX deficiency, idiopathic short stature, growth hormone deficiency, osteoarthritis, cleidocranial dysplasia, craniosynostosis (e.g., Muenke syndrome, Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome, or Crouzon dermoskeletal syndrome) Syndrome)), dactyly, brachydactyly, polydactyly, syndactyly, dysphagia, enchondromatosis, fibrous dysplasia, hereditary multiple exostosis, hypophosphatemic rickets, Jaffe-Lichtenstein syndrome, Marfan syndrome, McCune-Albright syndrome, osteopetrosis, osteomatosis, hemorrhagic shock, hypertension, restenosis, arteriosclerosis, acute decompensated heart failure, congestive heart failure, cardiac edema, renal edema, hepatic edema, acute renal failure, chronic renal failure, glaucoma, ocular hypertension, multiple myeloma, myeloproliferative syndrome, leukemia, plasma cell leukemia, lymphoma, gliablastoma, prostate cancer, bladder cancer, breast cancer, growth retardation, cranial deformity, orthodontic defectsThe following are selected from the group consisting of defects, cervical spinal cord compression, spinal cord stenosis, hydrocephalus, hearing loss due to chronic otitis, obesity, disorders involving abnormal RAS-mitogen-activated protein kinase signaling, pulmonary hypertension, vascular disorders, endothelial dysfunction, cirrhosis, hepatic ascites, hepatic fibrosis, hepatorenal syndrome, asthma, pulmonary fibrosis, chronic kidney disease, cardiorenal syndrome, dyspnea, and lysosomal storage disorders, such as mucopolysaccharidosis.

[0660] In a particular embodiment, the one or more diseases that can be treated, suppressed, delayed, or prevented by CNP include arrhythmias, such as cardiac arrhythmias or sinus arrhythmias; atrial fibrillation; atrial flutter; bradycardia; Brugada syndrome; premature contractions; commotio cordis; heart block; QT prolongation syndrome; paraconjunctival contractions; premature excitation syndrome; tachycardia; ventricular fibrillation; ventricular flutter; cardiac conduction disorders; low cardiac output; cardiac hypertrophy; dilated cardiomyopathy; hypertrophy such as left ventricular hypertrophy or right ventricular hypertrophy; cardiomyopathy such as alcoholic, dilated, hypertrophic, restrictive, diabetic, or Chagas cardiomyopathy; arrhythmogenic right ventricular dysplasia; endocardial fibroelastosis; endocardial myocardial fibrosis; glycogen storage disease type IIb; Kearns-Sayre syndrome; myocardial reperfusion injury; myocarditis; sarcoglycan disorders; endocarditis such as bacterial or non-infectious endocarditis; cardiac arrest; sudden Cardiac death; out-of-hospital cardiac arrest; cardiorenal syndrome; paroxysmal dyspnea; heart failure such as cardiac edema, diastolic or systolic heart failure; valvular heart disease; aortic regurgitation; aortic stenosis; valve prolapse; mitral regurgitation; mitral stenosis; pulmonary atresia; pulmonary valve regurgitation; pulmonary stenosis; tricuspid atresia; tricuspid regurgitation; tricuspid stenosis; myocardial ischemia; acute coronary syndrome; angina pectoris; coronary artery disease; Cornis syndrome; myocardial infarction; pulmonal heart disease; ventricular dysfunction such as left or right ventricular dysfunction; ventricular outflow tract obstruction; aortic stenosis, pulmonary stenosis; hypertension; atherosclerosis; restenosis; severe lower limb ischemia; peripheral artery disease; ischemia such as ischemia-reperfusion injury or ischemic injury; cardiac edema and abnormal fluid retention in myocardial edema.

[0661] In a particular embodiment, the one or more diseases that can be treated, suppressed, delayed, or prevented by CNP are selected from the group consisting of ischemic heart diseases such as myocardial infarction; congestive heart failure; arrhythmias and atherosclerosis.

[0662] In a particular embodiment, the one or more diseases that can be treated, suppressed, delayed, or prevented by CNP are one or more central nervous system diseases selected from the group consisting of: cerebral ischemia such as ischemic hypoxia; cerebral infarction; transient ischemic attack; vertebrobasilar insufficiency; cerebrovascular disease; stroke; intracranial hemorrhage; corneal neovascularization; corneal transplantation; graft-versus-host disease; graft rejection; glaucoma such as closed-angle, neovascular, open-angle, or low-tension glaucoma; ischemic optic neuropathy; central serous chorioretinopathy; retinopathy such as diabetic or hypertensive retinopathy; retinal degeneration; macular degeneration; geographical atrophy; macular edema; Stargardt disease; vitreomacular dystrophy; exudative macular degeneration; retinal schizophrenia; retinal detachment; retinal perforation; retinal hemorrhage; retinal neovascularization; retinal vein occlusion; retinal artery occlusion; retinopathy of prematurity; and proliferative vitreoretinopathy.

[0663] In a particular embodiment, the one or more diseases are selected from the group consisting of hypophosphatasia, achondroplasia, Muenke syndrome, hypertension, osteogenesis imperfecta, and achondroplasia.

[0664] In a particular embodiment, the one or more diseases treatable by the CNP invention is hypophosphatasia. In a particular embodiment, the one or more diseases treatable by CNP is achondroplasia. In a particular embodiment, the one or more diseases treatable by CNP is Muenke syndrome. In a particular embodiment, the one or more diseases treatable by CNP is hypertension. In a particular embodiment, the one or more diseases treatable by CNP is osteogenesis imperfecta. In a particular embodiment, the one or more diseases treatable by CNP is achondroplasia. [Examples]

[0665] Materials and methods Unless otherwise stated, all materials used were commercially available.

[0666] The content and purity of compound (1) were determined using RP-HPLC, and free CNP-38 was detected. Mobile phase A consisted of a 0.05% TFA aqueous solution, and mobile phase B consisted of a 0.04% TFA / acetonitrile solution. A Waters Acquity CSH C18, 130 Å, 1.7 μm, 2.1 × 100 mm column was used. The flow rate was set to 0.3 mL / min, detection was performed at a wavelength of 215 nm, and the column operating temperature was 60 °C (±1 °C). The sample was diluted with a formulation buffer containing 0.5% Tween®-20. The content was determined by comparing the peak area with that of the reference solution.

[0667] The purity of compound (1) was determined using SE-HPLC. The mobile phase was an aqueous solution consisting of 15 mM sodium phosphate, pH 7.40, 135 mM sodium chloride, and 0.2% Pluronic F-68. A GE Superdex 200 Increase 10 / 300 GL column was used. The flow rate was set to 0.75 mL / min, detection was performed at a wavelength of 215 nm, and the column operating temperature was room temperature. The sample was diluted with a formulation buffer containing 0.05% Pluronic F-68.

[0668] Peptide mapping of compound (1) was used to evaluate the conversion of aspartate (28) to isoaspartate (28) and the oxidation of methionine (33) to methionine oxide (33) (Met(O)). Thermolysine digestion of (1) was carried out at 37°C for 7 hours at pH 7.5 with a thermolysine / CNP-38 ratio of 1:20 (by weight). The resulting peptide mixture was separated by RP-HPLC using a Waters Acquity UPLCHSST3, 100 Å, 1.8 μm, 2.1 × 150 mm column with a mobile phase of 0.10 vol% TFA aqueous solution as mobile phase A and a mobile phase of 0.09% TFA / acetonitrile as mobile phase B, and detected at 210 nm. The flow rate was set to 0.28 mL / min and the column operating temperature was 45°C (±1°C). Thermolysin fragments containing aspartate (28) and methionine (33) were characterized via LC-MS. In the usual analysis, the fragments were compared to a reference mixture containing these fragment peptides. The fragments were quantified as relative values ​​based on their individual peak areas relative to the peak area of ​​the corresponding unmodified fragment. Under thermolysin digestion and subsequent RP-HPLC conditions, the formation of the isoaspartate product of aspartate (28) and the oxidation of methionine (33) could be quantified for (1).

[0669] The biological activity analysis was performed by in vitro release of CNP-38 from (1) and subsequent analysis of the biological activity of the released CNP-38 in cell assays.

[0670] In vitro release of CNP-38 from (1) and RP-HPLC quantification: (1) was incubated at pH 10.0 and 15°C for 24 hours. The pH was adjusted by a 1:3.5 (volume ratio) dilution with the release buffer of the regenerated formulation (0.5 M boric acid, 10 mM methionine, 2.383 g / L Pluronic F-68; pH adjusted to 10.0 using 4 M NaOH aqueous solution) (for example, 50 μL of the 3.6 mg CNP-38 equivalent / mL solution of (1) was diluted with 175 μL of the release buffer). After incubation, release was stopped by a 1:1 (volume ratio) dilution with 5% (volume ratio) acetic acid. The amount of released CNP-38 was determined by comparing the peak area to a CNP-38 reference solution with a known content.

[0671] Measurement of the biological activity of CNP-38 released by functional cGMP stimulation in HEK293 cells: An NPR-B overexpressing Hek293 cell line was constructed as follows. The coding region of the NPR-B reference sequence was cloned into a lentiviral vector under the CMV promoter for constitutive receptor expression. A bicistronic element located on the vector for puromycin resistance was used as a eukaryotic cell selection marker. After transduction, qRT-PCR was performed to confirm the receptor mRNA of a stably proliferating cell pool compared with that of parental Hek293 cells. Stimulation of the NPR-B receptor with CNP-38 induces intracellular production of secondary messenger cGMP, which can be detected by a commercially available cGMP assay.

[0672] Cells were cultured by conventional methods in DMEM / Glutamax / HEPES medium containing 10% FBS and 1% puromycin solution (370 μg / mL) at 37°C and 5% CO2. For each assay, cells were suspended in DMEM + 2% BSA and incubated at 37°C and 5% CO2 for 3 hours. Serial dilutions of the release CNP mixture stimulating buffer (DMEM + 2% BSA + 0.1 mM IBMX + 0.1% Tween®-20) were prepared and added to the cells (further diluted 1:2 with CNP-38 serial dilutions). After incubation at 37°C and 5% CO2 for 60 minutes, the cells were lysed and cGMP levels were determined using a commercially available cGMPTR-FRET assay (Cisbio, cGMP kit, catalog no. 62GM2PEB). The efficacy was determined by fitting a 4-parameter logistic curve in PLA software, validated by parallel line analysis, compared to the CNP-38 standard curve.

[0673] The amount of degraded CNP-38 (deimidized and aspartimide variants) was determined using RP-HPLC. Mobile phase A consisted of a 0.05% TFA aqueous solution, and mobile phase B consisted of a 0.04% TFA / acetonitrile solution. A Waters Acquity HSS T3 C18, 100 Å, 1.8 μm, 2.1 × 100 mm column was used. The flow rate was set to 0.5 mL / min, detection was performed at a wavelength of 215 nm, and the column operating temperature was set to 30 °C. The deamidated and aspartimide variants were quantified as relative values ​​to the peak area of ​​unmodified CNP-38.

[0674] [Example 1] Synthesis of compound (1) [ka] Compound (1) was synthesized with respect to conjugate 11i according to the method described in WO2017 / 118693.

[0675] [Example 2] Stability test of lyophilized formulation containing compound (1) Eight different formulations (F1-F8) containing compound (1) were prepared as shown in Table 1. 200 μL of each formulation was packed into vials and lyophilized. The water content of the lyophilized products was less than 0.4% for all formulations, as measured by Karl Fischer titration. Each formulation was then added with an appropriate amount of compound (1) to obtain a concentration of CNP-38 3.6 mg / mL after regeneration with 200 μL of water. The formulations were left standing in an incubator set to maintain a temperature of 25°C or 40°C. After 3 months (T3M), the formulations were regenerated with water and analyzed. The results showed a preferred purity profile of compound (1) in the trehalose-containing formulations compared to the mannitol-containing formulations. Furthermore, it was found that no additives were necessary to prevent methionine oxidation.

[0676] [Table 1]

[0677] [Table 2]

[0678] [Example 3] Stability test of liquid and lyophilized formulations containing compound (1) Preparation (F9) of (1) was prepared, 200 μL of the preparation was filled into a vial, and lyophilized. The lyophilized preparation was given an appropriate amount of CNP-38 to obtain a concentration of 3.0 mg / mL after regeneration with 200 μL of water. The lyophilized product and the liquid preparation used to prepare the lyophilized product were left standing in an incubator set to maintain a temperature of 40°C.

[0679] Twenty-one days later (T21D), the lyophilized material was rehydrated with water and the formulation was analyzed. The results indicate that lyophilization protects (1) from degradation such as methionine oxidation and isoaspartate formation.

[0680] [Table 3]

[0681] [Table 4]

[0682] [Example 4] (1) Stability test of formulations containing surfactants Three different formulations (F10-F12) of (1) were prepared, 1080 μL each were packed into vials, and lyophilized. Each formulation contained an appropriate amount of (1) to obtain a concentration of CNP-38 3.5 mg / mL after regeneration with 1000 μL of water. Some formulations contained polysorbate 20 (PS20) or polysorbate 80 (PS80) as a surfactant. The lyophilized formulations were placed in an incubator set to maintain 40°C / 75%RH. After 1 month (T1M) and 3 months (T3M), the formulations were regenerated with 1 mL of water and analyzed.

[0683] Formulations F11 and F12, which contain surfactants, show a slight increase in methionine oxidation of (1) under stress conditions and a clear effect on the regeneration time (without shaking) after the addition of 1 mL of water, compared to F10.

[0684] [Table 5]

[0685] [Table 6]

[0686] [Example 5] Long-term stability test of lyophilized formulation containing compound (1) A lyophilized formulation (F13) of compound (1) was prepared by lyophilizing 1080 μL in a vial. This formulation contained an appropriate amount of (1) to obtain nominal concentrations of CNP-38 3.9 mg / vial and CNP-38 3.6 mg / mL after regeneration with 1000 μL of water. The formulations were placed in incubators set to maintain 5°C, 25°C / 60%RH, 30°C / 65%RH, and 40°C / 75%RH, respectively. At 3 months (T3M), 4 months (T4M), 6 months (T6M), 9 months (T9M), 12 months (T12M), 18 months (T18M), and 24 months (T24M), the formulations were regenerated with 1000 μL of water and analyzed.

[0687] The results demonstrate the high stability of compound (1) in the lyophilized formulation F13, as indicated herein for content, purity, and bioactivity. Furthermore, the formulation showed good stability when tested by relevant pharmaceutical methods. The lyophilized formulation was characterized by a white cake, and no change in cake appearance was detected, regardless of storage. The residual moisture content was very low (0.03%) after lyophilization and increased only slightly during the test period. There was no significant change in regeneration time during storage. Throughout the testing of all samples, macroscopic examination revealed that the samples were substantially free of visible particles, with only low amounts of invisible particles, ≥25 μm and 71 ≥10 μm, observed regardless of storage temperature and time (measured by flow-through microscopy). A slight change in color tone from B9 to >B8 was observed during 12 months of storage at 5°C, but no increase in color was observed during 6 months of storage at 25°C and 30°C or 3 months of storage at 40°C (color was evaluated using a spectral colorimeter, and the absolute value of the color tone was evaluated according to the European Pharmacopoeia, 8th edition, monograph 2.2.2). There was no change in turbidity (measured using a turbidimeter) of freeze-dried samples stored for up to 12 months at 2-8°C, 25°C / 60% relative humidity, and 30°C / 65% relative humidity. A very slight increase in turbidity was measured in samples stored for 3 months at 40°C / 75% relative humidity. No change in appearance was observed during storage for up to 12 months at 5°C, and the value was less than 1 NTU (turbidimetric turbidity unit). The value was less than 1 NTU for 6 months at 25°C, 30°C, and 40°C. pH was not affected by storage. Finally, the osmotic pressure at T0 was within the physiological range, and no changes were detected during the test.

[0688] [Table 7]

[0689] [Table 8]

[0690] [Example 6] Stability Test of Low-Dose Formulation Containing Compound (1) In a vial, 1060 μL of lyophilization was used to prepare a lyophilized formulation (F14) of (1). The formulation was to contain an amount of (1) sufficient to obtain a nominal concentration of CNP-38 0.80 mg / vial and CNP-38 0.75 mg / mL after reconstitution. The formulation was placed in an incubator set to maintain 5°C, 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. After 1 month (T1M), 3 months (T3M), 6 months (T6M), and 12 months (T12M), the formulation was reconstituted with 1.0 mL of water and analyzed.

[0691] The results show high stability of Compound (1) in the lyophilized formulation F14, as shown herein for content, purity, and biological activity. Furthermore, the formulation showed good stability when tested by relevant pharmaceutical methods. The lyophilized formulation was characterized by a white cake, and no change in the cake appearance was detected regardless of storage. The residual moisture content was very low (0.31%) after lyophilization and increased slightly during the test period. There was no significant change in the reconstitution time during the storage period. Visual observation showed that the reconstituted solution essentially contained no visible particles at the available time points (evaluated according to Ph.Eur. 2.9.20 and USP <790>). Furthermore, for all samples, a low amount of invisible particles, i.e., particles of 0 ≥ 25 μm and 5 ≥ 10 μm, were observed regardless of the storage temperature and storage time (measured by flow-through microscopy). A slight increase in color tone from =WFI to <B9 was observed after 3 months of storage at 30°C and 40°C (determined according to Ph.Eur. 2.2.2 using the b-scale). During the 3-month storage period, the transparency was not affected, and the reconstituted solution was found to be =WFI (determined according to Ph.Eur. 2.2.1). The pH was not affected by storage. Finally, the osmotic pressure at T0 was within the physiological range, and no change was detected over 3 months.

[0692]

Table 9

[0693] [Table 10]

[0694] [Example 7] Stability of CNP-38 at different pH values To evaluate the stability of CNP-38 at different pH values, pre-formulation tests were performed. CNP-38 (synthesized according to the method described in WO2017 / 118693) was incubated at approximately 1 mg / mL in soluble form in succinate buffer at pH 4.0, 4.5, 5.0, 5.5, and 6.0 at 37°C. The amount of degraded CNP-38 (total of deamided CNP-38 and aspartimide variants) was evaluated by RP-HPLC after 7 days. The amounts of degraded CNP-38 were 2.7% at pH 4.0, 1.6% at pH 4.5, 1.0% at pH 5.0, 2.9% at pH 5.5, and 3.3% at pH 6.0, indicating that pH 5.0 is preferred for CNP-38 formulations.

[0695] [Example 8] Stability test of compound (1)-containing formulations regenerated with water containing antioxidants and / or preservatives. A lyophilized formulation (F13) of compound (1) was prepared by lyophilizing 1080 μL in a vial. The formulation contained an amount of (1) suitable for obtaining nominal concentrations of CNP-38 3.9 mg / vial and CNP-38 3.6 mg / mL. The water used contained antioxidants and / or preservatives (R1~R5, Table 11). Vials containing the regenerated formulation were placed in an incubator set to maintain a temperature of 5°C. After 4 weeks (T4W), the samples were analyzed.

[0696] The results indicate that compound (1) is stable after regeneration under the test conditions and is not affected by the presence of antioxidants and / or preservatives (Table 12). The pH of the regeneration solution was not affected by antioxidants and / or preservatives after regeneration.

[0697] [Table 11]

[0698] [Table 12]

[0699] abbreviation BSA-Bovine Serum Albumin cGMP-cyclic guanosine monophosphate CI - Confidence Interval DMEM-Dulbecco's Modified Eagle Medium FBS - Fetal Bovine Serum HEPES-4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid IBMX-3-isobutyl-1-methylxanthine Isoasp - Isoaspartate LC-MS (Liquid Chromatography-Coupled Mass Spectrometry) Met(O)-methionine sulfoxide PLA-Parallel Line Analysis PS20 - Polysorbate 20 PS80 - Polysorbate 80 RH - Relative Humidity RP-HPLC-Reverse-Phase High-Performance Liquid Chromatography SE-HPLC - Size Exclusion High-Performance Liquid Chromatography TFA-trifluoroacetic acid TR-FRET time-resolved fluorescence energy transfer UPLC - Ultra-high-performance liquid chromatography. Examples of embodiments of the present invention include the following. [Embodiment 1] A dry pharmaceutical preparation comprising a CNP conjugate, a buffer, and a volume extender, wherein the CNP conjugate comprises a CNP portion covalently and reversibly bonded to a polymer portion. [Embodiment 2] The dry pharmaceutical formulation according to Embodiment 1, wherein the buffering agent is selected from the group consisting of succinic acid, citric acid, lactic acid, acetic acid, glutamic acid, fumaric acid, aspartic acid, glutaric acid, phosphoric acid, histidine, gluconic acid, tartaric acid, malic acid, and mixtures thereof. [Embodiment 3] The dry pharmaceutical preparation according to Embodiment 1 or 2, wherein the buffering agent is succinic acid. [Embodiment 4] The dry pharmaceutical formulation according to any one of Embodiments 1 to 3, wherein the bulking agent is selected from the group consisting of trehalose, mannitol, sucrose, raffinose, gelatin, lactose, dipotassium hydrogen phosphate, sorbitol, xylitol, glycine, histidine, hydroxyethyl starch, dextrose, dextran, propylene glycol, and mixtures thereof. [Embodiment 5] The dry pharmaceutical preparation according to any one of Embodiments 1 to 4, wherein the volume extender is selected from the group consisting of trehalose, sucrose, and glycine. [Embodiment 6] The dry pharmaceutical preparation according to any one of Embodiments 1 to 5, wherein the volume-extending agent is trehalose. [Embodiment 7] The dry pharmaceutical formulation according to any one of Embodiments 1 to 6, wherein the dry pharmaceutical formulation of the present invention comprises one or more further excipients. [Embodiment 8] The dried pharmaceutical formulation according to Embodiment 7, wherein one or more further excipients are selected from the group consisting of preservatives, stabilizers, adsorption inhibitors, cryoprotectants, antioxidants, and other auxiliary agents. [Embodiment 9] The dried pharmaceutical formulation according to any one of Embodiments 1 to 8, wherein the dried pharmaceutical formulation of the present invention contains a stabilizer. [Embodiment 10] The dried pharmaceutical formulation according to any one of Embodiments 1 to 9, wherein the dried pharmaceutical formulation of the present invention contains a preservative. [Embodiment 11] The dry pharmaceutical formulation according to any one of Embodiments 1 to 10, wherein the dry pharmaceutical formulation of the present invention contains an adsorption inhibitor. [Embodiment 12] The dry pharmaceutical formulation according to any one of Embodiments 1 to 11, wherein the dry pharmaceutical formulation of the present invention contains a cryoprotective agent. [Embodiment 13] The dry pharmaceutical formulation according to any one of Embodiments 1 to 12, wherein the dry pharmaceutical formulation of the present invention contains an antioxidant. [Embodiment 14] The dry pharmaceutical formulation according to any one of Embodiments 1 to 13, wherein the dry pharmaceutical formulation of the present invention comprises a further excipient selected from the group consisting of a wetting agent, a viscosity modifier, and an antibiotic. [Embodiment 15] The aforementioned pharmaceutical formulation comprises a pH adjuster, as described in any of Embodiments 1 to 14. [Embodiment 16] The dry pharmaceutical formulation according to Embodiment 15, wherein the pH adjusting agent is selected from the group consisting of Tris, sodium hydroxide, potassium hydroxide, lysine, and mixtures thereof. [Embodiment 17] The dry pharmaceutical preparation according to embodiment 15 or 16, wherein the pH adjusting agent is Tris. [Embodiment 18] The dry pharmaceutical formulation according to any one of Embodiments 1 to 17, wherein the pharmaceutical formulation comprises CNP conjugate, succinic acid, trehalose, and Tris. [Embodiment 19] The dried pharmaceutical preparation according to any one of Embodiments 1 to 18, wherein the CNP portion has an sequence of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 30. [Embodiment 20] A dried pharmaceutical preparation according to any one of embodiments 1 to 19, wherein the CNP portion has the sequence of sequence number 24. [Embodiment 21] The polymer portion may be 2-methacryloyloxyethyl phosphorylcholine derivatives, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy)polymers, poly(amides), poly(amideamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylates). Poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyl oxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl oxazolines), poly(hydroxymethacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(hydroxypropyl oxazolines), Poly(iminocarbonates), poly(lactic acids), poly(lactic acid-coglycolates), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinyl methyl ethers), poly(vinylpyrrolidones), silicones, celluloses A dry pharmaceutical formulation according to any one of Embodiments 1 to 20, comprising a polymer selected from the group consisting of carbomethylcelluloses, hydroxypropylmethylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and their derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon polymers, xylans, and copolymers thereof. [Embodiment 22] The formulation is determined based on the total weight of the dried pharmaceutical formulation. CNP Conjugate: 1.3-45.4% by weight Succinic acid: 0.2-3.2% by weight Trehalose dihydrate: 52.6-98.4% by weight Tris: 0.1~5.6% by weight A dry pharmaceutical formulation according to any one of Embodiments 1 to 21, including the above. [Embodiment 23] The formulation is determined based on the total weight of the dried pharmaceutical formulation. CNP Conjugate: 1.3-38.7% by weight Succinic acid: 0.2-3.2% by weight Trehalose dihydrate: 52.6-98.4% by weight Tris: 0.1~5.6% by weight A dry pharmaceutical preparation according to any one of Embodiments 1 to 22, including the above. [Embodiment 24] A dried pharmaceutical preparation according to any one of Embodiments 1 to 23, wherein the CNP conjugate is of the following formula (Ia) or (Ib). [ka] [In the formula, -D is the CNP part; -L 1 - is the reversible linker part; -L 2 - represents a single chemical bond or spacer portion; -Z is the polymer part; x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16; y is an integer selected from the group consisting of 1, 2, 3, 4, and 5. [Embodiment 25] The dried pharmaceutical preparation according to Embodiment 24, wherein x in formula (Ia) is an integer selected from the group consisting of 1, 2, 3, 4, 6, and 8. [Embodiment 26] The dried pharmaceutical preparation according to Embodiment 24, wherein y in formula (Ib) is an integer selected from the group consisting of 2, 3, 4, and 5. [Embodiment 27] The dry pharmaceutical preparation according to Embodiment 24 or 25, wherein the CNP conjugate is of formula (Ia) and x is 1. [Embodiment 28] -L 1 A dry pharmaceutical formulation according to any one of embodiments 24 to 27, wherein - is linked to -D via an amide linkage. [Embodiment 29] -Z and -L 2 A dry pharmaceutical preparation according to any one of embodiments 24 to 28, wherein the connection between the two is a stable connection. [Embodiment 30] -L 2 - is a spacer portion, as described in any of embodiments 24 to 29. [Embodiment 31] -L 2 -A dry pharmaceutical preparation according to any one of embodiments 24 to 30, wherein - has a molecular weight in the range of 14 g / mol to 750 g / mol. [Embodiment 32] -L 2 A dry pharmaceutical formulation according to any one of embodiments 24 to 31, wherein the chain length of - is 1 to 20 atoms. [Embodiment 33] -L 2 A dry pharmaceutical preparation according to any of Embodiments 24 to 32, wherein - is of the following formula (i). [ka] [In the formula, The dotted line marked with an asterisk is -L 1 - indicates a connection to; Unmarked dotted lines indicate connections to -Z; -R 1 is -H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls; n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18; The part of equation (i) may be further substituted. [Embodiment 34] A dried pharmaceutical preparation according to Embodiment 33, wherein n in formula (i) is selected from the group consisting of 3, 4, 5, 6, 7, 8, and 9. [Embodiment 35] A dry pharmaceutical formulation according to any one of embodiments 24 to 34, wherein -Z has a molecular weight in the range of 5 to 200 kDa (including both ends). [Embodiment 36] -Z is 2-methacryloyloxyethyl phosphorylcholine derivatives, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy)polymers, poly(amides), poly(amideamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides). Poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyl oxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl oxazolines), poly(hydroxymethacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(imi) (Carbonates), poly(lactic acids), poly(lactic acid-coglycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinyl methyl ethers), poly(vinylpyrrolidones), silicones, celluloses, A dry pharmaceutical formulation according to any one of Embodiments 24 to 35, comprising a polymer selected from the group consisting of rubomethylcellulose, hydroxypropylmethylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other hydrocarbon polymers, xylan, and copolymers thereof. [Embodiment 37] A method for producing a dried pharmaceutical preparation according to any one of Embodiments 1 to 36, The method described above is (i) A step of mixing the CNP conjugate with at least a buffer and a bulking agent; (ii) A step of adjusting the pH of the mixture from step (i); (iii) Optionally, a step of filtering the mixture from step (ii); (iv) A step of transferring an amount of the mixture from step (ii) or (iii) to a container that corresponds to the desired number of doses; (v) A step of drying the mixture; (vi) The process of sealing the container. Includes; A method in which the order of steps (ii) and (iii) may be reversed. [Embodiment 38] A method for regenerating a dried pharmaceutical preparation according to any one of Embodiments 1 to 36, The method described above is (a) A step of bringing a dried pharmaceutical preparation according to any one of Embodiments 1 to 36 into contact with a regenerating solution, Methods that include... [Embodiment 39] A regenerative pharmaceutical preparation that can be obtained from the regeneration method of Embodiment 38. [Embodiment 40] A dried pharmaceutical preparation according to any of Embodiments 1 to 36, or a regenerative pharmaceutical preparation according to Embodiment 39, used as a pharmaceutical. [Embodiment 41] A dried pharmaceutical formulation according to any of Embodiments 1 to 36 or a regenerative pharmaceutical formulation according to Embodiment 39, used for the treatment, suppression, delay, or prevention of one or more diseases that can be treated, suppressed, delayed, or prevented by CNP. [Embodiment 42] A dry pharmaceutical formulation for use according to Embodiment 41, wherein the disease is selected from the group consisting of bone-related disorders, e.g., skeletal malformations; cancer; autoimmune diseases; fibrosis; inflammatory diseases; central nervous system diseases, e.g., neurodegenerative diseases; infectious diseases; lung diseases; cardiovascular diseases; metabolic diseases; and eye diseases. [Embodiment 43] A dry pharmaceutical formulation for use according to Embodiment 41 or 42, wherein the disease is chondrodysplasia. [Embodiment 44] A method for treating, suppressing, delaying, or preventing one or more diseases treatable by CNP in a patient, comprising administering to the patient a therapeutically effective amount of the regenerative medicine formulation described in Embodiment 39. [Embodiment 45] The method according to Embodiment 44, wherein the disease is selected from the group consisting of bone-related disorders, e.g., skeletal malformations; cancer; autoimmune diseases; fibrosis; inflammatory diseases; central nervous system diseases, e.g., neurodegenerative diseases; infectious diseases; lung diseases; cardiovascular diseases; metabolic diseases; and eye diseases. [Embodiment 46] The method according to embodiment 44 or 45, wherein the disease is chondrodysplasia.

[0700] This specification includes the following seque...

Claims

1. A dried pharmaceutical preparation comprising a CNP conjugate, a buffer, a volume extender, and a pH adjuster, The buffering agent is succinic acid, the bulking agent is trehalose dihydrate, and the pH adjusting agent is Tris. The aforementioned dried pharmaceutical preparation is determined based on the total weight of the dried pharmaceutical preparation. CNP conjugate: 1.3–45.4% by weight Succinic acid: 0.2–3.2% by weight Trehalose dihydrate: 52.6 to 98.4% by weight, and Tris: 0.1 to 5.6% by weight Includes, The aforementioned CNP conjugate is given by the following equation (IIf): 【Chemistry 1】 (In the formula, The unmarked dashed lines indicate the bonding of the CNP portion, -D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates structure: 【Chemistry 2】 This shows the bond to -Z as shown by, in the formula, The dashed line indicates the connection to equation (IIf) via the dashed line with an asterisk. Each -Z ａ teeth, 【Transformation 3】 (In the formula, each c1 is an independent integer in the range of 200 to 250.) It is a dry pharmaceutical preparation.

2. - The dried pharmaceutical preparation according to claim 1, wherein D has the sequence of sequence number 24.

3. The dried pharmaceutical formulation according to claim 2, wherein the unmarked dashed line in formula (IIf) indicates the bond to the amine functional group provided by the lysine side chain at position 26.

4. The formulation is determined based on the total weight of the dried pharmaceutical formulation. CNP conjugate: 1.3–38.7% by weight Succinic acid: 0.2–3.2% by weight Trehalose dihydrate: 52.6 to 98.4% by weight, and Tris: 0.1 to 5.6% by weight A dry pharmaceutical preparation according to any one of claims 1 to 3, including the above.

5. A method for producing a dried pharmaceutical preparation according to any one of claims 1 to 4, The method described above is (i) A step of mixing the CNP conjugate with at least succinic acid and trehalose dihydrate; (ii) A step of adjusting the pH of the mixture from step (i); (iii) Optionally, a step of filtering the mixture from step (ii); (iv) The step of transferring an amount of the mixture from step (ii) or (iii) to a container that corresponds to the desired number of doses; (v) A step of drying the mixture; and (vi) The process of sealing the container. Including; A method in which the order of steps (ii) and (iii) may be reversed.

6. The method according to claim 5, The method described above is (i) Mix the CNP conjugate with at least succinic acid and trehalose dihydrate, CNP conjugate: 0.9–82.1 mg / mL Succinic acid: 1.3–57.6 mM, Trehalose dihydrate: 67-111.6 mg / mL A process to obtain a formulation containing; (ii) A step of adjusting the pH of the mixture from step (i) to a pH in the range of pH 4.0 to pH 6.0; (iii) Optionally, a step of filtering the mixture from step (ii); (iv) A step of transferring an amount of the mixture from step (ii) or (iii) into a container that corresponds to the desired number of doses; (v) A step of drying the mixture; and (vi) The process of sealing the container. Including; A method in which the order of steps (ii) and (iii) may be reversed.

7. A method for regenerating a dried pharmaceutical preparation according to any one of claims 1 to 4, The method described above is (a) A step of bringing a dried pharmaceutical preparation according to any one of claims 1 to 4 into contact with a regeneration solution, Methods that include...

8. The method according to claim 7, wherein the regeneration solution is a sterilizing solution.

9. A dried pharmaceutical preparation according to any one of claims 1 to 4, for use as a pharmaceutical.

10. A dried pharmaceutical preparation according to any one of claims 1 to 4, for use in the treatment of one or more diseases selected from the group consisting of skeletal malformations and other bone-related disorders; cancer; autoimmune diseases; fibrosis; inflammatory diseases; central nervous system diseases such as neurodegenerative diseases; infectious diseases; lung diseases; cardiovascular diseases; metabolic diseases; and eye diseases.

11. The dry pharmaceutical preparation according to claim 10, wherein the disease is chondrodysplasia.

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